Haploidentical Hematopoietic Cell Transplantation Research Articles

Reassessing blood product irradiation in haploidentical transplantation: a single-center perspective

ABSTRACT Objectives: The main objective was to investigate the incidence of transfusion-associated graft-versus-host disease (TA-GVHD) in patients who underwent haploidentical hematopoietic cell transplants (HCT) and received non-irradiated leukoreduced blood components. The secondary objective was to describe our leukodepletion results in blood products obtained by the filters employed at our center. Study Design and Methods: Clinical records from 2018 to 2023 were retrospectively analyzed, along with a prospective evaluation of residual leukocytes in blood components from June to November 2023 in order to confirm effectivity of our leukodepletion method. Results: 150 patients were included, no cases of TA-GVHD were reported after using non-irradiated blood products. The incidence of grade 3–4 acute and moderate-severe chronic GVHD was 12.7% (n = 19) and 2.7% (n = 4), respectively. The cumulative incidence of death was 39.3% (n = 52) with a 3.7-year overall survival (CI 95%, 3.3- 4.1 years). Leukodepletion analysis showed a reduction of 99.93% in platelet concentrates and 99.98% in packed red blood cells. Discussion: TA-GVHD in HCT remains a concern traditionally mitigated using blood product irradiation. Recent evidence obtained in favor of leukoreduction techniques question this need, especially in resource-limited settings. Conclusion: These findings support leukoreduction as a primary TA-GVHD preventive measure,along with the advantage in cost reduction.

Efficacy of haploidentical allogeneic hematopoietic cell transplantation following two courses of venetoclax and azacytidine therapy in patients over 55 years old with acute myelogenous leukemia.

The combination of venetoclax (VEN) and azacytidine (AZA) has demonstrated potential in achieving rapid and effective remissions in elderly patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is a promising potential cure for high-risk AML, as VEN-based therapies have a worse prognosis in elderly patients. This study aimed to assess the efficacy of sequential haploidentical HSCT following two courses of VEN and AZA therapy in patients with AML aged 55 years and older. We conducted a retrospective study on AML patients aged 55 to 70 years who received intensive chemotherapy or two courses of VEN/AZA therapy, followed by haplo-HSCT based on disease risk degree, measurable residual disease status and patient's preference. Between January 2019 and December 2023, 141 newly diagnosed AML patients received initial treatment with intensive chemotherapy or VEN/AZA therapy. Among them, 64 patients received haplo-HSCT, while 77 did not. The 1-year over survival (OS) and relapse-free survival (RFS) of patients who received haplo-HSCT were significantly higher than those who did not receive haplo-HSCT (P<0.05). Among patients who received transplantation, there was no significant difference in 1-year OS and RFS between the VEN/AZA and intensive chemotherapy groups: 76.3% vs 69.3% (P = 0.367) for OS, and 74.5% vs 69.7% (P = 0.473) for RFS. High-risk ELN stratification and the presence of ≥4 gene mutations were associated with lower OS and RFS in both univariate and multivariate analysis. AML patients over 55 years of age who received haplo-HSCT after two courses of VEN/AZA therapy had outcomes similar to those who received haplo-HSCT after intensive chemotherapy, suggesting that two courses of VEN/AZA therapy as a bridge to halpo-HSCT are feasible for patients over 55 years old.

Chemotherapy and allo-HSCT for young patients with aggressive ATL

Adult T-cell leukemia-lymphoma (ATL) is an aggressive malignancy with a poor prognosis, especially for patients with the aggressive subtype. While conventional chemotherapy offers short-term disease control, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most promising curative approach for young, transplant-eligible patients. This review focuses on current treatment strategies for aggressive ATL in this specific population. We discuss the rationale for early upfront allo-HSCT following induction chemotherapy. The advent of allo-HSCT using alternative donors, particularly haploidentical HCT, has broadened the applicability of early upfront allo-HSCT in patients with aggressive ATL worldwide. Finally, we address emerging therapies that may improve outcomes in the context of allo-HSCT, paving the way for further advancements in the treatment of aggressive ATL.

