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National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide
Shaw, B. E., Jimenez-Jimenez, A. M., Burns, L. J., Logan, B. R., Khimani, F., Shaffer, B. C., Shah, N. N., Mussetter, A., Tang, X. Y., McCarty, J. M., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2003502
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Editor's Choice
Abstract
PURPOSE Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.
PICO Summary
Population
Patients aged 15-71 years old with haematological malignancy, lacking a matched donor (n=80)
Intervention
Mismatched unrelated donor with post-transplant cyclophosphamide (PTCy)
Comparison
Contemporary controls identified from the CIBMTR registry: MMUD receiving PBSC grafts (n=143), mismatched related donor recipients receiving BM grafts (n=398), or PBSC grafts (n=1191)
Outcome
The primary end point was met, with 1-year OS of 76% in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.
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Shortened-duration immunosuppressive therapy after nonmyeloablative, related HLA-haploidentical or unrelated peripheral blood grafts and post-transplantation cyclophosphamide
DeZern, A. E., Elmariah, H., Zahurak, M., Rosner, G. L., Gladstone, D. E., Ali, S. A., Huff, C. A., Swinnen, L. J., Imus, P., Borrello, I., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IS) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but, given the higher rates of GVHD with PB, excessive GVHD becomes an increased concern. We present a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB transplantation. Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BM transplantation and PTCy, received NMA PB allografts on trial. The primary objective was to evaluate the safety and feasibility of reduced-duration IS (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2). Of the 117 patients (median age 64 years, range 22-78), the most common diagnoses were myelodysplastic syndrome (33%), acute myeloid leukemia (with minimal residual disease or arising from antecedent disorder) (32%), myeloproliferative neoplasms (19%) myeloma (9%), and chronic lymphocytic leukemia (7%). Shortened IS was feasible in 75 pts (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 pts), followed by early relapse (11 pts), non-relapse mortality (NRM) (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned. Of the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV GVHD was 21 days and 32 days in the day 90 and day 60 cohorts respectively, with almost all cases developing within 40 days. Approximately one-third of these patients did restart IS. All outcome measures were similar in the 2 cohorts and to our historical outcomes with 180 days of IS. The cumulative incidence of grade 3-4 acute GVHD were low at 2 and 7% in D90 and D60, respectively. Severe chronic GVHD was 9% (D90) and 5% (D60) at 2 years. The two year overall survival was 67% for both the D90 and D60 cohorts, The two year progression free survival was 47% for the Day 90 cohort and 52% for the Day 60 cohort with the GVHD-free relapse-free survival less than 35% for both cohorts. These data suggest that reduced-duration IS in pts receiving NMA PB grafts with PTCy is feasible and carries an acceptable safety profile.
PICO Summary
Population
Patients with hematologic malignancies associated with higher rates of graft failure (n=117)
Intervention
Non-myeloablative haploidentical transplant with immunosuppression days 5-90 (D90 cohort, n=57)
Comparison
Non-myeloablative haploidentical transplant, with immunosuppression days 5-60 (D60 cohort, n=60)
Outcome
Shortened immunosuppression (IS) was feasible in 75 pts (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 pts), followed by early relapse (11 pts), non-relapse mortality (NRM) (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned. Of the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV GVHD was 21 days and 32 days in the day 90 and day 60 cohorts respectively, with almost all cases developing within 40 days. Approximately one-third of these patients did restart IS. All outcome measures were similar in the 2 cohorts and to our historical outcomes with 180 days of IS. The cumulative incidence of grade 3-4 acute GVHD were low at 2 and 7% in D90 and D60, respectively. Severe chronic GVHD was 9% (D90) and 5% (D60) at 2 years. The two year overall survival was 67% for both the D90 and D60 cohorts, The two year progression free survival was 47% for the Day 90 cohort and 52% for the Day 60 cohort with the GVHD-free relapse-free survival less than 35% for both cohorts.
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Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Webster, J. A., Luznik, L., Tsai, H. L., Imus, P. H., DeZern, A. E., Pratz, K. W., Levis, M. J., Gojo, I., Showel, M. M., Prince, G., et al
Blood advances. 2020;4(20):5078-5088
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Editor's Choice
Abstract
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.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Intervention
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Comparison
Patients in second or subsequent remission (CR2+, n=12)
Outcome
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%.
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Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70
Imus, P. H., Tsai, H. L., Luznik, L., Fuchs, E. J., Huff, C. A., Gladstone, D. E., Lowery, P., Ambinder, R. F., Borrello, I. M., Swinnen, L. J., et al
Blood advances. 2019;3(17):2608-2616
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Editor's Choice
Abstract
Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.
PICO Summary
Population
Consecutive patients older than 70 years with haematological malignancies (n=93)
Intervention
Haploidentical BMT with post-transplant cyclophosphamide GvHD prophylaxis
Comparison
None
Outcome
The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM.