Haploidentical Bone Marrow Transplantation Research Articles

Pattern of Immune Reconstitution Post Allogeneic Stem Cell Transplant: Data From a Resource Constraint Country.

To determine the Pattern of immune reconstitution (IR) post allogeneic stem cell transplant at six months. Prospective observational study. Place and duration of the study: This study was conducted at The Armed Forces Bone Marrow Transplant Centre (AFMBTC) Rawalpindi, Pakistan, from May 2022 to December 2022. After approval from the institutional review board, informed/written consents were taken from patients. All patients (both genders, irrespective of age) undergoing allogeneic hematopoietic stem cell transplant were included in the study. Patients undergoing haplo-identical or autologous bone marrow transplants were excluded from the study. Innate immune reconstitution was checked by complete blood count and adaptive immune reconstitution at six months was checked lymphocyte subset analysis and serum immunoglobulin levels. Data was entered in pre-designed proforma and was analyzed using IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp. This study analyzes 43 patients, including 67% (n=29) males. The median age at the time of HSCT was 11.19 years. Cellular and humoral reconstitution at six months after transplant was used to assess immune reconstitution. Innate immune reconstitution was checked by complete blood count for count recovery (Neutrophil engraftment), and adaptive immune reconstitution (cellular/humoral) at six months was checked lymphocyte subset analysis and serum immunoglobulin levels. By using chi-square, significant associations were found as pre-transplant condition regimen with CD4 (PChi= 0.001), GVHD prophylaxis with CD4 (PChi= 0.04), source of stem cells with CD19 (PChi= 0.008), patient-donor gender disparity with CD19 (PChi= 0.05), GVHD treatment low CD19 (PChi= 0.04), patient-donor relationship with IgA(PChi= 0.007), IgG (PChi= 0.001), and IgM (PChi= 0.001), gender of the patient with IgA (PChi= 0.04). Our data suggested thatat post-transplant six months, there was adequate immune reconstitution except for CD4 and CD4:CD8 ratio. Therefore, post-transplant, six months in Allo-HSCT could be considered for immunization.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease

AbstractIn the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative–related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier–based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate–severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Haploidentical bone marrow transplantation for AML in remission after TBF conditioning: a long-term follow-up

Haploidentical bone marrow transplantation for AML in remission after TBF conditioning: a long-term follow-up

Second haploidentical bone marrow transplantation with antithymocyte antibody-containing conditioning regimen for graft failure in eight patients with severe aplastic anemia

The effects of a second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen after graft failure in patients with severe aplastic anemia remain unclear. Eight severe aplastic anemia patients with graft failure with a median age of 12.5 (range, 3–22) years were retrospectively reviewed. At the second transplantation, they received a median mononuclear cell number of 15.7 (range, 11.2–20.9) × 108/kg or a median CD34+ cell number of 6.2 (range, 2.5–17.5) × 106/kg. They were all successfully engrafted, with a median time of 12.5 (range, 11–16) days for neutrophils and 24 (range, 14–50) days for platelets. Three patients developed skin acute graft-versus-host disease Grades I–II, and another 3 developed limited chronic graft-versus-host disease. All patients successfully recovered after treatment with methylprednisolone (0.5–1 mg/kg/day) and tacrolimus. One patient each died of respiratory failure caused by multidrug-resistant Klebsiella pneumoniae at 8 months and invasive fungal disease at 23 months after transplantation. Six patients survived with a 5-year estimated overall survival of 75% and a median follow-up time of 61 (range, 8–129) months. A second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen was feasible for saving severe aplastic anemia patients with graft failure.

Cerebral hemodynamic changes after haploidentical hematopoietic stem cell transplant in adults with sickle cell disease

AbstractPreliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507

Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is &amp;gt;90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, &amp;lt;15% of patients with SCD have MSD, and myeloablative conditioning can be prohibitively toxic in adults with SCD. Reduced intensity HLA-haploidentical BMT with post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Still, concerns about graft failure and graft-versus-host disease (GVHD) persist. We present the results of a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507, multi-center single-arm, phase-II, prospective clinical trial (clinicaltrials.gov #NCT03263559) of haploidentical-BMT with PTCy to estimate EFS at 2-years in adults with severe SCD. Pediatric stratum data is not included in the data presentation and will be available in 2-years. Study Design and Methods: Eligibility: SCD patients aged 15.00-45.99 years with prior stroke, recurrent ACS or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants were required to have an HLA-haploidentical first-degree relative donor, willing and able to donate bone marrow. The primary objective was EFS (survival without primary or secondary graft failure or second infusion of stem cells) at 2 years after haploidentical-BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes at 2 years post haploidentical-BMT. The protocol was opened for enrollment on 10/5/2017, completed accrual on 01/6/2021, and data are current as of 8/2023. Preconditioning with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10); Conditioning regimen included Thymoglobulin (rATG), Thiotepa, Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI). GVHD prophylaxis included PTCy, sirolimus, and mycophenolate mofetil, figure. Results: A total of 54 eligible participants enrolled from 19 sites; 42 (78%) proceeded to transplant. Amongst enrolled participants, 59.3% are male, 92.6% are Black, and 3.7% are Hispanic. 10 participants started HU but did not proceed to BMT, and 2 did not start HU or proceed to BMT. Reasons included donor issues (n=4), withdrawal of consent (n=2), insurance coverage (n=2), death (n=1), and other (n=3). 38/42 (90%) participants completed the study as planned; 2 participants withdrew consent, and 2 were lost to follow-up. The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had Hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8. Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant. Only 13 (31%) participants achieved the intended 30 mg/kg/day dosing of HU preconditioning. Estimated 2-year EFS is 88% (95% CI: 73.5%, 94.8%); all except one qualifying event occurred within 12 months. The 2-year overall survival (OS) post-HU was 93.0% (95% CI: 79.8%, 97.7%), and the 2-year OS post-transplant was 95.0% (95% CI: 81.5%, 98.7%); 2 (4.8%) participants had primary graft failure, and 1 (2.4%) had secondary graft failure before day +100. The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2% (95% CI: 14.0%, 40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI: 0.9%, 14.4%). There were two deaths in the first year post-BMT (1 -organ failure; 1-ARDS), none in the second year; 33 (78.6%) participants reported at least one re-admission post-BMT, mainly due to either bacterial infection (n=41) or viral reactivation (n=36), table. Conclusion: This multi-center phase-II trial of a reduced intensity haploidentical-BMT in adults with SCD shows durable donor engraftment at 2-years with low mortality. The 2-year EFS and OS are comparable to that reported after MSD myeloablative BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials.

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Post-Transplant Cyclophosphamide for the Prevention of Graft-vs.-Host Disease in Allogeneic Hematopoietic Cell Transplantation: A Guide to Management for the Advanced Practitioner.

Cyclophosphamide remains a critical component to haploidentical transplant conditioning regimens. Post-transplant cyclophosphamide (PTCy) emerged as an effective component of graft-vs.-host disease (GVHD) prophylaxis in the nonmyeloablative haploidentical bone marrow transplant setting. The relative ease of administration compared with ex vivo manipulations and efficacy in reducing GVHD has led to increasing PTCy use in transplant centers around the world. The role of PTCy has expanded to haploidentical transplantation with myeloablative conditioning regimens and peripheral blood progenitor cells as the donor source. Moreover, encouraging results in GVHD management have been shown with the use of PTCy alone or in combination with other immunosuppressives in the human leukocyte antigen-matched donor setting. The toxicity profile of cyclophosphamide varies extensively depending on dose, duration, overall drug exposure, and, potentially, pharmacogenetics. This review highlights the pharmacology, pharmacokinetics, and toxic effects of cyclophosphamide and offers practical guidance for clinical application in the post-transplant setting. We summarize data on the management of high-dose cyclophosphamide toxicities and provide insights into the pharmacogenetic implications on drug efficacy and safety data.

Impaired thymic iNKT cell differentiation at early precursor stage in murine haploidentical bone marrow transplantation with GvHD.

