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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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Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience
Ambinder, A., Smith, M., Tsai, H. L., Varadhan, R., DeZern, A., Dalton, W., Gocke, C., Webster, J., Gondek, L., Gojo, I., et al
Clinical lymphoma, myeloma & leukemia. 2021
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Abstract
INTRODUCTION Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. PATIENTS AND METHODS In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. RESULTS Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). CONCLUSION Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).
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Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: a Retrospective Cohort Study
Paul, S., Zahurak, M., Luznik, L., Ambinder, R. F., Fuchs, E. J., Bolanos-Meade, J., Wagner-Johnston, N., Swinnen, L. J., Schoch, L., Varadhan, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI pre-treated cHL patients remain unclear. The aim of this study is to assess outcomes of cHL patients receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. METHODS We performed a retrospective study of relapsed/refractory cHL patients undergoing alloBMT with PTCy at Johns Hopkins between Nov 2004 and Sept 2019. Engraftment, GVHD incidence, non-relapse mortality (NRM), progression free survival (PFS) and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. FINDINGS We identified 105 consecutive relapsed/refractory cHL patients, of which 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78%, [hazard ratio (HR) 0.35 (95% CI: 0.08-1.56), P=0.17) and a 3-year estimated PFS of 90% and 65% [HR 0.3 (95 % CI: 0.09-1), P=0.05], respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II-IV GVHD or in the 24-month incidence of chronic GVHD. INTERPRETATION ICIs do not increase acute or chronic GVHD incidence compared to salvage chemotherapy. cHL patients receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus ICI therapy is safe in cHL patients when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival. FUNDING National Institutes of Health, National Cancer Institute grants.
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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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Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplant Cyclophosphamide in Chronic Lymphocytic Leukemia
Paul, S., Tsai, H. L., Lowery, P., Fuchs, E. J., Luznik, L., Bolanos-Meade, J., Swinnen, L. J., Shanbhag, S., Wagner-Johnston, N., Varadhan, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic blood or marrow transplantation (alloBMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. While post-transplant cyclophosphamide (PTCy) reduces alloBMT toxicity by decreasing graft-versus-host disease (GVHD), its effect on CLL alloBMT outcomes is unknown. We studied 64 consecutive CLL patients undergoing non-myeloablative (NMA) haploidentical alloBMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. The 4-year overall survival (OS) was 52% (95% confidence interval [CI]: 40-68%) and progression free survival (PFS) was 37% (95% CI: 26-54%) for all 64 patients undergoing alloBMT. In total, 6 patients suffered from engraftment failure. PTCy prophylaxis was associated with a modest cumulative GVHD incidence: 27% (95% CI: 15-38%) 1-year grade II-IV acute GVHD, and 17% (95% CI: 7-26%) 2-year chronic GVHD. We demonstrate NMA haploidentical alloBMT with PTCy is a safe and effective treatment option.
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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.
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Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors
Elmariah, H., Kasamon, Y. L., Zahurak, M., Macfarlane, K. W., Tucker, N., Rosner, G. L., Bolanos-Meade, J., Fuchs, E. J., Wagner-Johnston, N., Swinnen, L. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age 56 years) with hematologic malignancies who underwent NMA haplo T-cell replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grade II-IV acute GVHD (aGVHD) at day 180 was 24% (90% CI: 9-38%). Only 1 patient experienced grade III-IV aGVHD. At 1 year, the CuI of chronic GVHD was 10% (90% CI: 0-21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI: 0-14%). At 1 year, the probability of relapse was 31% (90% CI: 12-49%), progression-free survival was 64% (90% CI: 48-86%) and overall survival was 95% (90% CI: 87-100%). The 1-year probability of GVHD-free, relapse free survival was 57% (90% CI: 41-79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first degree relatives.