Matched Sibling Donor Hematopoietic Stem Cell Transplantation Research Articles

Comparing between HLA-matched sibling donor allogenic HSCT and non-sibling matched related donor allogenic HSCT outcome in pediatric patients; single center retrospective study.

Extended family donor search other than siblings may yield an HLA matched donor in communities with high rate of consanguinity. The outcome of patients who are transplanted from non-sibling matched related donors (NS-MRD) including engraftment and graft versus host disease (GVHD) are scarce in comparison with matched sibling donor (MSD). We retrospectively reviewed the outcome of all our pediatric hematopoietic stem cell transplantation (HSCT) patients who had non-sibling matched related donor and controlled them with matched sibling donor HSCT (based on age, indication of HSCT, conditioning regimen, GVHD prophylaxis, serotherapy, stem cell source and cytomegalovirus status). A total of 76 patients were reviewed during study period. Thirty patients (39.5%) in NS-MRD arm and 46 patients in MSD (60.5%) were identified after matching in age, disease, and conditioning regimens. All patients had similar approach including stem cell source and GVHD prophylaxis (CNI + 2nd agent). Out of the NS-MRD group, 18 patients (59%) had one of their parents as a donor and the rest as second degree relatives. Both groups were equally distributed and were homogeneous. Both groups had no statistically significant difference in outcome including engraftment, GVHD and Chimerism tests results. GVHD was seen in (13%) NS-MRD patients compared to (11%) in MSD patients. All patients remain alive with median follow up of 1249 days (431-3525). This study showed no significant difference in allogenic HSCT outcomes between matched sibling donors and non-sibling matched related donors and support using the same management approach in terms of conditioning therapy, GVHD prophylaxis, and serotherapy only if indicated.

Basiliximab Treatment for Patients With Steroid-Refractory Acute Graft-Versus-Host Disease Following Matched Sibling Donor Hematopoietic Stem Cell Transplantation.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III-IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67-3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%-72.2%) and 55.4% (95% CI = 44.3%-69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%-29.5%) and 33.8% (95% CI = 21.8%-45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

Efficacy analysis of anti-thymocyte globulin regimens with different timing strategies for matched sibling donor hematopoietic stem cell transplantation

Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/μl vs 852 cells/μl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.

FLT3-ITD Allelic Ratio and NPM1 Mutation Do Not Impact Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Propensity Score- Matching Study

FLT3-ITD mutation has consistently been correlated with poor outcomes in AML patients. Allo-HSCT (allogeneic hematopoietic stem cell transplantation) plays a major role in curing blood diseases. Whether allo-HSCT can eliminate the detrimental effects of FLT3-ITD mutation in AML patients remains debatable. In addition, studies showed that FLT3-ITD allelic ratio (AR) and NPM1 mutation appear to further influence the prognostic utility of FLT3-ITD in patients with FLT3-ITD-mutated AML. The influence of NPM1 mutation and AR on FLT3-ITDmut patients remains unclear in our database. To compare the survival outcomes following allo-HSCT between FLT3-ITDmut and FLT3-ITDwt patients and further analyze the influence of NPM1 and AR on outcomes. 118 FLT3-ITDmut patients and 497 FLT3-ITDwt patients with allo-HSCT were matched 1:3 on the propensity score using a nearest-neighbor matching with a caliper size of 0.2. 430 AML patients were considered, including 116 FLT3-ITDmut patients and 314 FLT3-ITDwt patients. OS (overall survival) and LFS (leukemia-free survival) of FLT3-ITDmut patients were similar to FLT3-ITDwt (2-year OS:78.5% vs 82.6%, P=0.374; 2-year LFS: 75.1% vs 80.8%, P= 0.215). A cut-off of 0.50 was applied to define subgroups with a low or high AR of FLT3-ITD, no significant CIR (cumulative incidence of relapse) and LFS differences were observed between the low AR and high AR groups (2-year CIR: P=0.617; 2-year LFS: P=0.563). CIR and LFS were comparable when patients were grouped according to the presence or absence of NPM1 and FLT3-ITD (2-year CIR: P=0.356; 2-year LFS: P=0.159). Additionally, the CIR and LFS of FLT3-ITDmut and FLT3-ITDwt patients tended to be different after MSD-HSCT (matched-sibling donor hematopoietic stem cell transplantation) (2-year CIR: P= 0.072; 2-year LFS: P= 0.084), however, the differences were not observed in patients with haplo-HSCT (2-year CIR: P= 0.59; 2-year LFS: P= 0.794). The presence of MRD before transplantation and non-CR1 were risk factors related to inferior outcomes in a multivariate analysis, regardless of FLT3-ITD or NPM1 status. Our results suggested that allo-HSCT, especially haplo-HSCT, may overcome the adverse effect of FLT3-ITD mutation, regardless of the NPM1 status or AR. Allo-HSCT could be an ideal option for AML patients with FLT3-ITD.

Comparison of efficacies of haploidentical transplantation and matched sibling donor transplantation in treating T‐cell lymphoblastic lymphoma

To investigate the differences in efficacy and safety between haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and matched sibling donor HSCT (MSD-HSCT) in patients with T-cell lymphoblastic lymphoma (T-LBL). In this retrospective analysis, we enrolled 38 patients who had undergone allogeneic HSCT at our institution between 2013 and 2021. The study participants included 28 patients who underwent HID-HSCT and 10 patients who underwent MSD-HSCT. We compared the patient characteristics and treatment effectiveness and safety between the two groups and evaluated potential prognostic variables for patients with T-LBL. The median follow-up durations in the HID-HSCT and MSD-HSCT groups were 23.5 (range: 4-111) and 28.5 (range: 13-56) months, respectively. All patients showed full-donor chimerism after hematopoietic stem cell transplantation (HSCT). Except for two patients in the HID-HSCT cohort who developed poor graft function, all patients showed neutrophil and platelet engraftments after HSCT. The cumulative incidences of grades III-IV acute graft-versus-host disease were 37.5% and 28.57% in the HID-HSCT and MSD-HSCT groups, respectively (p = 0.84). The cumulative incidences of limited (34.13% vs. 28.57%, p = 0.82) and extensive (31.22% vs. 37.50%, p = 0.53) chronic graft-versus-host disease did not differ between the two cohorts. In the HID-HSCT and MSD-HSCT cohorts, the estimated 2-year overall survival rates were 70.3% (95% confidence interval [CI]: 54.9%-90.0%) and 56.2% (95% CI: 31.6%-100%), respectively (p = 1.00), and the estimated 2-year progression-free survival (PFS) rates were 48.5% (95% CI: 32.8%-71.6%) and 48.0% (95% CI: 24.6%-93.8%), respectively (p = 0.94). Furthermore, the Cox proportional-hazards model showed that a positive positron emission tomography/computed tomography (PET/CT) status before HSCT in patients who had completed chemotherapy was an independent risk factor for PFS in the multivariate analysis (p = 0.0367). This study showed that HID-HSCT had comparable effectiveness and safety to MSD-HSCT in treating T-LBL. HID-HSCT could serve as an alternate treatment option for T-LBL in patients without an eligible identical donor. Achievement of the PET/CT-negative status before HSCT may contribute to better survival.

Comparison of Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for Patients with Severe Hepatitis-Associated Aplastic Anemia

Background：Hepatitis-associated aplastic anemia (HAAA) is known as a rare variant of acquired aplastic anemia, characterized by a syndrome of bone marrow failure following the development of hepatitis. Immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) could provide lifesaving opportunities for severe HAAA patients. However, to date, no cohort has characterized treatment outcome and long-term survival between those patients receiving IST and HSCT. In this study, we aim to retrospectively evaluate the outcome of these two therapies for severe HAAA in China. Methods: Patients consecutively diagnosed as severe HAAA between August 2008 and Jan 2021 were enrolled in this study. The definition of severe HAAA is that severe aplastic anemia developed within three months after documented hepatitis. The enrollments were patients who received HSCT or IST as a first-line treatment. Patients with HSCT were conditioned as described previously with cyclophosphamide (Cy, 120-150 mg/kg, divided doses on days -6 to -2), and rabbit ATG (Thymoglobulin®, Genzyme, Cambridge, MA) (2.5mg/kg once i.v. daily on days -6 to -2) or p-ALG (Anti-lymphocyte Immunoglobulin®, Wuhan Institute of Biological Products Co., Ltd., China) (20mg/kg once i.v. daily on days -6 to -2), Fludarabine 150 mg/m2 i.v.in divided doses on days -6 to -2, with or without Busulfan (Bu, 0.8 mg/kg four times i.v. daily on days -7 and -6). IST consisted of both rabbit ATG (rATG) (3~3.75mg/kg once i.v. daily on 5 days), porcine antilymphocyte globulin (pALG)(20mg/kg once i.v. daily on 5 days), combined with a six-month course of cyclosporine (3mg per kilogram per day orally, with adjustment of the dose to maintain a blood level between 200 and 400 ng per milliliter). Probabilities of overall survival (OS), failure-free survival (FFS), and treatment-related-mortality (TRM) were calculated by Kaplan-Meier method. Results and Discussion: This study retrospectively included 94 consecutive HAAA patients, including 68 patients underwent HSCT and 26 patients receiving IST. The IST and HSCT groups were similar with respect to age and gender ratio. The median follow up were 1752 (±153.62, 95%CI 1450.90~2053.10) days, and 2648 (±321.41, 95%CI 2018.05-3277.96) days among alive patients in the IST and HSCT group, respectively. In HSCT group, all patients achieved neutrophil engraftment. No primary or secondary graft failures (GF) was documented. Compared with patients receiving alternative donor HSCT (n=11), patients in matched sibling donor HSCT (MSD-HSCT) group (n=15) had a significant lower cumulative incidence of acute graft versus host disease (aGVHD) (20±10.33% vs 56.4±15.47%, p=0.048), and lower incidence of cytomegalovirus (CMV) reactivation group (72.73% vs 13.33%, p=0.004). No clinical significance of chronic graft versus host disease (cGVHD) incidence group (43.4±18.85% vs 50±35.4%, p=0.78) and bacterial/fungus infection (26.67% vs 36.36%, p=0.683) was found between MSD-HSCT group and alternative donor-HSCT. Attributable causes of death were pneumonias and severe infection in patients receiving HSCT. In IST group, the hematology response rate to treatment evaluated at 3m, 6m and 12m was 27.68%, 52.94%, and 60.23%, respectively. There were thirteen patients were non-evaluable, including six patients transferred to perform HSCT, two patients were diagnosed MDS/AML transformation and one patient relapsed. The 5-year overall survival (OS) and failure-free survival (FFS) rate was 85.5±4.44% (95% CI, 0.772, 0.946) and 69.6± 5.35% (95% CI, 0.599,0.809) of all enrolled HAAA patients, respectively (Figure 1). For patients receiving different therapy, the 5-year OS rates were 92.86 ± 6.88% in MSD-HSCT group, 72.7± 13.43% in alternative donor-HSCT, and 84.1 ± 7.28% in the IST group (P = 0.56). Otherwise, the 5-year estimated FFS rate was 56.0± 11.51% in the IST group, compared with 92.86 ± 6.88% in the MSD-HSCT group and 72.7± 13.43% in alternative donor-HSCT group (P = 0.10). The cumulative incidence of treatment-related-mortality (TRM) of MSD-HSCT, alternative-HSCT and IST was 7.1±6.9% (95% CI, 80.30-100), 27.3±13.4% (95% CI, 50.60-100), 14±5.54% % (95% CI, 7.58-97.6) (p=0.22), respectively. Even there was no difference between the HSCT and IST groups in OS, MSD-HSCT group still showed superior FFS. Patients receiving alternative donor HSCT, and IST showed comparable OS and FFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination of Cytogenetic Classification and MRD Status Correlates with Outcomes of Autologous Versus Allogeneic Stem Cell Transplantation in Adults with B Cell-Acute Lymphoblastic Leukemia in First Remission

Objectives: To analyze overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of patients with B cell-acute lymphoblastic leukemia (B-ALL) who received autologous or allogeneic stem cell transplantation and to provide the basis for the choice of transplantation method. Methods: We retrospectively investigated the outcomes of 388 adult patients with B-ALL in our center. The OS, LFS, CIR and NRM rate and the impact of minimal residual disease (MRD) within 3 chemotherapy cycles along with risk classification were explored. Results: Both univariate and multivariate analysis found that negative MRD within 3 chemotherapy cycles was the important factor associated with the prognosis. As to 355 patients who obtained first complete remission (CR1), we divided patients into 3 groups according to the risk stratification and MRD status within 3 chemotherapy cycles. For patients with negative MRD within 3 chemotherapy cycles and standard-risk group, the 3-year OS (82.5% vs 74.1%, P=0.364), LFS (74.5% vs 74.1%, P=0.904), CIR (25.5% vs 17.6%, P=0.648) and NRM rates(0% vs 8.3%, P=0.234) were not significantly different between autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) group（Figure 1）. In patients with negative MRD and high-risk factors, although auto-HSCT group and allo-HSCT group had similar 3-year OS(72.7% vs 68.5%, P=0.436) and LFS rate (62.8% vs 56.0%, P=0.375) , the lower NRM (1.5% vs 25.1%, P=0.000) was offset by higher CIR(35.7% vs 18.9%, P=0.018) in auto-HSCT group compared with allo-HSCT group（Figure 2）. As for other patients with high-risk factors and positive MRD after 3 chemotherapy cycles, the prognosis of auto-HSCT group was evidently worse than those of allo-HSCT group as there was a lower trend of 3-year OS (50.0% vs 66.0%, P=0.077), LFS rate (30.8% vs 47.1%, P=0.398) and significantly higher CIR rate(71.4% vs 39.1%, P=0.018) in auto-HSCT group compared to allo-HSCT group（Figure 3）. MRD within 3 chemotherapy cycles was also related to the selection of allogeneic transplantation methods and pretreatment schemes. The 3-year OS (67.4% vs 60.8% vs 65.2%, p=0.735), LFS (56.3% vs 48.3% vs 58.3%, P=0.538), CIR (21.7% vs 23.3% vs 13.3%, P=0.784) and NRM rate (22.1% vs 28.4% vs 28.3%, P=0.672) were similar in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT), haploid hematopoietic stem cell transplantation (haplo-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT) group patients who achieved negative MRD within 3 chemotherapy cycles. While MSD-HSCT group tended to have lower 3-year LFS (33.0% vs 54.1% vs 41.7%, P=0.198) and higher CIR rate (53.2% vs 33.7% vs 46.2%, P=0.233) when comparing with haplo-HSCT and URD-HSCT group patients whose MRD were still positive within 3 chemotherapy cycles. Moreover, in patients who achieved negative MRD within 3 chemotherapy cycles, there was no significant difference in 3-year CIR rate (24.5% vs 23.1%, P=0.784) between TBI group and non-TBI group, but the lower OS (64.2% vs 76.3%, P=0.027) and LFS (54.4% vs 71.3%, P=0.091) was mainly due to the higher NRM rate (17.8% vs 5.6%, P=0.062) in TBI group. For MRD positive patients, TBI group had advantages over non-TBI group, demonstrating a trend of higher 3-year OS (65.0% vs 42.9%, P=0.105), LFS (44.8% vs 27.1%, P=0.138), lower CIR (43.6% vs 63.8%, P=0.106) and similar NRM rate (11.7% vs 9.1%, P=0.671). In addition, we found that 8 most frequently mutated genes were KMT2D、FAT1、NRAS、PAX5、KRAS、SETD2、ASXL1、PTPN11 in 175 patients with preliminary second generation sequencing results（Figure 4）. Mutations in CARD11 and NOTCH signaling pathway were correlated with lower LFS (CARD11: 56.3% vs 16.7%, P=0.002; NOTCH signaling pathway: 59.2% vs 38.8%, P=0.049)（Figure 5）. Conclusions: Auto-HSCT with maintenance therapy after HSCT and non-TBI pretreatment schemes appears to be an attractive treatment option for patients with B-ALL especially for those who achieved negative MRD within 3 chemotherapy cycles. For MRD positive patients, allogeneic transplantation and TBI pretreatment schemes may be more effective. Key words: auto-HSCT, allo-HSCT, acute lymphoblastic leukemia, minimal residual disease Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S105: ADDING AZATHIOPRINE/HYDROXYUREA PRECONDITIONING TO ALEMTUZUMAB/TBI CONDITIONING IMPROVES DONOR CHIMERISM IN MATCHED SIBLING DONOR STEM CELL TRANSPLANTATION IN ADULT SICKLE CELL DISEASE PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) has shown promising results in adult SCD patients.1,2 Patients treated with this regimen had their sickle cell phenotype corrected with only mild complications and no reports of graft-versus-host disease (GvHD). However, most of the described patients did not reach complete donor chimerism with graft failure rates of 13%. Furthermore, in almost 10% of patients, immunosuppressives could not be withdrawn because of too low T cell chimerism (<50%).2 We hypothesized that adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism, reduce the risk of graft failure and improve successful withdrawal of immunosuppressives. Aims: In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning on donor chimerism and graft failure in patients receiving non-myeloablative MSD HSCT for SCD. Methods: Adult SCD patients who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day –10, aiming for HbS <30%. Conditioning with alemtuzumab/TBI was started on day –7. Graft versus host disease (GvHD) prophylaxis consisted of sirolimus. Results: As of October 2021, 13 SCD patients (median age 30.6 (range 19–49) years) were transplanted. Twelve patients (92.3%) engrafted successfully. After a median follow-up of 24 months, median donor myeloid and T cell chimerism of engrafted patients were 100% (IQR 84–100%) and 77% (IQR 70.5%-82.5%), respectively. These donor chimerism percentages are higher than previously reported with alemtuzumab/TBI only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Patients reaching 1-year post-transplantation were able to stop sirolimus without decreases in chimerism. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI results in improved donor chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T cell chimerism >50% at 1-year post-transplantation and were able to stop immunosuppressives as scheduled.