The transplantation effect of pegylated granulocyte colony-stimulating factor mobilized hematopoietic stem cells may be superior to that of G-CSF mobilized hematopoietic stem cells in haploidentical allogeneic hematopoietic cell transplantation

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells have become the preferred source of hematopoietic stem cells. We compared the effectiveness of G-CSF and pegylated G-CSF (peg-G-CSF) for hematopoietic stem cell mobilization in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) donors, and evaluated the transplant outcomes. We conducted a matched retrospective cohort study. Donors mobilized with peg-G-CSF (n = 70) and G-CSF (n = 70). 140 consecutive patients diagnosed with acute leukemia who underwent haplo-HSCT were included in this study. The findings revealed that the peg-G-CSF cohort exhibited significantly elevated myeloid-derived suppressor cells (MDSCs) levels in their grafts when compared to the G-CSF cohort (P < 0.001). The 100-day cumulative incidence (CI) of grade III-IV acute graft-versus-host disease (GVHD) and 1-year CI of moderate-to-severe chronic GVHD were 4.3% vs 14.3 % (P = 0.047) and 11.2% vs 27.4 % (P = 0.023), in the peg-G-CSF group and G-CSF group. Patients reveiving mobilized stem cell with peg-G-CSF had a significantly greater likelihood of 1-year GVHD-free relapse-free survival (GRFS) compared to patients reveiving mobilized stem cell with G-CSF (74.9% vs 37.9 %, P < 0.001). The higher graft MDSCs proportion was associated with lower grade II-IV aGVHD, cGVHD (P < 0.05) and higher GRFS in the univariate analysis (P < 0.05). Multivariate analysis showed that MDSCs proportion higher than 11.36 % (HR, 0.305; 95 % CI, 0.154–0.606; P = 0.001) and peg-G-CSF for stem cell mobilization (HR, 0.466; 95 % CI, 0.251–0.865; P = 0.016) were independent prognostic factors of GRFS. The superior survival rates observed in recipients of peg-G-CSF-mobilized cells are likely due to reduced acute GVHD, potentially mediated by the increased MDSCs within the grafts.

Galectin-1 is associated with hematopoietic cell engraftment in murine MHC-mismatched allotransplantation.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is associated with an increased risk of allograft rejection. Here, we employed a major histocompatibility complex (MHC)-mismatched allogeneic HCT (allo-HCT) murine model to better understand the role of Gal-1 in immune tolerance. Transplanted mice were classified into either rejected or engrafted based on donor chimerism levels. We noted significantly higher frequencies of CD4+ T cells, CD8+ T cells, natural killer cells, IFN-γ and TNF-α producing CD4+ T cells, and IFN-γ producing dendritic cells and macrophages in rejected mice. Conversely, we found significantly increased frequencies of regulatory T cells (Tregs), predominantly Helios+, IL-10-producing CD4+ T cells, type 1 regulatory (Tr1) cells, and the proportion of Tr1+Gal-1+ cells in engrafted mice. Further, Gal-1 specific blockade in Tregs reduced suppression of effector T cells in engrafted mice. Lastly, effector T cells from engrafted mice were more prone to undergo apoptosis. Collectively, we have shown that Gal-1 may favor HSC engraftment in an MHC-mismatched murine model. Our results demonstrate that Gal-1-expressing Tregs, especially at earlier time points post-transplant, are associated with inducing immune tolerance and stable mixed chimerism after HCT.

Haploidentical hematopoietic cell transplantation as a platform for natural killer cell immunotherapy.

An innovative approach is crucially needed to manage relapse after allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematological malignancies. This review explores key aspects of haploidentical HCT with post-transplant cyclophosphamide, highlighting the potential and suitability of this platform for natural killer (NK) cell immunotherapy. NK cells, known for their unique abilities to eliminate cancer cells, can also exhibit memory-like features and enhanced cytotoxicity when activated by cytokines. By discussing promising results from clinical trials, the review delves into the recent major advances: donor-derived NK cells can be expanded ex vivo in large numbers, cytokine activation may enhance NK cell persistence and efficacy in vivo, and post-HCT NK cell infusion can improve outcomes in high-risk and/or relapsed myeloid malignancies without increasing the risk of graft-versus-host disease, severe cytokine release syndrome, or neurotoxicity. Looking ahead, cytokine-activated NK cells can be synergized with immunomodulatory agents and/or genetically engineered to enhance their tumor-targeting specificity, cytotoxicity, and persistence while preventing exhaustion. The ongoing exploration of these strategies holds promising preliminary results and could be rapidly translated into clinical applications for the benefit of the patients.

