Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Blood advances. 2020;4(20):5078-5088
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Patients in second or subsequent remission (CR2+, n=12)
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.
Clinical Outcomes in Patients With FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplant After Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD?positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P?=?0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia - results from an international collaborative study
Acute myeloid leukemia with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of acute myeloid leukemia cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation may improve survival if applied early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 (range: 16-76) years, acute myeloid leukemia was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow-up of 5.43 years, estimated overall survival at 5 years was 38% (95%-CI, 31-47%). Allogeneic hematopoietic cell transplantation was performed in 117 (66%) patients, including 89 in first complete remission. Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45% [95%-CI, 35-59%] and 53% [95%-CI, 42-66%], vs. 7% [95%-CI, 3-19%] and 23% [95%-CI, 13-38%]. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first (53% [95%-CI, 42-66%]), or second complete remission (58% [95%-CI, 31-100%]; n=10) or with active disease/relapse (54% [95%-CI, 34-84%]; n=18) (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) acute myeloid leukemias are poor with chemotherapy, and can be substantially improved with allogeneic hematopoietic cell transplantation.
Patients with patients with acute myeloid leukaemia and a t(6;9)(p22;q34) mutation (n=178)
Allogeneic haematopoietic stem cell transplant (n=144)
Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45 and 53% vs. 7% and 23%. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first or second complete remission or with active disease/relapse. Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival.
Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide
Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.
Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide
Blood Advances. 2017;1(4):288-292
Allogeneic blood or marrow transplantation (BMT) candidates may lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Barriers to partially HLA-mismatched, unrelated donor (mMUD) BMT include excess graft-versus-host disease (GVHD), graft failure, and death. We prospectively studied nonmyeloablative (NMA) mMUD BMT with high-dose posttransplantation cyclophosphamide (PTCy) for patients with hematologic malignancies. Three transplants were performed with busulfan/fludarabine conditioning, with subsequent change to fludarabine/Cy/total body irradiation (flu/Cy/TBI). Twenty mMUD transplants are reported using flu/Cy/TBI, T-cell replete bone marrow grafts, and PTCy, mycophenolate mofetil, and sirolimus or tacrolimus (1 patient) for GVHD prophylaxis. The median patient age was 56. Ofthese unrelated grafts, 45% had >=2 mismatched HLA loci, 25% had >=3 mismatched loci, and 50% had HLA-C mismatches. No graft failure or grades 3-4 acute GVHD occurred. The median times to neutrophil recovery (>=500/muL) and platelet recovery (>=20 000/muL) were 19 days and 31 days, respectively. Full-donor chimerism was achieved in 95% of evaluable patients by day 60. The 180-day probability of grades 2-4 acute GVHD (all grade 2) was 25%, and the 1-year probability of any chronic GVHD was 16% (none severe). The 2-year nonrelapse mortality probability was 6%. With 4-year median follow-up, the 1-year progression-free and overall survival probabilities were 65% and 75%, respectively. NMA, T-cell replete mMUD BMT is thus a potentially viable option for patients without other suitable donors. This trial was registered at www.clinicaltrials.gov as #NCT01203722. Conflict-of-interest disclosure: The authors declare no competing financial interests.