Comparable Outcome of CD3+-/CD19+ Depleted Haploidentical with Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Advanced Stage Sickle Cell Disease: Result of a Pilot Study

IntroductionSickle cell disease (SCD) is an inherited disorder with an estimate of 300.000 affected newborns per year worldwide. Despite significant improvements in preventive measures, supportive care and conventional therapy, substantial morbidity and mortality with a reduced life expectancy persists. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care for SCD patients (pts). But MSD and unrelated matched donor availability is <20% and graft- versus-host disease (GvHD) remains to be associated with significant morbidity and mortality with T cell repleted grafts and standard GvHD prophylaxis, which is unacceptable, particularly in pts with non-malignant diseases. A T cell depleted haploidentical HSCT (T-haplo-SCT) expands donor availability while exhibiting low GvHD rates. In our single center pilot study, we compared T-haplo-SCT with a MSD HSCT in pts with advanced stage SCD, using almost identical transplant conditions except donor source and GvHD prophylaxis.Methods17 pts were transplanted for advanced stage SCD-related complications. Five SCD pts received bone marrow (BM) from a MSD and 12 peripheral blood stem cells (PBSC) from a haploidentical donor. The conditioning regimen for both groups consisted of thiotepa (2x5mg/kg), fludarabine (4x40mg/m2), treosulfan (3x14g/m2) and anti-thymocyte globulin (ATG, Neovii, 3x15mg/kg), given on day -9 to -7 for T-haplo-SCT and on days -3 to -1 for MSD. In addition, Cyclosporine A (CSA) or Tacrolimus and MMF was applied for GvHD prophylaxis. All pts underwent exchange transfusions prior to conditioning and means of fertility preservation. The MSD pts included four females and one male, median age 22 years (range 9 to 25 years). Three suffered from homozygous SCD, two from HbS/ß-thalassemia. The BM graft consisted of a median of 2,2 x 106 CD34+ cells/kg bodyweight, with a A/S in three and a A/A genotype in two donors. In T-haplo-SCT, five were females and seven were males. Median age was 18 yrs (range 3 to 28 yrs). Nine had homozygous SCD, three HbS/ß-thalassemia. The PB grafts consisted of a median of 12,2 x 106 CD34+ cells, 11,2 x 103 CD3+ and 23,3 x 103 CD19+ cells/kg. Haploidentical donors were fully haplotype mismatched relatives (1 mother, 8 fathers, 1 cousin, 1 sister and one step sister). Donor genotype was Hb A/A in one and Hb A/S in all others.ResultsThe median follow-up was 21 months in the MSD group and 26 months in T-haplo-SCT group. The median hospitalization was 38 days for both. The median time to engraftment was faster in T-haplo-SCT versus MSD: 16 versus 23 days for leukocytes, 18 versus 23 days for granulocytes and 11 versus 21 days for thrombocytes. The median T (>500/µl) and B cell recovery (>100/µl) in T-haplo-SCT versus MSD was 115 versus 103 days and 85 versus 140 days, respectively.Two pts in the T-haplo-SCT group developed a stable mixed PB chimerism with no SCD-related complications off immunosuppression. Lineage specific chimerism analyses of red cell precursors (CD235a, glycophorine A) in the BM of these pts showed a complete red cell chimerism. The median HbS level off immunosuppression was comparable in both groups (37-38%). In all 17 pts, the conditioning regimen was well tolerated. Mild veno-occlusive disease (VOD/SOS) was diagnosed in 1 MSD patient and a transient thromboembolic event in one T-haplo-SCT patient. One patient developed a life threatening capillary leak syndrome during ATG treatment and subsequent PRES and was rescued by a switch to everolimus MMF prophylaxis. One patient from the T-haplo-SCT succumbed to a CMV pneumonitis combined with rotavirus gastroenteritis. None of our pts developed a grade III-IV acute GvHD. Five T-haplo-SCT and one MSD patient developed steroid responsive grade I-II acute GvHD. One of five MSD and three of twelve T-haplo-SCT pts developed mild to moderate steroid responsive chronic GvHD, which resolved in the meantime. CMV and EBV reactivations were observed but could be treated with standard of care except one patient mentioned above. One patient after T-haplo-SCT developed BK virus nephritis. All pts are stably engrafted off immunosuppression and free of SCD-related complications.ConclusionsIn our experience T-haplo-SCT with CD3+/CD19+ depleted PBSC is safe and efficient with a very low incidence of GvHD and is at least comparable to MSD HSCT, even for advanced stage SCD pts. DisclosuresCorbacioglu:Jazz Pharmaceuticals: Consultancy, Honoraria.

Reduced-Intensity Conditioning Is Successful in Matched Sibling Bone Marrow Transplantation As a Cure for Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is the most common genetic disease in this country, affecting 1 in every 72,000 individuals in the United States, with sickle cell trait found in 1 in 12 African-Americans. Without curative therapy, disease related mortality is as high as 14% in adolescents and young adults, with a decreased life expectancy compared to individuals without SCD. Hematopoietic stem cell transplantation (HSCT) is the only established cure, and matched sibling HCST have been performed for 30 years with great success. Unfortunately, only about 14% of SCD patients have a matched sibling. Most SCD HSCT protocols use myeloablative (MAB) conditioning in matched sibling transplants with average overall survival (OS) and disease-free survival (DFS) of 90% and 95% respectively, but with potential long-term complications including infertility following its use. Reduced Intensity Conditioning (RIC) has been used in young patients with malignancies with better tolerance and fewer complications. In an attempt to minimize risk and maximize cure, our study examined the use of a RIC regimen for both matched sibling and alternative donor HSCT in SCD patients ages 2-30.Primary Objective: To determine DFS after matched sibling or unrelated transplant after a conditioning regimen consisting of Alemtuzumab, Fludarabine, and Melphalan.Methods: The Institutional Review Board of Hackensack University Medical Center approved this study for human subjects. Strict stopping rules were established for graft rejection and death. Eligibility criteria included a diagnosis of SCD for patients receiving matched sibling donor HSCTs, but did not require any specific complications. For alternative donor HSCTs, eligibility criteria included specific complications associated with severe disease, and required a 9-10/10 unrelated donor or 5-6/6 UCB in the donor registry. All patients underwent partial exchange transfusions for a goal of HbS <45% at the start of conditioning. Conditioning initially consisted of Alemtuzumab beginning on d -22 followed by Fludarabine and Melphalan. However, Alemtuzumab was moved up to d -16 after 7 patients were enrolled to reduce graft vs host disease (GVHD). Due to increasing host chimerisms in 3 patients, the Alemtuzumab was moved back to d-22 after an additional 7 patients were enrolled. Post-HSCT, GVHD prophylaxis consisted of Tacrolimus (trough goal of 10-20) through d+100, mycophenolate mofetil through d+45, and steroids (for unrelated donors) through d+28. Patients were monitored closely for signs of infection with weekly PCRs for adenovirus, CMV and EBV. Donor chimerism by STR and HbS percentages by electropheresis were assessed at d+30, d+60, d+100, 1 year and 2 years post HSCT.Results: A total of 20 patients (17 related, 3 unrelated) were enrolled, with age at transplant ranging from 2.25 to 25.4 years. 3 patients were initially consented to the related arm, but then were found to be ineligible due to organ dysfunction or compliance issues. OS and DFS in patients with related donors were 100% and 94%, with one patient suffering secondary graft rejection. The OS and DFS in patients with unrelated donors were 66% and 33%, with one patient dying from GVHD complications and a second patient suffering secondary graft rejection. The unrelated patient with graft failure did receive a second HSCT off study, but died due to GVHD complications. Mean neutrophil engraftment occurred at d+14 and d+11 and platelet engraftment occurred at d+40 and d+26 for related and unrelated donors, respectively. The incidence of acute GVHD stage II-IV was 35% (7/20 patients), occurring in 6/17 (35%) related and 1/3 (33%) unrelated BMT patients. Chronic GVHD was noted in 20% of patients (4/20), occurring in 3/17 (18%) related and 1/3 (33%) unrelated BMT patients. Chimerisms ranged from 20-100% with HbS% of 0-62%.Conclusions : Our results show that a RIC regimen is well-tolerated with successful engraftment in patients undergoing matched sibling HSCT. However, the complications of GVHD & graft rejection in unrelated transplants greatly affected the DFS. The results are promising for continued use of this regimen for related HSCT even in SCD patients with minimal complications, but other alternatives need to be developed for unrelated HSCT. DisclosuresNo relevant conflicts of interest to declare.

Comparable Outcomes After Alternative and Matched Sibling Donor Hematopoietic Stem Cell Transplantation and the Role of Molecular Measurable Residual Disease for Acute Myeloid Leukemia in Elderly Patients

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective postremission therapy conferring the chance of cure for acute myeloid leukemia (AML), including elderly patients. Although the number of transplantations for elderly patients with AML (eAML) is increasing owing to greater availability of various graft sources together with the adoption of advanced supportive care and reduced-intensity conditioning (RIC) regimen, there are relatively limited data on the impact of donor type in eAML compared to younger patients. In addition, few studies have evaluated the role of pretransplantation measurable residual disease (MRD) in the elderly population. Given the lack of prospective comparative study, we retrospectively compared transplantation outcomes of elderly patient with AML receiving allo-HSCT from matched sibling donor (MSD-HSCT), matched unrelated donor (MUD-HSCT) or haploidentical related donor (Haplo-HSCT), or autologous HSCT (Auto-HSCT). A total of 154 patients with a median age of 63 years (range 60-74) underwent MSD-HSCT (n = 41), MUD-HSCT (n = 36), Haplo-HSCT (n = 55), or Auto-HSCT (n = 22) for AML. RIC regimens were used in the majority of patients. In Haplo-HSCT, T-cell-replete peripheral blood stem cells with unique RIC regimens using anti-thymocyte globulin (ATG)-based GVHD prophylaxis was used. In the analysis, adjustment for MRD status at the time of transplantation was performed. MRD was measured by the quantitative molecular assays of the targets, including RUNX1-RUNX1T1, CBFB-MYH11, and NPM1, or WT1 in the absence of abnormalities in the aforementioned targets. At a median follow-up of 48 months, survival rates were similar between different donor types, whereas nonrelapse mortality (NRM) was lower in MUD-HSCT compared to MSD-HSCT (P = .002). MSD-HSCT, in which the majority of patients received a conditioning regimen not including ATG, showed more frequent severe chronic graft-versus-host disease (cGVHD). The major causes of non-relapse deaths in MSD-HSCT were related to cGVHD (71%), whereas infectious complications were mainly related to NRM in Haplo-HSCT (50%) or Auto-HSCT (100%). In the MUD-HSCT, GVHD (57%) and infection (43%) contributed similarly to non-relapse death. Cytomegalovirus infection was more frequent in Haplo-HSCT. In multivariate models, pre-transplant MRD-positivity was an independent risk factor for relapse (P = .001), whereas older age (P = .002) and the hematopoietic cell transplantation-comorbidity index (P = .009) were useful in predicting NRM. The current study demonstrated comparable outcomes after alternative and matched sibling donor HSCT in eAML aged 60 years or older, and the results also suggest the necessity for more sophisticated strategies to reduce NRM or relapse according to each donor type. The usefulness of molecular MRD assays demonstrated herein will facilitate trials for MRD-driven decision-making or risk-adaptive approaches in eAML.

