Haploidentical Hematopoietic Cell Transplantation Research Articles

Donor Derived Myelodysplastic Syndrome after Sex Matched Haploidentical Allograft for AML with Monosomy 7 in Both Diseases: Importance of Donor Chimerism Assessment By Two Independent Techniques

Donor-derived leukaemia is a rare outcome in patients following allogeneic hematopoietic cell transplant (HCT) accounting for ~ 0.1-5% of relapsed cases although the true incidence is likely underestimated. A 39-year-old male patient with a history of ulcerative colitis treated with mercaptopurine was subsequently diagnosed with therapy related acute myeloid leukaemia (AML) and karyotype showed 45,XY,-7. The patient achieved remission after two cycles of treatment and proceeded to a paternal haploidentical HCT. Complete remission with no detectable disease by flow cytometry and fluorescent in-situ hybridisation (FISH) was achieved by day 40 of transplantation with whole blood and T-cell chimerism of 97% as assessed by routine short tandem repeat (STR) chimerism analysis. With withdrawal of immunosuppression this increased to 100% in both fractions. At 11 months post-transplant evidence of low-level cytogenetic relapse emerged with monosomy 7 seen by FISH in 15/200 interphase cells. Chimerism remained stable at 99% with aspirate findings indicating 2-3% blasts and some trilineage dysplasia. Two subsequent marrows showed persistence of monosomy 7 by FISH with full donor STR chimerism. Although a possibility of donor derived myelodysplastic syndrome (DD-MDS) was considered, due to the monosomy 7, donor lymphocyte infusion (DLI) therapy was administered at 16 and 19 months post-transplant. Monosomy 7 persisted on FISH and standard cytogenetic analysis. To confirm validity of STR chimerism and to distinguish between DD-MDS and relapse of original disease, HLA typing by next generation sequencing (NGS) to exclude HLA loss related relapse and potentially guide rescue decisions was performed alongside NGS chimerism assessment. NGS chimerism utilises genetic markers with population independent discriminative power distributed across 17 chromosomes and further selected to allow sensitive detection combined with accurate and precise quantification of mixed chimerism. NGS chimerism is demonstrated to be sensitive enough to detect a minor DNA contributor comprising down to 0.5% of the sample, detection of low level mixed chimerism and therefore clinical utility in better predicting relapse compared to conventional techniques. Original stored donor cells were tested and showed no evidence of monosomy 7 by FISH. After confirming DD-MDS a second HCT was considered. Originally unsuccessful unrelated donor search was re-opened and wide family donor search initiated. With azacytidine therapy the patient achieved a short lived cytogenetic remission, but subsequently relapsed and progressed to AML with karyotype of 45,XY,-7,der(16)t(11;16)(q13;p13.1)[9]/46,XY[1] and died 33 months after HCT prior to initiation of a second HCT. This case was complicated by the presence of monosomy 7 detected by karyotyping in both the initial diagnostic t-AML and in the DD MDS. Monosomy 7 is the most common abnormality found in DD-MDS but a review of the literature available does not seem to indicate any cases where it was also present in the patient's initial diagnostic sample as a separate disease entity. The pathogenesis of DD-MDS remains unclear. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetics of Mycophenolic Acid in Haploidentical Transplant Recipients Receiving Post-Transplant Cyclophosphamide Based GvHD Prophylaxis

