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Myeloablative Fractionated Busulfan for Allogeneic Stem Cell Transplant in Older Patients or Patients with Comorbidities
Popat, U. R., Pasvolsky, O., Bassett, R., Mehta, R. S., Olson, A. L., Chen, J., Alousi, A. M., Al-Atrash, G., Bashir, Q., Gulbis, A. M., et al
Blood advances. 2023
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Editor's Choice
Abstract
Traditional conditioning regimens for patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce non-relapse mortality (NRM), while retaining anti-leukemic effects. Here, we performed a phase II trial for adults with hematological malignancies receiving matched related or unrelated alloHCT. Participants received busulfan 80mg/m2 outpatient on days -20 and -13 before transplant. Fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve a target area under the curve of 20,000mol/min for the whole course. The primary endpoint was day 100 NRM. Seventy-eight patients were included, with a median age of 61 (range 39-70) years, transplanted for acute leukemia (24%), MDS (27%), or MPD/CML (44%). HCT specific comorbidity index (HCT-CI) was >3 in 34 (44%). With a median follow-up of 36.4 (range 2.9-51.5) months, 100-day, 1-year and 3-year NRM was 3.8% (95%CI, 0-8.1%), 8% (95%CI, 2-14%), and 9.3% (95%CI, 2.6-15.9%), without a significant difference by age or HCT-CI score. One-year and 3-year relapse incidence was 10% (95%CI, 4-17%) and 18% (95%CI, 9-27%), respectively. Three-year overall survival was 80% (95%CI, 72-90%) and was similar for patients >60 and <60 years of age, as well as those with HCT-CI>3 and HCT-CI<3. Overall, we found that a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities.
PICO Summary
Population
Adults with haematological malignancies receiving matched related or unrelated allogeneic transplant, from a single centre in USA (n=78).
Intervention
Busulfan 80mg/m2 outpatient on days -20 and -13 before transplant, fludarabine 40mg/m2 on days -6 to -2 followed by busulfan dosed to achieve a target area under the curve of 20,000mol/min for the whole course
Comparison
None
Outcome
With a median follow-up of 36.4 (range 2.9-51.5) months, 100-day, 1-year and 3-year non-relapse mortality was 3.8% (95%CI, 0-8.1%), 8% (95%CI, 2-14%), and 9.3% (95%CI, 2.6-15.9%), without a significant difference by age or HCT-CI score. One-year and 3-year relapse incidence was 10% (95%CI, 4-17%) and 18% (95%CI, 9-27%), respectively. Three-year overall survival was 80% (95%CI, 72-90%) and was similar for patients >60 and <60 years of age, as well as those with HCT-CI>3 and HCT-CI<3.
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2.
Transplant Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning
Joseph, J., Srour, S. A., Milton, D. R., Ramdial, J. L., Saini, N. Y., Olson, A. L., Bashir, Q., Oran, B., Alousi, A. M., Hosing, C., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Outcomes of myelofibrosis with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade and are partly related to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplant outcomes. However, most studies lack homogeneity in the conditioning regimen used, which limits their ability to assess prognostic factors on transplant outcomes. OBJECTIVE We aimed to determine the risk factors that predict transplant outcomes in patients with myelofibrosis who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. STUDY DESIGN This single-center study included patients with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. RESULTS Sixty-five patients with myelofibrosis met the criteria and were included in the study. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]; p = 0.048). For NRM, HCT-CI (≥3 vs. <3, 10.09 [2.09-48.76]; p=0.004) and donor type (MUD vs. MRD, 5.38 [1.14-25.30]; p=0.033 and MMUD vs. MRD, 10.73 [1.05-109.4]; p=0.045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 vs. <3, 3.31 [1.22-8.99]; p = 0.019) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]; p = 0.016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. ≤12 months: NRM, 7.20 [0.96-53.94]; p=0.055 and OS, 2.60 [0.95-7.14]; p=0.06). CONCLUSIONS In a homogenous cohort of myelofibrosis patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we showed that donor choice and HCT-CI are the two strongest predictors for improved survival after allo-SCT.
PICO Summary
Population
People with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) at a single centre in USA (n=176)
Intervention
Cohort for analysis: all who received myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis (n=65)
Comparison
None
Outcome
At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]). For NRM, HCT-CI (>/=3 vs. <3, 10.09 [2.09-48.76]) and donor type (MUD vs. MRD, 5.38 [1.14-25.30] and MMUD vs. MRD, 10.73 [1.05-109.4]) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (>/=3 vs. <3, 3.31 [1.22-8.99];) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. </=12 months: NRM, 7.20 [0.96-53.94] and OS, 2.60 [0.95-7.14]).