Early recovery of donor-derived invariant natural killer T (iNKT) cells are associated with reduced risk of graft-versus-host disease (GvHD) and overall survival. Patients with severe GvHD, however, had much slower iNKT cell reconstitution relative to conventional T cells. To characterize the delay of iNKT cell reconstitution and explore its possible causes, we used a haploidentical bone marrow transplantation (haplo-BMT) mouse model with GvHD. We found the delayed recovery of thymic and peripheral iNKT cell numbers with markedly decreased thymic NKT1 subset in GvHD mice. The defective generation of thymic iNKT precursors with egress capability contributed to the reduced peripheral iNKT cells in GvHD mice. We further identified intermediate NK1.1- NKT1 precursor subpopulations under steady-state conditions and found that the differentiation of these subpopulations was impaired in the thymi of GvHD mice. Detailed characterization of iNKT precursors and thymic microenvironment showed a close association of elevated TCR/co-stimulatory signaling provided by double positive thymocytes and macrophages with defective down-regulation of proliferation, metabolism, and NKT2 signature in iNKT precursor cells. Correspondingly, NKT2 but not NKT1 differentiation was favored in GvHD mice. These data underline the important roles of TCR and co-stimulatory signaling in the differentiation of thymic iNKT subsets under transplantation conditions.

Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML)

BackgroundKIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy.ResultsIn contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+R and KIR2DS2D/C1+R mismatch versus KIR2DL1D/C2−R mm, KIR2DL2/3D/C1−R mm and KIR3DL1D/Bw4− mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04).ConclusionThis analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

Use of CD122+ natural killer cell precursors for superior anti-leukemia response.

Abstract Acute Myeloid Leukemia (AML) is an aggressive blood cancer in adults. Intensive induction therapy successfully induces a complete response in up to 80% of the adult patients but a fraction of them is refractory or relapses. The fraction of non-responsive or relapsing patients is especially high amongst medically unfit and older patients, who cannot undergo aggressive chemotherapy treatment. Therefore, offering patients failing on first line intensive chemotherapy and medically unfit and older patients an effective treatment option for long-term control or even cure of disease represents a significant yet unmet clinical need. As a component of the innate immunity, NK cells have recently shown great promise for the treatment of patients with different malignancies. Here, we show that injection of human interleukin-2 (IL-2) complexes (IL-2cx) induce the de novo generation and massive expansion of NK cell precursors in vivo. Furthermore, IL-2cx-expanded NK cells exert effector functions with the capacity to control the growth of non-self MHC class I-deficient RMA-S lymphoma cells in vivo, while remaining tolerant towards MHC class-expressing self RMA cells. In an experimental setup mimicking the clinical case of refractory patients after intensive AML induction therapy, IL-2cx treatment mediated strong anti-AML responses following haploidentical bone marrow transplantation without the need for adoptive transfer of donor-derived or in vitro autologous expanded NK cells. Thus, this study demonstrates that IL-2cx immunotherapy allows the in vivo generation and expansion of functionally mature NK cells to achieve long-term response in AML paving the way to an effective treatment option. We are sponsored partly by the Cell Evaluation &amp; Therapy Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and an ACS-IRG to CK.

393 - ABO Incompatibility Did Not Impact Outcomes after Haploidentical Bone Marrow Transplantation with Posttransplant Cyclophosphamide for Patients with Sickle Cell Disease: Single Center Experience

393 - ABO Incompatibility Did Not Impact Outcomes after Haploidentical Bone Marrow Transplantation with Posttransplant Cyclophosphamide for Patients with Sickle Cell Disease: Single Center Experience

389 - The Combination of Rituximab, Plasmapheresis, Intravenous Immunoglobulins and Pre-Transplant Immunosuppression Is an Effective Desensitization Strategy for Patients with Sickle Cell Disease and High Donor Specific Anti-Human Leukocyte Antigen Titer Undergoing Haploidentical Bone Marrow Transplant

389 - The Combination of Rituximab, Plasmapheresis, Intravenous Immunoglobulins and Pre-Transplant Immunosuppression Is an Effective Desensitization Strategy for Patients with Sickle Cell Disease and High Donor Specific Anti-Human Leukocyte Antigen Titer Undergoing Haploidentical Bone Marrow Transplant

Peritransplantation Glucocorticoid Haploidentical Stem Cell Transplantation Is a Promising Strategy for AML Patients With High Leukemic Burden: Comparison With Transplantations Using Other Donor Types