Post-transplant Cyclophosphamide (PTCy) based Graft versus Host disease (GvHD) prophylaxis has improved the success of Haploidentical transplantation (HaploHCT) in recent years. Therapeutic drug monitoring (TDM) of Mycophenolic acid [MPA-active metabolite of Mycophenolate Mofetil (MMF)] has proved beneficial in solid organ transplantation; however, there are no TDM recommendations in the HCT setting yet. In the present study, we sought to create a population pharmacokinetic (POPPK) model of oral MMF in haploidentical HCT recipients receiving PTCy/MMF/CyclosporineA (CsA) based GvHD prophylaxis and to evaluate the feasibility of TDM by assessing the impact of MPA exposure on clinical outcomes. Thirty-six patients with various underlying diagnoses who underwent HaploHCT between October 2021 and June 2022 were enrolled. All patients received GvHD prophylaxis comprising of Cyclophosphamide (I.V. 50 mg/kg/day x 2days (day+3 & +4) and i.v. Cyclosporine (2.5mg/kg; Q12H) with oral MMF (15 mg/kg; Q8H) from day +5 post HCT. Plasma was separated from the peripheral blood collected at predetermined time points at day+8 post HCT. Plasma MPA was analyzed using a validated HPLC-UV method, and the concentration was expressed as ug/ml. MPA PK was estimated using nonlinear mixed effects modeling via Monolix (version 2021R2). The covariates tested for MPA PK were: age, sex, body weight, BSA, and Creatinine clearance. The PK parameters AUC, CL, V, and k were estimated on day+8 for MPA. The influence of MPA PK on GvHD and graft rejection was assessed by the Mann-Whitney test (GraphPad Prism 8). MPA levels were available for thirty-one patients. A one-compartment model with first-order absorption best described MPA PK. We observed a 5-fold inter-individual variation (IIV) in MPA exposure. None of the covariates explained IIV in MPA PK. Two patients died before engraftment, while graft rejection was noted in 3 patients (1 primary and 2 secondary). Fifteen patients experienced acute GvHD, and there were nine deaths (25%) at the last follow-up of 3.7 ± 2.4 months. Interestingly, POPPK analysis revealed that all the 31 patients had MPA underexposure [Median: 14.1 (4.5 - 24.0)ug*hr/ml lesser than the lower limit of the therapeutic range of 30ug*hr/ml]. No associations were observed with clinical outcomes, including acute GvHD (p=0.8) or graft rejection (p=0.6). The MPA underexposure in the present study could be attributed to potential drug-drug interaction (DDI) with concomitant CsA administration that inhibits MRP2-mediated enterohepatic circulation causing decreased systemic MPA exposure. Numerous transplant centers across the globe use cyclosporine and tacrolimus interchangeably (Ruggeri et al. TCT 2020). However, the available retrospective data comparing the two calcineurin inhibitors appears to be conflicting (Castagna et al. BMT 2016, de Lima VJT et al. Ann Hematol 2022). On the PTCy platform for haploidentical transplantation, our results highlight that concomitant administration of CsA reduces systemic exposure of MPA. The impact of this effect on the clinical outcomes needs to be studied further and may potentially affect the choice of the calcineurin inhibitor for the PTCy platform. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Alternative Transplantation With Post-Transplantation Cyclophosphamide in Aplastic Anemia: A Retrospective Report From the BMF-WG of Hunan Province, China

Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested recently, transplantation strategies are still being investigated. We established a novel post-transplantation cyclophosphamide-based HCT protocol for patients with SAA in prior studies. We explores the effectiveness and safety of this HCT approach either as first-line or as salvage treatment in SAA patients. Outcomes of 71 consecutive young patients, who received HCT from unrelated or haploidentical donors, were retrospectively analyzed. According to their treatment before transplantation, the patients were classified into treatment-naive (TN) and relapsed or refractory (R/R) patients. The R/R patients were designated as such when a patient did not respond to previous immunosuppressive therapy or relapsed. We administered an antithymocyte globulin (ATG)–free, total body irradiation (TBI)–free conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine, all in an intravenous formula. We used a thorough post-transplantation prophylaxis regimen for GVHD, including post-transplantation cyclophosphamide (PTCy) and short-term methotrexate and long-term cyclosporine A. The median age of the cohort was 16 (95% confidence interval, 12-20) years at transplantation. Most patients (61 of 71) received HCT from haploidentical donors, and the others received HCT from unrelated donors. TN patients (n = 38) were younger and had a shorter time-to-transplant and lower HCT-specific comorbidity index than patients with R/R diseases (n = 33). The frequencies of graft failure, grade II-IV acute graft-versus-host disease (GVHD), and moderate-severe chronic GVHD were similar, at 5.3% versus 6.5% (P = .057), 8.3% versus 0% (P = .109), and 5.7% versus 0% (P = .199) between R/R and TN patients. With a median 42-month follow-up, the frequencies of overall survival (OS) and event-free survival (EFS) were higher in the TN group than in the R/R group (100% versus 84.8% [P = .013] and 86.8% versus 75.8% [P = .255], respectively). All patients who achieved successful engraftment showed full donor chimerism. Four patients, all in the R/R group, suffered from donor-type aplasia; of these, 2 died, 1 was salvaged with another transplantation, and the final one was still receiving transfusion at the last follow-up. Currently, 93.9% (62 of 66) of the patients are alive more than 12 months after transplantation; of these 93.5% (58 of 62) no longer receive immunosuppression, including 91.7% (33 of 34) of the TN group and 89.3% (25 of 28) in the R/R group. This novel TBI-free and ATG-free HCT protocol using a reduced-intensity conditioning regimen followed by modified PTCy achieved promising engraftment, minimal GVHD risk, and encouraging OS and EFS. Our study suggests that unrelated or haploidentical HCT with PTCy can be used as a first-line treatment for young patients with SAA. Nevertheless, further efforts are needed to explore possibilities for older patients and patients with a poor performance status.

T-cell depleted haploidentical hematopoietic cell transplantation for pediatric malignancy.

