Progress in Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic cell transplantation (HaploHCT), with cells from HLA-half-matched first degree related donors (siblings, children and parents), could revolutionize hematopoietic transplantation as it expands this form of treatment to approximately 40% of patients who do not have an HLA-matched donor in USA. This need is particularly acute in developing countries, which usually do not have an unrelated donor registry and/or cost is a major issue in acquiring unrelated donor stem cells. Accordingly, the number of haploSCTs done in USA, Europe, China, and developing countries is on the rise. Advantages to HaploHCT include almost universal (more than 95% of patients will have a half-matched related donor) and immediate availability of donor progenitor cells, the opportunity to select the best donor among family members to minimize treatment-related mortality, decrease relapse rate and improve outcomes [2], and the possibility to collect donor cells for cellular therapy post-transplantation, with the goal to enhance the anti-tumor effects of the graft. Despite its potential advantages, until recently, high donor-recipient HLA-histoincompatibility has proven very difficult to overcome

Donor Specific Anti-HLA Antibody and Risk of Graft Failure in Haploidentical Stem Cell Transplantation

Outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT) using HLA-half matched related donors (haploidentical) have recently improved due to better control of alloreactive reactions in both graft-versus-host and host-versus-graft directions. The recognition of the role of humoral rejection in the development of primary graft failure in this setting has broadened our understanding about causes of engraftment failure in these patients, helped us better select donors for patients in need of AHSCT, and developed rational therapeutic measures for HLA sensitized patients to prevent this unfortunate event, which is usually associated with a very high mortality rate. With these recent advances the rate of graft failure in haploidentical transplantation has decreased to less than 5%

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide.

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P \u3c .001) and chronic (HR, 0.35; P \u3c .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation

AbstractDetection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT

Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping

Increasing Use of Allogeneic Hematopoietic Cell Transplantation in Patients Aged 70 Years and Older in the United States

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥ 70 years with hematologic malignancies across the United States. Adults ≥ 70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥ 70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P \u3c .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥ 3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥ 70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults