Highlights from the 2020 Transplantation and Cellular Therapy Meetings of the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research

Denae Beckman, PharmD BCOP

denae-beckman

Clinical Oncology Pharmacist
The University of Kansas Health System
Kansas City, KS

The 25th Annual Transplantation and Cellular Therapy (TCT) Meetings of the American Society for Blood and Marrow Transplantation (ASBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) were held in Orlando, FL, February 19–23, 2020. Nearly 4,000 attendees gathered to discuss updates on a wide range of topics, including advances in chimeric antigen receptor (CAR) T cells, chemotherapy preparative regimens, targeted therapies, and supportive care.

Best Abstracts
KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Results of the Phase 2 ZUMA-2 Study1
Michael Wang, MD, from MD Anderson Cancer Center, presented results of this phase 2 trial of 60 patients with relapsed or refractory mantle cell lymphoma (R/R MCL) who received KTE-X19, an autologous anti-CD19 CAR T-cell therapy. Patients had received up to five prior lines of therapy, including chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase (BTK) inhibitor. At the time of presentation, 60 patients had received KTE-X19, with a median follow-up of 12.3 months. The objective response rate was 93%, with 67% achieving a complete response and 27% achieving a partial response. Median time to response was 1 month (range = 0.8–3.1 months). Responses were also durable; the median duration of response has not been reached. The adverse events (AEs) were similar to those seen with current FDA-approved CAR T-cell therapies in patients with non-Hodgkin lymphoma. The authors concluded that with ≥ 1-year follow-up, KTE-X19 demonstrated significant and durable clinical benefit, with a manageable safety profile in patients with R/R MCL for whom no curative treatment options exist.

Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study2
Uday Popat, MD, from MD Anderson Cancer Center, presented results of this phase 2 trial investigating an innovative approach to busulfan preparative dosing. Patients between 18 and 70 years of age with matched related or unrelated donors received myeloablative dosing of busulfan in combination with fludarabine over a 3-week period. Patients received a fixed dose of busulfan 80 mg/m2 as an outpatient on days -20 and -13. Then, fludarabine 40 mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 µmol-min for the entire course based on pharmacokinetic (PK) analysis. Graft-versus-host disease (GVHD) prophylaxis consisted of posttransplant cyclophosphamide (PTCy) and tacrolimus. Mycophenolate mofetil was added for recipients from unrelated donors. Enrolled patients (N = 52) had a median age of 62 years. With a median follow-up of 14 months, nonrelapse mortality (NRM) at day 100 was 1.9% and 8% at 1 year. Overall survival, progression-free survival, and relapse at 1 year were 83%, 78%, and 14%, respectively. Day-100 grade II–IV and III–IV acute GVHD rates were 37% and 6%, respectively. The authors concluded that myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients and has a low incidence of severe acute GVHD and NRM. This regimen has the potential to reduce both relapse and nonrelapse mortality in older patients.

Presentations at the Pharmacy Special Interest Group (SIG) Meeting
Busulfan Harmonization3
Jeannine McCune, PharmD, from City of Hope, presented updates from an international task force working on unit harmonization for busulfan exposure. Busulfan is a frequently used chemotherapy agent in hematopoietic cell transplant (HCT) conditioning regimens. Therapeutic drug monitoring (TDM) of busulfan has revolutionized its use to increase rates of engraftment and decrease hepatotoxicity. However, many of the trials studying busulfan pharmacokinetics (PK) are single-center trials, and institutions have used various measurements, including AUC or concentration at steady state (Css). The goals of the busulfan task force included identifying one busulfan plasma exposure unit (BPEU) for international harmonization to allow for a multicenter database to create evidence-based busulfan exposure guidelines and to minimize the risk of busulfan dosing errors. AUC measured in  was determined to be the ideal BPEU and has been endorsed by 10 major professional societies, including HOPA, as the harmonized BPEU for reporting to stem cell transplant registry databases and for use in future protocols and publications. Beginning January 1, 2021, PK-directed busulfan dosing should be reported in AUC  by clinicians, study protocols, laboratories, and publications. Multiple resources are available to help in converting between commonly used busulfan exposure units to the harmonized unit, including the ASTCT app.

A Real Time Pharmacokinetic Assay to Allow for Targeted Melphalan Dosing in Multiple Myeloma Patients Undergoing Transplant4
Karen Sweiss, PharmD, from the University of Illinois at Chicago, presented research on the feasibility of PK dosing of melphalan to treat multiple myeloma. Melphalan exhibits high interpatient variability when body surface area (BSA)-based dosing is used. Previous research has demonstrated that melphalan AUC predicts survival and toxicity.5 Currently there are no standardized approaches for melphalan PK testing because of variability in melphalan infusion times and melphalan dosing schedules and because there is no standard PK sampling window. High-dose melphalan administered at a dose of 100 mg/m2 on day -2 and -1 allows for potential modification of the day -1 dose if PK testing with rapid turnaround can be performed on day -2. An in-house melphalan assay was developed to perform PK analysis. Initial testing revealed that there was low intrapatient variability and that the AUC from day -2 correlated with day -1, establishing that day -2 PK could be used to adjust the day -1 dose using linear, dose-proportional calculations. Dose simulation calculations found that doses ranging from 133 to 308 mg/m2 were required to target the total median AUC. The authors concluded that the development of personalized melphalan dosing will decrease interpatient variability and has the potential to improve multiple myeloma outcomes.

CYP2C19 Metabolizer Status Does Not Influence the Safety or Efficacy of Pentamidine6
Nicholas Ambrosino, PharmD, from Cincinnati Children’s Hospital Medical Center, presented a single-center retrospective study evaluating the impact of CYP2C19 polymorphisms on the safety of pentamidine. Pentamidine has been shown to be effective as a second-line option for prevention of Pneumocystis jirovecii (PJP) pneumonia. Pentamidine is a substrate of CYP2C19 with known polymorphisms that can affect activity. The primary objective of the study was to determine the influence of CYP2C19 metabolizer status on the safety and efficacy of pentamidine in treating the pediatric HCT population. Analysis of single-nucleotide polymorphisms of CYP2C19 were performed on 319 patients. The majority of patients had a normal CYP2C19 phenotype (38%) followed by intermediate (30%), ultra-rapid (24%), and poor (8%). There was no difference in the number of patients who discontinued therapy because of adverse events among metabolizer status groups, nor was there a difference in the number of breakthrough PJP infections. The authors concluded that it is safe and efficacious to administer pentamidine in pediatric stem cell transplant patients regardless of CYP2C19 metabolizer status.

The above summary briefly highlights only a selection of the research presented at the meeting. To find further information and view additional abstracts, visit www.astct.org. The 26th Annual TCT Meetings will take place February 10–14, 2021, in Honolulu, HI.

References

  1. Wang M, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Results of the Phase 2 ZUMA-2 Study. Abstract #1. Presented at the 2020 TCT Annual Meeting, February 21, 2020.
  2. Popat U, Mehta RS, Bassett R, et al. Myeloablative fractionated busulfan conditioning regimen in older patients: results of a phase II study. Abstract #6. Presented at the 2020 TCT Annual Meeting, February 21, 2020.
  3. McCune JS, Quinones CM, Ritchie J, et al. Harmonization of busulfan plasma exposure unit (BPEU): a community-initiated consensus statement. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
  4. Sweiss K, Vemu B, Sampang G, et al. A real time pharmacokinetic assay to allow for targeted melphalan dosing in multiple myeloma patients undergoing transplant. Abstract #125. Presented at the 2020 TCT Annual Meeting, February 21, 2020.
  5. Nath CE, Trotman J, Tiley C, et al. High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. Br J Clin Pharmacol. 2016;82(1):149-159. 
  6. Ambrosino N, Teusink-Cross A, Lane A, et al. CYP2C19 metabolizer status does not influence the safety or efficacy of pentamidine. Abstract #126. Presented at the 2020 TCT Annual Meeting, February 21, 2020.