Matched Sibling Donor Transplantation Research Articles

Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Outcomes Following Matched Sibling Donor Transplant for Severe Combined Immunodeficiency: A Report from the Pidtc

Outcomes Following Matched Sibling Donor Transplant for Severe Combined Immunodeficiency: A Report from the Pidtc

Allogenic hematopoietic stem cell transplantation outcomes of patients aged ≥ 55 years with acute myeloid leukemia or myelodysplastic syndromes in China: a retrospective study

BackgroundElderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe.MethodsOur retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests.ResultsThe median age of the cohort was 57 years (range: 55–75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P < 0.001, HR = 0.596), higher incidence of relapses (HR = 2.300, P = 0.013), and inferior relapse-free survival (RFS) (HR = 1.740, HR = 0.016) regardless of donor type. When it came to graft-versus-host-disease-free, relapse-free survival (GRFS), MUDs turned out to be superior to HIDs (HR = 0.472, P = 0.026) according to the multivariable analysis. In contrast, we found MSDs had an inferior GRFS to HIDs in parallel (HR = 1.621, P = 0.043).ConclusionThe choice of donor type did not significantly affect the outcomes of allo-HSCT. However, when considering the quality of post-transplant life, MUDs or HIDs from younger donors may be the optimal choice for elderly patients.

Relapse and transformation to myelodysplastic syndrome and acute myeloid leukemia following immunosuppressive therapy for aplastic anemia is more common as compared to allogeneic stem cell transplantation with a negative impact on survival.

We studied the incidence of relapse, transformation to myelodysplastic syndrome/acute myeloid leukemia, and survival in patients with aplastic anemia (AA) surviving more than 1year after ATG/ALG-based immunosuppressive therapy (IST) between 1985 and 2020. Four-hundred seventy patients (413 adults and 57 children) were studied, and data were compared with 223 patients who underwent matched sibling donor transplant (MSD HSCT). Median follow-up is 50months (12-359). Relapse occurred in 21.9% at a median time of 33.5months (5-228) post IST. Twenty-six (5.5%) patients progressed to PNH, while 20 (4.3%) evolved to MDS/AML. Ten-year estimated overall survival (OS) is 80.9 ± 3% and was significantly better in patients without an event (85.1 ± 4%) compared to relapse (74.6% ± 6.2%) or clonal evolution (12.8% ± 11.8%) (p = 0.024). While the severity of AA (p = 0.011) and type of ATG (p = 0.028) used predicted relapse, only age at IST administration influenced clonal evolution (p = 0.018). Among HSCT recipients, relapse rates were 4.9% with no clonal evolution, and the 10-year OS was 94.5 ± 2%. In patients who survived 1year following IST, outcomes were good except with clonal evolution to MDS/AML. These outcomes, however, were still inferior compared to matched sibling donor HSCT.

Post Transplant Cyclophosphamide (PTCY) in Peripheral Blood Stem Cell Transplant Results in Successful Engraftment and Substantially Low Frequency of Chronic Graft Versus Host Disease (GvHD), without Impaired Cellular Immune Reconstitution