Using a murine haploidentical bone marrow transplantation (BMT) model, we recently showed that peritransplantation administration of glucocorticoid (GC) redistributed donor T cells from the gastrointestinal tract to bone marrow, which resulted in a significant reduction of graft-versus-host disease (GVHD) while promoting graft-versus-leukemia effects. Furthermore, in a retrospective clinical study of patients with acute myelogenous leukemia (AML) undergoing transplantation in non-remission, we also showed that haploidentical stem cell transplantation (haplo-SCT) using peritransplantation GC administration led to a significantly lower relapse rate and better overall survival rate compared with haplo-SCT using post-transplantation cyclophosphamide. In the present study, using the same dataset of patients undergoing GC haplo-SCT, we retrospectively compared with patients with AML undergoing transplantation in non-remission using 3 other donor types: matched sibling donor (MSD), matched unrelated donor (MUD), and umbilical cord blood (UCB). For GC haplo-SCT, 44 patients underwent peripheral blood stem cell transplantation in a single center (Hyogo College of Medicine), with the conditioning treatment consisting of fludarabine, melphalan, anti-thymocyte globulin (2.5 mg/kg), and TBI 3 Gy. Methylprednisolone was given from the start of conditioning treatment, and the GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). The transplantation outcomes were compared with data of 1889 patients undergoing MSD-SCT (n = 449), MUD-BMT (n = 493), or UCB transplantation (UCBT) (n = 947) in non-CR, which were extracted from the Transplant Registry Unified Management Program data, the largest data registry in Japan. For donor engraftment, significantly faster neutrophil and platelet engraftment was achieved with GC haplo-SCT compared with allo-SCT using the 3 other donor types. Neutrophil engraftment was achieved at a median of 10 days for GC haplo-SCT, and 20 days for MSD-, MUD-, and UCB-transplants. Platelet engraftment was achieved at a median of 19.5 days for GC haplo-SCT, 42 days for MSD-SCT and MUD-BMT, and 43 days for UCBT, respectively. The incidence of grade II-IV acute GVHD was lower after allo-SCTs using MSD (hazard ratio [HR] = 0.465, P = .003), MUD (HR = 0.524, P = .010), and UCB (HR = 0.647, P = .067) compared with GC haplo-SCT. There was no significant difference in the incidence of chronic GVHD between GC haplo-SCT and allo-SCT using the other 3 donor types. Regarding relapse, GC haplo-SCT was associated with a significantly lower risk compared with MSD-SCT (P < .001) or MUD-BMT (P = .004). GC haplo-SCT tended to have a lower risk compared with UCBT (P = .063). Especially, all the 43 evaluable GC haplo-SCT recipients achieved CR after transplantation, whereas 23.9%, 22.8%, and 27.0% of patients who underwent MSD-SCT, MUD-BMT, and UCBT could not achieve CR after transplantation, respectively. Regarding non-relapse mortality, GC haplo-SCT was associated with a significantly higher risk compared with MUD-BMT (P = .014), and tended to have a higher risk compared with MSD-SCT (P = .061). There was no significant difference between GC haplo-SCT and UCBT (P = .600). Allo-SCTs using MSD (HR = 2.548, P < .001), MUD (HR = 2.134, P = .005), and UCB (HR = 2.376, P = .001) lead to significantly higher overall mortality compared with GC haplo-SCT; the adjusted overall survival at 3 years was 19.8% for MSD, 26.1% for MUD, 28.0% for UCB, and 65.1% for GC haplo. Thus GC haplo-SCT is a promising treatment option for patients with AML with a high leukemic burden.

