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Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration
Jain, T., Tsai, H. L., Elmariah, H., Vachhani, P., Karantanos, T., Wall, S. A., Gondek, L. P., Bashey, A., Keyzner, A., Tamari, R., et al
Haematologica. 2023
Abstract
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in 7/120 (6%) of patients. At 3 years, nonrelapse mortality (NRM) was 25% (95%CI 17-34%), relapse 27% (95%CI 18-36%), grade 3-4 acute graft versus host disease (GVHD) 12% (95%CI 6-18%), chronic GVHD requiring systemic immunosuppression 14% (95%CI 7-20%), progression-free survival (PFS) 48% (95%CI 39-59%), and overall survival (OS) 56% (95%CI 47-67%). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, sdHR 3.28, 95%CI 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR 2.61, 95%CI 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR 1.98, 95% 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR 2.01, 95% CI 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
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2.
Improved Access to HCT with Reduced Racial Disparities Through Integration with Leukemia Care and Haploidentical Donors
Bashey, A., Zhang, X., Morris, L. E., Holland, H. K., Bachier-Rodriguez, L., Solomon, S. R., Solh, M. M.
Blood advances. 2023
Abstract
Few patients with non-favorable risk (NFR) acute leukemia and MDS (AL/MDS) have historically accessed allogeneic transplantation (HCT). We assessed whether this can be improved by the integration of HCT/leukemia care and use of haploidentical donors (HID). Of 256 consecutive patients aged ≤75 who received initial therapy at our center for NFR AL/MDS from 2016 to 2021, 147 (57%) proceeded to planned HCT (70% for patients aged <60). On logistic regression analysis, age (OR 1.50 per 10-year increment, p<0.001), race- black vs white (OR 2.05, p=0.023), were significant factors for failure to receive HCT. Reasons for no HCT were: comorbidities (37%), poor KPS, lack of adequate caregiver support, refractory malignancy (19% each) and patient refusal (17%). Lack of donor or insurance were rarely cited (3% each). In older patients (≥60 years), comorbidities (49 vs. 15%, p<0.001) and KPS (25% vs. 10%, p=0.06) were more common reasons, and lack of caregiver support was less common (13% vs. 30%, p=0.031). In black vs. white patients, lack of caregivers (37% vs 11%, p=0.002) was more frequent. Median time from initial treatment to HCT was 118 days and was similar for black vs white patients (112 vs 122 days, p=0.80). On landmark analysis, HCT within 6 months of initial treatment resulted in better survival. On multivariable analysis, HCT resulted in a significant survival benefit (HR 0.60, p=0.020). With the above approach, the majority of currently treated patents aged ≤75 can access planned HCT. Black patients remain at higher risk for not receiving HCT.
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3.
Galectin-3 predicts acute GvHD and overall mortality post reduced intensity allo-HCT: a BMT-CTN biorepository study
McCarthy, P. L., Attwood, K. M., Liu, X., Chen, G. L., Minderman, H., Alousi, A., Bashey, A., Lowsky, R., Miklos, D. B., Hansen, J., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602; P = 0.045] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning [P = 0.028] but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL; P = 0.046]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT.
PICO Summary
Population
Samples selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) biorepository from people who received allogeneic transplant (n=203)
Intervention
Identification of new biomarker models to predict aGvHD and overall mortality.
Comparison
None
Outcome
Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4).
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Hematopoietic Stem Cell Mobilization for Allogeneic Stem Cell Transplantation by Motixafortide, a Novel CXCR4 Inhibitor
Crees, Z. D., Rettig, M. P., Bashey, A., Devine, S. M., Jaglowski, S. M., Wan, F., Zhou, A., Harding, M., Vainstein-Haras, A., Sorani, E., et al
Blood advances. 2023
Abstract
Peripheral blood stem cells are the most common source of hematopoietic stem and progenitor cells (HSPCs) used for hematopoietic cell transplantation (HCT). HSPC mobilization with G-CSF +/- plerixafor results in suboptimal HSPC yields in up to 30% of patients, despite multiple injections and leukapheresis procedures (LP). We evaluated motixafortide (BL-8040), a high-affinity, long-acting CXCR4 inhibitor with rapid mobilizing kinetics, in a multi-center, open-label, single-arm, 2-part, Phase II study to mobilize HSPCs in allogeneic HCT donors (NCT02639559). The primary endpoint was the efficacy of 1 dose of motixafortide to mobilize greater than or equal to 2.0×10^6 CD34+ cells/kg within 2 LPs. Twenty-five donor-recipient pairs were enrolled. Motixafortide was well-tolerated with 22/24 (92%) evaluable donors meeting the primary endpoint, including 11/11 donors receiving motixafortide at 1.25mg/kg. Engraftment and GVHD rates were comparable to historical data. Motixafortide preferentially mobilized large numbers of multipotent HSPCs and a smaller proportion of CD34+ plasmacytoid dendritic cell precursors with high CD123 expression. Motixafortide induced pan-mobilization of all major myeloid and lymphoid subsets, with maximum relative changes in plasmacytoid/myeloid dendritic cells, B-cells, basophils, CD8 T-cells and classical monocytes. In conclusion, a single injection of motixafortide results in rapid and sustained mobilization of multipotent HSPCs for allogeneic HCT.
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A Simple Prognostic System in Myelofibrosis Patients Undergoing Allogeneic Stem Cell Transplant: A CIBMTR/EBMT analysis
Tamari, R., McLornan, D. P., Ahn, K. W., Estrada-Merly, N., Hernandez-Boluda, J. C., Giralt, S. A., Palmer, J. M., Gale, R. P., DeFilipp, Z., Marks, D., et al
Blood advances. 2023
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Editor's Choice
Abstract
To develop a prognostic model for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) for myelofibrosis (MF). We examined 623 patients undergoing allo-HCT between 2000 - 2016 in the USA (CIBMTR cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients transplanted in Europe (EBMT cohort) (n = 623). Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively (P. < 0.001). Increasing score was predictive of increased transplant related mortality (TRM) (P .0017) but not for relapse (P. 0.12). The derived score was predictive for OS (P. < 0.001) and TRM (P. 0.002) but not relapse (P. 17) in the EBMT cohort as well. The proposed system was prognostic of survival in two large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF on transplant outcomes.
PICO Summary
Population
Adults aged 40 or over undergoing allogeneic transplantation for myelofibrosis and reported to the CIBMTR or EBMT registries (n=1246)
Intervention
Cox regression model of prognostic factors developed with patients from the CIBMTR registry (n=623)
Comparison
Validation of the model using a cohort from the EBMT registry (n=623)
Outcome
Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively. Increasing score was predictive of increased transplant related mortality (TRM) but not for relapse. The derived score was predictive for OS and TRM but not relapse in the EBMT cohort as well.
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Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study
Kunte, S., Rybicki, L., Viswabandya, A., Tamari, R., Bashey, A., Keyzner, A., Iqbal, M., Grunwald, M. R., Dholaria, B., Elmariah, H., et al
Leukemia. 2022;36(3):856-864
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Abstract
We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.
Clinical Commentary
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7.
Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD)
Solh, M. M., Farnham, C., Solomon, S. R., Bashey, A., Morris, L. E., Holland, H. K., Zhang, X.
Bone marrow transplantation. 2022
Abstract
Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.
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Lineage-Specific Relapse Prediction Following Haploidentical Transplant with Post-Transplant Cyclophosphamide Based on Recipient HLA-B-Leader Genotype and HLA-C-Group KIR Ligand
Solomon, S. R., Aubrey, M. T., Zhang, X., Jackson, K. C., Roark, C. L., Freed, B. M., Morris, L. E., Holland, H. K., Solh, M. M., Bashey, A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The role of NK cell alloreactivity on outcomes following T cell-replete haploidentical donor transplantation (HIDT) remains uncertain. Post-transplant, newly formed NK cells are licensed through interactions of donor inhibitory KIR (iKIR) and NKG2A receptors with their cognate ligands on recipient cells. Donor NKG2A recognizes HLA-E bound by recipient HLA class I leader peptides, a process requiring methionine (M) at position -21 of the leader sequence. A rs1050458C/T dimorphism results in approximately 40% of individuals expressing at least on copy of -21M HLA-B (M/M or M/T [M+]), allowing ligand expression. OBJECTIVES We assessed the impact of recipient HLA-B-leader genotype (M+ vs M- [T/T]) and HLA-C-group iKIR missing ligand (ML, C1C1/C2C2 vs. C1C2) on relapse and disease-free survival (DFS) in recipients of post-transplant cyclophosphamide (PTCy)-based HIDT. Based on pre-clinical data, we hypothesized that the relative impact of each variable may depend on disease lineage (lymphoid vs. myeloid). STUDY DESIGN To this end, we analyzed outcomes of 322 consecutive PTCy-based HIDT recipients with hematologic malignancy transplanted at a single institution using standardized supportive care measures with mature follow-up (median 45 months). Primary endpoints were relapse and DFS of patients based on HLA-B-leader genotype and HLA-C-group iKIR ML. Planned subgroup analysis included patient with lymphoid vs. myeloid malignancy. RESULTS M+ HLA-B-leader genotype and HLA-C-group iKIR ML were seen in 42% and 49% of recipients, respectively. The presence of a recipient M+ B-leader (vs. M-) improved OS and DFS and lowered cumulative incidence of relapse (CIR), an effect primarily seen in lymphoid malignancies (80% vs. 51%, 72% vs. 41%, 16% vs. 42%, respectively). In contrast, myeloid malignancy patients benefited most from HLA-C-group iKIR ML with better OS, DFS and lower CIR (67% vs. 51%, 64% vs. 44%, 25% vs. 45%, respectively). Multivariate analysis confirmed the disease-specific associations of improved relapse/DFS with M+ HLA-B-leader in lymphoid malignancy (HR 0.20, p<0.001 / HR 0.34, p<0.001) and HLA-C-group iKIR ML in myeloid malignancy (HR 0.44, p=0.004 / HR 0.54, p=0.009). Neither HLA-B-leader nor iKIR ML were associated with the incidence of NRM, acute or chronic GVHD. CONCLUSION Two distinct NK cell education pathways predict relapse and DFS after HIDT-PTCy in a disease-specific manner: the presence of recipient M+ HLA-B-leader genotype improves outcome in patients with lymphoid malignancies, whereas HLA-C-group iKIR ML improves outcome in patients with myeloid malignancies.. These findings strengthen the essential role of NK cells for optimal GVL in the context of HIDT-PTCy and may suggest different approaches to improving transplant outcome depending on disease type.
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High-dose Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Conditioning Prior to Autologous Transplantation for Patients with Multiple Myeloma
Solomon, S. R., Brown, S., Shegda, N., Jackson, K. C., Zhang, X., Bashey, A., Holland, H. K., Morris, L. E., Solh, M.
Transplantation and cellular therapy. 2022
Abstract
Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was day +100 complete response rate. Sixty-five patients with a median (range) age of 59 (40, 69) years were transplanted from 2015-2020. Other characteristics included KPS<80%, HCT-CI≥3, ISS III, and high-risk FISH in 35%, 46%, 26% and 44% respectively. ASCT following BeEAM was well tolerated, and there were no non-relapse deaths through one-year post-transplant. Although at least one non-hematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. Day +100 response rate was ≥CR1 and ≥VGPR1 in 40% and 89%, respectively. With a median f/u of 44 (13, 70) months, 3-year overall survival was 92%, 96% and 90% for all patients and those with standard- and high-risk FISH respectively. Corresponding values for 3-year progression-free survival was 57%, 72% and 40% respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen prior to up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan is the front-line setting may be warranted.
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10.
Trajectories of quality of life recovery and symptom burden after autologous hematopoietic cell transplantation in multiple myeloma
D'Souza, A., Brazauskas, R., Stadtmauer, E. A., Pasquini, M. C., Hari, P., Bashey, A., Callander, N., Devine, S., Efebera, Y., Ganguly, S., et al
American journal of hematology. 2022
Abstract
Early autologous hematopoietic cell transplantation (AHCT) with post-transplant maintenance therapy is standard of care in multiple myeloma (MM). While short term quality of life (QOL) deterioration after AHCT is known, the long-term trajectories and symptom burden are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N=758), was conducted. FACT-BMT scores up to four years post-AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as 'none/mild' for scores 0-2 and 'moderate/severe' for scores of 3/4. Patients with no 'moderate/severe' symptom ratings were considered to have low symptom burden at 1-year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow-up was 6 years (range, 0.4-8.5 years). FACT-BMT scores improved between enrollment and 1-year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1-year, and 32% at 4 years post-AHCT. Predictors of low symptom burden at 1-year included low symptom burden at baseline: OR 2.7 (1.8-4.1), p<0.0001; older age: OR 2.1 (1.3-3.2), p=0.0007; and was related to being employed: OR 2.1 (1.4-3.2), p=0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT-BMT and subscale scores to population norms by 1-year post-transplant, though many patients continue to report moderate to severe severity in some symptoms at 1-year and beyond. This article is protected by copyright. All rights reserved.