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Cannabinoids Reduce Inflammation but Inhibit Lymphocyte Recovery in Murine Models of Bone Marrow Transplantation

Cannabinoids, the biologically active constituents of Cannabis, have potent neuronal and immunological effects. However, the basic and medical research dedicated to medical cannabis and cannabinoids is limited. The influence of these treatments on hematologic reconstitution and on the development of graft versus host disease (GVHD) after bone marrow transplantation (BMT) is largely unknown. In this research, we compared the influence of D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on lymphocyte activation in vitro and in murine BMT models. Our in vitro results demonstrate that these treatments decrease activated lymphocyte proliferation and affect cytokine secretion. We also discovered that CBD and THC utilize different receptors to mediate these effects. In vivo, in a syngeneic transplantation model, we demonstrate that all treatments inhibit lymphocyte reconstitution and show the inhibitory role of the cannabinoid receptor type 2 (CB2) on lymphocyte recovery. Although pure cannabinoids exhibited a superior effect in vitro, in an allogeneic (C57BL/6 to BALB/c) BMT mouse model, THC-high and CBD-high cannabis extracts treatment reduced the severity of GVHD and improved survival significantly better than the pure cannabinoids. Our results highlights the complexity of using cannabinoids-based treatments and the need for additional comparative scientific results.

1. Introduction

In recent years, there has been a rapid increase in the medical use of cannabis (Marijuana). While cannabis is not registered as a drug or a medical product, the potential of cannabis-based medicines for the treatment of various conditions [1] has led many countries around the world to authorize the clinical use of such treatments. However, the basic and medical research dedicated to medical cannabis is currently limited.

Cannabis contains numerous molecules, including more than 60 chemical compounds classified as cannabinoids, and the different sub-strains vary in their cannabinoid composition [2]. Two cannabinoids have been the focus of most of the studies examining medical uses: D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). THC and some of the other cannabinoids mediate their actions primarily through the Gi protein-coupled seven transmembrane cannabinoid receptors: (1) Cannabinoid receptor 1 (CB1), which is mainly expressed in the brain and to some extent in peripheral tissues such as immune tissues and (2) Cannabinoid receptor type 2 (CB2), which is highly expressed in immune cells. The expression of CB2 is higher in lymph nodes and spleen than in peripheral blood cells and is different in various immune cell populations (B cells > NK cells > monocytes > neutrophils > CD8 T cells > CD4 T cells) [3]. CBD has a very weak affinity to CB1 and CB2 [4]. Several reports have demonstrated CBD signaling through non-cannabinoid receptor mechanisms, such as transient receptor potential cation (TRP) channels, G protein-coupled receptor 55 (GPR55) and the nuclear receptor: Peroxisome Proliferator-Activated Receptor gamma (PPAR-γ) [5,6].

In addition to their effect on the nervous system, both phyto and endogenous cannabinoids have important immunological effects. They possess a wide range of anti-inflammatory properties as they induce the production of anti-inflammatory cytokines such as IL-4, IL-5 and IL-10, and affect the differentiation and function of several types of immune cells [7,8]. The involvement of cannabinoid receptor signaling in the biology of hematopoietic stem and progenitor cells has also been reported [9,10]. Importantly, different cannabinoids were shown to differentially affect immune cell function [11].

Bone Marrow Transplantation (BMT) is a well-established treatment for malignant and non-malignant hematological diseases [12]. Allogeneic BMT can cause the inflammatory condition, Graft versus Host Disease (GVHD), a major cause of morbidity and mortality in BMT patients [13]. In addition, slow, impaired or dysregulated reconstitution of donor-derived immune cell populations, together with GVHD and other post-transplant complications, causes susceptibility to both common and rare infections. The early post-engraftment period is characterized by a progressive recovery of cell-mediated immunity; however, full reconstitution of the hematological components may take years [14].

Although there is a lot of information regarding the influence of cannabis and cannabinoids on the immune system, the effect of THC, CBD and cannabis extracts was never compared. In addition, the effect of these treatments on the reconstitution of the hematological system after BMT and their efficacy in treating GVHD patients is largely unknown. Moreover, the role of the endocannabinoid receptor CB2 in these processes is not clear. Studies in the past generally focused on a single cannabinoid. THC treatment was shown to reduce GVHD in a mouse semi-allogeneic model that did not include both conditioning regimen and BMT (C57BL/6 spleen cells into C57BL/6 × DBA/2 F1) [15], and a recent publication demonstrated the beneficial effect of the cannabinoid CBD in GVHD prophylaxis in patients [16], but the differential effects of the cannabinoids was not examined.

We hypothesize that each cannabinoid has selective effects on hematopoietic and immune cell differentiation and function, and hence, a different impact on hematopoiesis and GVHD. In our research, we compared the consequences of treatment with THC and CBD in vitro and in murine BMT models. Since it has been suggested that the combination of cannabinoids with other active molecules in the plant may achieve better clinical results than pure cannabinoids (known as the entourage effect) [17], we also examined the differences between the effects of the pure cannabinoids and high THC/high CBD cannabis extracts. We show here that all the treatments reduce activated lymphocyte proliferation in vitro, but pure cannabinoids, particularly CBD, have a stronger inhibitory effect. We also found that CBD and THC utilize different receptors to mediate these effects. Using a syngeneic transplantation model, we demonstrate that all treatments, pure THC in particular, inhibit lymphocyte reconstitution after transplantation; in addition, we also show the inhibitory role of the cannabinoid receptor CB2 on lymphocyte recovery. Although pure cannabinoids had a superior effect in vitro, cannabis extracts were better at reducing the severity of disease and improving survival in the GVHD model than pure cannabinoids.

Our results highlight both similarities and the differences between various cannabis-based drugs in BMT. As different strains of cannabis contain a wide range of cannabinoids and other molecules that may influence the clinical outcome of the treatment, a better understanding of the effects of each molecule on hematological recovery and GVHD pathology will assist physicians in providing the best possible treatment for their patients.

2. Results

2.1. CBD Is a Stronger Inhibitor of In Vitro Activated Lymphocyte Proliferation Than THC

In order to learn about the effects of pure CBD/THC and cannabis extracts on lymphocyte function, we decided to utilize in vitro methods first. Cannabis extracts with a high content (20–30%) of CBD or THC were named CBD Botanical Drug Substance (BDS) or THC BDS, respectively. We used these extracts in addition to the pure cannabinoids for two reasons: First, most patients are currently treated with cannabis-based medications and not with pure cannabinoids. Second, we wanted to examine the possible advantage of the entourage effect [17].

The effect of cannabis/cannabinoids on the proliferation of activated lymphocytes was analyzed. Succinimidyl ester (CFSE)-labeled C57BL/6 or BALB/c mouse splenocytes were activated with anti-CD3 antibodies for 4 days in the presence of pure cannabinoids, CBD BDS or THC BDS at various concentrations. Cell proliferation was assessed using CFSE FACS analysis. Interestingly, in vitro the inhibitory effect of pure cannabinoids on lymphocyte activation was stronger than that of cannabis extracts. Whether in the form of pure cannabinoids or cannabis extract, CBD inhibited proliferation significantly better than THC ( Figure 1 A,B and Figure S1A). The treatments, in the concentrations used, were not toxic to the cells (Figure S1B). Similar results were obtained using human Peripheral Blood Mononuclear Cells (PBMC) (Figure S1C). Upon anti-CD3 activation, the percentage of CD8 cells in the samples is elevated ( Figure 1 C). CBD, CBD BDS and, to a lesser extent, THC BDS treatments significantly inhibited this elevation.

The influence of pure CBD/THC and cannabis extracts on lymphocyte activation. Proliferation of CFSE-stained, CD3-activated splenocytes from C57BL/6 (A,C) and Balb/c (B) mice was analyzed on day 4 after activation using flow cytometry analysis. (A) Summary of six independent experiments. When Comparing all treatments to control, the differences are significant starting from 3 µg/mL. The differences between THC/CBD and THC BDS/CBD BDS are significant starting from 5 µg/mL. (B) Summary of three independent experiments. When Comparing all treatments to control, THC to CBD and THC BDS to CBD BDS, significant differences were observed starting from 5 µg/mL. (C) Flow cytometry analysis of activated C57BL/6 splenocytes stained with anti-CD4 and anti-CD8 antibodies. Data is summarized from six independent experiments for pure cannabinoids and four independent experiments for BDS. Results are expressed as mean + SEM. p Value as compared to the activated control cells *, <0.05; **, <0.001; ***, <0.0001. (D) C57BL/6 splenocytes were activated for 4 h, stained with anti-CD69 antibodies and analyzed using flow cytometry. Data is summarized from three independent experiments. The differences of all treatments as compared to control are significant at 15 µg/mL, act: activated splenocytes, THC: D9 tetrahydrocannabinol, CBD: cannabidiol, BDS: Botanical Drug Substance.

CD69 is a classical early marker of lymphocyte activation due to its rapid appearance on the surface of the plasma membrane after stimulation [18]. To test the effect of pure CBD/THC and cannabis extracts on CD69 cell surface expression, C57BL/6 mouse splenocytes were activated with anti-CD3 antibodies for 4 h in the presence of cannabinoid treatments. Cells were stained with anti-CD69 antibodies and expression was assessed using FACS analysis. The lower concentrations of all treatments had a non-significant effect on CD69 expression. Higher concentrations of 10–15 µg/mL induced inhibition of CD69 surface expression upon activation. CBD treatment had no effect in 3–5 µg/mL, but caused 87% inhibition in 15 µg/mL samples. In 15 µg/mL CBD BDS samples, surface expression of CD69 was reduced only by 22% ( Figure 1 D and Figure S2A).

Next, we used the supernatant from the C57BL/6 experiments ( Figure 1 A) to test the effect of cannabinoid treatment on cytokine secretion upon lymphocyte activation. We tested four different cytokines: IL-17, secreted in the Th17 response; IL-10 an indicator for immune regulation, secreted by Tregs and other cells; TNFα, secreted in the Th1 response; and IL-5, secreted in the Th2 response. The levels of secreted cytokines were examined using ELISA. We show the results obtained using 3 µg/mL treatment with pure cannabinoids and 10 µg/mL treatment with the cannabis extracts, which contain approximately 30% of the designated cannabinoid. The results for IL-17 and IL-10 after treatment with various other concentrations can be found in the Supplementary Data.

All treatments significantly reduced IL-17 secretion ( Figure 2 A, Figure S2). CBD BDS had the strongest effect with only 0.25% IL-17 in the supernatant as compared to untreated activated lymphocytes (control). IL-10 secretion was significantly increased by all treatments ( Figure 2 B, Figure S2). Pure CBD had the strongest effect, with 1806% IL-10 in the supernatant (compared to control). All treatments led to a small increase in TNFα secretion ( Figure 2 C), which was significant in all treatments except THC BDS. The levels of IL-5 secretion were affected only by THC BDS and pure CBD treatments ( Figure 2 D).

The influence of pure CBD/THC and cannabis extracts on cytokine secretion. Quantification of IL-17a (A), IL-10 (B), TNFα (C), and IL-5 (D) secretion from C57bl/6 splenocytes activated for 4 days which were treated with cannabinoids/cannabis, was performed using enzyme-linked immunosorbent assay on culture medium of activated cells. Data are summarized for five independent experiments for CBD BDS and six independent experiments for the other treatments. Results are expressed as mean + SEM. p Value as compared to activated control cells *, <0.05; **, <0.001; ***, <0.0001, act: activated splenocytes, THC: D9 tetrahydrocannabinol, CBD: cannabidiol, BDS: Botanical Drug Substance.

Overall, these results show that the cannabinoids CBD and THC have an inhibitory effect on lymphocyte activation, which is associated with a reduction in the secretion of the inflammatory IL-17 cytokine and an elevation in the secretion of the regulatory cytokine IL-10.

2.2. THC and CBD Utilize Different Receptors to Affect Lymphocyte Proliferation

The cannabinoid receptor CB2 is highly expressed in immune cells [19,20]. To elucidate whether CB2 is involved in the effects of THC and CBD on lymphocytes, we used CB2 knock-out mice (CNR2 −/− ). First, we used splenocytes extracted from CNR2 −/− mice (Figure S3A,B) in a CFSE lymphocyte proliferation assay. The inhibitory effect of pure THC, but not pure CBD, was abolished in CNR2 −/− -derived splenocytes ( Figure 3 A). Interestingly, the inhibitory effect of THC BDS was maintained.

Receptors involved in THC and CBD’s effect on lymphocyte proliferation. (A) Proliferation of CFSE-stained, 4 days CD3-activated, splenocytes from CB2 knockout mice was analyzed using flow cytometry. Summary of four independent experiments. The differences of CBD, THC BDS and CBD BDS as compared to control are significant starting from 3 µg/mL. The differences of THC as compared to control are significant starting from 10 µg/mL. The differences of THC when compared to CBD is significant starting from 3 µg/mL. (B) The influence of PPARγ antagonist, GW9662, on CBD’s effect on lymphocyte activation. Proliferation of CFSE-stained, CD3-activated murine splenocytes was analyzed using flow cytometry analysis. Summary of eight independent experiments. p Value—samples were compared to act spl + CBD (right) or act spl (left). (C) Real time PCR analysis for the expression of cyp1a1 in activated splenocytes treated with THC or CBD. Summary of four independent experiments. Results are expressed as mean + SEM. p Value *, <0.05; **, <0.001;, act spl: activated splenocytes, THC: D9 tetrahydrocannabinol, CBD: cannabidiol, BDS: Botanical Drug Substance.

Our results indicate that the CB2 receptor is the main mediator for THC’s effect on lymphocytes, whereas CBD’s effect clearly does not involve CB2 signaling. Several molecules have been proposed as mediators for CBD’s effects on mammalian cells [5,6]. To search for the molecules which are involved in CBD’s effect on lymphocyte activation, we used several inhibitors together with CBD in a CFSE lymphocyte proliferation assay. A967079, BCTC and GSK2193874 are antagonists to TRP channels TRPA1, TRPV1 and TRPV4 respectively, which have been demonstrated to mediate CBD signaling. However, we found that none of these antagonists interfered with CBD’s inhibitory effect on lymphocyte activation (Figure S4A–C). CID16020046, an antagonist to GPR55, also had no effect (Figure S4D). Another potential mediator of CBD signaling is the nuclear receptor PPAR-γ [21]. We found that GW9662, a PPAR-γ antagonist, could partially reverse the effect of CBD on lymphocyte proliferation ( Figure 3 B). The nuclear receptor aryl hydrocarbon receptor (AhR) is involved in the regulation of Treg and Th17 cell differentiation [22], and can be activated by cannabinoids, as demonstrated in a human hepatoma cell line [23]. Since CBD and THC affected IL-17 and IL-10 secretion from activated lymphocytes, we decided to test the possible function of these cannabinoids in AhR activation by examining the levels of expression of an AhR regulated gene, cyp1a1, in treated cells. Only CBD treatment significantly elevated the expression of cyp1a1 ( Figure 3 C).

2.3. Cannabinoid Treatment Alters Hematologic Recovery after Bone Marrow Transplantation

To investigate the effect of THC, CBD and cannabis extracts on hematopoiesis after BMT, we utilized a syngeneic transplantation model. C57BL/6 mice underwent lethal whole-body irradiation and were reconstituted with 8 × 10 6 donor C57BL/6 BM cells the following day ( Figure 4 A). Five mg/kg of cannabis extracts/pure cannabinoids/vehicle were administered intraperitoneally (IP) from the day of transplantation, every other day, for 2 weeks. Once a week, starting 1 week after transplantation, blood was collected from mice tails and CBC with differentials was performed. Both pure cannabinoids and cannabis extracts had a significant inhibitory effect on lymphocyte recovery ( Figure 4 B,C). Among the tested compounds, pure THC had the strongest effect with a mean of 39% inhibition compared to vehicle-treated mice (control), 3 weeks after transplantation ( Figure 4 B, right). The inhibitory effect of CBD treatment was significantly lower. Interestingly, there was no significant difference between CBD BDS and THC BDS treatment ( Figure 4 C, right). The number of monocytes and granulocytes was not affected by the treatment (data not shown). Platelet recovery was significantly improved only in the group that received THC BDS treatment, with a mean of 10% improvement compared to control, 2 weeks after transplantation ( Figure 4 D,E).