Quality of Life in Patients Undergoing Double Umbilical Cord Blood Vs. Haploidentical Marrow Transplantation: A QOL Analysis Report of BMT CTN 1101

Introduction BMT CTN 1101 was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QOL) of patients with hematological malignancies receiving double umbilical cord blood transplants (dUCBT) or haploidentical bone marrow transplants (haplo) with post-transplant cyclophosphamide after reduced intensity conditioning. Extended follow-up at 5 years showed that there were no significant differences in progression free survival (PFS) or overall survival (OS) between the two cohorts. However, the hazard ratio for NRM was 2.69 in favor of haplo transplants with all of the difference seen in the first 18 months post-transplant. The impact of donor source on QOL, however, is unknown. Thus, the objectives of this analysis are to compare longitudinal QOL between dUCBT and haplo and to investigate the association of QOL and clinical outcomes. Methods Enrollment occurred from 6/2012-6/2018, and included 368 patients (n=186 dUCBT, n=182 haplo), age 18-70 with 2 year follow up. QOL assessments included the FACT-BMT measure; the MOS Short Form 36 Physical Component Score (PCS) and Mental Component Score (MCS); the EQ-5D; and the Global QOL Scale. These were completed pre-transplant and at 12 and 24 months post-transplant. To account for missing assessments, scores were compared between arms using an inverse probability weighted-independent estimating equations (IPW-IEE) method that models scores in surviving patients while accounting for baseline variables (age, race/ethnicity, primary disease, disease risk, performance status, and HCT-CI) and follow-up outcomes that impact the likelihood of missingness. Cox models evaluated potential associations of pre-transplant QOL scores with OS and PFS while adjusting for these baseline variables. Analyses were performed using intention-to-treat (ITT) patient assignment from the time of randomization. A threshold of 1% was used to determine statistical significance for all analyses. Results No significant differences were observed between treatment arms in baseline patient, disease, and transplant characteristics (previously described) among patients who participated in at least one QOL assessment. In the UCB arm, PRO response rates were 145/186 (78%) pre-transplant, 67/105 (64%) at 12 months, and 47/85 (55%) at 24 months. In the haplo arm, PRO response rates were 134/182 (74%) pre-transplant, 79/115 (69%) at 12 months, and 50/102 (49%) at 24 months. HCT-CI >3 pre-transplant and relapse at 12 and 24 months were the most consistent factors significantly associated with lower completion of QOL questionnaires at respective time points. We found no significant difference in any of the QOL scores at pre-transplant, 12, and 24 months between the treatment arms (Figure 1). In multivariable IPW-IEE models, pre-transplant FACT-BMT total score, SF-36 PCS, and EQ-5D scores were the only significant predictors of post-transplant QOL scores. There was no significant association of treatment arm or baseline clinical variables with FACT-BMT or SF-36 PCS scores post-transplant. Age >60 was associated with higher mean EQ-5D (0.08, 99% CI 0.025-0.131, p=0.0002) and SF-36 MCS scores (4.45, 99% CI 0.288-8.622, p=0.0059) on post-transplant assessments. There was no significant impact of treatment arm on Global QOL score or subscale scores post-transplant. We evaluated the association of post-transplant clinical events with primary QOL endpoints (Table 1). Relapse and Grade III-IV aGVHD were associated with significant declines in mean FACT-BMT and SF-36 PCS scores. cGVHD was associated with a decline in mean EQ-5D utility scores. We found no significant association between pre-transplant QOL scores and OS or PFS (p>0.10 for all models). There were no significant interactions between treatment groups and baseline characteristics on QOL measures. Conclusions This longitudinal QOL analysis of BMT CTN 1101 showed that donor type did not impact post-transplant QOL. Pre-transplant QOL scores were the only predictor of post-transplant 12 and 24 month scores which, however, were not associated with OS or PFS in either treatment arm. Clinical events of GVHD and relapse were associated with declines in QOL scores. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Donor T-Cell Engraftment Is Critical for Immune Tolerance in Reduced Intensity Haploidentical Bone Marrow Transplant with Post-Transplant Cyclophosphamide for Sickle Cell Disease: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Introduction: Global application of bone marrow transplant (BMT) for sickle cell disease (SCD) requires a protocol that addresses the core limitations of this approach - namely donor availability, graft-versus-host disease (GVHD) and engraftment. To meet these demands, we developed the Vanderbilt Haploidentical Learning Collaborative across 10 countries and 22 sites with a common related HLA-haploidentical (haploBMT) reduced intensity platform. Our phase II trial (ClinicalTrials.gov identifier NCT01850108) was successfully employed with a probability of overall survival of 96.7% (95% CI 87.1- 99.2%) at one year, but a high rate of graft failure (GF) in pediatric patients (<18 years), prompting us to perform an in-depth analysis of engraftment kinetics. Methods: Seven Institutional Review Board approved sites enrolled patients undergoing a haploBMT for SCD from 8/14/2014-2/28/2022. Common conditioning included: thymoglobulin 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included post-transplant cyclophosphamide 100 mg/kg, mycophenolate mofetil, and sirolimus (de la Fuente et al. BBMT 2019). Hydroxyurea and hypertransfusion to lower the percentage hemoglobin S <30% for at least 60 days pre-conditioning was variably employed. Primary GF was defined as <5% donor myeloid/lymphoid or whole blood (WB) chimerism at one-month (M1) post-haploBMT. Secondary GF was defined <5% donor myeloid/lymphoid or WB chimerism with prior documentation of >5% donor cells at M1. Categorical variables were compared using Fisher's exact test. Continuous variables were compared using Wilcoxon rank sum test. Results: A total of 41 pediatric and 39 adult subjects were enrolled for data analysis. GF was only noted in the pediatric cohort with 4 (10%) and 6 (15%) developing primary and secondary GF, respectively. Primary GF was associated with lack of a hypertransfusion pre-conditioning (0% vs 54%) and CMV reactivation (75% vs 21%) compared to engrafted patients. For secondary GF, we evaluated the mechanisms of prolonged tolerance including early donor T-cell engraftment. Although our data was limited by only 28% (n=22) having lymphocyte subsets at M1, pediatric patients had lower T-cell counts (median 45.0 cells/µL, IQR: 6.50-118) compared to adults (median 723 cells/µL, IQR 618-1325) (Figure). Older recipient age and positive recipient CMV status were the only variables significantly associated with both CD4+ plus CD8+ count >100 cells/µL and donor CD3+ chimerism >90% (Table). Pediatric T-cell engraftment matched adult values at later time points except in patients with secondary GF and improvement in T-cell counts above 500 cells/µL at M2 was associated with a higher TNC dose (median 4.57x108 cells/µL, IQR 2.86-5.75 vs 1.74x108 cells/µL, IQR 1.55-2.24). We next evaluated the impact of low donor T-cell engraftment at M1. Patients with low donor T-cell engraftment had significantly higher rates of immune-mediated complications including secondary GF (CD3+ chimerism <90%: 42.9% vs 0%, p=0.001) and chronic GVHD (CD4+ plus CD8+ <100 cells/µL: 63.6% vs 9.1%, p=0.024). Incidence of viral reactivation was not different between cohorts. Disease and GVHD-free survival positively trended with donor T-cell engraftment (Table), and patients with both CD4+ plus CD8+ count <100 cells/µL and donor CD3+ chimerism <90% at M1 had severe immune-mediated complications, implicating an association of inadequate immune control with poor early donor T-cell engraftment. Conclusions: This analysis illustrates the importance of early T-cell engraftment in developing bi-directional immune tolerance following haploBMT. Although our study identified recipient age and CMV status as important factors in T-cell engraftment, the mechanism behind these factors, such as age-associated differences in drug metabolism and the role of CMV in promoting donor T-cell expansion, and how donor T cells promote tolerance require additional investigation. Our study demonstrates the importance of monitoring T-cell counts and sorted chimerism early post haploBMT and raises the question of how best to intervene in patients with low donor T-cell engraftment at M1. Our consortium plans to prospectively evaluate immune tolerance, including regulatory T-cell dynamics and impact of immune interventions at M1, to answer these important questions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Dose Ruxolitinib in Indian Haplo-Identical Transplant Patients with Steroid Refractory Acute Graft Versus Host Disease

