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1.
Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Bolaños-Meade, J., Hamadani, M., Wu, J., Al Malki, M. M., Martens, M. J., Runaas, L., Elmariah, H., Rezvani, A. R., Gooptu, M., Larkin, K. T., et al
The New England journal of medicine. 2023;388(25):2338-2348
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Editor's Choice
Abstract
BACKGROUND In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
PICO Summary
Population
Adults with hematologic cancers undergoing HLA-matched related donor or a matched or 7/8 mismatched unrelated donor transplant, enrolled in an RCT in multiple centres in USA (n=431)
Intervention
Cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis, n=214)
Comparison
Tacrolimus-methotrexate (standard prophylaxis (standard prophylaxis, n=217)
Outcome
GVHD-free, relapse-free survival was significantly more common among patients in the experimental-prophylaxis group than among the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
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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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HLA-Matching with PTCy: A Reanalysis of a CIBMTR Dataset with Propensity Score Matching and Donor Age
Ambinder, A. J., Jain, T., Tsai, H. L., Horowitz, M. M., Jones, R. J., Varadhan, R.
Blood advances. 2022
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Editor's Choice
Abstract
Blood or marrow transplantation (BMT) outcomes using haploidentical donors (Haplo) and post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GVHD) prophylaxis compare favorably to using HLA-matched donors with calcineurin inhibitor-based GVHD prophylaxis. A recent CIBMTR analysis of patients receiving homogenous PTCy-based prophylaxis found that, with reduced intensity conditioning, Haplo BMTs had worse outcomes than matched unrelated donor (MUD) BMTs. Due to significant differences in characteristics between the groups, we reanalyzed the dataset using propensity score matching and, additionally, added a donor age variable. MUD BMTs were matched to Haplo BMTs in a 1:5 ratio. After matching, no significant differences were found between groups across all measured baseline characteristics. Outcomes analyses demonstrated no significant differences in overall survival (HR of mortality with MUD vs Haplo [95% CI], 0.95[0.65-1.16], P=0.75), disease free survival (HR of relapse or death, 0.98[0.73-1.18], P=0.89), relapse rate (HR, 1.06[0.77-1.38], P=0.69), or non-relapse mortality (HR, 0.85[0.42-1.13], P=0.49) between the two groups. After stratification by conditioning intensity, MUD BMTs in the RIC cohort had a lower risk of NRM (HR, 0.56 [0.14-0.99], P=0.05), with no significant difference in other clinical outcomes. These results suggest that the effect of HLA matching on BMT outcomes with PTCy is less meaningful than previously reported and observed differences resulted in part from differences in donor age. Timely identification of a young, at least half-matched (related or unrelated) donor may be more important than finding a matched donor, if the latter leads to a substantial delay in BMT or use of an older donor.
PICO Summary
Population
Adults with acute myeloid leukaemia, acute lymphoblastic leukaemia in first or second complete remission, or myelodysplastic syndromes attending 111 bone marrow transplantation (BMT) centres across the USA and reported to the CIBMTR registry (n=837)
Intervention
BMT from haploidentical donors (Haplo, n=637, subset receiving reduced-intensity conditioning (RIC) n=341)
Comparison
BMT from matched unrelated donors (MUD, n=200, subset receiving RIC n=114)
Outcome
After matching, no significant differences were found between groups across all measured baseline characteristics. Outcomes analyses demonstrated no significant differences in overall survival (HR of mortality with MUD vs Haplo [95% CI], 0.95[0.65-1.16]), disease free survival (HR of relapse or death, 0.98[0.73-1.18]), relapse rate (HR, 1.06[0.77-1.38]), or non-relapse mortality (HR, 0.85[0.42-1.13]) between the two groups. After stratification by conditioning intensity, MUD BMTs in the RIC cohort had a lower risk of non-relapse mortality (HR, 0.56 [0.14-0.99]), with no significant difference in other clinical outcomes.
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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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Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies
Luznik, L., Pasquini, M. C., Logan, B., Soiffer, R. J., Wu, J., Devine, S. M., Geller, N., Giralt, S., Heslop, H. E., Horowitz, M. M., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2102293
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Editor's Choice
Abstract
PURPOSE Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.
PICO Summary
Population
Patients 65 years and under with acute leukaemia or myelodysplasia undergoing matched donor allogeneic HSCT at 26 centres in the USA (n=346)
Intervention
CD34 selected graft (n=114) or Post-transplant cyclophosphamide (PTCy, n=114)
Comparison
Tacrolimus and methotrexate (Control, n=118)
Outcome
Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80), 76.2% (HR, 1.02; 0.60 to 1.72), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96)
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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.
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Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Imus, P. H., Tsai, H. L., DeZern, A. E., Jerde, K., Swinnen, L. J., Bolaños-Meade, J., Luznik, L., Fuchs, E. J., Wagner-Johnston, N., Huff, C. A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
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.
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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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Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)
Bolanos-Meade, J., Reshef, R., Fraser, R., Fei, M., Abhyankar, S., Al-Kadhimi, Z., Alousi, A. M., Antin, J. H., Arai, S., Bickett, K., et al
The Lancet. Haematology. 2019;6(3):e132-e143
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Editor's Choice
Abstract
BACKGROUND Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. METHODS In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1.3 mg/m(2) intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m(2) intravenous bolus on day 1 and 10 mg/m(2) intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0.05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. FINDINGS Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0.72 (90% CI 0.54-0.94; p=0.044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0.98 (0.76-1.27; p=0.92) for tacrolimus, methotrexate, and bortezomib, and 1.10 (0.86-1.41; p=0.49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). INTERPRETATION Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. FUNDING US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
PICO Summary
Population
Adults aged 18-75 who received reduced-intensity conditioning HCT
Intervention
3 arms, assigned randomly: 1) tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 2) tacrolimus, methotrexate, and bortezomib; or 3) tacrolimus, methotrexate, and maraviroc.
Comparison
Control group who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial.
Outcome
Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS. Compared with controls, the hazard ratio for GRFS was 0.72 for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0.98 for tacrolimus, methotrexate, and bortezomib, and 1.10 for tacrolimus, methotrexate, and maraviroc.
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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.