The Post-Transplant Cyclophosphamide (PTCY) approach was first studied in the haploidentical transplant setting, and it resulted in high percentages of engraftment and reduced frequency of acute and mainly chronic GvHD as well as non-relapsed mortality. PTCY is now increasingly being used in HLA-partially and fully matched unrelated, as well as matched related donors. The aim of this study was to investigate the impact of PTCY on the incidence of chronic GvHD, disease relapse and infections because of possible cellular immune impairment. Fifty-one consecutive patients who underwent allogeneic hematopoietic stem cell transplant from an unrelated donor were studied. PTCΥ was administered on days +3 and +4 post-transplant at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day +5. In patients with no evidence of GvHD, immunosuppression was gradually tapered, and eventually stopped by day +90. We evaluated the safety and efficacy of PTCY, focusing on toxicity, engraftment, aGvHD and cGvHD frequency, relapse, non-relapse mortality, survival and immune reconstitution. We performed 51 unrelated donor transplants with PTCY from January 2021 to May 2023 in patients with a median age of 52 (18-69) years. The indication for transplant was AML/MDS (n=36), NHL/CLL, (n=2), pMF (n=2), CML (n=2) και ALL (n=9). Disease risk index (DRI) was intermediate for most patients (34/51), 7 had low and 10 had high DRI. Thirty-seven patients received myeloablative conditioning and 14 reduced-intensity. Overall, three patients were transplanted from a matched sibling, 36 from an 8/8 matched unrelated donor and 12 from an 7/8 HLA-matched unrelated donor. All patients received a peripheral blood graft with a median CD34+ cell dose of 6.97×10e6/kg (3.27-15.82). The most common toxicities observed were mucositis (n=34), diarrhea (n=40), vomit (n=12), liver toxicity (n=3) and acute kidney injury (n=4) - which in all cases were grade Ι-ΙΙ. Engraftment, defined as neutrophils &amp;gt;500/μl, was achieved in 46 cases in a median of 16 (13-27) days. Three patients died before day +28 due to NRM and two additional patients with myelofibrosis and MDS respectively had primary graft failure. The cumulative incidence of aGvHD, grade ΙΙ-IV at 100 days was 46.7% (95%CI: 34.1-63.8). However, aGvHD, grade ΙΙΙ-IV was only 3.9% (95%CI: 1.0-15.5). The cumulative incidence of cGvHD at 18 months was 13,4% (95%CI: 5.8-31.0), with only one case of extensive cGvHD. In a median follow-up of 14.5 (1-28) months, disease free (DFS) was 76,8% (95%CI: 65.5-90.0) at 18 months and overall survival (OS) was 76.3% (95%CI: 64.9-89.8) and 71.6% (95%CI: 58.6-88.3) respectively. There was no statistically significant difference in survival rates for patients who received an HLA mismatched and those who received an HLA-matched unrelated-donor transplant. cGvHD-Relapse-Free Survival was 63.5% (95%CI: 50.3-80.1). Two patients died of their disease and non-relapse mortality was 19.1%. Specifically, 6 patients died of Infections, 1 due to primary graft failure, 1 due to heart failure, and 1 due to Idiopathic Pulmonary Syndrome. Immune reconstitution at month 6 was 420 cells/ul (20-2225) and 179 (13-594) for CD8 and CD4 respectively. At month 12 CD8 and CD4 were 552 (55-3002) and 364 (60-787). 31 viral infections were documented in 28 patients (Respiratory viruses n=13, BKV n=11, CMV n=7). In regard with opportunistic infections, 2 patients had fungal infections and 1 patient atypical mycobacterium. We used PTCY for GvHD prophylaxis in mismatched, full-matched unrelated and matched sibling donor transplants with peripheral blood stem cell graft. This approach was well tolerated. Engraftment was documented in most patients, with a low incidence of grade III-IV aGvHD. Importantly cGvHD, which is the most important barrier in unrelated donor transplant, was substantially low with this method. Cellular immune reconstitution was adequate for CD8 but somewhat impaired for CD4. However, the incidence of viral and opportunistic infections was not increased. Overall, there are implications that PTCY may revert the negative impact of HLA mismatch on the outcomes of unrelated donor transplantation, while it is also a viable option for MUD and MSD transplant.

Outcomes and Late Complications after Umbilical Cord Blood Transplantation for Fanconi Anemia: A Study on Behalf of Eurocord and Severe Aplastic Anemia Working Party - EBMT