Background: The number of allogeneic bone marrow transplants done in India is increasing by year. Unlike west, this region had got its own unique complications in the post-transplant period especially multi drug resistant gram negative bacterial sepsis reflecting in a higher transplant related mortality. With increasing number of Haplo-identical transplants, the problem of steroid refractory Graft versus host disease (GVHD) is a major reason for post-transplant morbidity and mortality. As most available immunosuppressive agents worsen cytopenia and in turn sepsis, we need a relatively safer method of managing steroid refractory GVHD in our setting. In this observational study, we used a lower dose of 5mg per day Ruxolitinib for a period of minimum 60 days post-transplant to look into clinical benefit. This dose was chosen considering the recovering platelet count and financial considerations in our resource limited setting. Method: This observational study was conducted from July 2019 to January 2022. A total of 11 steroid refractory GVHD Haploidentical transplant patients were chosen for data analysis that completed the scheduled dosage regimen of Ruxolitinib. Nine out of 11 patients were Acute Myeloid leukemia and two were Acute Lymphoblastic leukemia. The standard conditioning regimen in all was Fludarabine / Busulfan & Cyclophosphamide based conditioning. Additional GVHD medications used were PTCy, Tacrolimus, MMF and steroids with oral budesonide. Tab Ruxolitinib was started around Day +5 post steroids in people who were fitting into steroid refractory acyte GVHD at a fixed dose of 5mg OD for a minimum period of ten weeks. Two cases had one week dose interruption due to cytopenia. Results : At start of Ruxolitinib seven patients had Grade III gut and liver GVHD and rest four had grade II GVHD. Skin was grade II in all patients. When evaluated at Day +58 of Ruxolitinib, all patients were alive and nine of them were on tapering doses of steroids. All continued Tacrolimus at therapeutic doses. No excess bleeding or cytopenia requiring transfusion support happened during this period. As mentioned earlier two cases Ruxolitinib was stopped in view of platelet counts going below 20,000. On evaluation at day +100 post transplant, two patients continued to have grade II Liver, gut and skin GVH and one patient expired on day +48 to sepsis. Rest of eight patients had a Grade I skin, liver and gut GVHD and were able to continue Ruxolitinib further. We started Ruxolitinib taper in cases where steroids were stopped. As case numbers were very low and it's a pilot observation study, we didn't do detailed statistical analysis which may be misleading and give false promises. Conclusion: In our setup, we were finding it a difficulty to use the prescribed 10mg BD Ruxolitinib dose in adults due to fear of worsening cytopenia /sepsis and financial toxicity. We tried to observe the benefit of a lower dose in steroid refractory GVHD post Haplo-identical bone marrow transplant. No pharmaco-genetic assays were done and it's a very small sample size. This observational study revealed a better efficacy and tolerability of this dosing regimen in Indian Haplo-identical patients with a considerable response without compromising blood counts. The results are looking more promising to conduct this study in a bigger scale to benefit our patients from resource limited settings. Reference Zhao Y, Shi J, Luo Y, Gao F, Tan Y, Lai X, Yu J, Wei G, Huang H. Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 May;26(5):e128-e133. doi: 10.1016/j.bbmt.2020.01.012. Epub 2020 Jan 23. PMID: 31982545.

