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Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines
DeFilipp, Z., Ciurea, S. O., Cutler, C., Robin, M., Warlick, E. D., Nakamura, R., Brunner, A. M., Dholaria, B., Walker, A. R., Kröger, N., et al
Transplantation and Cellular Therapy. 2023;29(2):71-81
Abstract
The sole curative therapy for myelodysplastic syndrome (MDS) is allogeneic hematopoietic cell transplantation (HCT). Here this therapeutic modality is reviewed and critically evaluated in the context of the evidence. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of MDS experts comprising transplantation and nontransplantation physicians developed consensus treatment recommendations. This review summarizes the standard MDS indications for HCT and addresses areas of controversy. Recent prospective trials have confirmed that allogeneic HCT confers survival benefits in patients with advanced or high-risk MDS compared with nontransplantation approaches, and the use of HCT is increasing in older patients with good performance status. However, patients with high-risk cytogenetic or molecular mutations remain at high risk for relapse. It is unknown whether administration of novel therapies before or after transplantation may decrease the risk of disease relapse in selected populations. Ongoing and future studies will investigate revised approaches to disease risk stratification, patient selection, and post-transplantation approaches to optimize allogeneic HCT outcomes for patients with MDS.
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Prognostic landscape of mitochondrial genome in myelodysplastic syndrome after stem-cell transplantation
Dong, J., Buradagunta, C. S., Zhang, T., Spellman, S., Bolon, Y. T., DeZern, A. E., Gadalla, S. M., Deeg, H. J., Nazha, A., Cutler, C., et al
Journal of hematology & oncology. 2023;16(1):21
Abstract
Despite mitochondrial DNA (mtDNA) mutations are common events in cancer, their global frequency and clinical impact have not been comprehensively characterized in patients with myelodysplastic neoplasia (also known as myelodysplastic syndromes, MDS). Here we performed whole-genome sequencing (WGS) on samples obtained before allogenic hematopoietic cell transplantation (allo-HCT) from 494 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research. We evaluated the impact of mtDNA mutations on transplantation outcomes, including overall survival (OS), relapse, relapse-free survival (RFS), and transplant-related mortality (TRM). A random survival forest algorithm was applied to evaluate the prognostic performance of models that include mtDNA mutations alone and combined with MDS- and HCT-related clinical factors. A total of 2666 mtDNA mutations were identified, including 411 potential pathogenic variants. We found that overall, an increased number of mtDNA mutations was associated with inferior transplantation outcomes. Mutations in several frequently mutated mtDNA genes (e.g., MT-CYB and MT-ND5) were identified as independent predictors of OS, RFS, relapse and/or TRM after allo-HCT. Integration of mtDNA mutations into the models based on the Revised International Prognostic Scores (IPSS-R) and clinical factors related to MDS and allo-HCT could capture more prognostic information and significantly improve the prognostic stratification efforts. Our study represents the first WGS effort in MDS receiving allo-HCT and shows that there may be clinical utility of mtDNA variants to predict allo-HCT outcomes in combination with more standard clinical parameters.
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Posttransplantation Cyclophosphamide-based Graft versus Host Disease Prophylaxis with Non-myeloablative Conditioning for Blood or Marrow Transplantation for Myelofibrosis
Jain, T., Tsai, H. L., DeZern, A. E., Gondek, L. P., Elmariah, H., Bolaños-Meade, J., Luznik, L., Fuchs, E., Ambinder, R., Gladstone, D. E., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
We describe outcomes with posttransplantation cyclophosphamide and non-myeloablative conditioning based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched, family or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide and total body irradiation. Forty-two patients, with a median age of 63 years, were included, of whom 19% had intermediate-1, 60% had intermediate-2, and 21% had high-risk DIPSS-plus disease, and 60% had atleast one high-risk somatic mutation. Over 90% patients engrafted neutrophils at a median of 19.5 days and 7% had graft failure. At 1 and 3-years, respectively, the overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and non-relapse mortality was 30% and 30%. Acute graft versus host disease grade 3-4 was noted in 17% at 1 year and chronic graft versus host disease requiring systemic therapy in 12% patients. Spleen size ≥ 17 cm or prior splenectomy was associated with inferior relapse-free survival (HR 3.50, 95% CI 1.18-10.37, P=0.02) and higher relapse rate (SDHR not calculable, P=0.01). Age > 60 years (SDHR 0.26, 95% CI: 0.08-0.80, P=0.02) and peripheral blood graft (SDHR 0.34, 95% CI 0.11-0.99, P=0.05) was associated with lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome although ASXL1 was suggestive of inferior survival (SDHR 2.36. 95% CI 0.85-6.6, P=0.09). Overall, this approach shows comparable outcomes as previously reported and underscores the importance of spleen size in evaluation of transplant candidates.
PICO Summary
Population
Patients with high-risk Dynamic International Prognostic Scoring System (DIPSS)-plus myelofibrosis (n=42)
Intervention
Matched or mismatched allogeneic transplantation with non-myeloablative conditioning, and post-transplant cyclophosphamide
Comparison
None
Outcome
Over 90% patients engrafted neutrophils at a median of 19.5 days and 7% had graft failure. At 1 and 3-years, respectively, the overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and non-relapse mortality was 30% and 30%. Acute graft versus host disease grade 3-4 was noted in 17% at 1 year and chronic graft versus host disease requiring systemic therapy in 12% patients. Spleen size ≥ 17 cm or prior splenectomy was associated with inferior relapse-free survival (HR 3.50, 95% CI 1.18-10.37) and higher relapse rate (SDHR not calculable). Age > 60 years (SDHR 0.26, 95% CI: 0.08-0.80) and peripheral blood graft (SDHR 0.34, 95% CI 0.11-0.99) was associated with lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome although ASXL1 was suggestive of inferior survival (SDHR 2.36. 95% CI 0.85-6.6).
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Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study
Kunte, S., Rybicki, L., Viswabandya, A., Tamari, R., Bashey, A., Keyzner, A., Iqbal, M., Grunwald, M. R., Dholaria, B., Elmariah, H., et al
Leukemia. 2022;36(3):856-864
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Abstract
We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.
Clinical Commentary
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NIHMS1867052
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Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial
DeZern, A. E., Eapen, M., Wu, J., Talano, J. A., Solh, M., Dávila Saldaña, B. J., Karanes, C., Horwitz, M. E., Mallhi, K., Arai, S., et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation. METHODS We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/kg daily for 5 days, total body irradiation 200 cGy in a single fraction), related HLA-haploidentical donors, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Additionally, for GVHD prophylaxis, mycophenolate mofetil was given orally at a dose of 15 mg/kg three times a day up to 1 g three times a day (maximum dose 3000 mg per day) from day 5 to day 35, and tacrolimus was given orally or intravenously from day 5 to day 180 as per institutional standards to maintain a serum concentration of 10-15 ng/mL. The primary endpoint was overall survival 1 year after bone marrow transplantation. All patients treated per protocol were analysed. This study is complete and is registered with ClinicalTrials.gov, NCT02918292. FINDINGS Between May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4-51·3), and median follow-up was 24·3 months (IQR 12·1-29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation. INTERPRETATION Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (>2·5 × 10(8) nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach. FUNDING US National Heart, Lung, and Blood Institute and US National Cancer Institute.
PICO Summary
Population
Children and adults up to 75 years with severe refractory aplastic anaemia, from transplant centres in USA (n=32)
Intervention
Haploidentical transplantation with reduced intensity conditioning
Comparison
None
Outcome
31 received transplant. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation.
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Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes
Mishra, A., Tamari, R., DeZern, A. E., Byrne, M. T., Gooptu, M., Chen, Y. B., Deeg, H. J., Sallman, D., Gallacher, P., Wennborg, A., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2200181
Abstract
PURPOSE Outcomes are poor in TP53-mutant (mTP53) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), even after allogeneic hematopoietic stem-cell transplant (HCT). Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. PATIENTS AND METHODS We conducted a phase II, multicenter, open-label trial to assess efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT (ClinicalTrials.gov identifier: NCT03931291). Patients with mTP53 MDS or AML received up to 12 cycles of eprenetapopt 3.7 g once daily intravenously on days 1-4 and azacitidine 36 mg/m(2) once daily intravenously/subcutaneously on days 1-5 in 28-day cycles. The primary outcomes were relapse-free survival (RFS) and safety. RESULTS Of the 84 patients screened for eligibility before HCT, 55 received a transplant. Thirty-three patients ultimately received maintenance treatment (14 AML and 19 MDS); the median age was 65 (range 40-74) years. The median number of eprenetapopt cycles was 7 (range 1-12). With a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable) and the 1-year RFS probability was 59.9% (95% CI, 41 to 74). With a median follow-up of 17.0 months, the median overall survival (OS) was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3). Thirty-day and 60-day mortalities from the first dose were 0% and 6% (n = 2), respectively. Acute and chronic (all grade) graft-versus-host disease adverse events were reported in 12% (n = 4) and 33% (n = 11) of patients, respectively. CONCLUSION In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population.
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Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide
DeZern, A. E., Zahurak, M. L., Symons, H. J., Cooke, K. R., Rosner, G. L., Gladstone, D. E., Huff, C. A., Swinnen, L. J., Imus, P., Borrello, I., et al
Blood advances. 2020;4(8):1770-1779
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Abstract
Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naive (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.