Résumé
Background: Adult T-cell leukemia/lymphoma (ATLL) is a T-cell malignancy driven by the human T-cell lymphotropic virus type I (HTLV-1) that is associated with a dismal prognosis. Allogeneic stem-cell transplantation (Allo-SCT) has shown promising results but is associated with serious complications such as graft-versus-host disease (GVHD). Moreover, as a disease that disproportionately affects minorities, which are underrepresented in the National Marrow Donor Program (NMDP), there are significant barriers to access this potentially curative modality. Post-transplantation cyclophosphamide (PTCy) and abatacept (aba) have dramatically improved outcomes and greatly increased access to transplantation by enabling utilization of mismatched donors.
Patients and Methods: This is a retrospective single center analysis with 23 HTLV-1-associated North American ATLL patients (NA-ATLL) that underwent Allo-SCT from 2012 to 2024. Two cohorts were analyzed based on the use of PTCy and abatacept (Cohort A: No PTCy/Aba except for PTCy in haploidentical donors, Cohort B: PTCy + Aba regardless of HLA match). Variables collected in each cohort include age, sex, ethnicity, CMV/HTLV1 serologies, ECOG Performance Status (ECOG), Karnofsky Performance Status (KPS), diagnosis date, disease subtype, number of prior therapy lines, status at transplant, transplant date, donor sex, CMV/HTLV1 serologies, stem cell source, donor type, in-vivo T-cell depletion, engraftment, conditioning regimen, GVHD prophylaxis, maximum acute and chronic GVHD grade, relapse date when applicable, and main cause of death. Kaplan Meier estimates were used for overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS). Differences in time-to-event distributions between groups were checked with a log rank test. Patients who relapsed before 90 days were not included in these analyses.
Results: Twenty-three patients met eligibility criteria, 29-74 years old, 18 Black patients and 5 Hispanic. Cohort A had a median follow-up of 443 days and Cohort B had a median follow-up of 238 days. In Cohort A (n=16), 9 patients (56.2%) had acute ATLL and 7 (43.8%) lymphomatous. 8 (50.0%) patients were transplanted in first completed remission (CR1), and 13 (81.2%) had ECOG ≤1 and 12 (75.0%) had KPS ≥90. 7 patients had matched related donors (MRD), 1 match unrelated (MUD), 6 haploidentical (haplo), and 2 mismatched unrelated (MMUD). Donors were CMV positive in 10 cases and HTLV-1 positive in 3. In Cohort B (n=7), 2 patients (28.6%) had acute ATLL and 5 (71.4%) lymphomatous. 5 (71.4%) patients were transplanted in CR1, and 7 (100.0%) had ECOG ≤1 and 7 (100.0%) had KPS ≥90. 3 patients had MRD, 0 MUD, 2 haplo, and 2 MMUD. Donors were CMV positive in 6 cases and HTLV-1 positive in 1. All patients in Cohort B are alive at the time of this analysis whereas only 4 (25.0%) are alive in Cohort A. The main causes of death included progression of disease in 5 patients, GVHD in 2, infection in 1, and veno-occlusive disease in 1. We observed improved GRFS in Cohort B when compared with Cohort A (p=0.042), but there was no significant difference in PFS (p=0.14). There were 5 cases of grade 3-4 acute GVHD/extensive chronic GVHD in Cohort A. There were no cases of severe GVHD in Cohort B. Surprisingly, we observed Donor CMV positivity as associated with improved OS (p=0.019), PFS (p<0.001), and GRFS (p=0.016). All recipients were CMV positive except for 1 in Cohort A. CMV reactivation was observed in 15 patients (68.2%) despite use of letermovir which was used in all patients starting in 2018.
Conclusion: PTCy and abatacept are associated with improved outcomes, increased safe utilization of mismatched donors, and elimination of grade 3-4 GVHD and early mortality associated with it in our previous cohort. Although this is the largest NA-ATLL single center cohort outside of Europe and Japan, further studies are needed to determine the scalability of these results.
Reef:Regeneron Pharmaceuticals: Current equity holder in publicly-traded company. Steidl:Roche: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Trillium Therapeutics: Consultancy; Vor Biopharma: Consultancy; Pieris Pharmaceuticals: Consultancy; Stelexis: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bayer Healthcare: Consultancy, Research Funding; Celgene: Consultancy. Shastri:NACE & PeerView: Honoraria; Gilead, Rigel, Kymera: Consultancy; Jassen: Consultancy; Kymera: Research Funding; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau. Ramos:Acrotech Biopharma Inc.: Consultancy. Konopleva:Janssen: Consultancy, Other: clinical trials; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Other: Clinical Trials; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Legend Biotech: Consultancy; MEI Pharma: Consultancy, Research Funding; Reata Pharmaceutical: Other: IP; Redona: Consultancy; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Allogene: Research Funding; Boehringer: Consultancy; Pfizer: Other: clinical trials; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Sellas: Consultancy; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceutical: Research Funding; Precision Biosciences: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Bioconvergent health: Current equity holder in private company; Prelude: Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squib: Research Funding; Halia: Research Funding; Clinstreet: Current equity holder in private company; Calico: Membership on an entity's Board of Directors or advisory committees; Stelexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Janakiram:FATE THERAPEUTICS: Research Funding; JANNSEN: Honoraria, Research Funding; LEGEND: Honoraria, Research Funding; BMS: Honoraria, Research Funding.