Cannabis/Cannabinoids administration to syngeneic BMT model. (A) Recipient C57BL/6 mice received lethal whole-body irradiation and were reconstituted with 8 × 10 6 donor C57BL/6 bone marrow cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. Blood samples for CBC were obtained once a week. Average lymphocyte counts in pure cannabinoid-treated groups (B) and BDS-treated groups (C) are presented. Average counts at different time points (left) and day 21 after transplantation counts (right). (D) Average platelet counts in pure cannabinoid-treated groups (left) and BDS-treated groups (right), day 14 after transplantation. Data are summarized from four independent experiments (lymphocytes) and three independent experiments (platelets). p Value *, <0.05; **, <0.001; ***, <0.0001. % of normal-% of the mean cell concentrations (cells/µL) in healthy C57BL/6 mice, non act: non-activated, act spl: activated splenocytes, THC: D9 tetrahydrocannabinol, CBD: cannabidiol, BDS: Botanical Drug Substance, ns: not significant.

These results demonstrate that cannabis/cannabinoids treatments affect hematological reconstitution after BMT and that different cannabinoid formulations have different effects.

2.4. CB2 Receptor Has an Inhibitory Effect on Lymphocyte Recovery

Since THC had the strongest inhibitory effect on lymphocyte recovery, we wanted to examine the involvement of CB2 in this process. First, we administered syngeneic BMT mice with the CB2 inverse agonist SR144528 once a day for 1 week from the day of transplantation. Once a week, starting 1 week after transplantation, blood was collected from mice tails and CBC with differentials was performed. In this model, the mice did not receive any cannabinoid treatment. Our results demonstrate significantly improved lymphocyte recovery in the treated group ( Figure 5 A).

The role of CB2 in lymphocyte recovery. (A) Recipient C57BL/6 mice underwent syngeneic BMT. CB2 reverse agonist, SR144528, was administered IP once a day for 1 week from the day of transplantation. Blood samples were obtained once a week. Average lymphocyte counts. (B) Syngeneic BMT from CB2 KO donor mice to C57BL/6 WT mice. Average counts at different time points (left) and day 21 after transplantation (right). (C) Syngeneic BMT from C57BL/6 WT donor mice to CB2 KO mice. Average counts at different time points (left) and day 21 after transplantation (right). Data are summarized from three independent experiments. p Value ***, <0.0001. % of normal-% of the mean cell concentrations (cells/µL) in healthy C57BL/6 mice. WT: wild type, CB2KO: CB2 knock out.

To clarify whether this improvement is due to an effect on the grafted cells or on the accepting environment, we used CB2 KO mice as donors/acceptors in BMT experiments. The normal blood counts of CB2 KO female mice were similar to the WT C57BL/6 counts (Figure S3B). C57BL/6 mice underwent lethal whole-body irradiation and were reconstituted with 8 × 10 6 donor CB2 KO or C57BL/6 BM cells the following day. There were a significantly higher number of lymphocytes in the group that received CB2 KO transplant compared to control, starting from the second week after transplantation ( Figure 5 B). When C57BL/6 BM cells were transplanted to CB2 KO or C57BL/6 recipient mice, lymphocyte counts were not significantly different ( Figure 5 C).

Altogether, these experiments demonstrate the inhibitory role of CB2 in the recovery of blood lymphocytes after bone marrow transplantation

2.5. Cannabis/Cannabinoids Administration for GVHD Prophylaxis

Several studies, as well as our in vitro assays ( Figure 1 ), indicate that cannabinoids have an anti-inflammatory function [8]. Yeshurun, et.al demonstrated the beneficial effect of the cannabinoid CBD in GVHD prophylaxis in patients [16]. We therefore decided to compare the immunosuppressive effect of CBD/THC and cannabis extracts on GVHD prophylaxis in a murine model.

BALB/c mice underwent whole-body irradiation followed by allogeneic BMT from C57BL/6 donor mice. Five mg/kg of cannabis extracts/pure cannabinoids/vehicle were administered IP, from the day of transplantation, every other day, for 2 weeks ( Figure 6 A). Mice chimerism was not affected by the treatment (Figure S5). In our model, both CBD BDS and THC BDS significantly improved survival ( Figure 6 B, right), while pure cannabinoids had a smaller effect ( Figure 6 B, left). The difference between THC and THC BDS is significant. Moreover, GVHD scores were significantly lower in mice administered cannabis extracts ( Figure 6 C).

Cannabis/Cannabinoids administration for GVHD prophylaxis. (A) Recipient BALB/c mice received lethal whole-body irradiation and were reconstituted with 8 × 10 6 donor C57BL/6 bone marrow cells and 2 × 10 6 spleen cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. The clinical condition of the mice was evaluated for up to 67 days after transplantation. (B) Survival curve. Differences between control and THC BDS as well as CBD BDS is significant. The difference between THC and THC BDS is also significant. Data are summarized from two independent experiments, six mice/group in each experiment. (C) Average GVHD score (Days 15–26). Differences between THC BDS/CBD BDS to the control group are significant. The same control group is shown in the left and right graph.

These results demonstrate that cannabis extracts are more potent modulators of allogeneic activation in vivo than pure THC or CBD.

3. Discussion

Cannabis contains hundreds of chemical compounds [2]. Different sub-strains of cannabis comprise unique sets of cannabinoids and other molecules which influence the clinical outcome of the treatment. The scientific data regarding the use of a specific strain or isolated cannabinoid for the treatment of each disease is currently very limited.

The increased demand for medical cannabis around the world results in an urgent need for scientific evaluation of cannabinoids-based medicines as a therapy. In this study, we decided to compare the effect of the most abundant cannabinoids, THC and CBD, and to also examine cannabis extracts from THC- and CBD-rich plants. We used the extracts because they are most commonly used by patients and also because of the suggested entourage effect [17]. We have used in vitro assays as well as syngeneic and allogeneic murine models to test the effect of these cannabis-based treatments on BMT. Our results demonstrate that all of these cannabinoid-based treatments suppress lymphocyte proliferation and influence cytokine secretion. Decreased surface expression of the early activation marker CD69 was evident in higher concentrations of treatment. CBD, CBD BDS and THC BDS significantly inhibited the elevation of %CD8 in the culture upon activation. In accordance with its known anti-inflammatory activity [5], CBD had the most profound effect on cell proliferation. The induction of IL-10 together with inhibition of IL-17 secretion by all treatments may indicate an influence on the Th17/Treg balance. Th17 cells are known to participate in the pathophysiology of GVHD [24] and several autoimmune diseases and, therefore, this effect is most clinically relevant. Notably, our results resemble previous data for cannabinoid treatment in an experimental autoimmune encephalomyelitis (EAE) mice model for multiple sclerosis and in an animal model of asthma [25,26]. IL-10 elevation and IL-17 reduction were also evident in cultured CD4 + T cells from cannabinoid addicts [27]. Interestingly, we did not find any correlation between the effect of the treatment on cytokine secretion and its effect on proliferation. For example, 10 µg/mL THC BDS reduced cell proliferation by only 25%, but induced a relatively high secretion of the regulatory cytokine IL-10.

CD69 surface expression, 4h after stimulation, was only slightly affected by the cannabinoid-based treatments in 3–5 µg/mL concentrations. Although CD69 is a well-known activation marker, it was also found to be involved in downregulation of the immune response through controlling the production of the pleiotropic cytokine transforming growth factor-β (TGF-β) [28], which has a role both in Treg and in Th17 differentiation. Therefore, these results correspond with our results of the late activation markers tested, i.e., proliferation and cytokine secretion.

We utilized CB2 knockout mice and antagonists/inverse agonists of different receptors to screen for signal transduction mediators used by CBD and THC to inhibit lymphocyte activation. We found that CB2 was the main mediator of THC’s effect but was not involved in the effect of CBD. The tested TRP channels we examined and GPR55 were also not found to mediate CBD’s inhibitory function. PPARγ was found to mediate part of CBD’s inhibitory effect on lymphocyte activation. PPARγ is a nuclear hormone receptor widely expressed in adipose tissue and in immune/inflammatory cells, colonic mucosa and placenta [29]. PPARγ activation attenuates inflammatory processes associated with several diseases and it was found to be involved in the inhibition of Th17 differentiation [30]. The involvement of PPARγ in CBD signaling has been shown in various tissues [21]. For example, in biopsies from patients with ulcerative colitis, CBD treatment ex vivo reduces signs of inflammation that can be blocked with a PPARγ antagonist [31]. We also found that CBD is able to activate another nuclear receptor, AhR. This activation may contribute to CBD’s effect on T cell differentiation. The involvement of other receptors in CBD-related signaling in lymphocytes has yet to be found.

There are several obstacles to a good clinical outcome of BMT. The toxicity of the conditioning protocol leads to a period of low hematological counts which makes the patients susceptible to common and unusual infections [14]. Our results demonstrate that all the cannabinoids-based treatments we have used significantly delay lymphocyte reconstitution after transplantation. This finding is of great importance since delayed lymphocyte re-constitution may have a deleterious effect on the clinical outcome. On the other hand, THC BDS treatment improved platelet recovery. The involvement of endocannabinoids in thrombogenesis was previously demonstrated [32,33,34]. However, it is not known yet which component is responsible for this effect in our model and if this result can be repeated with THC BDS from different sources.

The finding that cannabinoids-based treatments inhibited lymphocyte recovery rather than provoked it was unexpected. Patinkin et al. demonstrated that endocannabinoids increase the number of several hematopoietic cell’s colony-forming units (CFU) in vitro [32], and Jiang et al. showed elevation of CFU in bone marrow of sub-lethally irradiated mice treated with the CB2 agonist AM1241 [35]. Importantly, our results clearly identify CB2 as an inhibitory receptor of lymphocyte recovery. We demonstrate that THC, a CB2 agonist, has the strongest inhibitory effect on lymphocyte recovery. CB2 antagonist treatment in syngeneic transplanted mice improved lymphocyte recovery, and similarly, CNR −/− bone marrow transplanted into WT mice resulted in improved recovery of lymphocytes. Wild type bone marrow transplanted into CNR −/− mice did not affect the recovery rate, indicating a role for CB2 expression on the transplanted cells rather than on the cells of the accepting environment. Our results can possibly be explained by the role of cannabinoids in hematopoietic stems and progenitor cell homing to the bone marrow niche. Kose et al. recently demonstrated that endocannabinoids can stimulate the migration of human hematopoietic stem cells in a cannabinoid receptors-dependent manner [36]. They also showed that the concentration of the endocannabinoid 2AG in blood plasma is higher than in bone marrow plasma, in healthy individuals. Pereira et al. proved that CB2 has a role in the retention of immature B cells in bone marrow [37], and Hoggatt et al. demonstrated a significant decrease in CXCR4 in bone marrow cells treated with the CB1/CB2 agonist CP55940 [10]. Together, these results point to an important role for the endocannabinoid system in the migration of the hematopoietic stem and progenitor cells, an issue that requires further investigation.

In contrast to the greater effect of the pure cannabinoids in vitro and in the syngeneic transplantation model, the cannabis extracts had more of an effect on GVHD prophylaxis. This result together with the cytokine results from our in vitro experiments and the syngeneic model experiments demonstrate that the effects of the extracts are different from the effects of pure cannabinoids. There are two possible explanations for this phenomenon. The unique effects of the extract could result either from other molecules in the plant (not THC/CBD) or from a synergistic function of THC/CBD with other molecules.

The clinical use of medical cannabis and cannabinoids is different from other evolving medications because it is administered to patients despite the shortage of scientific pre-clinical research-based evidences. Our results highlight the complexity of using cannabinoids-based drugs and the need for additional comparative scientific results. The results of this study may influence the treatment of BMT patients with cannabinoids-based medicines by facilitating the choice of which particular drug should be used to treat their specific clinical condition.

4. Materials and Methods

4.1. Cannabis Extracts and Cannabinoids

This research was performed under the approval of The Medical Cannabis Unit in the Israeli Ministry of Health (REQ46). Pure THC was kindly provided by the laboratory of Prof. Raphael Mechoulam. Synthetic CBD was purchased from STI Pharmaceuticals LTD., Newtown, UK. Cannabis Sativa and Indika extract with high (20–30%) content in THC or CBD (i.e., THC-BDS/CBD BDS respectively) were supplied by Cannabliss (Cannabliss LTD., Tel Aviv, Israel). This company is authorized by the Israeli ministry of health to supply medical cannabis products to patients and for research. Extraction was obtained using Ethanol, and evaporated. The THC, CBN and CBD contents of the extract were quantified against a commercial THC, CBN and CBD standards (Izun Pharma, Jerusalem, Israel). THC BDS: 20–30% THC, 1% > CBD, 1% > CBG, 2% > CBN. CBD BDS: 1% > THC, 20–30% CBD, 1% > CBG, 2% > CBN.

4.2. Inhibitors

SR144528—a CB2 receptor antagonist, was purchased from Abcam, Cambridge, UK. A967079—a TRPA1 Receptor antagonist and BCTC—a TRPV1 Receptor antagonist, were purchased from Alomone Labs, Jerusalem, Israel. GSK2193874—a TRPV4 antagonist, was purchased from SIGMA-ALDRICH, Rehovot, Israel. CID16020046—a GPR55 antagonist, was purchased from Cayman, MI, USA and GW9662—a PPARγ antagonist, was purchased from Enzo Life Sciences, New York, NY, USA.

4.3. Mice

Female 8- to 11-week-old C57BL/6 and BALB/c mice were purchased from Envigo, Jerusalem, Israel, and Cannabinoid Receptor 2 (CB2) knockout mice (CNR2 −/− ) [38] were bred in the specific pathogen-free (SPF) facility of the Authority of Biological and Biomedical Models at the Hebrew University of Jerusalem. The study was approved by the Institutional Animal Care and Use Committee of the Hebrew University of Jerusalem in accordance with national laws and regulations for the protection of animals (MD-15-14619-5, approved 16 July 2016), and the mice were housed under specific SPF conditions.

4.4. Lymphocyte Activation Assays

CFSE assays-spleens were harvested from healthy C57BL/6 or BALB/c mice. Splenocytes were centrifuged on a Ficoll-Paque gradient (Fresenius Kabi Norge AS, Oslo, Norway); mononuclear cells were isolated from the interphase layer washed and labeled with carboxyfluorescin diacetate succinimidyl ester (CFSE). A total of 1 × 10 6 labeled cells/well were plated in 96-well flat bottom plates with RPMI 1640 medium supplemented with 10% FCS, 1% penicillin/streptomycin, and 1% l -glutamine (Biological Industries, Beit Haemek, Israel). Splenocytes were activated with 1 µg/mL anti-CD3 antibodies (Biolegend, San Diego, CA, USA) in the presence of the indicated concentrations of cannabis extracts/cannabinoids for 4 days. CFSE levels in the cells were determined using FACS analysis. The CD8/CD4 ratio was determined by anti-CD4 and anti-CD8 florescent antibodies staining (Biolegend, San Diego, CA, USA) followed by FACS analysis. Cytokine concentration in the culture media was quantified using ELISA Ready SET Go kits (eBioscience, San Diego, CA, USA), according to the manufacturer’s instructions. All determinations were made in triplicates.

