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An increased risk of infections has been described after T cell-replete haploidentical cell transplantation (haploHCT). Cytokine release syndrome (CRS) after haploHCT is a known phenomenon, but the impact of CRS severity on the risk of infections remains unexplored. We retrospectively evaluated 78 consecutive adult haploHCT recipients from 2012 to 2018 for the development of CRS (graded based on the criteria of Lee et al) and examined the incidence and mortality due to infections in correlation with CRS severity. In our study cohort, which was stratified into 3 groups by severity of CRS, 80% of the patients developed infections within 180 days of HCT. Significantly higher proportions of patients with CRS grade 2 (89%) and grade ≥3 (90%) than patients with CRS grade 0-1 (68%) had at least 1 infection in the first 100 days (P = .04). Bloodstream infections (BSIs) were seen more frequently in patients with CRS grade 2 and grade ≥3 in the first 6 months. Multivariable analysis for time to infection showed that CRS grade ≥3 was independently associated with an elevated risk of any infection compared with CRS grade 0-1 (hazard ratio [HR], 3.05; P = .007). CRS grade ≥3 was also associated with a higher hazard of viral (HR, 3.42; P = .04) and bacterial infections (HR, 2.83; P = .03) compared with CRS grade 0-1. After adjusting for time to neutrophil engraftment as a time-dependent covariate, CRS grade ≥3 still had a significant effect on viral infections (HR, 2.49; P = .03), but not on bacterial infections (HR, 1.32; P = .57). CRS grade was also a significant predictor for infection density (overall, bacterial, and viral). The incidence of infection-related mortality by day +100 was higher in patients with severe CRS. Severe CRS developing after post-transplantation cyclophosphamide-based haploHCT is independently associated with viral infections and an increased risk of bacterial infections, likely through delayed neutrophil engraftment.

Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report the clinical outcomes from our pilot study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100, followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS (graded by Lee criteria). Peripheral blood and serum samples were banked prior to conditioning and on days -1, 1, 3, 7, 14, 28, 60, 100, end of treatment, and time of diagnosis of acute GVHD. Matched control samples were collected from patients undergoing haplo-HCT off clinical trials. Correlative studies include flow cytometry (FACS) with five 28-color panels for cellular subsets, mass cytometry (CyTOF) with 40-colors for intracellular signaling events, single cell RNA sequencing, and serum cytokine and chemokine measurements. Results: Twenty of a planned 20 patients completed enrollment and underwent haplo-HCT between 11/2019 and 3/2021. Median age at transplant was 49 (21-74). Diagnoses were AML (13), ALL (5) and NHL (2). Median follow up is 319 days, with 18/20 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment (historical 16 and 25 days, respectively). There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD on day 100 was 15%. Two patients developed grade I-II skin acute GVHD during itacitinib taper and responded to resumption of a higher dose. There were no cases of extensive chronic GVHD. There were no cases of severe CRS (historical rate 17%), with 90% of patients having grade 1 CRS and 10% having no CRS. Furthermore, no anti-IL6R or steroid therapy was used. Overall survival at day 180 was 90% (95% CI 75-100%) by Kaplan-Meier estimate. Incidence of relapse at 180 days was 5.5% (95% CI 0-15.6%). Refined GVHD and relapse-free survival at 180 days was 83% (95% CI 68-100%). All patients had full donor engraftment and >95% chimerism at day 100. FACS and CyTOF have been performed and analyzed for the day 28 time point from 14 patients and four controls. Flow cytometry revealed no difference in cell subset numbers between controls and patient samples. CyTOF revealed differences in intracellular signaling molecules between itacitinib and control patients - including higher Ki-67, pNF-κB, and Caspase3 in controls. Phospho-Stat1 and pStat3 were lower CD4 T subsets. FACS and CyTOF at remaining time points, single cell RNA sequencing, and serum cytokine and chemokine measurements are underway and will be presented at the ASH 2021 meeting. Conclusions: Itacitinib with PB haplo-HCT was safe with no engraftment failure and prompt engraftment. Rates of acute and chronic GVHD were low, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. Flow cytometry demonstrated comparable immune reconstitution in terms of cell lineage and number between treated patients and controls. Mass cytometry revealed lower Ki-67, pNF-κB, and caspase3 levels, among other markers, which suggest lower immune cell activity, proliferation, and apoptosis. An extension cohort of 20 additional patients is enrolling. Multi-platform correlative studies are underway, comparing samples from haplo-HCT patients treated with and without itacitinib. Figure 1 Figure 1. Disclosures Uy: Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; Agios: Consultancy; Jazz: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Macrogenics: Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Pusic: Syndax: Other: Advisory Board. Schroeder: Equillium Inc: Honoraria; Janssen: Honoraria; Sanofi Genzyme: Honoraria.