Successful Salvage Therapy by Second Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in a Severe Aplastic Anemia Patient Presenting Donor-Specific Anti-HLA Antibodies After Graft Failure From Matched Sibling Donor HSCT: A Case Report and Review

Hematopoietic stem cell transplantation (HSCT) is potentially curative for severe aplastic anemia (SAA). Graft failure (GF) remains a life-threatening complication after HSCT. Preexisting anti-HLA antibodies, especially HLA-specific antibodies (DSA), have been demonstrated as a risk of GF. This report describes a woman with acquired SAA who presented with anti-HLA antibodies and GF. After the treatment of anti-HLA antibodies, engraftment was achieved through a second alternative donor HSCT. This work complied with the Declaration of Helsinki and the Declaration of Istanbul. Based on our experience in treating this case, we hold that the presence of preoperative anti-HLA antibodies could discount the efficacy of HSCT and anti-HLA antibody screening should be performed before HSCT. Additionally, a second HSCT is feasible to prolong survival.

Feasibility of reduced-dose posttransplant cyclophosphamide and cotransplantation of peripheral blood stem cells and umbilical cord-derived mesenchymal stem cells for SAA

Posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis is an effective strategie for patients receiving matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and haploidentical HSCT (haplo-HSCT). We evaluated the effectiveness and safety of reduced-dose cyclophosphamide, 20 mg/kg for 13 patients in MSD-HSCT cohort and 25 mg/kg for 22 patients in haplo-HSCT cohort, on days + 3, + 4 combined with cotransplantation of peripheral blood stem cells (PBSCs) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for severe aplastic anemia (SAA). In MSD-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the MSD-control cohort (P < 0.05). The cumulative incidence of acute GVHD (aGVHD) at day + 100 (15.4%) was lower than that in the MSD-control cohort (P = 0.050). No patient developed chronic GVHD (cGVHD). The 1-year overall survival (OS) and event-free survival (EFS) rates were 100% and 92.3%. In haplo-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the haplo-control cohort (P < 0.05). The cumulative incidences of aGVHD at day + 100 and 1-year cGVHD were 31.8% and 18.2%, and the 1-year OS and EFS rates were 81.8% and 66.9%. Reduced-dose PTCy and cotransplantation of PBSCs and UC-MSCs is an acceptable alternative to patients with SAA.

Hematopoietic stem cell transplant referral patterns for children with sickle cell disease vary among pediatric hematologist/oncologists' practice focus: A Sickle Cell Transplant Advocacy and Research Alliance (STAR) study.

Hematopoietic stem cell transplantation (HSCT) provides a curative therapy for children severely affected by sickle cell disease (SCD). Rejection-free survival after matched sibling donor (MSD) HSCT is very high, but adoption of HSCT as a curative SCD therapy has been slow. In this study, we assess providers' perceptions about MSD HSCT for children with variable SCD severity, and determine the influence of provider characteristics on HSCT referrals. After our Institutional Review Board deemed the study exempt, American Society of Pediatric Hematology/Oncology Clinical Forum listserv subscribers and American Society of Hematology members who self-identified as pediatric hematologists/oncologists (PHO) were emailed a survey. Analysis was performed to describe and evaluate correlations between participant demographics (including practice focus within PHO) and likelihood of HSCT referral for each scenario. Spearman's rank correlation analysis did not reveal any significant relationship between demographic characteristics except practice focus and likelihood to refer to HSCT for any scenarios. Providers focused on SCD and HSCT were more likely to refer a child who had never been admitted to the hospital or had suboptimal adherence to hydroxyurea than general PHOs. A significantly higher proportion of all respondents would refer a child with β-thalassemia major (87%) than an asymptomatic child with HbSS (47%, P<.00001) or non-HbSS variant (23%, P<.00001). PSCD and HSCT physicians are more likely to refer for MSD HSCT in almost every condition than general PHO practitioners, likely because of increased awareness of long-term effects of SCD and safety of MSD HSCT for children with SCD.

Matched sibling donor stem cell transplantation for sickle cell disease: Results from the Spanish group for bone marrow transplantation in children.

The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain. Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS). Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged≤5 presented 100% EFS and OS. An early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged≤5years and for older pediatric patients who present complications derived from the disease.

Impact of Low-Dose rATG Prior to Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: Reduced Risk of Chronic Graft-versus-Host Disease and Improved Survival Outcomes.