Biologically Randomized Comparison of Haploidentical Versus Human Leukocyte Antigen-Matched Related Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

Haploidentical vs HLA-matched sibling donor HCT with PTCy prophylaxis: HLA factors and donor age considerations

AbstractHLA-matched sibling donors (MSDs) are preferred for hematopoietic cell transplantation (HCT). However, the use of alternative donors, especially haploidentical, is increasing, as is our understanding of the impact of HLA factors such as B-leader and DRB1-matching on its outcomes. Yet, data comparing these donor types, particularly considering these HLA factors, is lacking. Herein, we compared haploidentical-HCT (n = 1052) with MSD-HCT (n = 400), both with posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis. In multivariate analysis, haploidentical group had similar overall survival (OS; hazard ratio (HR), 0.94; 95% confidence interval [CI], 0.78-1.14; P = .54), nonrelapse mortality (HR, 0.98; 95% CI, 0.72-1.32; P = .87), and relapse (HR, 0.87; 95% CI, 0.70-1.08; P = .20) as the MSD group. Younger donor age was a significant predictor of improved OS. Next, we directly compared the outcomes of “younger” haploidentical (donor age <35 years, n = 347) vs an “older” MSD (donor age ≥50 years, n = 143) in older recipients (patient age ≥50 years). Patients with younger haploidentical B-leader–matched donors had significantly superior OS (HR, 0.65; 95% CI, 0.48-0.90; P = .009) than the older MSD group. Additionally, patients with younger DRB1-mismatched haploidentical donors (HR, 0.63; 95% CI, 0.46-0.87; P = .004) had significantly lower risk of relapse than older MSDs. Our study suggests that haploidentical-HCT may offer comparable outcomes to MSD-PTCy HCT. Moreover, among older patients, a younger haploidentical B-leader–matched donor might be preferable to an older MSD. These findings need validation in larger data sets.

Predictors of fluid overload in allogeneic hematopoietic cell transplant patients receiving post-transplant cyclophosphamide.

Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic cell transplantation (HCT). Grade 2-4 FO is associated with day +100 non-relapse mortality.1 Post-transplant cyclophosphamide (PTCY) for graft-versus-host disease prevention requires aggressive IV hydration to prevent hemorrhagic cystitis. This is a single-center, retrospective, observational study conducted at an academic medical center via electronic chart review. Included patients received allogeneic HCT followed by PTCY on days +3 and +4. Patients were excluded for age < 18 years or incarceration. Primary endpoints are incidence of Grade 2-4 FO and associated risk factors. Descriptive and inferential statistics (i.e., Fisher's exact test, multivariable regression analysis) were used. Of 97 patients screened, 95 were included and 2 were excluded due to absence of weight measurements needed to grade FO. Median age was 60 years, 66.3% were male, 91.6% received reduced-intensity conditioning, 72.6% received haploidentical HCT, 44.2% were ECOG 0, and 11.6% had diastolic dysfunction. Incidence of grade 2-4 FO was 33.7% (n = 32). Univariate analyses found age (continuous; p = 0.04) and BSA < 1.7 m2 (p = 0.006) as independent factors associated with grade 2-4 FO. Multivariable regression analysis found 3.3% higher risk with every 1-year increase in age ranging from f 20 to 78 years (OR 1.033, 95% CI 1.001, 1.006; p = 0.0453) and 82.8% lower risk with BSA ≥ 1.7 m2 (OR 0.172, 95% CI 0.051, 0.588; p = 0.005) after adjusting for co-variates. Increasing age and BSA < 1.7 m2 are risk factors associated with grade 2-4 FO during hospitalization for allogeneic HCT with PTCY.

Lower Weight-Based Mycophenolate Mofetil Dosing is Associated with Superior Outcomes after Haploidentical Hematopoietic Cell Transplant with Post-transplant Cyclophosphamide

Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR = 0.45, 95% CI: 0.21 to 0.94, P = .03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR = 0.58, 95% CI: 0.34 to 0.99, P = .045). MMF relative dose exposure was not associated with engraftment, GVHD, nonrelapse mortality, or OS. In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen.

Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19–depleted pediatric haploidentical HCT for hematologic malignancy

AbstractWe hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ/CD19 T-cell–depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures of rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (<12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D− serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. These trials were registered at www.ClinicalTrials.gov as #NCT02646839 and NCT04337515.

211At-Labeled Anti-CD45 Antibody as a Nonmyeloablative Conditioning for Canine DLA-Haploidentical Stem Cell Transplantation.

