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1.
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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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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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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4.
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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5.
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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6.
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.
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Is There an Optimal Conditioning for Older Patients with AML Receiving Allogeneic Hematopoietic Cell Transplantation?
Ciurea, S. O., Kongtim, P., Varma, A., Rondon, G., Chen, J., Srour, S., Bashir, Q., Alousi, A., Mehta, R. S., Oran, B., et al
Blood. 2019
Abstract
The optimal conditioning regimen for older patients with AML remains unclear. Here we compared outcomes of AML patients above 60 years receiving AHCT at our institution. All 404 consecutively treated patients received one of the following conditioning regimens: 1) fludarabine + melphalan 100mg/m2 (FM100), 2) fludarabine + melphalan 140mg/m2 (FM140), 3) fludarabine + IV busulfan AUC{greater than or equal to}5,000/day x 4 days (Bu{greater than or equal to}20000), and 4) fludarabine + IV busulfan AUC 4,000/day x 4 days (Bu16000) were included. A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, FM100 group had a significantly better long-term survival with 5-year progression-free survival (PFS) of 49% vs. 30%, 34% and 23%, respectively. The benefit of FM100 regimen resulted primarily from a lower non-relapse mortality associated with this regimen, effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better post-transplant survival, while no significantly differences were seen between other regimen groups. In conclusion, older patients with AML benefit from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival despite the fact that was primarily used in patients who could not receive more intense conditioning regimen.
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Optimal Conditioning for Older Patients with Acute Myeloid Leukemia (AML) Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Propensity Score Analysis
Ciurea, S. O., Varma, A., Kongtim, P., Srour, S., Bashir, Q., Alousi, A. M., Mehta, R. S., Oran, B., Popat, U., Hosing, C., et al
Blood. 2019;134(Supplement_1):42
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Myeloablative vs reduced intensity T-cell-replete haploidentical transplantation for hematologic malignancy
Solomon, S. R., St Martin, A., Shah, N. N., Fatobene, G., Al Malki, M. M., Ballen, K. K., Bashey, A., Bejanyan, N., Bolanos Meade, J., Brunstein, C. G., et al
Blood advances. 2019;3(19):2836-2844
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Editor's Choice
Abstract
In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell-replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.
PICO Summary
Population
Patients with haematological malignancies (n=1325)
Intervention
Myeloablative conditioning regimen (n=526)
Comparison
Reduced-intensity conditioning regimen (n=799)
Outcome
For patients aged 18 to 54 years, disease-free survival was lower and relapse was higher with a reduced-intensity regimen compared with a myeloablative regimen. Non-relapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival and relapse did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens.
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A Novel Disease Risk Model for Patients with AML Receiving Allogeneic Hematopoietic Cell Transplantation
Kongtim, P., Hasan, O., Perez, J. M. R., Varma, A., Wang, S. A., Patel, K. P., Chen, J., Rondon, G., Srour, S., Bashir, Q., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
BACKGROUND Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in AML patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific Disease Risk Group (AML-DRG) and revised our previously developed Hematopoietic Cell Transplant - Composite Risk (HCT-CR) model by incorporating molecular data and MRD status to predict outcomes of patients with AML. METHODS The study included 1414 consecutively treated adult AML patients, who received first AHCT. Patients were randomly assigned into a training (N=944) and validation set (N=470). To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox's regression analysis in a training dataset was converted into scores, while the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. RESULTS The AML-DRG was developed by assigning the following scores; 1 point to secondary AML; 1 point to the ELN adverse risk; 2 points to complete remission (CR) with MRD positive/unknown; and 4 points to active disease. These scores were used to generate 3 risk groups of the AML-DRG with significantly different OS. By adding score for significant patient-related factors (HCT-CI/age), we created 4 risk groups of AML-HCT-CR with distinct survival outcomes. Both the AML-DRG and AML-HCT-CR provided significantly better discriminative capacity compared with the disease-risk index, ELN genetic risk and cytogenetic risk model. CONCLUSIONS Prognostic models incorporating molecular data and MRD status allow better stratification and improved survival estimates of AML patients post-transplant.