Access to allogenic hematopoietic cell transplantation (HCT), a potentially curative treatment for chemotherapy-resistant hematologic malignancies, can be limited if no human leukocyte antigen (HLA) identical related or unrelated donor is available. Alternative donors include Cord Blood as well as HLA-mismatched unrelated or related donors. If the goal is to minimize the number of HLA disparities, partially matched unrelated donors are more likely to share 8 or 9 of 10 HLA alleles with the recipient. However, over the last decade, there has been success with haploidentical HCT performed using the stem cells from HLA half-matched related donors. As the majority of patients have at least one eligible and motivated haploidentical donor, recruitment of haploidentical related donors is frequently more rapid than of unrelated donors. This advantage in the accessibility has historically been offset by the increased risks of graft rejection, graft-versus-host disease and delayed immune reconstitution. Various ex vivo T-cell depletion (TCD) methods have been investigated to overcome the immunological barrier and facilitate immune reconstitution after a haploidentical HCT. This review summarizes historical and contemporary clinical trials of haploidentical TCD-HCT, mainly in pediatric malignancy, and describes the evolution of these approaches with a focus on serial improvements in the kinetics of immune reconstitution. Methods of TCD discussed include in vivo as well as ex vivo positive and negative selection. In addition, haploidentical TCD as a platform for post-HCT cellular therapies is discussed. The present review highlights that, as a result of the remarkable progress over half a century, haploidentical TCD-HCT can now be considered as a preferred alternative donor option for children with hematological malignancy in need of allogeneic HCT.

Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review.

PurposeTMI utilizes IMRT to deliver organ sparing targeted radiotherapy in patients undergoing hematopoietic cell transplantation (HCT). TMI addresses an unmet need, specifically patients with refractory or relapsed (R/R) hematologic malignancies who have poor outcomes with standard HCT regimens and where attempts to improve outcomes by adding or dose escalating TBI are not possible due to increased toxicities. Over 500 patients have received TMI at this center. This review summarizes this experience including planning and delivery, clinical results, and future directions.MethodsPatients were treated on prospective allogeneic HCT trials using helical tomographic or VMAT IMRT delivery. Target structures included the bone/marrow only (TMI), or the addition of lymph nodes, and spleen (total marrow and lymphoid irradiation, TMLI). Total dose ranged from 12 to 20 Gy at 1.5-2.0 Gy fractions twice daily.ResultsTrials demonstrate engraftment in all patients and a low incidence of radiation related toxicities and extramedullary relapses. In R/R acute leukemia TMLI 20 Gy, etoposide, and cyclophosphamide (Cy) results in a 1-year non-relapse mortality (NRM) rate of 6% and 2-year overall survival (OS) of 48%; TMLI 12 Gy added to fludarabine (flu) and melphalan (mel) in older patients (≥ 60 years old) results in a NRM rate of 33% comparable to flu/mel alone, and 5-year OS of 42%; and TMLI 20 Gy/flu/Cy and post-transplant Cy (PTCy) in haplo-identical HCT results in a 2-year NRM rate of 13% and 1-year OS of 83%. In AML in complete remission, TMLI 20 Gy and PTCy results in 2-year NRM, OS, and GVHD free/relapse-free survival (GRFS) rates of 0%, 86·7%, and 59.3%, respectively.ConclusionTMI/TMLI shows significant promise, low NRM rates, the ability to offer myeloablative radiation containing regimens to older patients, the ability to dose escalate, and response and survival rates that compare favorably to published results. Collaboration between radiation oncology and hematology is key to successful implementation. TMI/TMLI represents a paradigm shift from TBI towards novel strategies to integrate a safer and more effective target-specific radiation therapy into HCT conditioning beyond what is possible with TBI and will help expand and redefine the role of radiotherapy in HCT.

CT-026 Prevalence and Impact of Donor Specific Anti-HLA Antibodies in the Setting of Myeloablative Haploidentical Transplant for Malignant Hematological Diseases: Single-Center Experience

To study the outcomes, prevalence, and impact of DSA and anti-HLA of myeloablative haploidentical transplant for malignant hematological diseases. We conducted retrospective analysis of our blood and marrow transplant database. We identified 107 patients who received myeloablative haploidentical hematopoietic cell transplantation between January 2013 and December 2020. Sixty-two recipients were male (58%) and 45 were female (48%). The median recipient age was 22 (range: 1-56). Most pairs had matched ABO blood groups (76 pairs [71%]). The graft source was bone marrow in 83 patients (78%). The median infused CD34 cell dose was 4.02×106/kg (range: 1.3-13.1). Sixty-one recipients (57%) had positive anti-HLA; of these, 17 had DSA (15% of the total number of patients, 28% of patients with anti-HLA antibodies). The median cumulative mean fluorescence intensity was 2,062 (IQR: 1,038-6,500). Overall survival, cumulative incidence of relapse, acute graft-versus-host disease, and chronic graft-versus-host disease were comparable between patients with anti-HLA antibodies and those without and between patients with DSA and those without. Recipient and donor gender and recipient/donor gender mismatch showed statistical association with the incidence of anti-HLA antibodies but not DSA. Of the 17 patients with DSA, five underwent desensitization. C1q assay was done pre and post desensitization. Three patients developed GF (2.8%): one was primary (0.9%) due to low CD34 dose, and two had secondary GF (1.9%). None of these cases occurred in patients with anti-HLA antibodies or DSA. The median time from transplant to GF was 2.23 months (range: 0.8-2.89). The median time to absolute neutrophil count and platelet engraftment was 16 days. Our study shows that desensitization may not be required in the setting of myeloablative transplant for malignant hematological disorders. This warrants further investigations in prospective trials.

