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%.
Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: a Retrospective Cohort Study
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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.
Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide
Blood advances. 2020;4(8):1770-1779
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.
Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.
Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70
Blood advances. 2019;3(17):2608-2616
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.
Consecutive patients older than 70 years with haematological malignancies (n=93)
Haploidentical BMT with post-transplant cyclophosphamide 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.
Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplant Cyclophosphamide in Chronic Lymphocytic Leukemia
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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.
Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;:Jco1800690
PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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.