Introduction: Severe sickle cell disease is associated with progressive end-organ damage and early mortality in adults. While allogeneic hematopoietic cell transplant from a matched related donor is curative, the vast majority of patients do not have a compatible sibling. Accordingly, platforms using haploidentical donors have been developed, which provide near-universal availability. Areas covered: This review focuses on the two commonly used approaches for haploidentical hematopoietic transplants, namely T-cell deplete and T-cell replete, each of which is associated with unique benefits and drawbacks. The purpose of this paper is to facilitate individualized decision-making for patients and providers by reviewing the pros- and cons of these differing approaches. Expert opinion: Individuals with sickle cell disease eligible for a hematopoietic cell transplant can be considered based on recent results. Comparable outcomes are seen with T-cell deplete and T-cell replete approaches. The choice depends largely on institutional preference.

Optimal donor choice for a second allogeneic hematopoietic cell transplant (allo-HCT) in relapsed acute lymphoblastic leukemia (ALL) remains undefined. We compared outcomes using HLA-matched unrelated donors (MUD) versus haploidentical donors in this population. Primary endpoint was overall survival (OS). The MUD allo-HCT group comprised 104 patients (male = 56, 54%), median age 36 years, mostly (76%) with B-cell phenotype in complete remission (CR) (CR2/CR3 + = 76, 73%). The 61 patients (male = 38, 62%) in the haploidentical group were younger, median age 30 years (p = 0.002), had mostly (79%) a B-cell phenotype and the majority were also in CR at time of the second allo-HCT (CR2/CR3 + = 40, 66%). Peripheral blood stem cells was the most common cell source in both, but a significantly higher number in the haploidentical group received bone marrow cells (26% vs. 4%, p < 0.0001). A haploidentical donor second allo-HCT had a 1.5-fold higher 2-year OS (49% vs. 31%), albeit not statistically significant (p = 0.13). A longer time from first allo-HCT to relapse was associated with improved OS, leukemia-free survival, graft-versus-host disease-free-relapse-free survival, and lower cumulative incidences of relapse and non-relapse mortality. Results suggest no major OS difference when choosing either a MUD or haploidentical donor for ALL patients needing a second allo-HCT.

The specific description, risk factors, and outcomes of aGVHD in pediatric haplo-HSCT using TCR protocols without PT-Cy have not been well described previously. We evaluated the incidence, risk factors, and outcomes of aGVHD in 350 consecutive pediatric patients receiving TCR haplo-HSCT without PT-Cy according to the Glucksberg and NIH aGVHD classifications between January 2015 and December 2017 at Peking University Institute of Hematology. The cumulative incidences of grade I, II, III, and IV aGVHD were 28%, 29.7%, 8.3%, and 5.1%, respectively. The type of aGVHD onset was classic in 243 patients (97.2%), and persistent/recurrent/late-onset aGVHD was in seven patients (2.8%). None of the considered variables significantly influenced the incidence of grade III-IV aGVHD. The 3-year OS, DFS, cumulative incidence of NRM, and relapse in malignant disease between severe aGVHD (III-IV) group and grade 0-II aGVHD group were 61.5% vs 77.2% (P = .027), 58.6% vs 75.1% (P = .014), 19.8% vs 5.3% (P = .002), and 21.6% vs 19.6% (P = .59), respectively; in non-malignant diseases, the 3-year OS, DFS, and NRM were 81.8% vs 97.4% (P = .05), 81.8% vs 97.4% (P = .05), and 18.2% vs 2.6% (P = .05), respectively. Under the protocol of pediatric TCR haplo-HSCT without PT-Cy, the persistent/recurrent/late-onset aGVHD was rare, and the incidence of severe aGVHD was acceptable and significantly contributed to NRM and lower survival in both malignant disease and non-malignant diseases.