IMPROVING OUTCOMES AFTER HEMATOPOIETIC CELL TRANSPLANTATION IN FA IN LOW-RESOURCES COUNTRIES: THE EXPERIENCE FROM CURITIBA

Fanconi Anemia (FA) is a rare and challenging disease to manage, and there is a substantial gap between treatments available in high- versus low- and middle-income countries. Although hematopoietic cell transplantation (HCT) is the only curative treatment for the hematological complications related to this disease, this procedure is highly complex, requiring sophisticated infrastructures and trained personnel. Describe the outcomes after matched related, unrelated and haploidentical HCT for 216 FA patients in aplastic phase in Curitiba, Brazil. The median age was 9-years (range: 3-32); all patients were in aplastic phase and received bone marrow as the stem cell source. 1st group: Matched Related Donors (MRD): 101 pts were transplanted between 1999-2021. Median follow-up: 9.6 years; 83 received HCT from matched siblings while 18 had other MRD. All patients received a simple preparatory regimen with Cyclophophamide (CY) 60 mg/kg with (n = 12) or without rabbit-ATG (n = 89) and GVHD-prophylaxis with cyclosporine and methotrexate (csa + MTX;96%) or mycophenolate (csa+MMF;4%). Six patients had primary or secondary graft failure (GF), all received a 2nd transplant, and 5 are alive and engrafted. Eight patients died at a median of 545 days after transplant (range: 3- 6271). Two-year transplant-related-mortality (TRM):4%. 10-year overall survival (OS) was 94%, and all patients transplanted in the past ten years are alive (n = 42). This regimen was well tolerated with a low TRM and acute and chronic GVHD incidence. 2nd group: Unrelated donors:75pts were transplanted between 2003-2021; median follow-up:6-years. HLA-compatibility: 10/10 (n = 68) and 9/10 (n = 7). 73% of donors were found in the Brazilian donor registry. All patients received a non-irradiation regimen including CY 60 mg/kg + Fludarabine + ATG, and the majority received csa + MTX as GVHD prophylaxis. GF was observed in two patients, and one is alive and well after a 2nd transplant.15pts died at a median of 117 days post-HCT (range: 3-4379), and infections were the major cause of death in 60% of patients. The day-100 CI of acute GVHD and 2-year CI of chronic GVHD was 17% and 25%, respectively. 5-year OS was 79%. 3rd group: Haploidentical donors:40pts were transplanted between 07/2013 to 01/2022, 31 patients received a preparatory regimen with Fludarabine + TBI (200) + rabbit-ATG, and 9 received Fludarabine + TBI(200) + Campath. GVHD prophylaxis with post-transplantation cyclophosphamide (PTCy) 50-60 mg/kg (total dose) + csa + MMF. Three patients in the ATG group had primary or secondary GF, received a 2nd haplo-PTCy transplant, and died. The CI of day-100 acute GVHD was 27%. The 2-year CI of chronic GVHD was 51% for the ATG group and 25% for the Campath group (p = 0.15). Six patients died at a median of 209 days due to rejection (n = 3) or GVHD (n = 3). 3-year OS was 85%. All patients in the Campath group are alive. These results show the feasibility of performing HCT for patients with FA in aplastic phase in Brazil. This experience also reflects more than 40 years of dedication to the treatment of FA and is based on strong national and international collaborations. These simple but effective preparatory regimens can lead to excellent outcomes, serve as a guideline, and be reproducible in other countries with similar resources.

