Erika Wass, PharmD BCOP
Stem Cell Transplant (Blood and Marrow Transplantation) Clinical Pharmacy Specialist
Loma Linda University Medical Center
Loma Linda, CA

The Blood and Marrow Transplantation (BMT) Tandem Meetings are the combined annual meetings of the Center for International Blood and Marrow Transplant Research (CIBMTR) and the American Society for Blood and Marrow Transplantation (ASBMT). More than 3,700 attendees registered for the 2018 BMT Tandem Meetings held in Salt Lake City, UT, February 21-25, 2018—setting a new attendance record. The joint scientific meeting had sessions on all 5 days, and a number of peripheral meetings took place for 1–3 days each. These included meetings of the BMT Nursing, BMT Pharmacists, and Pediatric BMT groups; the BMT Clinical Education Conference (for nurse practitioners, physician assistants, fellows, and junior faculty members); and meetings for BMT coordinators and clinical research professionals. In addition, two poster sessions highlighting innovative research from hematopoietic cell transplant (HCT) professionals were held.

ASBMT Pharmacy Special Interest Group (SIG) Update (presented by LeAnne Kennedy, PharmD BCOP CPP FHOPA)

The ASBMT Pharmacy SIG has grown exponentially since its beginning, with more than 250 members as of December 2017. The monthly Pharmacy SIG Newsletter is now shared with all ASBMT members because of high demand from other disciplines. The Beyond Fundamentals of Hematopoietic Cell Transplantation (HCT) course offered during the 2017 BMT Tandem Meetings attracted more than 100 attendees from multiple disciplines. The course was also offered at HOPA’s 2018 Annual Conference.

The three highlighted publications from members of the ASBMT Pharmacy SIG included “Challenges Around Access to and Cost of Life-Saving Medications After Allogeneic Hematopoietic Cell Transplantation for Medicare Patients,”¹ “Characterization of Collaborative Practice Agreements Held by Hematopoietic Stem Cell Transplant Pharmacists,” ² and “The Hematopoietic Cell Transplant Pharmacist: Roles, Responsibilities, and Recommendations from the ASBMT Pharmacy SIG.”³

Best Pharmacy Abstracts and Pharmacy SIG New Investigator Research Award

“Outcomes of a Novel Rituximab-Based Non-Ablative Conditioning Regimen for Hematopoietic Cell Transplantation in Severe Aplastic Anemia”⁴ discussed the implementation of a non-ablative fludarabine, cyclophosphamide, and rituximab conditioning regimen for severe aplastic anemia patients who are older than 40 years or who have extensive comorbidities. With a total of 11 patients and median follow-up of 302 days, overall survival (OS) was 100%, with a low incidence of severe acute graft-versus-host disease and viral reactivation. “Maintenance Azacitidine after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancies”^5,6 compared time to disease relapse in patients who received maintenance azacitidine post-HCT versus a control group via retrospective review. Maintenance azacitidine was not associated with a change in time to relapse in patients with acute myeloid leukemia or myelodysplastic syndromes after myeloablative HCT, and trends toward higher toxicity were seen in the azacitidine group.

“A Survey of Outpatient Medication Adherence in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients”⁷ used an electronic patient survey to identify the prevalence of, and risk factors for, medication nonadherence. Over 50% of patients off immunosuppressive therapy and 40% of patients on immunosuppressive therapy reported nonadherence. Risk factors for nonadherence included distress level and increased number of medications.

“Amlodipine and Calcineurin Inhibitor Induced Nephrotoxicity Following Allogeneic Hematopoietic Stem Cell Transplant”⁸ analyzed the use of amlodipine in allogeneic HCT patients on calcineurin inhibitors, specifically with regard to renal function changes. The researchers observed a slower decline in creatinine clearance (CrCl) during the first 6 months, as well as lower incidence of hospitalization for acute kidney injury in the amlodipine cohort.

The inaugural ASBMT Pharmacy SIG New Investigator Research Award was presented to Dragos Plesca, PharmD PhD BCOP. With the help of this 2-year $50,000 grant, he will be investigating acquired immunity in multiple myeloma patients undergoing maintenance therapy following autologous stem cell transplantation.

Maintenance Strategies (presented by Kelly G. Hawks, PharmD BCOP)

With relapse remaining a significant cause of mortality following HCT, an increasing body of research is focused on identifying optimal maintenance strategies to keep the patient in remission with low toxicity levels so that the patient can maintain a good quality of life.

The largest amount of data on maintenance therapy is on multiple myeloma, with a number of published trials using lenalidomide. The three main trials supporting lenalidomide maintenance—CALGB 100104, IFM 2005-02, and GIMEMA—used different lenalidomide doses and schedules but showed improved time to progression (TTP) or progression-free survival (PFS) when compared with placebo or observation. Unfortunately, lenalidomide is associated with some problematic adverse events (AEs), most notably myelosuppression and the potential for secondary malignancies.

Recently, a meta-analysis was conducted at the request of the U.S. Food and Drug Administration (FDA) with a primary endpoint of OS and median follow-up of 79.5 months. The three trials mentioned above were included in the analysis. The median PFS was 52.8 months with lenalidomide versus 23.5 months in the control arm, and the PFS after next line of therapy (PFS2) was 73.3 months with lenalidomide versus 56.7 months in the control arm; both results were statistically significant. This PFS benefit was seen in almost every subgroup, with the exception of patients with CrCl less than 50 ml/min, those with elevated lactate dehydrogenase, and those with poor-risk cytogenetics.⁹ Although secondary malignancies were seen with lenalidomide, the TTP was longer, which perhaps outweighed the risk of secondary malignancy. Though lenalidomide maintenance following autologous HCT in multiple myeloma seems to be the new standard of care, it remains to be determined which patients derive the most benefit from maintenance therapy and what the optimal dose and duration of lenalidomide are.

Cannabinoid Consult Service: Fostering Safe Use of Medical Marijuana in the Hospital Setting (presented by Amy Carver, PharmD)

This session had by far the largest number of attendees at the pharmacy meeting and showcased how Children’s Hospital Colorado (CHCO) safely integrates the use of medical marijuana into hospital treatment plans. As medical and recreational marijuana becomes legal in more states, concerns about AEs, ideal dosing, and drug interactions come to the forefront, especially for pharmacists.

The session opened with a review of the available cannabis formulations and the pros and cons of each formulation. Oral formulations have an increased risk of toxicity because of their slow onset and extended duration of action. Inhaled formulations have the quickest onset but have the highest risk of infection because of possible fungal contamination of the plant. Transdermal formulations are the safest but may not be particularly effective because of the different rates of absorption in cannabidiol (CBD) and tetrahydrocannabinol (THC).¹⁰ The CHCO policy regarding patient use of medical marijuana was enacted in March 2016 and allows only for the use of oral or topical dosage forms. Patients or family members are required to sign a release and waiver of liability, and they are responsible for product storage and administration. Each administration is acknowledged on the medication administration record by the nurse per patient or family member reporting. This allows for drug interaction checking and the ability to correlate AEs with doses. CBD is a strong inhibitor of CYP3A4 and 2D6, so it is important to withhold CBD products during chemotherapy. THC is an inducer of CYP1A2 and a substrate of CYP2C9, 2C19, and 3A4, with many interactions that must be monitored for.^11,12

CHCO also has a cannabinoid education team made of pharmacists and social workers that aims to ensure the safest possible use of medical marijuana products within the institution. By accepting that medical marijuana products are becoming a large part of therapy for some patients and allowing administration by the patient or a family member without judgment or the involvement of law enforcement, CHCO has created a safe way for patients to continue using these potentially helpful products during a hospital stay.

Best Practices: CAR-T Therapies and CRS Management (presented by Wendy Covert, PharmD BCOP; Christina Bachmeier, PharmD BCOP; and Craig W. Freyer, PharmD BCOP)

With chimeric antigen receptor (CAR)-T cell therapies gaining FDA approval for an increasing number of indications, more institutions are faced with handling the unique toxicities of these novel therapies. After a review of the mechanisms of CD19-targeted CAR-T products, the session moved into a discussion of strategies to prevent and manage cytokine release syndrome (CRS) and CAR-T related neurotoxicity.

CRS is the most common toxicity with CAR-T therapy and usually occurs within 2 weeks after cell infusion. CRS typically presents with hypoxia, fever, and hypotension and can also include diarrhea, nausea and vomiting, coagulopathies, capillary leak, rash, cardiotoxicity, encephalopathy, transaminitis, renal dysfunction, and myalgia. Although management was slightly different at each facility, the main method of treating CRS was tocilizumab and corticosteroids, depending on CRS grade.

CAR-T cell–related encephalopathy syndrome (CRES) tends to have a biphasic presentation. Early CRES may occur with CRS and tends to be mild or self-limiting. Late CRES typically occurs after CRS, is unrelated to CRS, and does not respond to tocilizumab. Currently, the best treatment for CRES is corticosteroids, preferably dexamethasone. CRS and CRES rates vary according to the product used and the indication.

2019 BMT Meeting

Beginning in 2019, the BMT Tandem Meetings will become the Transplantation and Cellular Therapy (TCT) Meetings. The 2019 meeting will take place in Houston, TX, February 20–24. More information can be found at https://www.asbmt.org/meetings-events/tctmeetings.

References

1. Farnia S, Ganetsky A, Silver A, et al. Challenges around access to and cost of life-saving medications after allogeneic hematopoietic cell transplantation for Medicare patients. Biol Blood Marrow Transplant.  2017;23(8):1387-1392.
2. Bryk A, Koontz S, Mayor J, et al. Characterization of collaborative practice agreements held by hematopoietic stem cell transplant pharmacists. J Oncol Pharm Pract. 2017. http://journals.sagepub.com/doi/10.1177/1078155217745145
3. Clemmons AB, Alexander M, DeGregory K, Kennedy L. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT pharmacy SIG. Biol Blood Marrow Transplant.  2018;24(5):914-922.
4. Gatwood KS, Culos KA, Binari L, et al. Outcomes of a novel rituximab-based non-ablative conditioning regimen for hematopoietic cell transplantation in severe aplastic anemia. Biol Blood Marrow Transplant.  2018:S119-120.
5. Maples KT, Sabo R, McCarty JM, Toor AA, Hawks, KG. Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies. Biol Blood Marrow Transplant.  2018: S120-21.
6. Maples KT, Sabo RT, McCarty JM, Toor AA, Hawks, KG. Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies. Leuk Lymphoma. 2018;1-6. doi:10.1080/10428194.2018.1443334. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29616863
7. Ice LL, Merten J, Bartoo G, et al. A survey of outpatient medication adherence in adult allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant.  2018;S121.
8. Jensen RR, Healy R, Ford CD, et al. Amlodipine and calcineurin inhibitor induced nephrotoxicity following allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2018;S121-122.
9. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29):3279-3289.
10. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770-1804.
11. Horn JR, Hansten PD. Drug interactions with marijuana. 2014.  https://www.pharmacytimes.com/publications/issue/2014/december2014/drug-interactions-with-marijuana
12. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86-95.