Effective Desensitization Strategy for Patients with Sickle Cell Disease with High Donor Specific Antibodies Undergoing Haploidentical Bone Marrow Transplant with Posttransplant Cyclophosphamide

Effective Desensitization Strategy for Patients with Sickle Cell Disease with High Donor Specific Antibodies Undergoing Haploidentical Bone Marrow Transplant with Posttransplant Cyclophosphamide

Haploidentical Hematopoietic Cell Transplantation for Myelofibrosis in the Ruxolitinib Era

Haploidentical stem cell transplantation is a viable strategy in the absence of an HLA-identical donor, but in myelofibrosis (MF), concerns may rise due to the risk of graft failure. Considering that engraftment is a major issue in MF, we sought to highlight its impact on survival outcomes. In addition, we explored the impact of pretransplantation ruxolitinib administration as an independent variable on outcomes. Here we report the results of a retrospective, monocentric experience with T cell-replete haploidentical bone marrow transplantation with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis in 51 consecutive MF-affected patients. The median duration of follow-up was 47 months. All 51 patients received a double-alkylating conditioning regimen, and 21 patients (41%) received pretransplantation ruxolitinib. Thirty-seven of 49 evaluable patients (76%) achieved full donor chimerism with neutrophil engraftment, 8 of 49 (16%) experienced graft rejection, and 4 of 49 (8%) had primary poor graft function. Splenectomy was more frequent among patients who engrafted (P=.06). Graft rejection was the sole factor negatively impacting overall survival (hazard ratio [HR], 4.19; 95% confidence interval [CI], 1.37 to 12.80; P=.01) and the major determinant for nonrelapse mortality (HR, 10.31; 95% CI, 2.54 to 41.82; P=.001). The 24-month incidence of relapse was 19% and was negatively impacted by splenectomy (HR, 5.84; 95% CI, 1.28 to 26.72; P=.02). The cumulative incidence of grade II-IV acute GVHD was 27% (95% CI, 20% to 33%), and that of grade III-IV acute GVHD was 8% (95% CI, 4% to 12%). The 24-month cumulative incidence of all-grade chronic GVHD was 28% (95% CI, 21% to 35%). Our data show that T cell-replete haploidentical bone marrow transplantation following double-alkylating conditioning in patients with MF is associated with favorable rates of GVHD and an acceptable relapse risk; nevertheless, rejection is not negligible and is associated with significant mortality. Splenectomy, which favors engraftment, is predictive of a higher risk of relapse.

O-09: DURABLE ENGRAFTMENT AFTER PHARMACOLOGICAL PRE-TRANSPLANT IMMUNOSUPPRESSION FOLLOWED BY REDUCED-TOXICITY MYELOABLATIVE HAPLOIDENTICAL STEM CELL TRANSPLANTATION IN HIGHLY HLA-IMMUNIZED ADULTS WITH SICKLE CELL DISEASE

Purpose: Sickle cell disease (SCD) is the most common genetic disorder worldwide and despite advances in best supportive care, remains a disease with high morbidity and mortality. Allogeneic stem cell transplantation (AlloHSCT) is a curative treatment modality. Reports in adults are limited because of the high risk of transplant related toxicity, graft rejection and the lack of suitable donors. The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to AlloHSCT. Antibodies against donor-specific HLA (DSA) which are frequently detected in multi-transfused SCD patients increase the risk of engraftment failure in HLA mismatched AlloHSCT. Materials and methods: We report the results of five patients with severe SCD (22, 46, 27, 30 and 30 years old) and DSA who underwent an unmanipulated haploidentical bone marrow transplantation (HaploBMT) after a RT-MAC regimen. The conditioning regimen consisted in rabbit antithymoglobuline (ATG), fludarabine (flu) and busulfan. GVHD prophylaxis was performed with PT-Cy, cyclosporine A and mycophenolate mofetil. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immunosuppression (PTIS) phase was added prior to the conditioning regimen. This initially was based on flu in combination with dexamethasone and was later modified to include cyclophosphamide (cy) and ATG in patients with CNS involvement. The desensitization protocol of DSA consisted in rituximab, velcade and plasmapheresis followed by high dose intravenous immunoglobulins. (Figure 1) Importantly, the patients were highly immunized with severe hemolytic crises and high DSA titers (range, MFI 2000 – 10003); two patients had also a history of cerebrovascular complications whereas the 46 years old woman with sickle cell specific multi-organ damage. All donors were first degree family members (sibling, parent, child). Results: All patients successfully engrafted with neutrophil reconstitution on days 26, 31, 16, 24 and 21 days (median 23 days), respectively. The procedure was well tolerated with only mild toxicity. None of the patients developed acute GVHD. One patient developed moderate chronic skin GVHD at day +489 after HaploBMT with rapid response to conventional immunosuppressive therapy. After a follow-up of 2323, 1770, 994, 962 and 263 days (median 994 days) respectively, chimerism analysis and detection of hemoglobin S confirmed sustained donor engraftment. All patients were free of any pain symptoms with excellent quality of life. Conclusion: Our report shows that HaploHSCT after a busulfan-based RT-MAC regimen is feasible and safe and allows stable long-term engraftment and excellent disease control. Graft failure may be overcome by adding a PTIS phase prior to the conditioning regimen. Further studies are necessary to confirm these promising results and allow a widened access of this platform technology to patients with high-risk sickle cell disease.Desensitization procedure E. BERNIT declares a conflict of interest: Consultancy, Expert: NOVARTIS PHARMA