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Allogeneic Blood or Marrow Transplantation with High-Dose Post-transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Aged ≥55
Webster, J. A., Reed, M., Tsai, H. L., Ambinder, A., Jain, T., Dezern, A. E., Levis, M. J., Showel, M. M., Prince, G. T., Hourigan, C. S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients ≥55 years-old with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy with 5-year overall survival of ∼20%. Tyrosine kinase inhibitors and novel B-cell targeted therapies improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (AlloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplants with low rates of non-relapse mortality (NRM) and graft-versus-host disease (GVHD). METHODS The transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received alloBMT for ALL using PTCy. FINDINGS The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% CI 34-57) and 49% (95% CI 37-60). Grade 3-4 acute GVHD occurred in only 3% of patients and chronic GVHD in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (HR 4.65, p=0.001); while transplant in CR1 (HR 0.30, p=0.004), and transplant for Ph+ ALL vs. T ALL (HR 0.29, p=0.03) improved RFS. Of the 54 patients who received RIC alloBMT in CR1 for B ALL, 5-year RFS and OS were 62% (95% CI 47-74) and 65% (95% CI 51-77), respectively, with a 5-year relapse incidence of 16% (95% CI 7-27) and NRM of 24% (95% CI 13-36). INTERPRETATION RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. FUNDING NIH grants P01 CA225618 and P30 CA06973.
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"Allogeneic blood or marrow transplant with non-myeloablative conditioning and high dose cyclophosphamide-based graft-versus-host disease prophylaxis for secondary central nervous system lymphoma"
Sterling, C. H., Tsai, H. L., Holdhoff, M., Bolaños-Meade, J., Luznik, L., Fuchs, E. J., Huff, C. A., Gocke, C. B., Ali, S. A., Borrello, I. M., et al
Transplantation and cellular therapy. 2021
Abstract
Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplant (alloBMT) is widely used in relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. Here we review outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with non-myeloablative conditioning using fludarabine, cyclophosphamide, and 200cGy total-body irradiation. For graft-versus-host disease (GVHD) prophylaxis, all patients received post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI] 5.3 months - not reached). The cumulative incidence of relapse was 25% (95% CI 5-45%), and non-relapse mortality was 30% (95% CI 5-54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS / systemic. The use of alloBMT in CNS lymphoma deserves further investigation.
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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.