Outcomes of patients who underwent treatment for anti‐HLA donor‐specific antibodies before receiving a haploidentical hematopoietic cell transplant

Pediatric and adolescent and young adult (AYA) patients who receive many blood product transfusions, such as individuals with sickle cell disease (SCD), severe aplastic anemia (SAA) or indolent hematologic malignancies, are at high risk for developing donor-specific antibodies (DSA). DSAs with mean fluorescence intensity (MFI) greater than 5000 have been associated with significant graft failure, but lower MFI values between 2000 and 5000 may result in poor graft function after hematopoietic cell transplant (HCT). Desensitization strategies have been developed to reduce the DSA burden in HCT recipients before graft infusion, but the experience with these strategies in the pediatric and AYA populations is not well described in the literature. Here, we describe our experience with successful desensitization by using a combination of treatment strategies in five pediatric and AYA patients, including a novel use of daratumumab in a young adult patient who had refractory DSAs and had suffered serious side effects from conventional desensitization strategies. The presence of elevated DSAs in pediatric and AYA recipients of a human leukocyte antigen (HLA)-mismatched haploidentical HCT can be overcome by a multipronged treatment strategy.

Irradiation-free, T-cell replete haploidentical transplant for Fanconi anaemia, weighing the benefits.

The optimal haploidentical haematopoietic cell transplant approach for Fanconi anaemia (FA) patients is not well established, given the rarity of the disease, the increased sensitivity to DNA-damaging agents and the high risk of severe graft-versus-host disease (GVHD). The report by Xu et al. suggests that excellent engraftment and short-term survival can be achieved in FA patients without irradiation, but their retrospective cohort was plagued by a high rate of severe GVHD. Our commentary explores the outcomes in T-cell replete haploidentical haematopoietic cell transplantand ponders whether elimination of total body irradiation in FA patients is the best method if it limits the ability to safely administer post-transplant cyclophosphamide. Commentary on: Xu et al. Unmanipulated haploidentical haematopoietic cell transplantation with radiation-free conditioning in Fanconi anaemia: A retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group. Br J Haematol. 2022;199:401-410.

Costs of matched-sibling, unrelated, and haploidentical hematopoietic cell transplantation and risk factors for greater financial burden - a Brazilian FACT-accredited single-center analysis.

The complexity and costs of hematopoietic cell transplantation (HCT) have increased over the last decades with the popularization of unrelated donor (URD) transplantation and the introduction of haploidentical transplantation with posttransplant cyclophosphamide. Few studies have addressed this issue. The objective of this study was to analyze HCT costs in a single FACT-accredited private non-profit hospital. We included 79 patients who underwent HCT between 2018 and 2020. We have included all costs from admission day until D + 180. We used a lognormal regression. Median age was 53 y/o and most donors were unrelated (51%). Costs were higher with haploidentical donor (42%, p = 0.017, compared with URD), higher HCT-CI (15% for each point, p = 0.0056), and in patients with liver or gastrointestinal GVHD (45%, p = 0.033), and lower in patients who received CD34 > 2.5 × 10E6/kg (42%, p = 0.0038). We built a score based on the following risk factors: HCT-CI > 3, CD34 ≤ 2.5 × 10E6/kg, haploidentical donor, and donor age > 30 y/o. Patients with 2 + risk factors (N = 53) had a median cost of USD 226,156.00, compared with USD 93,048.00 in patients with zero or 1 point (N = 26, p < 0.0001). In summary, we have shown that HCT costs are higher with lower doses of CD34 cells, haploidentical HCT (provided that the costs of stem cell procurement and ATG are not included), and in patients with higher HCT-CI. Prospective and refined cost analyses comparing haploidentical and URD transplants, as well as effective strategies for patients with higher HCT-CI scores, are warranted. We found no difference in costs between URD and MSD transplantation.

Abstract 6 Projected Impact of Omidubicel on Racial and Ethnic Disparities in Allogeneic Hematopoietic Cell Transplant Access and Outcomes for Patients with Hematologic Malignancies in the U.S.

IntroductionPatients with hematologic malignancies (HM) who are eligible for allogeneic hematopoietic cell transplant (allo-HCT) often lack an HLA-matched related donor (MRD) and rely on unrelated donors for a matched or mismatched unrelated donor (MUD or MMUD) or on umbilical cord blood (UCB). It is well known that racial minorities are underrepresented in donor registries.ObjectiveOmidubicel, an advanced cell therapy for allo-HCT, demonstrated superior hematopoietic recovery and clinical outcomes compared with standard UCB (NCT02730299). We hypothesized the impact of omidubicel access on racial and ethnic health disparities in a projection model.MethodsA model was developed to project allo-HCT access and clinical outcomes in a hypothetical population of 10,000 allo-HCT-eligible US patients with HM lacking an HLA-MRD. Outcomes associated with omidubicel, MUD, MMUD, haploidentical or UCB HCT, or no transplant were assessed by race/ethnic group. Model inputs, including clinical outcomes for each HCT type, were drawn from clinical trials, public CIBMTR and US Department of Health and Human Services data, and published studies. Increasing omidubicel use was modeled, with proportional reductions in other allo-HCT types or no transplant.ResultsIn a modeled population of 10,000 patients, 5,956 (60%) received allo-HCT utilizing current donor sources (MUD, MMUD, haploidentical, UCB) with no omidubicel (status quo). While 80% of white patients underwent allo-HCT, only 40% of Hispanic, 32% of Asian, and 22% of Black patients underwent allo-HCT. Mean time from selecting graft to HCT was 11.5 weeks. Including those not transplanted, 1-year OS was 62% overall, ranging from 56% (Black) to 65% (White). Modeled increases in omidubicel use in eligible patients were associated with higher proportions of patients undergoing allo-HCT, decreased time to HCT, and increased 1-year OS. Improvements were greatest among racial minorities. Assuming 20% omidubicel use, the proportion of patients receiving allo-HCT increased by 71% in Black, 43% in Asian, 30% in Hispanic, and 5% in White patients. Modeled time to allo-HCT improved as well.DiscussionAccess to omidubicel is projected to decrease time to allo-HCT, improve outcomes overall, with greatest improvements among racial and ethnic groups underserved by the status quo, thus helping to reduce racial disparities and improving health equity in allo-HCT.

Impact of Cytogenetic Risk on Outcomes of Non-T-Cell–Depleted Haploidentical Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Baseline cytogenetics and disease status are key factors predicting the outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML). The importance of cytogenetic risk in patients with primary refractory or relapsed (R/R) AML undergoing haploidentical (Haplo) HCT is unknown. We studied the impact of cytogenetic risk in patients with R/R de novo AML with active disease who underwent non-T-cell–depleted Haplo-HCT with post-transplantation cyclophosphamide from 2010 to 2020. Four hundred forty patients with active disease at transplantation from the European Society for Blood and Marrow Transplantation database were analyzed (291 [66.1%] with intermediate-risk [AMLint] and 149 [44.1%] with adverse-risk cytogenetics [AMLadv]). Impact of baseline cytogenetic risk on various transplantation outcomes was evaluated. Pre-transplantation disease status was relapse in 48.1% and 26.8% and primary refractory in 51.9% and 73.2% of the patients with AMLint and AMLadv, respectively (P < .0001). Two-year leukemia-free survival (LFS, 35.5% versus 15.5%, P = .001) and overall survival (OS, 39.2% versus 20.1%, P = .001) were better in AMLint versus AMLadv. In multivariate analysis, the relapse rate was significantly higher (hazard ratio [HR] = 2.17 [95% confidence interval {CI} 1.57-3.0]) and LFS (HR = 1.71 [95% CI, 1.31-2.22]) and OS (HR = 1.69 [95% CI, 1.29-2.22]), significantly lower for patients with AMLadv compared to AMLint, conditioning intensity did not affect leukemia relapse rate. Non-relapse mortality (HR = 1.1 [95% CI, 0.7-1.74]) and graft-versus-host disease–free, relapse-free survival (HR = 1.37 [95% CI, 1.06-1.77]) did not differ significantly between the risk groups. Disease status before transplant (primary refractory versus relapsed) or conditioning intensity did not impact main transplant outcomes. Baseline cytogenetic risk remains a key prognostic factor for patients with R/R AML with persistent disease before non-T-cell–depleted Haplo-HCT.

Unmanipulated haploidentical haematopoietic cell transplantation with radiation-free conditioning in Fanconi anaemia: A retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group.

Haematopoietic cell transplantation (HCT) is the only curative treatment for haematological complications in patients with Fanconi anaemia (FA). Haploidentical (haplo-) HCT is a promising alternative for FA. We aimed to analyse the outcomes of unmanipulated haplo-HCT in patients with FA with radiation-free conditioning. A total of 56 patients from 11 centres between 2013 and 2021 in China were retrospectively analysed. The mean (SD) cumulative incidence was 96.4%(0.08%) for 30-day neutrophil engraftment and 85.5% (0.24%) for 100-day platelet engraftment. With a median (range) follow-up of 2.4(0.2-5.8)years, favourable mean (SD) overall survival of 80.9%(5.5%) and event-free survival of 79.3%(5.6%) were achieved. The mean (SD) incidences of acute graft-versus-host disease (aGvHD) Grade II-IV and Grade III-IV were 55.4%(0.45%) and 42.9(0.45%) respectively. The mean (SD) cumulative incidence of 3-year chronic graft-versus-host disease (cGvHD) was 34.7%(0.86%) and that of moderate-to-severe cGvHD was 9.0%(0.19%). Our data demonstrate that in unmanipulated haplo-HCT for patients with FA, radiation-free regimens based on fludarabine and low-dose cyclophosphamide ± busulfan achieved favourable engraftment and survival with relatively high incidences of aGvHD and cGvHD. These results prompt the use of low-intensity conditioning without radiation and intensive GvHD prophylaxis when considering unmanipulated haplo-HCT in patients with FA.