CD69 expression assays-spleens were harvested from healthy C57BL/6 mice. A total of 1 × 10 6 labeled cells/well were plated in 96-well flat bottom plates with RPMI 1640 medium supplemented with 10% FCS, 1% penicillin/streptomycin, and 1% l -glutamine (Biological Industries). Splenocytes were activated with 1 µg/mL anti-CD3 antibodies (Biolegend) in the presence of the indicated concentrations of cannabis extracts/cannabinoids for 4 days. CD69 surface expression was determined by anti-CD69 florescent antibodies staining (Biolegend) followed by FACS analysis.

4.5. RNA Extraction and Real Time PCR Analysis

Total cellular RNA was extracted using RNeasy ® Mini Kit columns (QIAGEN, Hilden, Germany) according to the manufacturer’s protocols. One microgram of total RNA was used to synthesize cDNA using the High-Capacity cDNA kit (Applied Biosystems, Foster city, CA, USA). The detection of transcript levels of cyp1a1 were performed using the TaqMan Gene Expression Assay Kit (Applied Biosystems), using hprt1 as a reference. All primers were purchased from Applied Biosystems. Real-Time PCR reactions were conducted using StepOne Plus (Applied Biosystems). Data was analyzed by StepOne Software version 2.2 (Applied Biosystems).

4.6. Syngeneic BMT Model

C57BL/6 or CB2 knockout mice underwent lethal whole-body irradiation by single exposure to 10 Gy and were reconstituted with 8 × 10 6 donor C57BL/6 or CB2 knockout BM cells the following day. Cannabis extracts/cannabinoids (5 mg/kg) were administered intraperitoneally (IP), every other day from the day of transplantation, for 2 weeks. Once a week, blood was collected from the mice tail into Ethylenediaminetetraacetic acid (EDTA)-coated capillary tubes. A complete blood count (CBC) with differentials was performed using a validated BC-2800Vet Auto Hematology Analyzer (Mindray, Shenzhen, China).

4.7. Allogeneic BMT Model

Balb/c mice underwent lethal whole-body irradiation by single exposure to 8 Gy and were reconstituted with 8 × 10 6 donor C57BL/6 BM cells and 2 × 10 6 spleen cells the following day. Cannabis extracts/cannabinoids (5 mg/kg) were administered IP every other day from the day of transplantation, for 2 weeks. For GVHD evaluation, mice were monitored daily for weight loss, diarrhea, ruffled skin, and survival. GVHD score, based on all of the aforementioned factors (rated on a scale of 0–4), was calculated as previously described [39].

4.8. Statistical Analysis

Data from the BMT studies are described as mean values on the dot plot, showing individual values (lymphocyte and platelet count) at the indicated time point. Linear graphs show mean values of the same groups of mice at different time points. Data from in vitro studies are represented as mean ± SE. The mean was calculated from the indicated number of experiments. The mean of triplicates from each experiment was used for this calculation. Single comparisons to control were made using two-tailed Student’s t-test, with p value < 0.05 considered statistically significant. In vitro proliferation tests, CD4, CD8 tests and the survival of the mice in the different treatment groups in the GVHD assay were compared using one tailed ANOVA test + Bonferroni’s multiple comparison, with a p value < 0.05 considered statistically significant.


We thank Raphael Mechoulam and Aviva Brener for the THC and for their helpful advice. We thank Cannabliss LTD for providing cannabis extracts. Cannabliss LTD had no role in study design, the collection, analysis and interpretation of results. We thank Alaa Abu-Diab for her technical assistance. We thank Zvi Granot for critical revision of the manuscript.

Supplementary Materials

Author Contributions

Conceptualization, O.A.-H. and R.O.; Methodology, I.K., O.A.-H. and Z.Y.; Validation, I.K., O.A.-H. and Z.Y.; Formal Analysis, I.K. and O.A.-H. Investigation, I.K. and O.A.-H.; Writing—Original Draft Preparation, I.K. and O.A.-H.; Writing—Review & Editing, O.A.-H. and R.O.; Supervision, O.A.-H. and R.O.; Project Administration, O.A.-H.; Funding Acquisition, R.O.


This study was supported (in part) by a grant from the Israeli ministry of Agriculture and Rural development. The sponsors of this study are public or nonprofit organizations that support science in general. They had no role in gathering, analyzing, or interpreting the data.

Board Update: The Common Denominator

David DeRemer, PharmD BCOP FCCP FHOPA
HOPA President (2020–2021)
Clinical Associate Professor, University of Florida College of Pharmacy
Assistant Director, Experimental Therapeutics, University of Florida Health Cancer Center
Gainesville, FL

As an unprecedented spring comes to an end, I know I speak for many as we face uncertainty about our immediate future, the strain of daily social distancing, and mental fatigue. The shift from normalcy to the present circumstances has led me to an even deeper appreciation of the dedication of elementary school teachers. My wife and I are now in charge of our children’s education because of school closures, so Google classroom, class Zoom meetings, and the occasional Khan Academy video have been incorporated into our daily routine. Despite these technological advances, many will agree with me that keeping a child focused on an educational task remains a challenge!

I am happy to report that, after sustained focus and practice, my daughter has mastered the mathematical concept of the least common denominator. The term common denominator can also be used to describe a feature shared by members of a group. HOPA continues to expand, with more than 3,600 members and a contingent of 300 volunteers serving on committees and task forces. Our organization has an important common denominator: to support pharmacy practitioners and promote and advance hematology/oncology pharmacy to optimize the care of individuals affected by cancer. And despite the challenges we now face, the board is focused on advancing our integrated strategic plan for 2020–2023. This effort is highly dependent on the tireless efforts of our volunteers. The board is cognizant of the constraining bandwidth of our members, and we are seeking to optimize the volunteer experience.

HOPA’s board and other leaders began to revitalize our strategic plan in 2019, following the completion of our 5-year plan at year 3. This remarkable achievement is a testament to the activity and energy of our membership and external partners. Our new 3-year strategic plan is aspirational, but flexible, particularly in view of the challenges that COVID-19 has imposed on our committee activities. Our vision (the common denominator mentioned above) has not changed: that all individuals affected by cancer have a hematology/oncology pharmacist as an integral member of their care team. I have provided progress notes on each strategic pillar below.

Goal 1: Professional Development
HOPA is expanding its educational activities in order to meet the evolving needs of pharmacists. This summer we will launch two large initiatives in this area. You asked for it, and now you have it: HOPA’s Board Certified Oncology Pharmacist (BCOP) Preparatory and Recertification Course! Our course will offer 25 content outlines, 14 webinars, 32 podcasts, 28 BCOP continuing education (CE) hours, and 33.5 Accreditation Council for Pharmacy Education CE hours. In addition, we are excited about “the Big Idea,” formally known as the Core Competency Certification Program, which consists of 12 modules designed to enhance the fundamental knowledge of practitioners.

Goal 2: Tools and Resources
HOPA is using new and diverse methods for delivering tools and resources to our members. By now, I hope you have become acquainted with our HOPA Now podcast series and all the learning opportunities it offers. We will continue to invite industry experts to discuss topics that have an impact on your practice and daily life. Integrating podcast learning into our BCOP education will help us meet the needs of an emerging younger demographic in our organization. Also, the Journal of Hematology Oncology Pharmacy has been named the official publication of HOPA. This journal will be an excellent place for HOPA members to publish their original research and exchange practice innovations relevant to the field of hematology/oncology pharmacy.

Goal 3: Research
The efforts of our Practice Outcomes and Professional Benchmarking Committee were recently published in a Journal of Oncology Pharmacy Practice article titled “Trends in the Delivery of Care to Oncology Patients in the United States: Emphasis on the Role of Pharmacists on the Healthcare Team.” This committee, along with our Basic and Translational Sciences Committee, continues to identify opportunities to support pharmacist researchers with funding for both early-stage and seasoned investigators.

Goal 4: Advocacy
Expanding HOPA’s footprint in the areas of safety, quality, and access to care is part of our advocacy initiative. In September 2019, HOPA’s Quality Oversight Committee organized a 1-day workshop as an introduction to the American Society of Clinical Oncology Quality Training Program. This workshop, attended by 26 HOPA members, was highly successful, and similar opportunities are planned for the near future. Another goal in this area is to expand successful partnerships with the Leukemia and Lymphoma Society, the Pancreatic Cancer Action Network, and the Society for Immunotherapy of Cancer.

I am honored to serve as the 17th president in our young organization’s history. I feel immensely blessed to lead this team. Despite the immediate challenges we face, HOPA’s board, committees, and task forces will elevate HOPA to continued successes in the coming year. Given the number and range of activities that will be offered in 2020–2021, I hope that this summer presents you and your family the opportunity to relax and perhaps even travel! Take care.

Cannabidiol Oil for Cancer Patients: Nature’s Best Remedy?

Bryan Glock
PharmD Candidate (2020)
University of Connecticut School of Pharmacy
Storrs, CT
Associate Clinical Professor
University of Connecticut School of Pharmacy
Storrs, CT
University of Connecticut Health
Neag Comprehensive Cancer Center
Farmington, CT

Cannabidiol (CBD) oil is a supplement that has gained tremendous popularity over the past few years. The compound is marketed for numerous indications and sold across the United States by various shops, gas stations, and online retailers. CBD is produced in a variety of formulations, one of the more prevalent being CBD oil. 1 One area in which CBD oil is gaining interest is the cancer setting, and because of its wide availability, it is likely that many cancer patients are turning to this alternative medicine to help manage their disease or symptoms. It is therefore important for healthcare professionals to educate themselves regarding the efficacy, safety, and legality of this compound.

CBD is a compound derived from the cannabis plant. Cannabis is the source of one of the oldest plant-based medicines known to man, and for thousands of years it has been cultivated by humans for various purposes. 2 Two common strains of the plant are marijuana, cultivated for its medicinal purposes, and hemp, cultivated for its use in food, clothing, and paper. 3 The cannabis plant contains various active components, two of which are cannabinoids and terpenes. 2 Researchers have identified up to 113 different cannabinoids and 120 different terpenes in cannabis. 4 The two cannabinoids delta-9-tetrahydrocannabinol (THC) and CBD are the most prevalent and well-known cannabis components. However, terpenes have also been shown to bind to receptors in animal studies, suggesting that they may play a role in the overall pharmacologic profile of cannabis. 2 Many people likely associate cannabis with marijuana and the “high” effect that it elicits. This psychoactive effect is a result of the action of THC on cannabidiol (CB)1 and CB2 receptors. 5 CBD does not act in the same way; in fact, it is thought to have antagonistic effects on the CB receptors. As a result, it does not produce the psychoactive effects seen in THC-containing cannabis. 5 CBD has a long list of proposed benefits, including potential antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects. 6 Medicinal marijuana products often contain a combination of THC and CBD but may also be pure THC or CBD alone. CBD oil, however, primarily contains the CBD, with minimal (<0.3%) THC content.

The legal status of cannabis and cannabis-related products in the United States can be difficult to understand. Federally, the Controlled Substances Act (CSA) of 1970 placed cannabis and its components into schedule I, the most restrictive category. 7 As of January 1, 2020, 33 individual states, along with Washington, DC, Puerto Rico, and Guam, have implemented laws that allow for medicinal cannabis use. Of these, 11 states plus Washington, DC, and Guam allow for recreational use. 8-10 These states can sell all types of cannabis products with varying contents of active ingredients (e.g., THC, CBD) and dosage forms. The 2018 Farm Bill removed hemp, defined as cannabis-derived product with less than 0.3% THC, from the CSA. 7 This has allowed for widespread commercial sales of CBD products outside of medical marijuana dispensaries. 11 The extracts that are produced from cannabis can range widely in their composition and effects, depending on which part of the plant is used. Hemp seed oil contains no THC and minimal CBD and is extracted from cannabis seeds. CBD oil and cannabis oils, which are extracted from the flower or plant material, contain CBD at variable levels; the difference is that CBD oil can contain only up to 0.3% THC. 3 The sale of these products is legal in all states but Idaho, Nebraska, and South Dakota, where no cannabis access laws currently exist. Because these CBD oils do not contain psychoactive levels of THC, they can be purchased and consumed without the recommendation or certification of a provider. 3

In 2018, the U.S. Food and Drug Administration (FDA) approved CBD oral solution (Epidiolex) for the treatment of seizures in Lennox-Gastaut and Dravet syndrome. 7 Epidiolex, a purified CBD oral solution that contains less than 0.1% THC, was placed into schedule V (low-abuse potential) by the U.S. Drug Enforcement Agency (DEA) in 2018. 12,13 This is currently the only FDA-approved CBD product, and it has not been evaluated in cancer patients. According to the DEA, all non-FDA-approved CBD products are still considered schedule I controlled substances. 13 The 2018 Farm Bill allows for exceptions to this status under certain conditions. In order for hemp-derived CBD to be considered legal, it must be produced by a licensed grower under specific conditions set forth by the Farm Bill, state regulations, and federal regulations. 14 This, along with the implementation of state laws on cannabis access, has made the regulation of CBD products a difficult task. 8 A 2016 study investigated the labeling accuracy of online-purchased CBD products. Researchers purchased 84 non-FDA-approved CBD products and tested their CBD and THC content. The alarming findings were that only 31% were accurately labeled within 10% of the reported CBD content, and 21% of the products contained unlabeled THC at a low level.15 The FDA has issued warnings regarding mislabeling to dozens of firms that market CBD products and has warned the public to beware of these products. 16

Cannabinoids have been used to treat patients with cancer since 1985, when dronabinol (Marinol), a synthetic THC product, was approved by the FDA to treat chemotherapy-induced nausea and vomiting. 17 The specific role of CBD in cancer treatment is still unclear. In vitro and in vivo studies have shown some evidence for CBD’s efficacy as an anticancer agent through mechanisms such as induction of apoptosis or inhibition of tumor growth and metastasis. 18,19 In vitro data supports the ability of CBD to induce tumor cell death in patients with glioblastoma. 20 Furthermore, case reports have been published showing a potential anticancer effect in lung cancer and ovarian cancer patients. 21,22 Regarding supportive care for cancer patients, the role of CBD is again unclear. Evidence exists for the use of cannabis for chemotherapy-induced nausea and vomiting, cancer pain, anorexia and cachexia, and appetite stimulation; however, most studies were poorly designed and evaluated products that also contained THC. 2 Until more human trial data become available, the appropriateness of using CBD oil in these indications remains uncertain. Several studies are investigating the use of CBD in patients with cancer for indications such as palliative care in cancer patients to reduce symptom burden; as standard-of-care treatments in patients with multiple myeloma, glioblastoma multiforme, and gastrointestinal malignancies; and for prevention of graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation. 23-25 Continuing research is necessary to understand CBD’s usefulness in treating cancer patients.

As noted, CBD lacks the psychoactive effects that are found with other cannabinoids. This does not mean that it can be used without concern. Epidiolex has been associated with hepatocellular injury, sedation, and suicidal behavior and ideation, in addition to more common side effects of decreased appetite (16–22%), diarrhea (9–20%), fatigue (11–12%), and insomnia (5–11%). It is important that patients using CBD be made aware of the possibility that they will test positive in a cannabis drug screen. 12 It should be noted that rigorous safety studies have been performed only with prescription Epidiolex, not with over-the-counter or other CBD oil products. Given that the strengths of CBD oil products vary greatly, it is difficult to fully understand the side-effect profile of CBD. Emerging evidence has also indicated the potential carcinogenicity of CBD, with one study finding that CBD can cause chromosomal damage in human-derived cell lines. 26 Also of note, CBD interacts with a number of common medications. CBD is a substrate for cytochrome (CYP) p450 enzymes CYP3A4 and CYP2C19; a dose reduction should therefore be considered when a patient is concomitantly using moderate or strong inhibitors of these enzymes, and a dose increase should be considered when a patient is using moderate or strong inducers. In addition, when CBD is used concomitantly with substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, CYP1A2, or CYP2B6, a dose reduction of the substrate should be considered. 12 The combination of potential side effects and drug interactions, along with the regulatory issues highlighted above, raises concerns about patient safety. As evidenced by the widespread use and current availability of CBD oil products, patients are likely to consume these products despite a lack of efficacy or safety data. Because of this likelihood, healthcare providers should provide guidance to their patients on selecting the safest product possible. (Table 1 – see PDF) lists considerations for choosing high-quality CBD oil products. 3

Overall, very little evidence exists to support the medical use of CBD oil for patients with cancer. Although some case reports have demonstrated benefit, the lack of data from well-designed human trials presents the single largest barrier to acceptance and routine use of CBD by medical professionals. In addition to the lack of evidence, CBD’s questionable legality also presents an obstacle to be overcome before providers can comfortably recommend it to their patients. In the meantime, as the CBD craze sweeps across the nation, providers should focus on educating themselves about the risks and benefits of CBD oil in order to manage expectations and avoid adverse effects and drug interactions in their patients who are curious about CBD.

  1. Projectcbd.org. What Is CBD? Definition of Cannabidiol and CBD Oil. Available at https://www.projectcbd.org/cbd-101/what-is-cbd. Accessed February 18, 2020.
  2. Klumpers LE, Thacker DL. A brief background on cannabis: from plant to medical indications. J AOAC Int. 2019;102:412-420.
  3. VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ guide to cannabidiol and hemp oils. Mayo Clin Proc. 2019;94:1840-1851.
  4. Aizpurua-Olaizola O, Soydaner U, Öztürk E, et al. Evolution of the cannabinoid and terpene content during the growth of cannabis sativa plants from different chemotypes. J Nat Prod. 2016;79:324-331.
  5. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.
  6. Bridgeman MB, Abazia DT. Medicinal Cannabis: History, Pharmacology, and Implications for the Acute Care Setting. P T. 2017;42(3):180-188. Available at https://www.ptcommunity.com/journal/article/full/2017/3/180/medicinal-cannabis-history-pharmacology-and-implications-acute-care. Accessed February 20, 2020.
  7. U.S. Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD): Questions and Answers. Available at https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed February 18, 2020.
  8. ProCon.org. Legal Medical Marijuana States and DC: Laws, Fees, and Possession Limits. Available at https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/. Accessed February 18, 2020.
  9. Sifferlin A. Puerto Rico governor signs executive order to legalize medical marijuana. Available at https://time.com/3845638/puerto-rico-medical-marijuana/. Published May 4, 2015. Accessed February 18, 2020.
  10. Perez J. Marijuana prohibition to end. SaipanTribune.com. Available at https://www.saipantribune.com/index.php/marijuana-prohibition-to-end/. Published February 5, 2019. Accessed February 18, 2020.
  11. Cohen PA, Sharfstein J. The opportunity of CBD—reforming the law. N Engl J Med. 2019;381:297-299.
  12. Epidiolex (cannabidiol) [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018.
  13. U.S. Drug Enforcement Administration. Schedules of controlled substances: placement in schedule V of certain FDA-approved drugs containing cannabidiol; corresponding change to permit requirements. 21 CFR Parts 1308, 1312 [Docket No. DEA-486]. Federal Register 2018;vol 83, no.189. Available at https://www.gpo.gov/fdsys/pkg/FR-2018-09-28/pdf/2018-21121.pdf. Accessed February 11, 2020.
  14. Hudak J. The Farm Bill, hemp legalization and the status of CBD: an explainer. Brookings. Available at https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/. Published December 14, 2018. Accessed February 20, 2020.
  15. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318:1708-1709.
  16. U.S. Food and Drug Administration. Warning letters and test results for cannabidiol-related products. Available at https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed February 19, 2020.
  17. Marinol (dronabinol) [package insert]. North Chicago, IL: AbbVie Inc.; 2017.
  18. Choipark WHD, Baek SH, Chu JP, et al. Cannabidiol induces cytotoxicity and cell death via apoptotic pathway in cancer cell lines. Biomolecules Ther. 2008;16:87-94.
  19. Yasmin-Karim S, Moreau M, Mueller R, et al. Enhancing the therapeutic efficacy of cancer treatment with cannabinoids. Front Oncol. 2018;8:114.
  20. Ivanov VN, Wu J, Wang TJC, Hei TK. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells. Oncotarget. 2019;10:825-46.
  21. Sulé-Suso J, Watson NA, van Pittius DG, Jegannathen A. Striking lung cancer response to self-administration of cannabidiol: a case report and literature review. SAGE Open Med Case Rep. 2019;7:2050313X19832160.
  22. Barrie AM, Gushue AC, Eskander RN. Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma. Gynecol Oncol Rep. 2019;29:10-12.
  23. Good P, Haywood A, Gogna G, et al. Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD). BMC Palliat Care. 2019;18:110.
  24. U.S. National Library of Medicine. A Study of the Efficacy of Cannabidiol in Patients With Multiple Myeloma, Glioblastoma Multiforme, and GI Malignancies. Available at https://clinicaltrials.gov/ct2/show/NCT03607643?term=cannabidiol&recrs=abde&cond=Cancer&draw=2&rank=1#wrapper. Accessed February 18, 2020.
  25. U.S. National Library of Medicine. Safety and Efficacy of Cannabidiol for Grade I/II Acute Graft Versus Host Disease (GVHD) After Allogeneic Stem Cell Transplantation. Available at https://clinicaltrials.gov/ct2/show/NCT01596075?term=cannabidiol+and+cancer&draw=2&rank=7#wrapper. Accessed February 18, 2020.
  26. Russo C, Ferk F, Mišík M, et al. Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells. Arch Toxicol. 2019;93:179-188.

Firstborn Turned 18: The Twin Cities Oncology Journal Club

Becky Fahrenbruch, PharmD BCOP FHOPA
Medical Science Liaison, Myeloid Hematology
Bristol Myers Squibb
Maple Grove, MN

In the fall of 2001, I successfully completed the second of my two postdoctoral residencies—they were in pharmacy practice and specialty hematology/oncology—and moved to Minnesota to start my first job as oncology clinical coordinator at Abbott Northwestern Hospital. As a young and ambitious pharmacist in the oncology/hematology field, I looked for many ways to get involved and make an impact in the profession. Luckily, I met Pam Jacobson, PharmD FCCP, a distinguished professor and associate department head in the department of experimental and clinical pharmacology at the University of Minnesota College of Pharmacy (COP). We worked collaboratively on the idea of an oncology journal club (OJC) and began to co-coordinate this meeting.

Our goals were simple: to get pharmacists interested in oncology/hematology together for a journal club and foster an environment for networking and education. Our first meeting was held on January 10, 2002. We had 17 pharmacists and 6 pharmaceutical company representatives in attendance and discussed a review titled “Epoetin Alfa Therapy Increases Hemoglobin Levels and Improves Quality of Life in Patients with Cancer-Related Anemia Who Are Not Receiving Chemotherapy and Patients with Anemia Who Are Receiving Chemotherapy.” Wow, have times changed! To date, we have had 108 journal club meetings and average around 70 attendees at each meeting.

OJC, an evening dinner program, begins in January and occurs in alternate months throughout the year. The program consists of a 30-minute presentation by a speaker or program representative from a pharmaceutical company, followed by 10 minutes for questions, and then a 60-minute presentation developed for pharmacists’ continuing education (CE). A pharmaceutical company sponsor provides the educational speaker and the meal. The location of the meeting rotates among Minneapolis, St. Paul, and other suburbs in the Twin Cities area.

Attendees are pharmacists, University of Minnesota COP students, residents, drug representatives, and medical science liaisons. For the past 5 years, 1 hour of CE credit has been available for pharmacists via this program through the Minnesota Board of Pharmacy. We are very fortunate to have a wide variety of speakers, including pharmacists, pharmacy residents (postgraduate year-1 and year-2 [PGY-1 and PGY-2]), University of Minnesota COP students, and industry speakers (doctors, medical science liaisons, pharmacists, nurse practitioners, etc.). Without our volunteer CE speakers and industry support, OJC would not be sustainable.

Over the past 18 years, topics across a wide range have been discussed at OJC, and varying formats have been used:

  • Overview of practice sites (patient population, number of beds/chairs, staffing, etc.)
  • “How We Do It” discussions (on topics like febrile neutropenia, nausea and vomiting, and mucositis)
  • Clinical Pearls articles from HOPA News
  • New drug updates
  • Case studies
  • Disease overviews
  • Major projects conducted by PGY-1 and PGY-2 residents
  • Pharmaceutical company presentations ranging from supportive care to unbranded disease education.

With such a longstanding program, change was inevitable. OJC was established with pharmaceutical company education grants, and an industry speaker was not required. This quickly changed when the Pharmaceutical Research and Manufacturers of America (PhRMA) Code on Interaction with Health Care Professionals was implemented in January 2009. OJC adapted its programming to the requirements of speakers from drug companies. In 2016, we began using Google to create a Gmail account, update contact lists, and create Google Forms to streamline the RSVP process. Beginning in 2020, OJC will be coordinated through the Upper Midwest Oncology Education Network (UMOEN), with the current board working on programming and CE credits. UMOEN may be considered my first-born grandchild, because it was born out of OJC. But that’s a story for another day, and honestly, I am far too young to be a grandmother! Luckily, I am on the board of UMOEN and will continue to be involved in this endeavor.

I have learned many things since starting OJC. First, surveys sent to the participants asking for topics of interest and suggestions of volunteers to speak at future meetings has helped ensure the longevity of OJC. Using a wide variety of speakers and choosing discussion topics from across various disease states in inpatient and outpatient practice help engage our diverse audience of pharmacy professionals. Every pharmaceutical company has different regulations, so establishing guidelines upfront can help prevent any issues arising with industry sponsorship and speaker roles. On the practical side, keeping people informed about upcoming dates so they can request certain work shifts has allowed more pharmacists to attend. And holding our meetings in a great location with easy parking has been helpful for an after-work evening program.

Finally, having more than one person involved in the planning of OJC has allowed us to continue to provide this education in Minnesota. I would like to thank Pam Jacobson, PharmD FCCP, and past OJC CE education coordinator Sara Smith, PharmD BCOP, of University of Minnesota Health for all their help. As they say, it takes a village.

Last September I presented on the Twin Cities OJC at HOPA Practice Management during the Practice Management Pearls session. Shortly afterward, I received a LinkedIn tag post from Sarah Francis, PharmD BCOP, thanking me for the presentation. Hearing about our OJC motivated Dr. Francis and her colleagues to schedule the first South Florida Oncology Pharmacy Journal Club! I was honored and happy to have helped start another OJC in the United States.

I have two children, ages 12 and 14, but my professional firstborn is OJC! I may be a bit biased, but I believe this is the oldest and largest specialty pharmacy OJC in the nation. I am so proud of having been able to provide oncology/hematology education in Minnesota for the past 18 years. The journal club has allowed for the flourishing of a fantastic professional networking group of pharmacists, students, residents, and industry representatives.

If you are interested in starting an OJC in your area, please contact me at This email address is being protected from spambots. You need JavaScript enabled to view it. with any questions.

Women in Oncology Pharmacy Leadership: Strides to Close the Gap—A Review of HOPA’s 2019 White Paper

Alana Ferrari, PharmD
PGY-2 Oncology Pharmacy Resident
Duke University Hospital
Durham, NC

In August 2019, The Journal of Oncology Pharmacy Practice published HOPA’s white paper on the issue of women in oncology pharmacy leadership. 1 The publication highlights the current disparity between women and men in oncology pharmacy leadership in the United States: women represent 58.1% of pharmacy professionals, but only 25% of those women hold leadership roles. 2 In an effort to understand how this disparity is affecting female oncology pharmacists, HOPA’s Leadership Development Committee held a summit in 2017 to deliberate on this issue and discuss the results of a national HOPA membership survey assessing the barriers that prevent female oncology pharmacists from assuming leadership roles. The authors of the white paper identify common sentiments expressed by survey respondents, describe key barriers, and provide suggestions to institutions and individuals on how the profession can encourage and promote female representation in oncology pharmacy leadership.

An online survey distributed to the HOPA membership through its e-mail discussion group in the summer of 2017 was returned by 160 respondents; the group was made up of men and women who had a range of experiences and years of service in oncology pharmacy practice. Opinions on resources available for leadership training were divergent. Approximately half of the respondents perceived a lack in leadership training resources, whereas the other half believed that numerous opportunities existed and that creating more leadership training experiences was unnecessary. However, there was a consensus among respondents about the benefit of providing more formal leadership training through educational efforts. The Leadership Development Committee noted that schools of pharmacy have already begun to add these leadership development practices to their foundational curricula and that the American Society of Health-System Pharmacists has integrated similar efforts into the goals and objectives for accredited residency programs. However, the implementation of these experiences varies greatly across residency programs. In the future, HOPA can support leadership development training programs by constructing a HOPA-sponsored leadership fundamentals course for postgraduate year-2 oncology residency programs and by encouraging engagement by trainees in HOPA.

The analysis of the survey results identified and described six main barriers affecting female oncology pharmacists. Two of the six were institutional barriers: a lack of succession planning by superiors and a lack of emphasis on formalized leadership training for continued career growth in the pharmacy profession. In a 2018 survey carried out by the American College of Healthcare Executives, succession planning was not reported as a priority for executives. 3 In addition, 70% of executives polled in another survey by the American College of Healthcare Executives denied having formalized succession plans in their workplaces. 4 The HOPA committee infers that if more workplaces were to develop formalized succession plans and consider female internal hires for leadership roles, internal talent would be nurtured and the proportion of women assuming leadership roles would increase. Regarding the lack of formalized professional development training, the Leadership Development Committee states that in some cases professional organizations are deficient in providing training courses that would help establish foundational leadership skills. Professional organizations like HOPA should continue to organize leadership workshops and mentorship programs with current leaders to help enhance leadership skills and support female leaders whose goals change throughout dynamic careers. Although these steps will help in the future, the immediate need is for opportunities in the workplace for professional training and managerial roles for women who have a strong bent toward leadership.

Another set of barriers identified were interpersonal: the problem of women bullying other women and the existence of sexual harassment. The Leadership Development Committee noted that a commonly expressed perception was a lack of support for other women among female leaders. This lack of support may be manifested as bullying behavior. The Leadership Development Committee members offer possible reasons for such behavior, but they emphasize the need for women to support other women in the field. By encouraging each other, opposing bullying, and creating supportive environments, women can help each other succeed and overcome discrimination in the workplace. HOPA has a large proportion of women in leadership roles, so HOPA leaders hope to set the precedent for other disciplines and professional organizations.

Unfortunately, sexual harassment remains an issue in the workplace and threatens affected employees’ sense of safety and value. Not only do such violations cause personal suffering, but they have an adverse impact on professional aspirations. Members of HOPA’s Leadership Development Committee believe that even though national stories of abuse have shed light on these occurrences, the eradication of sexual harassment will occur only when the broader culture changes. HOPA plans to include leadership training program strategies for addressing harassment and constructing supportive, respectful workplace environments. Although these efforts will not eradicate sexual harassment, they can provide tools to help leaders combat this societal epidemic, protect those who have been harmed or who are at risk, and prevent future occurrences.

