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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.
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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3.
"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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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.
Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA Haploidentical Transplant with Post-Transplant Cyclophosphamide
McCurdy, S. R., Kanakry, C. G., Tsai, H. L., Kasamon, Y. L., Showel, M. M., Bolanos-Meade, J., Huff, C. A., Borrello, I., Matsui, W. H., Brodsky, R. A., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were significantly different, at 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P=.05 and P=.009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P=.19) and .69 (95% CI, .48 to .98; P=.04). Higher nucleated cell graft dose was also associated with improved OS and PFS (HR, .88 [95% CI, .78 to 1.00; P=.05] and HR, .89 [95% CI, .79 to 1.0; P=.05], respectively) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P=.03). PTCy reduces grades III to IV aGVHD and cGVHD but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy. Copyright © 2017. Published by Elsevier Inc.
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8.
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.