The α-emitter 211At deposits a high amount of energy within a few cell diameters, resulting in irreparable DNA double-strand breaks while minimizing off-target toxicity. We investigated the use of the 211At-labeled anti-CD45 monoclonal antibody (mAb) 211At-CD45-B10 as a nonmyeloablative conditioning regimen for dog-leukocyte-antigen-haploidentical hematopoietic cell transplantation. Methods: Seventeen healthy dogs were injected with either a 0.50 (n = 14) or 0.75 (n = 3) mg/kg dose of anti-CD45 mAb labeled with 211At (8.436-23.199 MBq [0.228-0.627 mCi/kg]) on day -3. Peripheral blood stem cells from dog-leukocyte-antigen-haploidentical donors were given on day 0. Peripheral blood chimerism was calculated by polymerase chain reaction assays, and blood clearance of the radioimmunoconjugate was studied using enzyme-linked immunosorbent assay and radioactivity measurements of serial blood samples. Results: All dogs achieved donor chimerism by day 28 (range, 27%-100%). The hematopoietic engraftment rate was 100%, though engraftment durability was variable. No difference in absorbed dose to blood was seen for the 2 mAb dosing levels studied. Neutropenia (0-29 cells/μL), lymphocytopenia (36-130 cells/μL), and thrombocytopenia (1.5-9 × 103/μL) with prompt recovery were observed. The main adverse nonhematologic event related to 211At-CD45-B10 was mild reversible transaminitis. Graft-versus-host disease was not seen. Twelve of the 17 dogs survived over 30 d, with donor chimerism ranging from 3% to 99%. Conclusion: The results suggest that nonmyeloablative conditioning with 211At-CD45-B10 could be used in haploidentical hematopoietic cell transplantation though with variable engraftment.

Pretransplant desensitization of donor-specific anti-HLA antibodies with plasmapheresis and immunoglobulin produces equivalent outcomes to patients with no donor specific antibodies in haploidentical hematopoietic cell transplant

Haploidentical hematopoietic cell transplants (haplo-HCT) with donor-specific anti-HLA antibodies (DSAs) are associated with high rates of primary graft failure and poor overall survival (OS). Limited data exists regarding the effect of desensitization. Our institution began routine desensitization for patients with DSAs in 2014. Adult patients undergoing haplo-HCT at Washington University from 2009–2021 were identified and divided into three cohorts: no DSA, untreated DSA (2009–2014) or treated DSA (2014–2021). Desensitization therapy using plasmapheresis and IVIg was performed. Retrospectively, 304 patients were identified. 14 of 30 patients with DSAs underwent desensitization. By day +2, 57% of patients cleared all DSAs. After multivariable analysis, OS was similar between treated DSA and no DSA (HR: 0.69, p = 0.37). Untreated DSA had significantly lower OS compared to no DSA group (HR 1.80, p = 0.046). Desensitization with a backbone of plasmapheresis and IVIg before haplo-HCT may produce similar outcomes to patients without DSAs.

Tacrolimus versus cyclosporine a combined with post-transplantation cyclophosphamide for AML In first complete remission: a study from the acute leukemia working party (EBMT)

Choice of calcineurin inhibitor may impact the outcome of patients undergoing T-cell replete hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) and mycophenolate mofetil (MMF) for prophylaxis of graft-versus-host disease (GVHD). We retrospectively analyzed 2427 patients with acute myeloid leukemia (AML) in first remission transplanted from a haploidentical (n = 1844) or unrelated donor (UD, n = 583) using cyclosporine A (CSA, 63%) or tacrolimus (TAC, 37%) and PT-Cy/MMF. In univariate analysis, CSA and TAC groups did not differ in 2-year leukemia-free or overall survival, cumulative incidence (CI) of relapse or non-relapse mortality. CI of severe grade III-IV acute GVHD was lower with TAC (6.6% vs. 9.1%, p = 0.02), without difference in grade II-IV acute GVHD or grade III-IV acute GVHD/severe chronic GVHD, relapse-free survival (GRFS). In multivariate analysis, TAC was associated with a lower risk of severe grade III-IV acute GVHD solely with haploidentical donors (HR 0.64 [95% CI, 0.42–0.98], p = 0.04), but not UD (HR 0.49 [95% CI, 0.2–1.21], p = 0.12). There was no significant difference for chronic GVHD. In conclusion, PT-Cy/MMF-based GVHD prophylaxis resulted in favorable OS and GRFS, irrespective of the CNI added. In haploidentical HCT, TAC seemed to prevent severe acute GVHD more effectively than CSA without impact on other outcome parameters.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study

AbstractWe evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Early Tapering of Cyclosporine Is Feasible in Haploidentical Stem Cell Transplantation: A Single Center Experience.

Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p>0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p=0.6, p=0.5, respectively). CMV reactivation was more common in the GVHD group. In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.

Impact of cardiac arrhythmias on in-hospital mortality in patients with cytokine release syndrome: Insights from National Inpatient Sample.

e24017 Background: Cytokine release syndrome (CSR) is a pervasive inflammatory response characterized by elevated body temperature and multi-organ dysfunction. This syndrome is linked to chimeric antigen receptor (CAR)-T cell therapy, various immunotherapies, or haploidentical hematopoietic cell transplantation (HCT). It can manifest as a fever, fatigue, headache, rash, diarrhea, arthralgia, and myalgia. In some cases, it can progress to hypotension, hypoxia, and an uncontrolled systemic inflammatory response leading to circulatory collapse, pulmonary edema, renal damage, and multi-organ failure. Cardiac evaluation in the context of CSR is crucial for assessing these manifestations, but little is known about the arrhythmias associated with this therapy, and there is limited information in the literature. Methods: A retrospective study using the National Inpatient Sample to identify patients diagnosed with CRS, and the arrhythmias they experienced during their hospitalizations between January and December 2020. The primary endpoint was the incidence of various arrhythmias. Furthermore, Independent predictors of in-hospital mortality were analyzed, with p values, adjusted odds ratios (aOR) and confidence intervals (CI) calculated for each variable. Results: A total of 4675 patients were diagnosed with CRS in 2020, 39% of whom were females. The mortality rate of patients with CRS was 22%. In addition, the mortality rate of patients who developed arrhythmias was 43% while that of patients who did not was 17% (p &lt; 0.01). The mean age was higher in the arrhythmia cohort compared with the non-arrhythmia cohort (70 vs 60.7 years, p &lt; 0.01). Predictive factors associated with increased mortality included development of arrhythmias, age, hispanic race, asian or pacific islander race, obesity, previous myocardial infarction, and electrolyte abnormalities with an aOR of 2.22 (P &lt; 0.01, CI 1.51-3.28), 1.03 (P &lt; 0.01, CI 1.01-1.05), 1.85 (P = 0.04, CI 1.02-3.34), 2.57 (P = 0.014, CI 1.02-3.34), 1.72 (P = 0.018, CI 1.09-2.69), 3.26 (P = 0.008, CI 1.36-7.8), and 4.19 (P &lt; 0.01, CI 2.7-6.4) respectively. Female sex was found to be protective against mortality with an aOR of 0.5 (P = 0.004, CI 0.31-0.8). Conclusions: Our study reveals that developing arrhythmias is more common in older patients with CRS. Patients diagnosed with arrhythmias during their hospitalization experienced poorer outcomes. Adjusted predictors of mortality include the development of arrhythmias during hospitalization, age, hispanic race, asian or pacific islander race, obesity, previous myocardial infarction, and electrolyte imbalances. Additionally, female sex was found to be a protective against mortality. Given these findings, physicians should strive to be more vigilant when treating patients with CRS who have any of these predictors of mortality until further data is available.

Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial

sCoinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18–60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75–46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7–87.9 vs. 67.8% 95% CI 60.0–76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6–78.8 vs. 57.6%, 95% CI 49.6–67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0–12.2 vs. 30.3%, 95% CI 30.1–30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3–4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.

Postmortem pathologic findings in dogs that underwent total body irradiation and hematopoietic cell transplant: A case series of five dogs with B-cell multicentric lymphoma.

Alternative therapies that can help achieve complete remission in dogs with lymphoma include total body irradiation and hematopoietic cell transplant, though there are few reports describing successes and pathologic sequelae of these procedures. During a 10-year period, 94 dogs with multicentric lymphoma received a hematopoietic cell transplant following total body irradiation at North Carolina State University College of Veterinary Medicine. Seven of these 94 dogs (7%) died prior to discharge, five (5%) of which presented for postmortem examination. Of these dogs, four received an autologous hematopoietic cell transplant, while one received a haploidentical allogeneic hematopoietic cell transplant. All five dogs had bone marrow depletion with all hematopoietic lines affected. Three had systemic candidiasis, while two had bacterial infections. To the authors' knowledge, this is the first report to document pathologic findings and development of systemic mycoses in dogs post total-body irradiation therapy and hematopoietic cell transplant.