Background Developments in related haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have made two immune systems with incompatible human leukocyte antigens (HLA) adaptable, greatly reducing transplantation-related toxicity. In the haploidentical transplantation system, patient-specific HLA antigens are a primary way in which donor immune cells exert their graft-versus-leukemia effects by alloreactivity, and therefore patient-specific HLA genomic loss is often considered a mechanism of leukemia relapse. Although the incidence and characteristics of HLA loss have been investigated in patients with myeloid leukemia who relapsed after transplantation, patient-specific HLA genomic loss in lymphoid conditions and under different transplantation regimes remain enigmatical. We herein provide the data for HLA loss relapse in lymphoid disease, as well as offer data in myeloid disease based on antithymocyte globulin (ATG) T-cell-replete conditioning. Methods Between May 2012 and May 2021, 106 patients were enrolled in this study, including 104 had hematological relapse and 2 had minimal residual disease (MRD) recurrence after haplo-HSCT. All data were collected from centers within the Zhejiang Provincial Workgroup of HSCT. Firstly, the patients were divided into two groups according to the type of disease: myeloid and lymphoid conditions, and secondly, they were divided into the Classic Group and the Loss Group according to whether the patients had unshared HLA genomic loss at the time of relapse or not. A two-tailed P value of 0.05 was considered statistically significant. Univariate analysis is performed using the χ2 test, Fisher exact test, and Student t test, as appropriate. A multivariate model was used to calculate the odds ratio (OR) with a 95% confidence interval (CI). Post relapse overall survival (prOS) was estimated and plotted using the Kaplan-Meier method. Results Of all patients, HLA loss was detected in 50.9% (54/106) patients and the occurrence was not related to disease type (P=0.44). Patients having either myeloid malignancies or lymphoid malignancies with HLA loss experienced relapse later than those with classic relapse. The demographic and baseline characteristics of patients were summarized in Table 1, and the post-relapse parameters were presented in Table 2. We next determined what factors correlating with HLA loss at relapse by multivariate analysis. For patients with myeloid malignancies, a pre-transplant underweight status based on body mass index (BMI) was a factor strongly correlated with classic type when relapse (OR=0.095, 95%CI: 0.015~0.604, P=0.013); patients suffering de novo aGVHD had an OR of 4.844 (95%CI: 1.143~20.530, P=0.032) (Figure 1). As for lymphoid conditions, patients who experiencing MRD-positivity before hematological relapse (OR=22.623, 95% CI: 1.597~320.532, P=0.021), and >180 days from HSCT to relapse (OR=5.695, 95% CI: 1.073~30.211, P=0.041) were more likely to lose unshared HLA at relapse. Yet male patients (OR=0.037, 95% CI: 0.003~0.411, P=0.037) were inclined to have classic one when relapse (Figure 1). For prognosis, in patients with myeloid conditions, the median prOS was 217 days and 215 days in the Loss Group and Classic Group, respectively (P=0.34). In the Loss Group, the white blood cell (WBC) at diagnosis was related to prOS (>50ⅹ10 9/L vs. ≤50ⅹ10 9/L: median: 157 vs. 261 days, P=0.037). For patients having male donors, patient gender was related to prOS: median prOS was 386 days for male patients and 124 days for female patients (P=0.008). For patients with lymphoid malignancies, the median prOS was 285 days and 244 days in the Loss Group and Classic Group, respectively (P=0.24). The results of the univariate analysis from the Loss Group showed that male patients (median: 40 vs. 194 days; P=0.036) and cGVHD fare (median: 114 vs. 468 days; P=0.002) were related to inferior prOS. Conclusion The occurrence of patient-specific HLA genomic relapse after haplo-HSCT appears later than classic relapse. In myeloid malignancies, the patient pre-transplant BMI and aGVHD fare are associated with the relapsed type. In lymphoid conditions, patient sex, presence of MRD-positive results before relapse, and the time from transplantation to relapse correlate with HLA loss at relapse. Yet this study is based on a limited number of patients, further validation in other centers is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The presence of human leukocyte antigen (HLA) donor-specific antibodies (DSAs) increases the risk of graft failure in T-cell-replete haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT). We report a case of a 20-year-old male with high-risk thalassemia major who received a haploidentical-HSCT from his mother. Pretransplant recipient screening examination showed positive DSA levels against class I and class II HLAs. The patient underwent a desensitization program consisting of plasma exchange and polyvalent intravenous immunoglobulins. This protocol resulted in the disappearance of DSA class I and reduction in Mean Fluorescence Intensity (MFI) class II antibodies. Engraftment was prompt with stable full donor chimerism. This case report suggests that the adopted scheme is safe for reducing DSA levels and facilitating donor engraftment in patients scheduled for haploidentical-HSCT, though it needs evaluation in a large cohort of patients.