The impact of tocilizumab treatment for cytokine release syndrome on the incidence of early blood stream infections after peripheral blood haploidentical hematopoietic cell transplantation

Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT). Severe CRS has previously been associated with increased infection risk. IL-6 inhibitors, such as tocilizumab, are useful in moderate to severe CRS, but their effect on infection risk has not been established in this setting. We examined the effect of tocilizumab on blood stream infections (BSIs) in the early post-transplant period in 235 patients who underwent haplo-HCT from 2013 to 2020. Mild CRS was associated with a lower incidence of BSI than severe CRS (OR 0.31, 95% CI 0.13–0.74). In the tocilizumab group, 31% of patients had positive blood cultures versus 14% in the non-tocilizumab group (OR 1.61, 95% CI 0.30–8.60, p = 0.58). However, when controlling for CRS grade, tocilizumab was not independently associated with increased rates of BSIs, suggesting it does not further increase infection risk.

KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial

AbstractWe performed a prospective multicenter study of T-cell receptor αβ (TCR-αβ)/CD19–depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGVHD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19–depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.

P1333: PLASMA EXCHANGE, IMMUNOGLOBULIN &amp; PRE-TRANSPLANT IMMUNOSUPPRESSION: AN EFFECTIVE DESENSITISATION STRATEGY FOR DSA ALLOANTIBODIES IN HAPLOIDENTICAL HCT FOR PAEDIATRIC RED CELL DISORDERS

Background: Near universal availability of HCT is possible due to the feasibility of haploidentical transplantation [haplo HCT] with the use of post-transplantation cyclophosphamide or TCRαβ CD+19 depletion, enabling HCT for haemoglobinopathies and rare inherited anaemias for whom donors are underrepresented in registries. Patients with these disorders are at increased risk of developing anti-HLA antibodies having often received multiple transfusions pre-transplantation. HLA antibodies constituting donor specific antigens [DSA] affect approximately 15% of haplo HCT [Leffel, 2013] representing a significant cause of primary graft failure [Ciurea, 2009]. An effective desensitisation strategy is necessary as alternative donors for haploidentical HCT are often lacking. Several desensitisation approaches have been developed based on strategies used for solid organ transplantation, yet there exists no consensus in their application to haplo HCT for paediatric haemoglobinopathies where there is a particularly high risk of graft failure [de la Fuente, BBMT 2019, de la Fuente, ASH 2020]. Aims: To assess the efficacy of plasma exchange, high dose immunoglobulin and pre-transplant immunosuppression as a desensitisation strategy for DSA alloantibodies in paediatric patients undergoing haploidentical HCT for red cell disorders. Methods: Seven [17.5%] patients were found to have HLA class I DSA in 40 consecutive related reduced-intensity conditioning haplo HCT with post-transplant cyclophosphamide for red cell disorders performed at St Mary’s Hospital from 2013 to December 2021. The MFI cut off used was 2,000U. Transplant indications included homozygous sickle cell disease [n=5], HbSβ0 thalassaemia [n=1] and Diamond-Blackfan anaemia [n=1]. Median age was eight years [range 3-15 years]. Five children were female. Two patients had two different DSA. Each patient received a regimen based on the John Hopkins protocol [Leffel, 2013], comprising a single dose of rituximab 375mg/kg, four alternate day cycles of single volume plasmapheresis [replacing 100% volume with 5% albumin] and anti-CMV hyperimmune immunoglobulin 100mg/kg on days -16, -14, -12 and -10 before the initiation of the conditioning regimen and a further cycle of single volume plasmapheresis on D -1 and anti-CMV hyperimmune immunoglobulin 100mg/kg, and immunosuppression with tacrolimus and MMF to Day 0. HLA antibodies were measured on Day 0 prior to HSC infusion. If the MFI had not decreased <2000U, two further cycles of single volume plasmapheresis and anti-CMV hyperimmune immunoglobulin 100mg/kg were given on D+1 and D+2. Results: The median MFI at baseline was 5,974 U [range 1,544-22806U]. The protocol was well tolerated and completed without serious adverse events in all patients. Four patients required additional cycles on days +1 and +2. Median MFI at protocol completion was 230U [range 0-769U]. No patient suffered primary graft failure. Median time to neutrophil engraftment was 21 days [range 15-24]. All patients achieved full donor whole blood chimerism on D+28 and wheras there was mixed chimerism in the T cell fraction in three of the patients, this improved over time in all patients and no patient suffered secondary graft failure. Summary/Conclusion: The use of a desensitisation protocol comprising the combination of plasma exchange, high dose immunoglobulin and pre transplant immunosuppression constitutes an effective desensitisation strategy for DSA and abrogates the risk of graft failure in multiply transfused paediatric patients undergoing haploidentical HCT for red cell disorders, enabling HCT where no alternative donor exists.

