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1.
Allogeneic stem cell transplant for patients with myeloproliferative neoplasms in blast phase: improving outcomes in the recent era
Shah, M. V., Saliba, R. M., Verma, A., Ciurea, S. O., Oran, B., Olson, A., Bose, P., Bashir, Q., Masarova, L., Alousi, A. M., et al
British journal of haematology. 2021
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2.
Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial
Mehta, R. S., Bassett, R., Chen, J., Valdez, B. C., Kawedia, J., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients due to higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for six days over a two-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. OBJECTIVES The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. STUDY DESIGN The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80mg/m(2) busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40mg/m(2) and busulfan IV once daily. The dosing of busulfan was determined from PK analyses to achieve for the course a target AUC of 20,000±12% µmol.min, which is close to the average exposure of myeloablative dose of busulfan. 150 patients with high-risk hematological malignancies up to 75 years were enrolled on this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. RESULTS The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N=59, 39.3%), myelodysplastic syndrome (MDS; n=29, 19.3%), and myelofibrosis (MF; N=22, 14.7%). Most had an unrelated donor (n=93, 62%) and received peripheral blood graft (n=110, 73.3%). Over half had an HCT-Specific Comorbidity Index of =3 (n=79, 52.7%). The median follow-up among survivors was 43.4 months (IQR, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3 year OS was 66.7% (95% CI, 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancies was 8.7% (95% CI, 4.1-13.2%) at 3 years. CONCLUSION Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival.
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3.
Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML
Menghrajani, K., Gomez-Arteaga, A., Madero-Marroquin, R., Zhang, M. J., Bo-Subait, K., Sanchez, J., Wang, H. L., Aljurf, M., Assal, A., Bacher, U., et al
Blood advances. 2021
Abstract
Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
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4.
Validation of a Hematopoietic Cell Transplant - Composite Risk (HCT-CR) Model for Post Transplant Survival Prediction in Patients with Hematologic Malignancies
Ciurea, S. O., Kongtim, P., Hasan, O., Ramos Perez, J. M., Torres, J., Rondon, G., Champlin, R. E.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020
Abstract
PURPOSE Allogeneic hematopoietic stem cell transplantation (AHCT) outcomes depend on disease and patient characteristics. We previously developed a novel prognostic model, hematopoietic cell transplant composite-risk (HCT-CR) by incorporating the refined disease risk index (DRI-R) and hematopoietic cell transplant - comorbidity/age index (HCT-CI/Age) to predict post-transplant survival in patients with AML and MDS. Here we aimed to validate and prove the generalizability of the HCT-CR model in an independent cohort of patients with hematologic malignancies receiving AHCT. MATERIALS AND METHODS Data of consecutive adult patients receiving AHCT for various hematologic maliganacies were analyzed. Patients were stratified into 4 HCT-CR risk groups. The discrimination, calibration performance and clinical net benefit of the HCT-CR model were tested. RESULTS The HCT-CR model stratified patient into 4 risk groups with significantly different OS. Three-year OS was 67.4%, 50%, 37.5% and 29.9% for low, intermediate, high and very high-risk group, respectively (P<0.001). The HCT-CR model had better discrimination on OS prediction when compared with the DRI-R and HCT-CI/Age (C-idindex was 0.69 vs. 0.59 and 0.56, respectively, P<0.001). The decision curve analysis showed that HCT-CR model provided better clinical utility for patient selection for post-transplant clinical trial than the "treat all" or "treat none" strategy and the use of the DRI-R and HCT-CI/Age model separately. CONCLUSIONS The HCT-CR can be effectively used to predict post-transplant survival in patients with various hematologic malignancies. This composite model can identify patients who will benefit the most from transplantation and helps physicians in making decisions regarding post-transplant therapy to improve outcomes.
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5.
Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy
Dholaria, B., Savani, B. N., Hamilton, B. K., Oran, B., Liu, H. D., Tallman, M. S., Ciurea, S. O., Holtzman, N. G., Ii, G. L. P., Devine, S. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
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6.
Significance of minimal residual disease monitoring by real-time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes
Yalniz, F. F., Patel, K. P., Bashir, Q., Marin, D., Ahmed, S., Alousi, A. M., Chen, J., Ciurea, S. O., Rezvani, K., Popat, U. R., et al
Cancer. 2020
Abstract
BACKGROUND Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis. RESULTS MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2). CONCLUSIONS Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.
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7.
Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia
Olson, A. L., Saliba, R. M., Oran, B., Chen, J., Alousi, A., Ahmed, S., Bashir, Q., Ciurea, S. O., Hosing, C., Seon Im, J., et al
Acta haematologica. 2020;:1-8
Abstract
Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
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8.
Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors
Oran, B., Garcia-Manero, G., Saliba, R. M., Alfayez, M., Al-Atrash, G., Ciurea, S. O., Jabbour, E. J., Mehta, R. S., Popat, U. R., Ravandi, F., et al
Cancer. 2020
Abstract
BACKGROUND There have been concerns regarding increased peritransplantation complications, especially severe acute graft-versus-host disease (aGVHD), in patients with prior use of checkpoint inhibitors (CPI) before hematopoietic stem cell transplantation (HSCT). METHODS The authors performed a retrospective study of 43 patients with acute myeloid leukemia and/or myelodysplastic syndromes who were treated with an antiprogrammed cell death protein 1 (PD-1) (32 patients) or anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (9 patients) blockade or both (2 patients) prior to HSCT with the primary outcome of aGVHD by day 100 after HSCT. Outcome analyses were stratified by GVHD prophylaxis as use of post-HSCT cyclophosphamide (PTCy) (22 patients) or not (non-PTCy) (21 patients). RESULTS The PTCy group demonstrated a trend toward lower grade 3 to 4 aGVHD when compared with the non-PTCy group (5% vs 22%), although the rates of grade 2 to 4 aGVHD were comparable (49% vs 56%). The interval between CPI and HSCT did not appear to impact the incidence of aGVHD. However, a higher incidence of grade 3 to 4 aGVHD was observed in patients who received >4 treatments of CPI prior to HSCT if they were not given PTCy as GVHD prophylaxis (43% vs 12%). Matched control analyses using patients with no prior use of CPI confirmed the increase in grade 3 to 4 aGVHD with those agents. However, that increased risk was limited to patients who did not receive PTCy and was not observed in patients who received PTCy as GVHD prophylaxis. Despite persistent improvement in GVHD with the use of PTCy, disease control was not compromised and progression-free survival at 1 year was found to be superior for patients treated with PTCy compared with those not receiving PTCy among patients with prior use of CPI (55% vs 22%). CONCLUSIONS The results of the current study indicated that HSCT with prior use of CPI appears feasible in patients with acute myeloid leukemia and/or myelodysplastic syndromes and the use of PTCy as GVHD prophylaxis improves outcomes.
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9.
PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL
Dreger, P., Sureda, A., Ahn, K. W., Eapen, M., Litovich, C., Finel, H., Boumendil, A., Gopal, A., Herrera, A. F., Schmid, C., et al
Blood advances. 2019;3(3):360-369
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Abstract
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
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10.
Haploidentical Transplantation for Acute Myeloid Leukemia Patients with Minimal/ Measurable Residual Disease at Transplantation
Srour, S. A., Saliba, R. M., Bittencourt, M. C., Ramos Perez, J. M., Kongtim, P., Alousi, A., Al-Atrash, G., Olson, A., Betul, O., Mehta, R., et al
American journal of hematology. 2019
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Editor's Choice
Abstract
There have been conflicting results regarding impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = 0.002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = 0.1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Patients with acute myeloid leukaemia (n=143)
Intervention
Haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy).
Comparison
None
Outcome
The two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 and 2.3 respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes.