-
1.
Donor selection for KIR alloreactivity is associated with superior survival in haploidentical transplant with PTCy
Zou, J., Kongtim, P., Srour, S. A., Greenbaum, U., Schetelig, J., Heidenreich, F., Baldauf, H., Moore, B., Saengboon, S., Carmazzi, Y., et al
Frontiers in immunology. 2022;13:1033871
Abstract
With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age <58 years combined with cytomegalovirus-nonreactive recipient was associated with the best OS, whereas donor age >58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor <58 years old, a higher CF-iKIR was associated with superior OS. The 3-year OS rates were 73.9%, 54.1% (HR, 1.84; P = .044), 44.5% (HR, 2.01; P = .003), and 18.5% (HR, 5.44; P <.001) in the best, better, poor, and worse donor groups, respectively. Our results suggest that KIR alloreactivity assessed by CF-iKIR score can help optimize donor selection in haplo-HSCT.
-
2.
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
-
-
-
Free full text
-
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.
-
3.
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
-
-
-
Free full text
-
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
-
4.
Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation
Varma, A., Rondon, G., Srour, S. A., Chen, J., Ledesma, C., Champlin, R. E., Ciurea, S. O., Saliba, R. M.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity, and sought to determine whether the Endothelial Activation and Stress Index (EASIX), (defined as lactate dehydrogenase (U/L) x creatinine (mg/dL)/ platelets (10(9) cells per L), correlates with grade ≥2 FO in two cohorts of recipients of AHCT at our institution. METHODS We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors, and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors transplanted between 2010-2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis, and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on Receiver Operating Characteristics (ROC) curve analysis. RESULTS Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) in the two respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥ 2 FO in the study (cutoff: 4.4, HR=4.8, p<0.001) and in the validation (cutoff: 4.3, HR=4.8, p<0.001) cohorts. The significant effect of EASIX persisted in multivariate CART analysis in the study (HR=6.3, p<0.001) and the validation (HR=28, p=0.002) cohorts. Additional predictors in multivariate analysis included body weight below 80 kg in recipients older than >55 years (HR=4.5, p<0.001) in the study cohort, and diabetes (HR=34, p=0.001) and age >60 years (HR=9.6, p=0.04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% vs 17%, p=0.9) was not different between the diabetics and non-diabetics. CONCLUSIONS EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.
-
5.
Haploidentical Transplants for Patients with Graft Failure After the First Allograft
Kongtim, P., Bittencourt, M., Srour, S. A., Ramdial, J., Rondon, G., Chen, J., Khouri, I., Betul, O., Popat, U., Olson, A., et al
American journal of hematology. 2020
-
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
-
-
-
Free full text
-
Full text
-
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.
-
7.
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
-
-
-
Free full text
-
-
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.
-
8.
Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.