Impact of the Addition of Antithymocyte Globulin to Post-Transplantation Cyclophosphamide in Haploidentical Transplantation with Peripheral Blood Compared to Post-Transplantation Cyclophosphamide Alone in Acute Myelogenous Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat acute myelogenous leukemia (AML) is increasing. We explored whether the addition of antithymocyte globulin (ATG) to post-transplantation cyclophosphamide (PTCy) allows better outcomes compared with PTCy alone in haplo-HCT with PBSCs (haplo-PBSCT). We included 441 adult patients undergoing a first haplo-PBSCT for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n=374) or ATG plus PTCy (n=67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. All transplantations were performed between 2011 and 2019. No major imbalances were observed between the 2 groups. For both groups, the median patient age was 56 years, and the median year of haplo-PBSCT was 2017. Most patients received a reduced-intensity conditioning regimen (57% in the PTCy group and 61% in the ATG+PTCy group; P=.54). The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group (P=.59), and the rate of neutrophil engraftment in the 2 groups was 97% and 98%, respectively. In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of chronic GVHD compared with PTCy alone (hazard ratio, .46; 95% confidence interval, .23 to .93; P=.03). No between-group differences in the other transplantation outcomes were seen. In haplo-PBSCT, the addition of ATG to PTCy (with CsA and MMF) is feasible and better at preventing chronic GVHD and is associated with survival and transplantation outcomes comparable to those with PTCy alone, without increasing transplantation toxicity, mortality, or relapse incidence.

Post-transplant cyclophosphamide pharmacokinetics and haploidentical hematopoietic cell transplantation outcomes: an exploratory study

Pharmacokinetics of cyclophosphamide has been explored to optimize conditioning dosing. We hypothesized that post-transplant cyclophosphamide (PTCy) metabolite carboxy-ethyl phosphoramide mustard (CEPM) pharmacokinetics might impact haploidentical transplantation (haplo-HCT) outcomes. CEPM area under the curve (AUC0–48) was determined by eleven sampling timepoints on day +3/+4 using LC-MS/MS. The median CEPM AUC0–48 in a cohort of 30 patients was 14.2 (14) mg·hr/L. The incidence of severe chronic graft-versus-host disease (GVHD) (73% vs. 11%, p = 0.02), and GVHD-/relapse-free survival (GRFS) was significantly inferior in the CEPM AUC0–48 < 14 mg·hr/L group (54 days vs. 344 days, p = 0.02). There was, however, no difference in grade III-IV acute GVHD (38% vs. 14%, p = 0.12) and overall survival (295 days vs. not reached, p = 0.2). CEPM AUC0–48, is associated with severe chronic GVHD and GRFS post-haplo-HCT in this exploratory study. There is scope for personalizing day + 4 PTCy dose based on day + 3 CEPM AUC0–8.

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse.

BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

Risk factors for adverse outcomes following haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide: a two-center analysis.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases and alternative donors, including haploidentical, play a significant role in HCT. Despite the increasing use of haplo-HCT with PTCy, some questions remain open. The objective of the present study was to investigate risk factors for adverse outcomes after haplo-HCT with PTCy. This is a retrospective study conducted at two Brazilian centers. A total of 103 patients with hematologic malignancies who underwent first allogeneic, haploidentical HCT with PTCy were included. Risk factors for death were age at transplant (HR = 1.03 for each year; p = 0.002) and high/very high disease risk index (DRI; HR = 2.77; p = 0.0007) and mother as the donor compared with other donors (HR = 3.53; p = 0.005). In multivariate analysis, PFS was significantly poorer for older patients (HR = 1.02; p = 0.006), high/very high DRI (HR = 2.39; p = 0.003), and mother as the donor compared with other donors (HR = 3.18; p = 0.006). Relapse rate was higher for high/very high DRI (HR = 4.01; p = 0.002) and mother as the donor compared with other donors (HR = 2.52; p = 0.05). NRM was higher for older patients (HR = 1.03 for each year; p = 0.03). Tacrolimus was a protective factor for grades II-IV aGVHD (HR = 0.46; p = 0.04) compared with cyclosporine. Peripheral blood (PBSC) was a risk factor for cGVHD (HR = 3.48; p = 0.006), while tacrolimus was protective (HR = 0.30; p = 0.009). Mother as the donor compared with other donors was also a risk factor for poorer OS, PFS, and relapse, suggesting that this combination should be avoided. Tacrolimus was protective for both grades II-IV aGVHD and cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse. Prospective studies comparing tacrolimus with cyclosporine are awaited.