PurposeTo explore the efficacy of low-dose rabbit antithymocyte globulin (rATG) in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) for patients with acute leukemia or myelodysplastic syndrome.Patients and MethodsWe performed a retrospective study of 79 patients with hematologic malignancies who received MSD-HSCT. All patients received standard graft-versus-host disease (GVHD) prophylaxis comprising cyclosporine, mycophenolate mofetil and short-term methotrexate. Among them, 38 were administered 5 mg/kg rATG as part of GVHD prophylaxis. Clinical outcomes including overall survival (OS), GVHD and relapse were analyzed.ResultsNo graft failure occurred in the antithymocyte globulin (ATG) or non-ATG group. The cumulative incidences of grade 2–4 and 3–4 acute GVHD at day +100 were 13.3% versus 19.5% (p=0.507) and 5.7% versus 15.2% (p=0.196), respectively. The 2-year cumulative incidences of chronic GVHD (cGVHD) were 35.4% and 60.4% (p=0.039), and those of extensive cGVHD were 12.9% and 40.0% (p=0.015), respectively. In a multivariate analysis, the use of low-dose rATG was an independent protective factor for extensive cGVHD (hazard ratio [HR] 0.256; 95% confidence interval [CI], 0.080 to 0.822, p=0.022). The 2-year OS was 88.1% and 68.4% (p=0.038), respectively, and the use of low-dose rATG was the only protective factor in the multivariate analysis (HR 0.216; 95% CI, 0.059 to 0.792, p=0.021). There was no significant difference between the two groups in terms of the 2-year cumulative incidence of relapse, leukemia-free survival or GVHD-free and relapse-free survival.ConclusionLow-dose rATG used in MSD-HSCT as part of the conditioning regimen results in a reduced incidence of cGVHD and improves survival outcomes.

Role of pretransplant anti‐thymocyte globulin in matched sibling donor stem cell transplantation after reduced intensity conditioning for myelodysplastic syndrome

We investigated the role of anti-thymocyte globulin (ATG; Thymoglobulin) in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) after reduced intensity conditioning (RIC) in myelodysplastic syndrome (MDS). Forty-seven patients with 10mg/kg ATG (ATG group; median age 53years) and 33 without ATG (no-ATG group; median age 43, P<.0001) were compared. Median time to engraftment was similar. Two-year cumulative incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) was significantly lower in the ATG group (15% vs 55%, P<.0001), while that of acute GVHD was similar compared with the no-ATG group. After a median follow-up of 60months (range, 14-184), the 3-year cumulative incidences of non-relapse mortality and relapse were 9% and 21% for ATG group and 15% and 19% for no-ATG group (P=.408 and P=.717), respectively, leading to a significantly better 3-year GVHD-free and relapse-free survival (GRFS) in the ATG group (55% vs 19%, P=.006): The 3-year overall and disease-free survival were similar. Infectious complication occurred with similar frequencies in both groups. These findings suggest that ATG can be safely used to decrease moderate-to-severe chronic GVHD with improved GRFS for patients with MDS receiving MSD-HSCT in RIC setting.

Mendelian susceptibility to mycobacterial disease—Challenges in hematopoietic stem cell transplantation

We present our experience in the hematopoietic stem cell transplantation (HSCT) in two children diagnosed with Mendelian susceptibility to mycobacterial diseases. The first child underwent a haploidentical HSCT with posttransplant cyclophosphamide using a reduced intensity conditioning following which he had primary graft failure. He was subsequently found to have interferon-γ1 receptor deficiency. He had immune reconstitution and is on antitubercular therapy. The second child diagnosed with IL12RB1 gene mutation underwent matched sibling donor HSCT with myeloablative conditioning following pretransplant immunosuppression with fludarabine and dexamethasone. He is 13 months post-HSCT with complete and remains disease free.

Immune recovery after in vivo T-cell depletion myeloablative conditioning hematopoietic stem cell transplantation in severe beta-thalassemia children.

The clinical outcome of hematopoietic stem cell transplantation (HSCT) in those with severe beta-thalassemia (β-TM) is closely related to post-transplantation immune reconstitution (IR). However, the data on the IR in these settings are scarce. A prospective analysis of the clinical outcome and IR in 47 children with severe β-TM who underwent in vivo T-cell depletion myeloablative conditioning and matched sibling donor HSCT was performed. Immune reconstitution, including immune cell subset counts, as well as the generation of new T and B cells assays after HSCT, was measured. In the first year after HSCT, bacterial infections and cytomegalovirus (CMV) reactivation were observed in 70.2% and 36.2% of the patients, respectively. In the same period, poor CD4+ T-cell recovery was observed. The B cells recovered within 6months. Natural killer (NK) cells recovered as early as 1month, but their function was defective. Cord blood and bone marrow (CB+BM) group had slower T-cell recovery, and higher B cells and NK cells in comparison with peripheral blood and bone marrow (PB+BM) group. The high incidence of infection within 1year afterin vivo T-cell depletion myeloablative conditioning HSCT in severe β-TM was consistent with poor IR.

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.