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1.
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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2.
"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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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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4.
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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5.
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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6.
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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7.
Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation
Kasamon, Y. L., Fuchs, E. J., Zahurak, M., Rosner, G. L., Symons, H. J., Gladstone, D. E., Huff, C. A., Swinnen, L. J., Brodsky, R. A., Matsui, W. H., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(5):1022-1028
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Abstract
With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.
Clinical Commentary
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NIHMS969487
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8.
Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide
Kanakry, C. G., Bolanos-Meade, J., Kasamon, Y. L., Zahurak, M., Durakovic, N., Furlong, T., Mielcarek, M., Medeot, M., Gojo, I., Smith, B. D., et al
Blood. 2017;129(10):1389-1393
Abstract
The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.
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9.
Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide
McCurdy, S. R., Kasamon, Y. L., Kanakry, C. G., Bolanos-Meade, J., Tsai, H. L., Showel, M. M., Kanakry, J. A., Symons, H. J., Gojo, I., Smith, B. D., et al
Haematologica. 2017;102(2):391-400
Abstract
Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.
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10.
Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide
Lombardi, L. R., Kanakry, C. G., Zahurak, M., Durakovic, N., Bolanos-Meade, J., Kasamon, Y. L., Gladstone, D. E., Matsui, W., Borrello, I., Huff, C. A., et al
Leukemia & Lymphoma. 2016;57(3):666-75
Abstract
Busulfan (Bu)/cyclophosphamide (Cy) is a standard conditioning platform for allogeneic transplantation. We developed a strategy separating the Cy into two pre/post-transplantation doses (PTCy), providing myeloablative conditioning and single-agent graft-versus-host disease (GVHD) prophylaxis. We investigated the impact of Bu route on treatment-related toxicity for 131 consecutive adult patients. Busulfan was administered in four daily divided doses either orally (n=72) or intravenously (n=59) with pharmacokinetics on the first-dose and as necessary on subsequent doses to achieve a target area-under-the-concentration-curve (AUC) of 800-1400mumol*min/L per dose. BuCy/PTCy with pharmacokinetics is well-tolerated with low treatment-related toxicity. Hepatic veno-occlusive disease incidence was 6% with two fatal events. Bu administration route in the context of BuCy/PTCy did not statistically impact hepatotoxicity, GVHD, relapse, disease-free survival, or overall survival. The BuCy/PTCy platform has a low incidence of treatment-related toxicity, including hepatotoxicity, in hematologic malignancies when using pharmacokinetics for a target AUC of 800-1400mumol*min/L, irrespective of Bu administration route.