The last two barriers identified were concerns about work-life balance and perceived self-worth and confidence. Challenges in maintaining work-life balance are certainly faced not just by women: a 2015 study reported that 70% of women felt “unable to take any time off work” compared with 60% of men. 5 Balancing personal time and obligations with professional responsibilities can be a challenge. Endorsing the belief that work-life prioritization is a personal decision, the Leadership Development Committee advocates that female oncology pharmacists find a balance for themselves and seek continued professional involvement while taking time away from work. Workplace environments should provide equal opportunity for both job and personal satisfaction without allowing perceptions about gender roles to influence career placement decisions. HOPA also plans to provide resources to women throughout their career trajectories for maintaining their credentials while they choose to use family- or personal-leave time.

By creating more professional development programs for members, encouraging early involvement of trainees in HOPA, and developing training tools to fight discrimination in the workplace, HOPA demonstrates its commitment to the advancement of women in pharmacy leadership roles and to the reduction and elimination of disparities between men and women in pharmacy leadership. However, the HOPA Leadership Development Committee cannot be successful in these efforts without the involvement of members and cooperation from institutions. HOPA places the responsibility of creating cultural change on institutions and current women pharmacists. With members and healthcare institutions uniting to support changes that will facilitate progress, these efforts can be successful in the future.

  1. Shillingburg A, Michaud LB, Schwartz R, Anderson J, Henry DW; endorsed by the Hematology/Oncology Pharmacy Association (HOPA). Women in oncology pharmacy leadership: a white paper. J Oncol Pharm Pract. 2020;26:175-186. Epub September 25, 2019.
  2. Goldin C, Katz LF. A most egalitarian profession: pharmacy and the evolution of a family-friendly occupation. J Labor Econ. 2016;34:705-745.
  3. American College of Healthcare Executives. Survey: healthcare finance, governmental mandates, personnel shortages cited by CEOs as top issues confronting hospitals in 2018 [press release]. January 25, 2019. Available at https://www.ache.org/about-ache/news-and-awards/news-releases/top-issues-confronting-hospitals-in-2018. Accessed February 20, 2020.
  4. American College of Healthcare Executives. Succession planning practices and outcomes in U.S. hospital systems: final report. 2017. Available at www.academia.edu/270324/ Succession_Planning_Practices_and_Outcomes_In_US_ Hospital_Systems_Final_Report. 2007. Accessed February 20, 2020.
  5. HR in Asia. Is it true that women take more sick leave than men? October 9, 2015. Available at https://www.hrinasia.com/general/is-it-true-that-women-take-more-sick-leave-than-men/. Accessed February 20, 2020.

Pharmacists-in-Training Implementing Quality Initiatives in Oncology Care

Alyssa B. Bradshaw, PharmD
PGY-2 Oncology Pharmacy Resident
Wake Forest Baptist Health
Winston-Salem, NC
Michelle K. Azar
PharmD Candidate (2021)
University of Michigan College of Pharmacy
Ann Arbor, MI

Demonstrating the ability to provide high-quality and cost-efficient care by using process, outcome, and patient-reported metrics is now an essential part of health care and is linked to reimbursement and star ratings. The Centers for Medicare and Medicaid Services (CMS) created the Merit-Based Incentive Payment System and alternative-payment Oncology Care Model with the goal of promoting high-quality patient-centered care. CMS has approved the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) as a quality assessment program that can increase the potential for reimbursement by focusing on patient care and measuring quality in areas such as symptom management, evidence-based medicine, and cost mitigation. Oncology pharmacists are in an ideal position to influence the quality of care through financial stewardship by developing policies, improving patient outcomes through therapeutic management, and enhancing patient perceptions through direct education and enhanced supportive care. 1 Pharmacists-in-training make it possible to expand the services offered by a pharmacist. The impact of pharmacy residency training programs on quality improvement initiatives has been documented since at least 1996. 2 Although many projects remain unpublished and are being used solely for internal quality improvement, various publications demonstrate the involvement of pharmacy residents and students in efforts to improve quality metrics such as medication reconciliation, discharge follow-up, patient education, and patient engagement.

Leveraging Layered Learning to Expand Patient Care and Meet Quality Metrics for Oncology Patients

A study by Bates and colleagues published in 2016 evaluated the impact of leveraging pharmacists-in-training to expand care by conducting discharge medication reconciliation and counseling for malignant hematology and medical oncology patients. 3 The advanced pharmacy practice experience (APPE) student was focused on obtaining admission medication histories and counseling, while the resident was responsible for discharge medication reconciliation, patient education, documentation, order verification, and providing support for obtaining medications. The clinical pharmacist assisted and coordinated team activities. During the 60-day study period, 61 patients (51%) received discharge medication reconciliation and counseling. The number of medication-related problems (MRPs) identified at discharge (mean of 1.26 for malignant hematology patients; mean of 2.1 for medical oncology patients) was captured and showed that the majority of problems involved coordination of specialty medications for the malignant hematology group and the need for an additional drug in the medical oncology group. The pharmacy team made recommendations to resolve all MRPs; the acceptance rates were 89.7% and 78% for the malignant hematology and medical oncology teams, respectively. This study demonstrated that pharmacists-in-training can be integrated into efforts to expand pharmacist care and improve patient outcomes.

Student Pharmacist–Driven Medication Reconciliation

A number of studies have evaluated the impact of pharmacy student–led medication reconciliation in the ambulatory care setting, such as in the infusion center of a comprehensive cancer center. A study by Ashjian and colleagues involved students in their introductory pharmacy practice experiences who completed medication histories for 510 hematology/oncology patients and found that 88% had at least one discrepancy. 4 In a separate study, Phan and colleagues utilized APPE students to complete medication histories for 60 patients and found a similar rate of at least one discrepancy (83%), with 21% of those discrepancies involving a high-risk medication. 5 Pharmacists-in-training can add significant value to patient care by correcting discrepancies and reducing the likelihood of medication errors.

Pharmacy Resident and Clinical Pharmacist Postdischarge Follow-Up Telephone Program

Discharge planning and follow-up are essential components of patient care and the prevention of avoidable hospital readmissions and complications. Patients with cancer are at an increased risk of transitions-of-care errors because of the complexity of their medication regimens. Pharmacists at the University of Texas MD Anderson Cancer Center teamed up with a PGY-1 resident and an educational specialist to develop a pilot program for postdischarge telephone calls to assess medication adherence, provide education, and address medication-related concerns with patients. 6 Two hundred and six calls were made within 72 hours following discharge, and 150 (73%) of patients were successfully reached; 20 of the 206 patients who were contacted (9%) declined the call. Of the patients reached, 87 (58%) were found to have one or more discrepancies with their medications. Although it is known that scheduled follow-up with patients after hospitalization is beneficial, time and resources are a limiting factor. Pharmacists are well positioned to improve continuity of care and have a positive impact on medication-related issues, both of which are measures endorsed by the National Quality Forum and are National Patient Safety Goals, according to the Joint Commission.

Increased Patient Engagement Following Chemotherapy Consultation by a Pharmacist and Trainees

The literature is replete with evidence suggesting that patients who are engaged in their care have better outcomes and a lower cost of care. Patient engagement, or patient activation, refers to a patient’s knowledge, skills, and confidence to manage their own health and can be measured using the patient activation measure (PAM)-10 tool, with a higher score indicating improved outcomes. One study demonstrated this through a first-cycle chemotherapy consultation service, which was completed by a pharmacist or pharmacist-in-training. 7 This service included patient education, medication therapy management, and the addressing of MRPs. After administering a baseline PAM-10 survey, pharmacists or trainees called the patient within 2 days of discharge for a second PAM-10 survey. Of the 36 patients analyzed in this study, the PAM-10 scores were significantly improved following the intervention (68.5 vs. 75, pre- and postintervention, respectively; p = .001). This study highlights the effectiveness of using pharmacy residents and students to positively affect patient care and encourage patient involvement in the care process.


Oncology pharmacists have demonstrated their abilities to influence patient care and positively affect quality metrics endorsed by ASCO QOPI as part of their current scope of practice. Pharmacy residents and students are able to assist in this process and can be called upon to supplement quality care given by the team. They can help implement and expand on established pharmacy services. Although pharmacists and pharmacy trainees have made significant contributions to enhancing the quality of oncology care, additional opportunities for pharmacy involvement remain. Areas of well-established pharmacist-led impact on quality include patient education, symptom management, medication reconciliation, discharge follow-up, transitions of care, and increasing patient engagement and activation. Focusing on developing new services and activities to address quality metrics and using pharmacy trainees in the process is an essential responsibility and next step for oncology pharmacists to further improve patient care while also ensuring that reimbursement is optimized.

Acknowledgment: The authors acknowledge and thank Gayle Blouin, PharmD BCOP, for her guidance and her review of the article.

  1. Vulaj V, Hough S, Bedard L, et al. Oncology pharmacist opportunities: closing the gap in quality care. J Oncol Pract. 2018;14:e403-e411.
  2. LeRoy ML, Pruemer J. Impact of an oncology pharmacy residency training program on quality improvement initiatives in an oncology center. Pharm Pract Manag Q. 1996;16:59-65.
  3. Bates JS, Buie LW, Amerine LB, et al. Expanding care through a layered learning practice model. Am J Health Syst Pharm. 2016;73:1869-1875.
  4. Ashjian E, Salamin LB, Eschenburg K, et al. Evaluation of outpatient medication reconciliation involving student pharmacists at a comprehensive cancer center. J Am Pharm Assoc. 2015;55:540-545.
  5. Phan H, Williams M, McElroy K, et al. Implementation of a student pharmacist-driven medication history service for ambulatory oncology patients in a large academic medical center. J Oncol Pharm Pract. 2019;25:1419-1424.
  6. Patel SD, Nguyen PAA, Bachler M, Atkinson B. Implementation of post-discharge follow-up telephone calls at a comprehensive cancer center. Am J Health Syst Pharm. 2017;74:S42-S46.
  7. Bates JS, Auten J, Sketch MR, et al. Patient engagement in first cycle comprehensive chemotherapy consultation pharmacist services and impact on patient activation. J Oncol Pharm Pract. 2019;25:896-902.

Toxicity Management for Immune Checkpoint Inhibitors

Eris Tollkuci, PharmD BCOP
Assistant Professor of Pharmacy Practice
Rosalind Franklin University of Medicine and Science
North Chicago, IL
Clinical Pharmacy Specialist, Hematology/Oncology/Cell Therapy
Rush University Medical Center
Chicago, IL

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have become the mainstay of therapy for numerous oncologic indications (Table 1 – see PDF). Most U.S. Food and Drug Administration approvals pertain to treatment of advanced or metastatic cancers; however, agents such as atezolizumab have gained approval in the first-line setting (IMpower133). 1 An increasing number of patients are exposed to these therapies; therefore, it is imperative for healthcare providers in community and academic medical center settings to recognize and appropriately manage these unique toxicities. The purpose of this article is to provide an overview of immune checkpoint inhibitor (ICI) toxicity management while also highlighting resources available for clinicians managing these therapies in various clinical settings.

Checkpoint inhibitor–based immunotherapies have varying toxicity profile incidence and timing, which are often related to their unique mechanism of action, setting them apart from traditional cytotoxic chemotherapies. Toxicities can be divided into three categories: infusion reactions, immune-related adverse events (irAEs), and adverse events of special interest. The skin, colon, endocrine organs, liver, and lungs are the organs most frequently affected by irAEs. 2

Infusion-Related Reactions

Most infusion-related reactions are mild and are typically associated with low-grade fever, chills, headaches, or nausea (Table 2 – see PDF). Severe reactions are reported in less than 1% of patients. Infusion-related reactions have most commonly been reported with avelumab, with any-grade reactions occurring in 25% of patients. Recommendations for the management of infusion-related reactions are summarized in Table 2. The National Comprehensive Cancer Network (NCCN) guidelines recommend that clinicians refer to each product’s prescribing information for premedication recommendations. 9 Mild reactions are generally transient and do not require therapy interruption or any other interventions. Moderate reactions are generally managed by withholding the infusion or slowing down the rate of infusion per institutional guidelines. Treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, narcotics, or intravenous (IV) fluids may be used but typically isn’t required for longer than a 24-hour period. Severe reactions require urgent management and permanent discontinuation of the ICI.

Immune-Related Adverse Events

Successful management of irAEs begins with toxicity recognition and grading. Some of the most common toxicities and their management are highlighted in (Table 3 – see PDF). Clinicians should refer to national or institution-specific clinical guidelines to determine when withholding immunotherapy may be an appropriate management option for irAEs. Early recognition of symptoms is crucial for prompt intervention and treatment; counseling of patients regarding symptom recognition is therefore important before initiation of ICI therapy. Immunosuppression with corticosteroids is the mainstay of therapy, except in the case of selected endocrine irAEs, which may be managed with hormonal supplementation. 9

Dosing for systemic steroids such as prednisone or methylprednisolone depends on the toxicity grade or severity and can range between 0.5 and 2 mg/kg/day. Myocarditis is a rare but potentially severe adverse event of ICI therapy. Its symptoms are nonspecific, and management requires pulse-dose methylprednisolone administration at 1,000 mg IV daily for 3–5 days. 9 Steroid therapy is generally administered until symptoms resolve to grade 1 or lower (unless otherwise specified), followed by a taper over a 4- to 6-week period. Important considerations with high-dose or prolonged steroid therapy include the following: hyperglycemia, opportunistic fungal or bacterial infections, osteoporosis, and gastritis. Additional immunosuppression may be required for severe irAEs not responding to initial corticosteroid therapy in 48–72 hours. Consultation with any appropriate and relevant medical specialist is recommended at this point. 10

Tumor necrosis factor inhibitors such as infliximab can be used in steroid-refractory cases by means of targeting and inhibiting proinflammatory cytokines (IL-1 and IL-6). 11 These agents are particularly effective for immune-mediated colitis and inflammatory arthritis. Duration of therapy is not well defined in the setting of irAEs but is typically a single dose. Vedolizumab is a monoclonal antibody that binds and inhibits the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

A multicenter study evaluating vedolizumab in 28 patients with steroid-refractory enterocolitis found favorable outcomes and yielded good safety data. 12 Mycophenolic acid and mycophenolate mofetil (MMF) are immunosuppressive agents that decrease the proliferation of B and T cells, induce T-cell apoptosis, and suppress dendritic cells and IL-1. These agents have been used in steroid-refractory irAEs involving the liver, kidney, pancreas, and eyes. 9,13 Intravenous immunoglobulin (IVIG), with its immunomodulatory mechanism, can be used to manage neurologic inflammatory or autoimmune conditions. 9 Plasmapheresis or IVIG may be considered for severe or steroid-refractory neurological irAEs. 14,15 Additional therapies cited in the NCCN guidelines include rituximab, tacrolimus, tocilizumab, cyclosporine, cyclophosphamide, methotrexate, and antirheumatic agents. 9,16,17


The role of PD-1/PD-L1 inhibitors in the treatment of various cancers is rapidly expanding, and it is important for clinicians and patients to understand the unique toxicities associated with these therapies. Prompt symptom reporting and toxicity identification is imperative for appropriate toxicity management. To date, three clinical guidelines discuss the differences and similarities in the management of ICI toxicities: those of the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the European Society of Medical Oncology. 2,9,15 Understanding the available guidelines and resources is an important step for institutions as they develop and practice site-specific protocols for the management of irAEs.

  1. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med.2018;379:2220–2229.
  2. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2017;28:iv119–iv142. Published correction appears in Ann Oncol. 2018;29:iv264-iv266
  3. Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals Inc.; 2019.
  4. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2019.
  5. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck Sharpe and Dohme Corp.; 2019. Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech Inc.; 2019.
  6. Bavencio (avelumab) [package insert]. Rockland, MD: EMB Serono Inc.; 2019.
  7. Imfinzi (durvalumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2018.
  8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities. Version 1.2020 (December 16, 2019). Available at www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 6, 2020.
  9. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–168.
  10. Wolfe RM, Ang DC. Biologic therapies for autoimmune and connective tissue diseases. Immunol Allergy Clin North Am. 2017;37:283–299.
  11. Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study. J Immunother Cancer. 2018;6:142.
  12. Trinh S, Le A, Gowani S, La-Beck NM. Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines. Asia Pac J Oncol Nurs. 2019;6(2):154–160.
  13. Fellner A, Makranz C, Lotem M, et al. Neurologic complications of immune checkpoint inhibitors. J Neurooncol. 2018;137(3):601–609.
  14. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–1768.
  15. Stroud CR, Hegde A, Cherry C, et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract. 2019;25:551–557.
  16. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26: 2375–2391. Published correction appears in Ann Oncol. 2016 Jul;27:1362.

Establishing a New Practice Site in the Ambulatory Setting

Katherine Saunders, PharmD BCOP
Ambulatory Oncology Clinical Pharmacy Specialist
Georgia Cancer Center/Augusta University Health
Augusta, GA

The role of the oncology pharmacist on the care team continues to expand, and this growth is especially apparent in the ambulatory setting. Our training, skills, and pharmacotherapy knowledge place us in a unique position to care for this patient population, and other healthcare providers and administrators are seeing the potential for pharmacists to improve the quality of care for patients with cancer. Given this expanding role in the ambulatory setting, many current postgraduate year-2 (PGY-2) oncology residents find themselves applying and interviewing for positions that involve establishing a new practice site. But how does a brand-new graduate go about carrying out this task?

After completing my PGY-2 oncology residency at University of Wisconsin Health in Madison, WI, I took a position at Augusta University (AU) Health in Augusta, GA, in the ambulatory oncology setting. My mission: (1) to establish a new practice site in the solid tumor clinics that would enhance patient care and be successful enough to justify more positions in other oncology clinics and (2) to create a new learning experience for PGY-2 oncology residents, PGY-1 pharmacy residents, and advanced pharmacy practice experience students. Sounds simple enough, right? Having just completed my PGY-2 at an institution that launched new pharmacist positions in the oncology clinic at the beginning of my residency year, I had seen some of the challenges my preceptors faced as well as the projects that had been successful and well received. I had also once been a student and resident, so I felt confident that I could develop learning experiences while also establishing myself as an independent practitioner. I thought that I had set realistic expectations for myself and that I could reasonably achieve my goals during my first year at AU Health. Reflecting on my first year out of residency and the subsequent experiences I have had in my position has shown me that my expectations were not as realistic as I had hoped. I want to share what worked well for me, what was not successful, and what I recommend to anyone creating a new practice site.

First, the Dos

Do learn about the pharmacy department and oncology pharmacy service line.

Your initial onboarding is a key step in being successful in your clinic. This is your chance to see the priorities of the institution and pharmacy department in action. It is also an opportunity to see what initiatives other pharmacists are working on and what they struggle with in carrying out their daily duties. How do your goals for your position help the department? What can you do for your pharmacy team members? After completing a PGY-2 residency in oncology, you will be very familiar with the challenges involved in transitions of care. What initiatives are the inpatient oncology pharmacists working on? Can your role in the clinic help them be more successful in their jobs, and vice versa? The answer is yes, and when you are observing the inpatient practice site during your orientation, you will start to see how you can enhance their practice from the clinic.

Make sure your initial orientation to your position includes the opportunity to shadow pharmacists in other service lines. Even if the clinic position is new for oncology, the institution may have pharmacists in other clinics, such as those for internal medicine or infectious diseases. If this is the case, ask that your orientation schedule includes time in those clinics. How are those pharmacists integrated into the healthcare team? What clinical services do they provide? What challenges do they face in their clinics? Although the disease states are different, I have found that many of my ambulatory pharmacist colleagues face the same issues I do, and they can be great sounding boards for new ideas.

Finally, spend time in your infusion pharmacy to understand the operational opportunities in the cancer center. How can you improve the safety and efficiency of the production process? What challenges do the infusion pharmacy staff members face? Having a pharmacist in the ambulatory clinics will improve the communication between the infusion pharmacy and the providers, and improvements in this area will enhance patient care.

Do learn about your clinic.

When you are establishing a new pharmacy practice site, it is important to remember that the clinical practice site was likely already in existence. It has been successful enough to still be in operation and to expand services to include its own clinical pharmacist! One of the best pieces of advice I can give is to begin by listening and observing. You will be eager to provide several services: among them, patient education, supportive care management, cancer therapy optimization, and therapeutic drug monitoring. Make a list of services you think a pharmacist should be providing in clinic. Are these services being offered? Most likely, the answer is yes. Who is currently performing these duties? For example, in my practice site, the nurse navigators were responsible for patient education on new regimens. I wanted to learn the following from them:

  • How do you fit patient education into your workflow?
  • What resources do you use and provide to patients?
  • How do you document that education has been conducted?

Asking about their process taught me that, although they loved speaking with patients about their treatment plans, they had to balance that task with many other duties, such as receiving referrals for new patients and triaging calls from existing patients. Having this information, I realized that offering to help educate patients on medications meant I was doing something I was passionate about and that patients would benefit from, while also helping with the overall workflow of the clinic. Make it a collaborative decision and seek out their ideas on how a pharmacist can improve patient care.

Do find a mentor.

As a new graduate from residency, you are going to have a wealth of knowledge and experiences to call upon during difficult times in your position, but you (or anyone, for that matter) cannot know everything. Having someone who either practices in the same area you do or understands the challenges you are facing will be invaluable during your transition to becoming an independent practitioner. Seek out advice from other pharmacists and stay in touch with your preceptors from residency! This is something I wish I had recognized earlier in my career.

Do delegate, and say no if you need to.

This is a lesson I learned the hard way—you cannot do everything on your own. In addition, you do not have to take on every project offered to you. In my experience, many people were excited to have a pharmacist in their clinics and wanted to involve me as much as possible, but it is okay to tell someone you are not able to participate in a project if you truly feel you will not be able to dedicate the effort needed for it to be successful. Maybe you are not the right person for the project. Colleagues would much prefer that you be honest than overcommit and underdeliver. The transition from residency is tough, and it takes practice learning to say “no” when you want to help. Lean on your mentors and supervisor in these instances—they can help you navigate the process of establishing boundaries and prioritizing.

Now, the Don’ts

Don’t set unrealistic timelines.

You will have just completed residency, where everything needs to be achieved in 1–2 years. This is not the case in your first job as an independent practitioner, especially if it is a new practice site. It takes time to develop your job, and changes will be small at first. Pharmacists feel a significant amount of pressure to make interventions and justify their position, but it is okay to take time to create and learn the system, modify workflows, and establish boundaries. A strong foundation in these will help you be a more effective and efficient pharmacist.

Don’t take on learners too early.

I am a strong advocate for having protected time in your practice before taking on learners. You are still doing a considerable amount of learning yourself—about your institution, clinic, and the disease state(s) in which you are practicing. One thing we all love about oncology is the fast pace at which it changes, but this is also a challenge. It is difficult to teach and figure out how to integrate learners of all levels into your workflow when that workflow is not yet established. Ask when you will be expected to precept students and residents and be honest about your ability to effectively precept when that time comes.

Don’t get burned out.

This advice may seem like a given, but new pharmacy residency graduates are at particularly high risk of burnout, regardless of the position they take. Your institution likely has resources, such as employee assistance programs, to help with this transition. Be up-front and honest with your supervisor and your teammates if you are struggling or sense that you are getting burned out.

Establishing a new practice site can be daunting and will inevitably involve challenges you cannot expect. Making the time to learn the current practice and workflow will allow you to integrate yourself more successfully into a clinic. It is important to establish boundaries and be honest with your supervisor, your colleagues, and, most important, yourself about what you need to be successful.

Actionable Mutations in Solid Tumors

Amy M. Sion, PharmD BCOP
Clinical Pharmacy Specialist—Genitourinary/Head and Neck/Oncology Research
Medical University of South Carolina, Hollings Cancer Center
Charleston, SC
Emma Dion
PharmD candidate (2020)
University of South Carolina College of Pharmacy
Columbia, SC

It has long been understood that cancer develops due to an accumulation of genomic mutations in healthy cells. Alterations in oncogenes and tumor suppressor proteins, like p53, lead to dysregulation of cell cycle control resulting in transformation of normal cells to a cancer phenotype. The identification of mutations that drive the onset of cancer has led not only to a better understanding of cancer physiology but also to significant advancements in the development of drugs that target specific mutations in a tumor. Precision oncology is the term used to describe personalized cancer treatment based on the genetic changes in an individual patient’s tumor. The utility of precision oncology in clinical practice has been made possible by advances in technology such as next-generation sequencing (NGS), along with intensive research efforts made possible by funding from programs like the $200 million Precision Medicine Initiative announced by President Barack Obama in 2015. 1 This article summarizes the principles of precision oncology and provides guidance to pharmacists on using genomic information in clinical practice.

Types of Mutations and Clinical Significance

It is important to understand the type and function of a mutation and its biological significance when using genomic analyses to design a patient treatment plan. Tumor cells have both inherited and somatic variants in their genome. Hereditary mutations, referred to as germline mutations, are gene changes in the germ cells (sperm or oocyte) that are passed to every cell in the offspring. 2 Many germline mutations in cancer are known, such as BRCA1/2, TP53, ATM, and PALB2, and they are most often associated with increased cancer susceptibility and more aggressive cancer phenotypes. 3

Alternatively, somatic mutations are not present in germ cells and develop spontaneously in an individual’s DNA over time. These acquired changes in human oncogenes are known to play a role in the development of cancer. Moreover, the number of somatic mutations in the tumor can change over time, potentially leading to treatment resistance and disease progression.

Understanding common terms used to describe the clinical significance of cancer mutations is also essential. An actionable mutation is defined as a genetic aberration in a patient’s tumor that is targetable with an available anticancer treatment or is the target of novel therapeutics in development. A driver mutation is a mutation that may not be targetable with a specific treatment but is known to play a role in cancer development, resistance, or progression. Passenger mutations are nonpathogenic and are thought to have little or no biological significance to cancer biology but are linked to driver mutations on the same gene. 2-4 Thus, given the diversity of genetic aberrations in cancer, it is essential to understand the clinical relevance of each type of mutation in solid tumors.

Further, some genomic aberrations are predictive of treatment response, prognostic of outcomes, or both, depending on the tumor type. For example, mutations in the RAS genes KRAS and NRAS predict a poor response to epidermal growth factor receptor (EGFR) therapies, like cetuximab and panitumumab, in colorectal cancer. In non-small-cell lung cancer (NSCLC) tumors, the presence of a KRAS mutation predicts a poor response to EGFR tyrosine kinase inhibitors, like erlotinib. Prognostically, NSCLC tumors with mutant KRAS demonstrate poor survival compared with tumors having wild-type KRAS. 5 To date, no therapies specifically targeting Ras proteins have been approved by the U.S. Food and Drug Administration (FDA), so the clinical significance of KRAS in solid tumors remains as a predictor of treatment responses and a prognostic marker of clinical outcomes.

The presence of a germline BRCA1/2 mutation is known to increase the risk of developing breast and ovarian cancer. More so, it is well known that breast cancer patients with BRCA1/2 mutations have an overall worse prognosis compared to patients with sporadic breast cancer, and the presence of a BRCA1 mutation is associated with triple negative breast cancer, which has a worse prognosis than hormone receptor or human epidermal growth factor receptor 2 (HER2)–positive disease. 3 Likewise, the pivotal study by Antoniou and colleagues analyzed more than 8,000 cases of breast and ovarian cancer and showed that the cumulative risk of ovarian cancer development was 39% in patients with BRCA1 and 11% in patients with and BRCA2. 6 Interestingly, the presence of BRCA1/2 mutations in ovarian cancer has been shown to prolong survival and confer sensitivity to platinum chemotherapy. 7

Next-Generation Sequencing

The use of precision oncology to guide treatment decisions has increased because of recent advancements in NGS. NGS is a genomic profiling technology based on high-throughput DNA and RNA sequencing platforms that analyze specific gene panels for molecular changes and actionable driver mutations. 8 NGS technology can be used to analyze DNA or RNA from tumor tissue or circulating tumor DNA (ctDNA) from the blood, also called a liquid biopsy. ctDNA is composed of small fragments of tumor DNA shed by the tumor into the blood when cells undergo apoptosis. 9 Studies have shown that genomic changes detected using NGS from liquid biopsy have a strong correlation to NGS testing from tumor tissue. A liquid biopsy can be used in cases where tumor tissue is not available, cannot be obtained, or is of poor quality. Two FDA-approved liquid biopsy assays are available, Guardant360 and FoundationACT, which currently analyze more than 70 genes that are relevant in solid tumors. 10,11 For FDA-approved targeted therapies, companion NGS tests, both tissue- and liquid-based, are used to detect the presence of the associated mutation.

Taking Action on an Actionable Mutation

Essential questions need to be addressed when one is analyzing NGS reports to guide treatment decisions in solid tumors. Is a mutation benign or pathogenic (i.e., is it a driver mutation)? Is it prognostic of outcomes or predictive of response to certain therapies? Is the mutation a variant of known significance? Is there an approved targeted therapy?

Moreover, it is as important to identify mutations that do not convey response to targeted agents as it is to identify ones that correlate with efficacy. For example, fusions in neurotrophic-tropomyosin receptor kinase (NTRK) genes are known drivers of oncogenesis, and various solid tumors harboring

NTRK fusions have been shown to have response rates of up to 79% to NTRK inhibitors, like larotrectinib. On the other hand, point mutations in NTRK are associated with a lack of response to NTRK inhibitors. Therefore, an NTKR inhibitor should be used only in a patient with an NTRK fusion-positive tumor. 12

For FDA-approved targeted therapies, the relevance of a specific mutation and the efficacy of the associated treatment have been validated in clinical trials. (Table 1 – see PDF) summarizes known actionable mutations and their matched anticancer therapies. Although most targeted agents are approved for a specific tumor type harboring a mutation, clinical guidelines may recommend that these agents be used off-label in a different tumor type with the same mutation. Further, when a mutation of known significance is identified but no approved therapy exists, a clinical trial should be considered.

Last, it is important to consider the appropriate time to reevaluate NGS throughout the course of treatment in patients with advanced disease. The frequency of existing somatic mutations can fluctuate with a treatment response, and new somatic mutations may develop with disease progression; therefore, NGS may be most beneficial at the time of treatment failure or progression.

Microsatellite Instability and Deficient DNA Mismatch Repair

Microsatellite instability and deficient DNA mismatch repair (dMMR) can be conceptually hard to understand. Microsatellites are known short sequences of DNA with repeated nucleotides (e.g., CTGTGTGTGTGCA) that are inherited in all cells throughout the body. When a tumor cell contains a microsatellite with a different sequence compared to the same microsatellite in a normal cell, this is called microsatellite instability, or MSI. The frequency of abnormal microsatellites in a tumor determines whether it is characterized by an MSI-Low or MSI-High phenotype.

Tumors with dMMR are not able to repair DNA damage because of germline mutations in mismatch repair genes, allowing cancer cells to proliferate with aberrant DNA. Microsatellites are susceptible to errors during DNA replication because of the repetitive nucleotides, but without a functional DNA repair system, these errors are not repaired in proliferating tumor cells. MSI status is therefore a surrogate marker for dMMR in solid tumors. 13 MSI-H/dMMR status may be a useful biomarker for identifying a patient’s response to anti-programmed-death 1 (PD-1) and anti-programmed-death-ligand 1 (PD-L1) immunotherapies. Cancers that are considered MSI-H/dMMR harbor thousands of mutations that code for neoantigens that potentially increase the immunogenicity of the tumor and upregulate immune checkpoint blockade proteins. Hence, pembrolizumab is approved for tumors with MSI-H or dMMR regardless of the tumor’s origin. 14

Likewise, in tumors with BRCA1/2 mutations, the intrinsic DNA repair processes are often dysregulated. Poly (ADP-ribose) polymerase (PARP) is an enzyme that plays a critical role in DNA repair in BRCA1/2 deficient solid tumors. Currently, four PARP inhibitors have been approved for use in ovarian and breast cancers with BRCA1/2 mutations, and recent clinical trials have demonstrated efficacy of these agents in treating prostate and pancreatic cancers with BRCA1/2 deficiency. 15,16

The Role of the Pharmacist in Precision Oncology

Because genomic-based decision making has become a routine part of oncology clinical practice, it is important for pharmacists to know where to find up-to-date information on the clinical significance and actionability of a genomic variant. OncoKB and the Catalogue of Somatic Mutations in Cancer (COSMIC) are comprehensive and curated databases that provide evidence-based information about the clinical significance of somatic mutations in cancer. (Table 2 – see PDF) provides a list of resources for interpreting genomic variants in cancer. It is recommended that each patient’s genomic report undergo a comprehensive review under the guidance of a molecular tumor board (MTB) if one exists at the institution. If an MTB does not exist, it is recommended that all NGS findings be presented at an interdisciplinary tumor board when determining the best treatment approach for the patient. 17

Walko and colleagues published a report in 2016 detailing three pharmacist-led precision oncology models at different institutions. 18 Their report showed the different roles an oncology pharmacist can play in the implementation of precision medicine in clinical practice, including but not limited to participation in an MTB, selection of therapy, and procurement of off-label medications. Their report also recommends the development of continuing education programs for oncology pharmacists and the incorporation of precision oncology modules into residency programs and school of pharmacy curricula. As the genomic-guided approach to cancer care expands in practice, it will be imperative that practicing pharmacists have a strong understanding of precision oncology principles and access to appropriate tools and educational resources for confident decision making.

  1. Schaffhausen J. What precisely is precision medicine? Trends Pharmacol Sci. 2017;38:1-2.
  2. U.S. National Institutes of Health. National Cancer Institute Dictionary of Cancer Terms: Germline mutation. Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/germline-mutation, Accessed February 4, 2020.
  3. Sun J, Meng H, Yao L, et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23;6113-6119.
  4. Brown AL, Li M, Goncearenco A, Panchenko AR. Finding driver mutations in cancer: elucidating the role of background mutational processes. PLoS Comput Biol. 2019;15:e1006981.
  5. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900-5909.
  6. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130.
  7. Neff RT, Senter L, Salani R. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol. 2017;9:519-531.
  8. Allegretti M, Fabi A, Buglioni S, et al. Tearing down the walls: FDA approves next generation sequencing (NGS) assays for actionable cancer genomic aberrations. J Exp Clin Cancer Res. 2018;37:47.
  9. U.S. National Library of Medicine. What is circulating tumor DNA and how is it used to diagnose and manage cancer? Genetics Home Reference. https://ghr.nlm.nih.gov/primer/testing/circulatingtumordna. Accessed February 4, 2020.
  10. NewBridge Pharmaceuticals. The Guardant 360 Assay. Available at https://www.guardant360.com. Accessed February 4, 2020.
  11. Foundation Medicine. What is FoundationOne Liquid? Available at https://www.foundationmedicine.com/genomic-testing/foundation-one-liquid. Accessed February 4, 2020.
  12. Okamura R, Boichard A, Kato S, et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018; 2018.
  13. Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12:54.
  14. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38:1-10.
  15. Yap TA, Plummer R, Azad NS, Helleday T. The DNA damaging revolution: PARP inhibitors and beyond. Am Soc Clin Oncol Educ Book. 2019;39:185-195.
  16. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317-327.
  17. Knepper TC, Bell GC, Hicks JK, et al. Key lessons learned from Moffitt’s molecular tumor board: the Clinical Genomics Action Committee experience. Oncologist. 2017;22:144-151.
  18. Walko C, Kiel PJ, Kolesar J. Precision medicine in oncology: new practice models and roles for oncology pharmacists. Am J Health Syst Pharm. 2016;73:1935-1942.
  19. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version 3.2020 (January 17, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed February 28, 2020.
  20. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 3.2020 (March 6, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 12, 2020.
  21. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. Version 2.2020 (March 3, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed March 4, 2020.
  22. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Cutaneous Melanoma. Version 1.2020 (December 19, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed February 4, 2020.
  23. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 3.2020 (February 11, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed February 28, 2020.
  24. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2020 (March 11, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed February 4, 2020.
  25. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma. Version 1.2020 (November 26, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed February 28, 2020.
  26. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 4.2019. Version 1.2020 (March 16, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed March 19, 2020.
  27. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 6.2019 (February 10, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed February 28, 2020.
  28. Tsang H, Addepalli K, Davis SR. Resources for interpreting variants in precision genomic oncology applications. Front Oncol. 2017;7:214.
  29. Chakravarty D, Gao J, Phillips SM, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017; 2017. Epub May 16, 2017.

When the Continuum of Cancer Care Hits Close to Home

Laura Cannon, PharmD MPH
Clinical Assistant Professor and Oncology Pharmacist
The University of Texas at Austin College of Pharmacy and Dell Medical School Livestrong Cancer Institutes
Austin, TX

A young adult male presents with sudden-onset symptoms of constipation, abdominal pain, cramping, abdominal distention, and decreased appetite. What is the diagnosis? Gastroesophageal reflux disease, severe constipation, infectious colitis, and idiopathic gastroparesis. These were all diagnoses my 30-year-old husband, Tom, received over the span of a few months while we visited three emergency departments. He received more tests than I can count, and the final diagnosis was a mild, early case of Crohn’s disease. After that, we spent much of our time researching this new diagnosis and meeting with physicians to discuss management options. We had an overwhelming amount of information to process, but we were thankful to finally have an explanation for his symptoms. We were also thankful that the diagnosis didn’t include one word—cancer, the word we were most afraid of.

Four months later, Tom’s symptoms began to return. We attributed this to a change in his medications and what we thought was just life with Crohn’s disease. How could it be anything else? He was young and healthy, he had no family medical history that caused us concern, and we had seen so many doctors and run so many tests. His symptoms progressively worsened to the point that he was febrile with a pain so intense he was unable to stand up straight. He was a teacher, so he had probably just caught the stomach bug that was going around school, and it was nothing to worry about, we thought. We made our fourth visit to the emergency room that night. A new CT scan showed an 18-by 22-centimeter mass in his abdomen. Where did this come from? How long had it been there? How was that possible? We had done everything right.

Tom was admitted to the surgical service, and we gave an extensive history from the onset of his symptoms and including the diagnosis of Crohn’s disease. We were told that the mass could also represent an infection stemming from his recent colonoscopies and might be just an abscess. We were thinking about only one word, though—cancer—but that word was still not being discussed, at least not with us. The team started antibiotics for a possible abscess while we waited for the scheduling of a biopsy. As a postgraduate year-1 pharmacy resident interested in becoming an oncology pharmacist, I knew that biopsy was the gold standard for diagnosis of the word that we feared.

We waited…and waited…and waited, until about 5 days later, when Tom was finally taken to interventional radiology for a biopsy. When he came out of the procedure, he told us that the radiologist had asked what had happened because the appearance of the mass had changed significantly. The next few minutes of that day are very much a blur. I remember being excited—maybe it was just an abscess! That excitement was quickly stifled when the surgeon rushed in to say that my husband’s intestines had perforated during the wait for the biopsy, which explained why the imaging looked different. The excitement turned to panic, which amplified as we rushed to the operating room. Tom underwent an exploratory laparotomy, leaving him with an ileostomy, a surgical drain, and a ticket to the intensive care unit. We got the biopsy but not in the way it was originally planned.

About a week after surgery, we started hearing the dreaded C-word. Tom was finally diagnosed with cancer, what we had feared all along. Because this is not an article about treatment decisions, I will refrain from using details related to his specific diagnosis. However, I will say that his diagnosis was not straightforward. He received his chemotherapy treatment as an inpatient, and despite being very disheartened at the thought of spending so much time in the hospital, he tolerated the treatment with minimal issues. We even started to attempt to go back to our normal lives, what we craved the most.

Tom’s scans throughout treatment looked great and showed significant disease response. However, about 1 week before the appointment to review his final scan, he started showing clinical signs of disease progression. After yet another trip to the emergency room and a long discussion between the surgeon and the oncologist to determine whether the scan resembled postsurgical changes or disease burden, it was confirmed that Tom had progressive disease. His next-best treatment option was to participate in a clinical trial.

I do not know the behind-the-scenes proceedings of finding a clinical trial for Tom, but I do know about this process from my own clinical experience. It is not clearly established who owns the role of finding a clinical trial. The patient? The physician? An advocacy organization? A friend’s friend who heard that this place has a new drug they are studying? If the patient is lucky enough to find a clinical trial, getting the trial institution the correct information and managing a smooth transition is an entirely separate issue. Although significant travel was required, we were so thankful when we learned that there was an available trial for Tom. We showed up to our appointments, signed the consent forms, and did all the things we were instructed to do, but it still wasn’t enough.

On our second day of trial appointments, we received word in a phone call that Tom’s exact pathology did not match the inclusion criteria, and he could no longer be enrolled. After going to multiple trial appointments and traveling all this way, he was no longer a candidate. The difficulty of clinical trials goes far beyond the issue of finding the trial. It includes strict inclusion and exclusion criteria and protocol requirements, and unless you are lucky enough to have a local trial available, participation requires extensive patient travel and the need for sharing of records between institutions. This highlights an important issue for oncology patients: effective communication and record sharing. Cancer patients and their loved ones are already struggling to process the information they are receiving about their diagnosis and prognosis and to manage their day-to-day lives. Unfortunately, they also serve as their own medical record for disease-related information. Lack of communication and issues related to transferring medical records between institutions should not be a barrier to receiving timely cancer care, but they unfortunately are things that patients, including Tom, deal with routinely.

Because of his ineligibility for the clinical trial, we were now stuck—in a new city, with no promise of hope from a trial, but still with a rapidly progressing disease. We stayed and got a second opinion that did not differ much from the first. We tried a few more rounds of chemotherapy and attempted to get access to off-label medications without success. In my eyes, there were not many things left to try. In the physician’s eyes, Tom was young and had plenty of options; this was a perspective I came to see as a common barrier to care.

Sometimes in the healthcare setting we avoid difficult conversations, which ultimately can prevent patients from receiving the necessary information to make end-of-life decisions. Seeing my husband told that he had plenty of options when I knew that he didn’t was more than I could handle, because I knew that this burden would now fall on me, his wife. Just as the conversations about the initial diagnosis and treatment are important, so are the conversations about treatment goals and end-of-life wishes. Although I do not think it is within my scope as a pharmacist to have these conversations, I can serve as a reminder of their importance to the physicians I work with each day. I will carry this lesson with me as an oncology pharmacist forever.

Shortly after returning home and following an appropriate discussion about his goals, Tom transitioned to hospice care. He passed away about 6 weeks later, only 9 months after his initial diagnosis. Those 9 months spent as a caregiver, along with my experience as an oncology pharmacist, have illustrated a few of the barriers and roadblocks that cancer patients may encounter at the time of their diagnosis and throughout their treatment.

The first barrier is related to common frustrations with the healthcare system and the difficulty of scheduling appointments with specialists. For us this meant being told about an 18-by-22-centimeter mass while we were standing in the middle of the emergency room because there was not a room available. It meant our having to repeat Tom’s medical history, including all his tests and emergency room visits, to multiple teams of physicians and hoping we remembered the important details. It meant Tom’s waiting in the hospital for a biopsy and subsequently developing a perforation that resulted in emergency surgery. All of these are examples from my own experience, but we see similar situations so frequently in our healthcare systems. For patients and loved ones dealing with the thought of the C-word, nothing will ever happen in a timely enough manner—but sometimes delays can lead to more than just worsening anxiety.

The second barrier is the common assumption that because a patient is young or healthy, the diagnosis isn’t cancer. Looking back, I can see the avoidance of the word and the diagnosis. From the medical perspective, the diagnosis may not have been deemed worth discussing until it had been confirmed, but it was always crossing our minds.

The third barrier, though uncontrollable, is related to cancer itself. Sometimes you do everything right: you seek medical care for symptoms, you receive the appropriate tests, you are being closely followed by physicians you trust—and it is not enough. The cancer is too smart, too sneaky. That was the case with Tom.

In Tom’s story we had many things to be thankful for: we lived in close proximity to a cancer center, he had a family member with oncology knowledge, he had insurance coverage, we speak English as our first language, and the list could go on. However, we also ran into some of the most common and formidable barriers that arise in cancer care.

The purpose of this article is not to complain about Tom’s care or our circumstances, but to provide—from the viewpoint of both a caregiver and an oncology pharmacist—even the smallest insight into the issues that so many patients diagnosed with cancer encounter. It is my hope that, by sharing Tom’s story, I can raise awareness, spark empathy, and increase understanding of the day-to-day challenges that many cancer patients and their loved ones face.

Disclaimer: The account in this article is based on my memory of events as they occurred. It is meant in no way to criticize or discount the wonderful care my husband received from his healthcare team but to highlight the general need for improvement in areas surrounding cancer care.

Changes in Chemotherapy Treatment Plans Made as a Result of the Etoposide Shortage

Sarah Kraus Cimino, PharmD BCOP BCPS
Hematology/Oncology Clinical Pharmacy Specialist
Pennsylvania Hospital
Philadelphia, PA

Drug shortages have been unrelenting during the past 10 years, with 1,950 new drug shortages occurring from 2008 to 2018. Chemotherapy is consistently among the top five most common drug classes on shortage. 1 Chemotherapy drug shortages are of particular concern because the number of comparable therapeutic alternatives are limited. Specific chemotherapy drugs that have had shortages in the past 10 years include fluorouracil, cytarabine, and liposomal doxorubicin. 2,3

In 2018, a national shortage of etoposide injection occurred, requiring conservation strategies to be employed at Pennsylvania Hospital in Philadelphia, PA. Management of this drug shortage required a coordinated effort among prescribers, pharmacists, and drug suppliers. Because of the severity of the shortage, mitigation plans were also discussed across the health system, and a local strategy was approved through the hospital’s Ethics Committee and Pharmacy and Therapeutics Committee. The decision was made to prioritize etoposide supply for patients receiving treatment with curative intent. However, treatment was not withheld from other patients if supply was available.

Difficult decisions like these in response to drug shortages have the potential to affect patient care. Most of the literature on oncology drug shortages consists of provider surveys that report increased medication errors, increased costs, and the need for modification of therapy as a result of drug shortages. 2,3 Unfortunately, empirical data on the consequences of oncology drug shortages are sparse.

A 2018 study aimed to describe the clinical impact of the etoposide injection shortage. This single-center retrospective study consisted of chart review for patients treated between January and August 2018. 4 Patients were included if they had been prescribed an etoposide-containing chemotherapy regimen. The study timeframe was selected because the etoposide shortage at the institution was the most critical during this time. The primary aim of the study was to determine the percentage of patients who required a change in therapy during the shortage. Change in therapy was defined as (1) use of an alternative therapy other than etoposide injection, which included switching the patient to oral etoposide or Etopophos injection, or (2) omission of therapy, where the patient did not receive any formulation of etoposide in at least one treatment cycle. Secondary endpoints were assessed between two subgroups: patients who received etoposide injection and patients who received alternative etoposide formulations (oral etoposide or Etopophos injection). Secondary endpoints included incidence of adverse drug events, medication errors, delays of 3 days or more for scheduled chemotherapy, progression of disease, and associated drug costs.

A total of 22 patients were included in the study. The mean age was 60 years, and the most common types of cancer were lung cancer (n = 10), sarcoma (n = 6), and non-Hodgkin lymphoma (n = 4). For the primary endpoint, seven (32%) patients required a change in treatment during the etoposide injection shortage. Six (27%) patients received an alternative formulation of etoposide, and etoposide was withheld for one patient.

No significant difference was seen in secondary endpoints between patients who received etoposide and those who received alternative etoposide formulations. This included no difference in incidence of side effects (100% vs. 100%, p = 1.00), medication errors (0% vs. 0%, p = 1.00), treatment delays (7% vs. 0%, p = 1.00), or disease progression (53% vs. 33%, p = 0.64). The average wholesale acquisition cost for etoposide per cycle per patient was considerably higher for patients who received alternative formulations of etoposide ($58 USD for standard etoposide vs. $806 USD for alternative formulations).

To our knowledge, this was the first study to characterize the clinical impact of the etoposide injection shortage. At this institution, etoposide supply was prioritized and allocated on a cycle-by-cycle basis for patients. Other strategies include allocating the drug on a dose-by-dose basis or reserving the amount required to complete a full treatment course. In this study, approximately one-third of patients required a change in their chemotherapy treatment plan because of the shortage.

In an earlier study Becker and colleagues reported that 9.8% of patients required alternative therapy because of an oncology drug shortage. They also reported decreased use of drugs on shortage compared to historical use, which may indicate that a higher percentage of patients were actually affected. 5 In this study, one patient had treatment with etoposide omitted because of a delay in insurance approval for oral etoposide, and another patient had a delay in treatment. This second patient was scheduled to receive an autologous stem cell transplant with an etoposide-based conditioning regimen, but the transplant was delayed because of an inadequate supply of etoposide. Both scenarios reveal the possibility that consequences of oncology drug shortages are underreported. This earlier study by Becker and colleagues had notable limitations, including the small sample size from a single institution. Furthermore, the study was unable to capture patients who had never been prescribed etoposide and instead were initiated on alternative regimens because the prescriber had knowledge of the etoposide shortage. 5

It seems that no end to chemotherapy drug shortages is in sight. As part of an attempt to design a plan to eradicate drug shortages, the U.S. Food and Drug Administration Drug Shortages Task Force urges “quantification of the harms of drug shortages, particularly those that lead to worsened health outcomes for patients and increased cost for health care providers.” 6 Further research to characterize the impact that oncology drug shortages have on patients is needed as an impetus for change.

  1. American Society of Health-System Pharmacists. Drug shortages statistics. Available at https://www.ashp.org/Drug-Shortages/Shortage-Resources/Drug-Shortages-Statistics. Accessed November 22, 2019.
  2. McBride A, Holle LM, Westendorf C, et al. National survey on the effect of oncology drug shortages on cancer care. Am J Health Syst Pharm. 2013;70:609-617.
  3. Gogineni K, Shuman KL, Emanuel EJ. Survey on oncologists about shortages of cancer drugs. N Engl J Med. 2013;369:2463-2464.
  4. Li H, Cimino SK. Clinical impact of the etoposide injection shortage. J Oncol Pharm Pract. 2020;26:187-192.
  5. Becker DJ, Talwar S, Levy BP, et al. Impact of oncology drug shortages on patient therapy: unplanned treatment changes. J Oncol Pract. 2013;9:e122-e128.
  6. U.S. Food and Drug Administration. Drug shortages: root causes and potential solutions 2019. Available at https://www.fda.gov/media/131130/download. Accessed November 25, 2019.

Updates in HER2-Targeted Therapy for the Treatment of Metastatic Breast Cancer

Kelly Gaertner, PharmD BCOP BCPS
Oncology Clinical Pharmacy Specialist
Allegheny Health Network
Pittsburgh, PA
Danielle Roman, PharmD BCOP
Manager, Clinical Pharmacy Services
Allegheny Health Network
Pittsburgh, PA

Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related mortality in women. 1 Approximately 15%–20% of breast cancers overexpress the human epidermal growth factor receptor 2 (HER2) protein. 2 Compared with other subtypes of breast cancer, hormone receptor–negative, HER2-positive disease has a greater likelihood of metastasizing to the brain. 3-5 In the absence of systemic HER2-targeted therapy, HER2-positive breast cancer (HER2BC) has historically been associated with more aggressive disease and a worse prognosis. For patients with unresectable or metastatic HER2BC, the combination of docetaxel, pertuzumab, and trastuzumab has been established as the preferred initial therapy on the basis of progression-free survival (PFS) and overall survival (OS) benefits demonstrated in the phase 3 CLEOPATRA study. 6,7 In the phase 3 EMILIA trial, ado-trastuzumab emtansine showed an improvement in PFS and OS in the second-line setting following receipt of trastuzumab and a taxane. 8 Although these therapies have significantly extended survival outcomes for patients with metastatic HER2BC, disease progression continues to remain inevitable in most cases. Subsequent treatment options have primarily included trastuzumab plus chemotherapy, or capecitabine plus lapatinib or trastuzumab, with no previously established standard of care in the third-line setting. This article summarizes recent therapy updates and emerging treatments for metastatic HER2BC.

New Approvals

Fam-trastuzumab deruxtecan-nxki (Enhertu) is a new addition to the armamentarium for the treatment of metastatic HER2BC. The U.S. Food and Drug Administration (FDA) granted the drug accelerated approval on December 20, 2019, for patients with HER2-positive unresectable and/or metastatic breast cancer after at least two prior anti-HER2-based regimens in the metastatic setting. This antibody-drug conjugate (ADC), similar to ado-trastuzumab emtansine, consists of an HER2-directed antibody and cytotoxic drug joined by a cleavable linker. Fam-trastuzumab deruxtecan differs in several important ways from other currently available ADCs: notably, the inclusion of a potent topoisomerase I inhibitor as the cytotoxic drug, a higher drug-to-antibody ratio, and the ability of the cytotoxic portion to easily cross the cell membrane, which potentially allows for a more potent effect on nearby tumor cells regardless of target expression. 9

The FDA approval of fam-trastuzumab deruxtecan was based on the results of the DESTINY-Breast01 trial. 9 This was an open-label multicenter single-arm phase 2 study of fam-trastuzumab deruxtecan in females with HER2-positive unresectable or metastatic breast cancer who had received previous treatment with trastuzumab and ado-trastuzumab emtansine. The efficacy analysis was based on 184 patients who received the recommended dose of 5.4 mg/kg. The majority of patients were heavily pretreated, receiving a median of six prior lines of therapy (range 2–27). Thirteen percent of patients enrolled had stable, treated brain metastases. The primary endpoint of overall response rate was 60.9% by independent central review, primarily driven by partial responses (54.9%). The median PFS was 16.4 months, and median duration of response was 14.8 months. This benefit was observed across all subgroups, including patients with brain metastases. The most common adverse effects that occurred in 20% or more of the study population were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. Interstitial lung disease (ILD) developed in 13.6% of patients, of which the majority of cases were grade 1–2; however, four ILD-related deaths occurred during the study. The median time to onset was 4.1 months (range 1.2–8.3). 10

The recommended dose of fam-trastuzumab deruxtecan is 5.4 mg/kg administered by intravenous infusion every 3 weeks until disease progression occurred or an unacceptable level of toxicity was reached. Dose interruption or reduction recommendations exist for neutropenia, febrile neutropenia, left ventricular dysfunction, and ILD/pneumonitis. Black-box warnings exist for embryo-fetal toxicity and ILD/pneumonitis; patients should therefore be closely monitored for signs and symptoms, including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Prompt investigation with radiographic imaging, consultation with a pulmonologist, interruption of the drug, and possibly initiation of corticosteroids (based on grade) are recommended for suspected ILD. Similar to other HER2-targeting drugs, fam-trastuzumab deruxtecan may increase the risk of developing left ventricular dysfunction; however, only three cases of asymptomatic left ventricular ejection fraction (LVEF) decrease were reported in DESTINY-Breast01. 9 LVEF should be assessed prior to initiation of fam-trastuzumab deruxtecan and at regular intervals during treatment as clinically indicated. 10

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend fam-trastuzumab deruxtecan for metastatic HER2BC in accordance with FDA labeling. 11 Ongoing trials are focused on initiation of fam-trastuzumab deruxtecan earlier in the disease course (DESTINY-Breast0212 and DESTINY-Breast0313) and on the potential role of this agent in patients with HER2 low-expressing breast cancer. 14

Neratinib (Nerlynx) is an oral tyrosine kinase inhibitor (TKI) initially approved by the FDA for extended adjuvant treatment of early-stage HER2BC. 15 In the phase 3 NALA study, the combination of neratinib and capecitabine was compared to lapatinib and capecitabine in patients with HER2-positive metastatic breast cancer who had received at least two prior lines of therapy in the metastatic setting.16 Patients were randomized 1:1 to 21-day cycles of either neratinib 240 mg orally daily continuously plus capecitabine 750 mg/m 2 orally twice daily on days 1 through 14 or lapatinib 1,250 mg orally daily continuously plus capecitabine 1,000 mg/m 2 twice daily on days 1 through 14. Though PFS was significantly improved in the neratinib arm (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63–0.93; p = .006), OS benefit with neratinib did not reach statistical significance (HR, 0.88; 95% CI, 0.72–1.07; p = .2086). PFS and OS rates at 12 months with neratinib versus lapatinib were 28.8% versus 14.8% and 72.5% versus 66.7%, respectively. 16 Furthermore, the neratinib plus capecitabine combination delayed the time to intervention for symptomatic central nervous system disease (overall incidence, 22.8% vs. 29.2%; p = .043).

Although grade 3 diarrhea was more prevalent with neratinib than with lapatinib (24.4% vs. 12.5%), adverse events leading to treatment discontinuation were less common with neratinib (10.9% vs. 14.5%). On the basis of the NALA trial, the FDA approved the combination of neratinib plus capecitabine on February 24, 2020, for treatment of advanced or metastatic HER2BC after two or more prior anti-HER2-based regimens in the metastatic setting. 15 The combination was also added to the NCCN guidelines as an option among the other recommended regimens for HER2-positive metastatic breast cancer. 11

Another exciting HER2-directed therapy to emerge recently is tucatinib, an oral TKI that selectively inhibits HER2. 18 This high specificity for the HER2 domain with negligible inhibition of the epidermal growth factor receptor distinguishes tucatinib from other currently approved HER2-targeted small-molecule TKIs and affects the toxicity profile. 17,18 Tucatinib was evaluated in combination with capecitabine and trastuzumab in the phase 3 HER2CLIMB study. 18 Patients with HER2-positive advanced breast cancer were included if they had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Patients with brain metastases were included; those with leptomeningeal disease were not. A total of 612 patients were randomized 2:1 to receive either tucatinib 300 mg or placebo orally twice daily continuously, in combination with trastuzumab and capecitabine. Patients were heavily pretreated, with a median of three prior lines of therapy for metastatic disease (range 1–14). Approximately half (47.5%) had brain metastases. With regard to the primary endpoint of PFS in the first 480 randomized patients, the median PFS was 7.8 months with tucatinib versus 5.6 months with placebo (HR, 0.54, 95% CI, 0.42–0.71; p < .001) at 1 year. For patients with brain metastases, the median PFS was extended with the addition of tucatinib to 7.6 versus 5.4 months (HR, 0.48, 95% CI, 0.34–0.69; p < .001). Regarding safety, the most common adverse events of any grade that occurred more frequently with tucatinib included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, vomiting, and stomatitis. 18

On the basis of the results of the HER2CLIMB study, tucatinib (Tukysa) was approved by the FDA on April 17, 2020, in combination with trastuzumab and capecitabine for patients with advanced unresectable or metastatic HER2BC following receipt of at least one prior anti-HER2-based regimen in the metastatic setting. 19,20 Notably, the labeled indication specifically includes patients with brain metastases, and tucatinib is a welcome addition to the treatment options for this particular patient population. 20 Tucatinib is approved at a dose of 300 mg orally with or without food twice daily continuously, in combination with capecitabine 1,000 mg/m 2 orally twice daily on days 1 through 14 and trastuzumab at standard dose every 21 days.20 Dose interruption or reduction recommendations exist for diarrhea and hepatotoxicity. Patients should be counseled on the potential for severe diarrhea and appropriate management. Hepatic function should be monitored every 3 weeks or as clinically indicated. Empiric dose reductions of tucatinib are indicated in the setting of severe hepatic impairment and concurrent use with a strong CYP2C8 inhibitor. Tucatinib is associated with other clinically relevant drug-drug interactions, and a thorough drug interaction screen is recommended prior to initiation. 20

Emerging Therapies

Margetuximab is a monoclonal antibody derived from the parent compound of trastuzumab. Though both margetuximab and trastuzumab bind to the same epitope of HER2 and demonstrate similar affinity and antiproliferative activity, margetuximab’s Fc region is engineered to increase affinity for the activating Fc receptor (FcR) CD16A while decreasing affinity for the inhibitory FcR CD32B. 21-23 The randomized phase 3 open-label SOPHIA trial evaluated margetuximab in patients with metastatic HER2BC who had received one to three prior lines of therapy, including pertuzumab, in the metastatic setting. Patients were randomized 1:1 to margetuximab 15 mg/kg or trastuzumab intravenously every 3 weeks, in addition to capecitabine, eribulin, gemcitabine, or vinorelbine. Initial results were presented at the 2019 American Society of Clinical Oncology annual meeting. 22 In the intention-to-treat (ITT) analysis of 536 patients, margetuximab showed an improved PFS versus trastuzumab, with a median of 5.8 months versus 4.9 months (HR, 0.76; 95% CI, 0.59–0.98; p = .033). The subset of patients with CD16A genotypes containing a 158F allele (a population that has been found to be less responsive to trastuzumab) saw an even greater PFS benefit with margetuximab, with a median of 6.9 months versus 5.1 months (HR, 0.68; 95% CI, 0.52–0.90; p = .005). Data from the second interim OS analysis were presented at the 2019 San Antonio Breast Cancer Symposium. After a median follow-up of 15.6 months, the median OS in the ITT population was 21.6 months with margetuximab versus 19.8 months with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69–1.13; p = .326). 23 Again, the outcomes were more pronounced in the patients with CD16A 158F allele, with a median OS of 23.7 months with margetuximab versus 19.4 months with trastuzumab (HR, 0.79; 95% CI, 0.61–1.04; p = .087). Though the OS data on margetuximab are not yet mature, preliminary outcomes are promising, and it is hoped that they will lead to another option for HER2-directed therapy.


The recent advances in the treatment of HER2-positive metastatic breast cancer provide promising options for many patients who have exhausted first- and second-line therapies for this breast cancer subtype. Fam-trastuzumab deruxtecan, as well as the combinations of neratinib and capecitabine and of tucatinib, capecitabine, and trastuzumab, have gained recent FDA approvals for treating metastatic HER2BC. Margetuximab may add to future treatment paradigms. Further discussions and ongoing studies will seek to define the optimal sequencing of these recent approvals, as well as the use of fam-trastuzumab deruxtecan for patients with HER2-low- expressing breast cancer.