The development of different transplant programs using haploidentical donors without T cell depletion is knowing an exciting time. The feasibility and the toxic profile of T-cell replete haploidentical transplantation, very close to that obtained with conventional donors, are well demonstrated, making of these alternative donors a concrete opportunity for patients with severe disease. So far, the limit to donor availability in the right time for each patients does not exist anymore. In this chapter, we revised the most important results obtained with some of the several platforms developed worldwide in patients with malignant and nonmalignant hematological diseases.

This paper aims to study whether cyclosporine-A (CSA) levels have an impact on the clinical outcome of patients with T-cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed 140 consecutive patients who had been given T-cell replete haploidentical allo-HSCT in our institute to assess the effect of CSA concentration in the early stages of allo-HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease-free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo-HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II-IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II-IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II-IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15-6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients' hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri-engraftment period might improve clinical outcomes for those with T-cell replete haploidentical allo-HSCT.

Tacrolimus compared with cyclosporine A after haploidentical T-cell replete transplantation with post-infusion cyclophosphamide

Single institution experience with G-CSF mobilized T-cell replete haploidentical hematopoietic cell transplantation

To compare the efficacy of HLA6/6-matched haploidentical hematopoietic stem cell transplant (haplo-HSCT) with that of HLA3/6-matched HSCT in T-cell-replete transplants, we recruited 27 consecutive recipients from multiple centers who received HLA6/6-matched haplo-HSCT from a parent or child donor between February 2010 and May 2016. A matched-pair analysis was designed. For each recipient from the study cohort, two recipients were randomly selected from the control cohort and matched (according to patient age, patient sex, disease type, disease status, donor age, donor sex, and recipient-donor relationship). No significant differences were found in hematopoietic recovery. The incidence of grade II-IV and III-IV acute graft versus host disease was similar (18.5% vs. 31.5%, P=0.216; 11.1% vs. 9.3%, P=0.792) in the HLA6/6 and HLA3/6 groups, respectively. The 3-year cumulative incidence of relapse was 14.8% and 17.0% (P=0.800). The 3-year cumulative incidence of nonrelapse mortality was 12.1% and 17.6% (P=0.751). The estimated 3-year disease-free survival was 73.1% and 65.5% (P=0.489). The estimated 3-year overall survival was 74.7% and 74.0% (P=0.946). The data suggested the efficacy and safety of the HLA6/6- and the HLA3/6-matched haplo-HSCT between parents and children are comparable. That HLA-mismatch disparity is not correlated with T-cell-replete haplo-HSCT outcome was substantiated.