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3.
Haploidentical vs Matched Unrelated vs Matched Sibling Donor HCT with Post-Transplantation Cyclophosphamide
Mehta, R. S., Saliba, R. M., Ghanem, S., Alousi, A. M., Rondon, G., Anderlini, P., Al-Atrash, G., Bashir, Q., Hosing, C. M., Im, J. S., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching that of matched donors. We compared haploidentical versus HLA-matched (MUD) versus HLA-identical sibling (MSD) donors, where all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD). The most common diagnoses were acute myeloid leukemia or myelodysplastic syndrome. In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9, p<0.001), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4, p<0.001) and overall survival (HR 2.2, 95% CI 1.6-3, p<0.001) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior as compared to HLA-matched donor HCT.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndromes requiring hematopoietic cell transplantation in single centre in the USA (HCT, n=661)
Intervention
HCT from haploidentical donors (n=275)
Comparison
HCT from HLA-matched donors (MUD, n=246) or HLA-identical sibling donors (MSD, n=140)
Outcome
In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4) and overall survival (HR 2.2, 95% CI 1.6-3) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups.
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4.
Bone Marrow versus Peripheral Blood Graft for Haploidentical HCT with Post Transplantation Cyclophosphamide
Mehta, R. S., Saliba, R. M., Alsfeld, L. C., Jorgensen, J. L., Wang, S. A., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., Hosing, C. M., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND In the COVID-19 pandemic era, the numbers of haploidentical hematopoietic cell transplantation (HCT) with peripheral blood (PB) versus bone marrow (BM) grafts increased significantly, which may be associated with adverse outcomes. METHODS We compared outcomes of BM vs PB grafts in patients =18 years with hematological malignancy who underwent T-cell replete haploidentical HCT and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus and mycophenolate mofetil. FINDINGS Of 264 patients, 180 (68%) received BM and 84 (32%) received PB graft. Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%), p<0.01. The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3, p=0.006. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, p=0.005 and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18, p=0.004 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival. INTERPRETATION Our data suggest the use of BM over PB graft for haploidentical HCT.
PICO Summary
Population
Adult patients with haematological malignancies undergoing haploidentical transplantation (n=264)
Intervention
Bone marrow graft (n=180)
Comparison
Peripheral blood graft (n=84)
Outcome
Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%). The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival
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5.
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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6.
Haploidentical vs haplo-cord transplant in adults under 60 years receiving fludarabine and melphalan conditioning
van Besien, K., Artz, A., Champlin, R. E., Guarneri, D., Bishop, M. R., Chen, J., Gergis, U., Shore, T., Liu, H., Rondon, G., et al
Blood advances. 2019;3(12):1858-1867
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Editor's Choice
Abstract
Haplo-identical transplant with posttransplant cyclophosphamide (haplo) and umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) are competing approaches to alternative donor transplant. We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions. All received reduced intensity conditioning with fludarabine and melphalan +/- total body irradiation. GVHD prophylaxis for haplo consisted of cyclophosphamide, tacrolimus, and mycophenolate, whereas haplo-cord received antithymocyte globulin, tacrolimus, and mycophenolate. Haplo transplant used mostly bone marrow, and peripheral blood stem cells were used in haplo-cord transplants. Haplo-cord were older and had more advanced disease. Haplo-cord hastened median time to neutrophil (11 vs 18 days, P = .001) and platelet recovery (22 vs 25 days, P = .03). At 4 years, overall survival (OS) was 50% for haplo-cord vs 49% for haplo. Progression-free survival (PFS) was 40% for haplo-cord vs 45% for haplo. In multivariate analysis, the disease risk index was significant for OS (hazard ratio, 1.8; 95% confidence interval, 1.48-2.17; P = .00) and PFS. Total body irradiation was associated with decreased recurrence and improved PFS, age >40 with increased nonrelapse mortality. The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo (P < .0001), but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo (P < .0001). Haplo or haplo-cord results in similar and encouraging outcomes. Haplo-cord is associated with more rapid neutrophil and platelet recovery and lower acute and chronic GVHD. Institutional review board authorization for this retrospective study was obtained at each institution. Some patients participated in trials registered at www.clinicaltrials.gov as #NCT01810588 and NCT01050946.
PICO Summary
Population
We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (n=170)
Comparison
Umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) (n=137)
Outcome
The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo, but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo.