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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.
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2.
HLA Factors Versus Non-HLA Factors for Haploidentical Donor Selection
Mehta, R. S., Cao, K., Saliba, R. M., Al-Atrash, G., Alousi, A. M., Lontos, K., Marcoux, C., Carmazzi, Y., Rondon, G., Bashir, Q., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as a father vs mother, son vs daughter, or brother vs sister. Although traditionally, male donors are favored over female donors, particularly for male recipients and significant associations of individual HLA mis(matches) on outcomes are being recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific characteristics on outcomes, we analyzed 412 patients stratified by donor relationship: child donor [son (n=202) vs daughter (n=96)]; parent [(father: n=28 vs mother: n=29)] and sibling [non-inherited maternal (NIMA, n=29) vs paternal (NIPA, n=28)-mismatched]. Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival, and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses. Our data suggest that certain HLA factors may be more significant in some cases and should be given priority than simply selecting a donor based on relationship/gender.
PICO Summary
Population
Adults with haematological malignancy who underwent haploidentical transplantation at a single centre in USA (n=412
Intervention
Sibling donor: non-inherited maternal mismatched (NIMA, n=29); non-inherited paternal mismatch (NIPA, n=28)
Comparison
Child donor: son (n=202), daughter (n=96); Parent donor: father, (n=28), mother, (n=29)
Outcome
Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival (PFS), and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses.
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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.
Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.
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5.
Decrease post-transplant relapse using donor-derived expanded NK-cells
Ciurea, S. O., Kongtim, P., Soebbing, D., Trikha, P., Behbehani, G., Rondon, G., Olson, A., Bashir, Q., Gulbis, A. M., Indreshpal, K., et al
Leukemia. 2021
Abstract
In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1?×?10(5)-1?×?10(8) cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p?=?0.014), and disease-free survival (DFS) was 66% vs. 44% (p?=?0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p?=?0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).
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6.
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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Impact of graft composition on outcomes of haploidentical bone marrow stem cell transplantation
Saliba, R. M., Veltri, L., Rondon, G., Chen, J., Al-Atrash, G., Alousi, A., Martinez, C., Augustine, L., Hosing, C. M., Oran, B., et al
Haematologica. 2020
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8.
Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation
Zou, J., Ciurea, S. O., Kongtim, P., Yi, M., Carmazzi, Y., Rondon, G., Srour, S., Partlow, D., Champlin, R. E., Cao, K.
Blood advances. 2020;4(15):3474-3485
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Editor's Choice
Abstract
Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.
PICO Summary
Population
Patients receiving haploidentical transplantation (n=278)
Intervention
HLA disparity quantified by mismatched eplets (ME)
Comparison
None
Outcome
A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97) and class I loci (HR, 0.99) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19) without a concurrent increase in GVHD.
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9.
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.
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10.
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