GF is one of the fatal complications of allogeneic HSCT. To rescue patients with primary GF, a second HSCT should be conducted as soon as possible, but the optimal donor source and technique have yet to be established. In this study, we retrospectively analyzed six children with hematologic malignancies who received TCR-haploidentical second HSCT for primary GF. The median interval between the prior HSCT and the second HSCT was 37.5 days. All patients received fludarabine and ATG containing reduced-intensity re-conditioning before the second HSCT. All patients, except one who died early, achieved both neutrophil and Plt engraftment at a median time of 15 and 33 days, respectively. Chimerism analysis showed that all engrafted patients achieved complete donor chimerism within 3 weeks. Four patients developed acute GVHD, and three patients developed chronic GVHD. TRM occurred in two patients. Median follow-up of the four survivors was 6.8 years, and all remained in sustained remission until the last follow-up. These results suggested that a TCR-haploidentical second HSCT for pediatric patients is feasible, and this approach may provide a potent option for children with primary GF.

Background: Conflicting results have been reported regarding the predicative roles of alloreactive natural killer (NK) cells on the outcomes of transplantation in leukaemia patients. Methods: We prospectively analysed the human leukocyte antigen (HLA) typing of donor–recipient pairs and the KIR typing of the donors in 97 CML patients to address the predictive roles of NK cells in relapse undergoing T-cell-replete haploidentical transplantation. Results: Patients with class I ligands for the donor-inhibitory KIR gene exhibited decreased molecular and haematologic relapse rates (P=0.003 and P=0.015, respectively). There was a significantly reduced risk of molecular and haematologic relapse in patients with HLA-C1C2 or C2C2 who accepted donors with KIR2DS1 or in patients with HLA-Bw4 who accepted donors with KIR3DS1 (‘recipient with relevant KIR ligand for donor-activating KIR', n=25), compared with the remaining transplants (n=72, P=0.009 and P=0.009, respectively). In addition, the presence of class I ligand in the recipients of donor-activating KIR contributed to a decreased relapse rate in patients lacking class I ligand in the recipient of donor-inhibitory KIR (P=0.04 and P=0.03, respectively). Conclusions: This study suggests that the presence of class I ligands for the donor-activating or donor-inhibitory KIR gene in the recipient might confer some protection against leukaemic relapse in T-cell-replete haploidentical transplantation.

Background HaploHCT is a common alternative donor graft source for patients with hematological malignancies. A sepsis-like hyper-cytokine state referred to as cytokine release syndrome (CRS) has been described following haploHCT. Given the distinctive biology of CRS in haploHCT, understanding the infectious complications as a function of severity of CRS is critical. Methods We evaluated 78 consecutive adult haploHCT patients (pts) at our center for development of CRS (graded as per criteria by Lee et al. Blood 2014) and examined the incidence of infectious complications in correlation with CRS severity. All pts received haploHCT for malignancies between 04/2012-04/2018, using post-transplant cyclophosphamide (PTCY) and tacrolimus/mycophenolate mofetil for graft-versus-host disease prophylaxis. The incidence of infections was examined in two time periods in relation to day of stem cell infusion (day 0): day 0-100 (early) and day 101-180 (late). Results Among the 78 pts, 41 (53%) developed grade 0-1 CRS and 37 (47%) had grade 2-5 CRS. Overall, 61 patients (78%) experienced early infections whereas 19 (27%, n=70) experienced late infections. 44% of those with CRS grade 0-1 had early infections and 37% had late infections. In contrast, early and late infections occurred in 56% and 63% CRS grade 2-5 pts (p=.002 and p=.31). In CRS 0-1 cohort, blood-stream infections (BSI) were seen in 10% pts in first 180 days; the corresponding number was 46% in CRS 2-5 cohort (P Conclusion Infections are common post-transplant complications in first 6 months. The severity of CRS developing after haploHCT using PTCY-platform is associated with increased frequency of BSI. Viral and fungal infections do not have a higher risk post-haploHCT based on CRS severity.

In the original version of this article, author ‘Lucia Lopez-Corral’ was incorrectly listed as ‘Lucia Lopez’. This has now been corrected in both the PDF and HTML versions of the article to ‘Lucia Lopez-Corral’.

The patient’s CMV serological status affects clinical outcome after T-cell replete haplo-HSCT and post-transplant cyclophosphamide

Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting.