“Progress lies not in enhancing what is, but in advancing toward what will be.”
The Combined Annual Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) were held virtually from February 8–12, 2021. The scientific program addressed the most timely issues in hematopoietic cell transplantation and cellular therapy. For health-care professionals who may have missed the meeting proceedings, we provide a summary of selected abstracts highlighting some of the most important advances in transplantation and cellular therapies presented at the meeting.
Allogeneic Transplantation: Myelodysplastic Syndrome and Acute Leukemia
ABSTRACT 3: A multicenter (34 sites) biologic assignment trial comparing reduced-intensity conditioning allogeneic hematopoietic cell transplantation (allo-HCT) with hypomethylating therapy or best supportive care in patients (n = 260 vs 124, respectively) aged 50 to 75 years with intermediate-2 or high-risk myelodysplastic syndrome (MDS): Blood and Marrow Transplant Clinical Trials Network study 1102 (ClinicalTrials.gov identifier NCT02016781).1
Rationale: The introduction of reduced-intensity conditioning regimens has allowed allo-HCT to be offered to older adults with MDS. However, the relative risks and benefits of allo-HCT compared with nontransplant therapies continue to be debated.2
Methods: Patients with an HLA-matched (related or unrelated donor) were assigned to the donor arm. The primary outcome was 3-year overall survival. Secondary outcomes included leukemia-free survival, quality of life, and cost-effectiveness.1,2
Results: In an intent-to-treat analysis, adjusted overall survival at 3 years in the donor arm was 47.9% (95% confidence interval [CI] = 41.3%–54.1%) compared with 26.6% (95% CI = 18.4%–35.6%) in the nondonor arm (P = .0001). A sensitivity analysis excluding subjects assigned to the nondonor arm who died prior to the end of the 90-day search had a similar effect on outcomes (adjusted overall survival = 48.0% vs 28.1%, P = .0004).
Syed Ali Abutalib, MD
Stefan O. Ciurea, MD
Leukemia-free survival at 3 years was better in the donor arm (35.8%, 95% CI = 29.8%–41.8%) than in the nondonor arm (20.6%, 95% CI = 13.3%–29.1%, P = .003).
The advantage of overall survival and leukemia-free survival was seen across all subgroups. There were no clinically significant differences in quality of life between the two groups.
In an as-treated analysis, there was a significant advantage in the 3-year overall survival (47.4% vs 16.0%, P < .0001) and leukemia-free survival (39.3% vs 10.9%, P < .0001) for patients who underwent allo-HCT compared with those receiving hypomethylating therapy or best supportive care.
Clinical Implications: Findings from BMT-CTN 1102 confirm that older adults up to age 75 years with de novo MDS who have an HLA-matched donor should be considered for reduced intensity–conditioning allo-HCT. Importance must be given for consultation with a transplant physician early in the course of MDS. As such, this will allow sufficient time for pretransplant evaluation, which includes HLA typing, donor selection, and psychosocial assessment.
ABSTRACT LBA1: Calcineurin inhibitor–free graft-vs-host disease prophylaxis in allo-HCT with myeloablative conditioning regimens using HLA-matched (related and unrelated) grafts in patients with acute leukemia and MDS: Results of the BMT-CTN 1301 Progress II trial (NCT02345850).3
“Older adults with de novo myelodysplastic syndrome who have an HLA-matched donor should be considered for reduced intensity–based allo-HCT.”— Syed Ali Abutalib, MD, and Stefan O. Ciurea, MD
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Background: Calcineurin inhibitor–based regimens are standard graft-vs-host disease prevention for allo-HCT. Most recently, there has been increased interest in calcineurin inhibitor–free approaches using T-cell depletion, either by ex vivo CD34+ cell selection or in vivo using posttransplant cyclophosphamide. The latter approach is increasingly adopted in the real world due to its ease of administration and lower cost.
Methods: Patients aged ≤ 65 years with acute leukemia or MDS (blasts < 5%) were randomly assigned to one of the three arms: (1) CD34+ selected peripheral blood stem cell graft without posttransplant immune suppression; (2) posttransplant cyclophosphamide after marrow graft without additional immune suppression; or (3) tacrolimus and methotrexate after marrow graft (control group).
Results: Among the 346 patients with MDS and acute leukemia enrolled, 327 received allo-HCT, 300 according to the protocol. The group assigned to CD34+ cell selection had the highest rate of noncompliance, with 89 of 104 patients (86%) receiving protocol-based therapy.
Primary endpoint results: The rates of moderate-to-severe chronic graft-vs-host disease relapse-free survival at 1 year were 60.2% for CD34+ cell selection (hazard ratio [HR] compared with tacrolimus and methotrexate = 0.8, P = .23), 60.3% for posttransplant cyclophosphamide (HR = 0.86, P = .41), and 56.6% for tacrolimus and methotrexate; the hazard ratio for CD34+ vs posttransplant cyclophosphamide was 0.9 (P = .72).
Secondary endpoints results: The corresponding rates of overall survival were 75.7% (HR = 1.74, P = .02), 84.6% (HR = 1.02, P = .95), and 84.2%, respectively. The hazard ratio for CD34+ vs posttransplant cyclophosphamide for overall survival was 1.77 (P = .02). Treatment-related mortality rates at 12 months were 16.5% (HR = 2.76 vs tacrolimus-and-methotrexate group, P = .01), 12% (HR = 2.01 vs control, P = .09), and 7% for CD34+, posttransplant cyclophosphamide, and tacrolimus-and-methotrexate groups, respectively. The corresponding rates for -relapse were 19.4% (HR = 0.91, P = .74), 9.2% (HR = 0.52, P = .04), and 22.9%, respectively. No differences were noted in quality-of-life assessments across the three groups.
Clinical Implications: This study showed no difference in moderate-to-severe chronic graft-vs-host disease–free, relapse-free survival across the three treatment groups. Single-agent posttransplant cyclophosphamide and tacrolimus with methotrexate and marrow grafts seemed to be equivalent strategies for graft-vs-host disease prophylaxis after myeloablative conditioning using HLA-matched donors in younger (≤ 65 years) patients with MDS and acute leukemia. However, it appears that the relapse rates may be lower and a trend for higher treatment-related mortality was noted with posttransplant cyclophosphamide-based graft-vs-host disease prophylaxis. Patients who received CD34+ cell selected peripheral blood grafts had worse overall survival driven by higher treatment-related mortality, which may offset any benefit from improvements in incidence of chronic graft-vs-host disease.
Cellular Therapy: Large B-Cell Lymphoma
ABSTRACT 4: Interim analysis of ZUMA-12 study: A phase II open-label single-arm study of axicabtagene ciloleucel as an earlier line of therapy in patients with high-risk large B-cell lymphoma (LBCL; NCT03761056).4
Background: Axicabtagene ciloleucel is currently approved for treatment of adults with relapsed or refractory LBCL who already have received at least two lines of systemic therapies, based on the pivotal ZUMA-1 study.5 The phase II, open-label, single-arm, multicenter ZUMA-12 trial expands on the ZUMA-1 indications and explores the use of this agent in an earlier phase of disease in patients with high-risk LBCL who had a positive interim FDG-PET scan after two cycles of front-line therapy.
“The relapse rates may be lower and a trend for higher treatment-related mortality with posttransplant cyclophosphamide.”— Syed Ali Abutalib, MD, and Stefan O. Ciurea, MD
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Methods: Eligible adults (≥ 18 years) met two criteria for high-risk LBCL: (1) double- or triple-hit lymphoma by fluorescent in situ hybridization or LBCL with International Prognostic Index (IPI) score ≥ 3; and (2) positive interim positron-emission tomography (PET; Deauville score of 4 or 5) after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen. Patients with central nervous system involvement, Richter’s transformation of chronic lymphocytic leukemia, or primary mediastinal B-cell lymphoma were excluded. As of July 15, 2020, 31 patients received axicabtagene ciloleucel; 15 patients had at least 3 months of follow-up as of January 24, 2020 (planned interim analysis cutoff date). Approximately 60% had double- or triple-hit rearrangements; 67% had an IPI score ≥ 3; and 40% and 60% of patients had a Deauville score of 4 and 5, respectively.
Results: Complete remission rates: Of 12 response-evaluable patients, the complete remission rate was 75%. Of 15 safety-evaluable patients, the complete remission rate was 80%.
Safety: Of 15 safety-evaluable patients, grade ≥ 3 adverse events occurred in 80%, with the most common being decrease in white blood cell count (40%), anemia (27%), and encephalopathy (27%). Grade ≥ 3 cytokine-release syndrome and neurologic events occurred in 20% and 27% of patients, respectively. Grade 3 infection and neutropenia were reported in 27% and 20%, respectively. No grade 5 adverse events were reported.
Pharmacology of CAR T-cell therapy: The median peak of CAR T-cell levels was higher in ZUMA-12 compared with ZUMA-1 (due to presumed better T-cell fitness).
Clinical Implications: ZUMA-12 evaluated axicabtagene ciloleucel as an earlier line of therapy (“early salvage”) in protocol-defined “high-risk” LBCL with complete remission rates of 75% to 80%. A small number of patients have been analyzed to date.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Ciurea has served as a consultant or advisor to CytoSen, Kiadis Pharma, Spectrum, MolMed, Cellularity, Allogene, and CareDx; has received research funding from Miltenyi Biotec and Kiadis; and has been reimbursed for travel, accommodations, or other expenses by CytoSen, Kiadis Pharma, MolMed, and CareDx.
1. Nakamura R, Saber W, Ramirez A, et al: A multicenter biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplantation to hypomethylating therapy or best supportive care in patients aged 50-75 with advanced myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102. 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 3. Presented February 12, 2021.
2. Saber W, Le Rademacher J, Sekeres M, et al: Multicenter biologic assignment trial comparing reduced-intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 study rationale, design, and methods. Biol Blood Marrow Transplant 20:1566-1572, 2014.
3. Pasquini MC, Logan B, Wu JM, et al: Calcineurin inhibitor-free graft-versus-host disease prophylaxis in hematopoietic cell transplantation with myeloablative conditioning regimens and HLA-matched donors: Results of the BMT CTN 1301 Progress II Trial. 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract LBA1. Presented February 12, 2021.
4. Neelapu SS, Dickinson M, Oluwole OO, et al: Interim analysis of ZUMA-12: A phase 2 study of axicabtagene ciloleucel as first-line therapy in patients with high-risk large B cell lymphoma. 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 4. Presented February 12, 2021.
5. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-celll lymphoma. N Engl J Med 377:2531-2544, 2017.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy Journal. Dr. Ciurea isProfessor of Clinical Medicine and Director of the Hematopoietic Stem Cell Transplant and Cellular Therapy Program within the Division of Hematology/Oncology, Department of Medicine at the Chao Family Comprehensive Cancer Center, University of California.