Fanconi Anemia (FA) remains a disease with poor prognosis for which hematopoïetic cell transplantation (HCT) offers the only available curative option, with particular good results observed after matched sibling donor transplants. This study aimed to assess transplant outcomes and describe late complications in a large cohort of patients with FA who underwent umbilical cord blood transplantation (UCBT) in the European Society for Blood and Marrow Transplantation (EBMT) affiliated centres. Methods: We retrospectively reviewed all cases of FA whoreceived UCBT as first allogeneic transplant between 1988 and 2021. Data on late effects were collected with a questionnaire completed by transplant centres for patients who survived &amp;gt;2 years (y) after UCBT. Results: A total of 205 patients with FA received UCBT (55 related and 150 unrelated) in 77 transplant centres. Indications for UCBT were bone marrow failure in 191 patients (BMF, 93%) and acute leukemia/myelodysplasia in 14 patients (AL/MDS, 7%). Median age at transplant was 8.8 y (1.2-43) and 90% (n=185) were children &amp;lt;18y old. Graft sources included single (n=164), double (n=23) or UCB co-infused with other cell sources (n=18). Recipients and UCB pairs had 0-1/6 HLA mismatches in 48% (n=99). Most patients (n=196, 97%) received reduced intensity conditioning. Flu Cy-based (n=116; 57%) and Bu Cy ± Flu (n=48, 23%) were the most frequently used regimens. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were administered to 28% (n=58) of patients at doses &amp;lt; 8 Gy. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=8; 4%). Graft- vs-host disease (GVHD) prophylaxis was mainly based on CSA ± steroids (65%) or MMF ± steroids (32%). Median follow-up was 88 months (3-345). The cumulative incidence (CI) of neutrophil recovery was 79% (67-79) at day 60,with a median time of 20 (7-62) days (d). The 100d CI of grades II-IV acute GVHD (aGVHD) was 29.8% (24-37). The 5y CI of chronic GVHD (cGVHD) was 30.4% (24-38) with 12% extensive forms. The 1y-CI of non-relapse mortality (NRM) was 37.4% (31-45). At 5y follow-up, event-free survival (EFS) was54% ± 3 and overall survival (OS) was 55% ± 3. In multivariate analysis, HLA matching 0-1/6 (HR 2.0, p=0.01) and related UCBT (HR 2.4; p=0.001) were predictive of better engraftment. None of the tested factors had statistical significant impact on incidence of aGVHD or cGVHD. Negative recipient CMV serology (HR 0.29, p=0.003) and transplant year ≥2013 (HR 0.29; p=0.004) were the only factors associated with improved OS. Both factors were also predictive of better NRM and EFS. Fifty-one recipients of UCBT (3 related and 48 unrelated) experienced primary graft failure (GF). Twenty-six patients underwent subsequent allogeneic HCT within a median of 1.8 months (0.8 -6.8) after first UCBT. Seven subsequent HCT recipients (1 related bone marrow (BM), 1 related peripheral blood, 1 unrelated BM, and 4 unrelated UCB) were alive at last follow-up. Second neoplasms developed in 8 patients (4%) within a median interval of 9.7 y post-UCBT (3.6-13.5) and included one donor derived-AML and 7 solidtumors (1 skin, 2 upper GI, 4 oral cavity) . A totalof93 patients (45%) died from transplant related toxicity (n=85, including 42 who died after GF), second neoplasms (n=6) or unknown cause (n=2). Survival &amp;gt;2y was observed in 106 patients, but comprehensive data for late transplant complications were available only in 45 long-term survivors. For these 45, median post transplant follow-up was 8.7y (2.7-28.8). Late organ impairments ( table 1) included: endocrine disorders (32%), lung (24%), eyes (20%), kidneys (20%), immune system (18%), liver (16%), musculoskeletal, and bone (16%) diseases. Other dysfunctions involved: oral mucosa (11%), neurologic system (7%), gastrointestinal (4%), genital (13%) and urinary tracts (4%). Cardiovascular complications were rare (1 case of chronic pericarditis). Conclusion: Improved outcomes have been observed in recent years in FA patients receiving unrelated UCBT likely due to improved conditioning regimens, effective post-transplant care and better HLA parity. With longer survival, late multi-organ complications are observed. Identification of risk factors and life-long screening for early management of organ impairments and second neoplasms are mandatory to improve quality of life of transplant survivors and decrease late mortality.

Allogeneic Hematopoietic Cell Transplantation in the Elderly Results in Similar Survival with Matched Related or Unrelated and Haploidentical Donors: A Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Introduction Higher patient age is no longer considered to be a barrier for allogeneic hematopoietic cell transplantation (HCT). We sought to study the impact of different types of donors on the outcomes of HCT in subjects aged 65 years (y) or more, and to evaluate the determinants of these outcomes. Methods SFGM-TC registry data on first HCTs performed between January 2013 and July 2021 in patients aged 65 y or more, with myeloablative or reduced-intensity conditioning, and a 10/10 human leukocyte antigen (HLA) matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAP) were analyzed. Main exclusion criteria were: MSD/MUD-HCT performed without anti-T lymphocyte globulin (ATG), and HAP-HCT performed without post-transplant cyclophosphamide (PTCY). Univariate analyses according to donor type, as well as multivariable analyses were performed. Results A total of 1176 patients met the eligibility criteria (215 MSD, 721 MUD, 240 HAP). Median follow-up was 2.8 y. In univariate analysis, there was no difference between donor types in terms of 3-y overall survival (OS: MSD 50%, MUD 49%, HAP 49%, p=0.52), progression-free survival (PFS: MSD 41%, MUD 45%, HAP 44%, p=0.51) and graft-versus-host disease-free, relapse-free survival (GRFS: MSD 34%, MUD 32%, HAP 35%, p=0.67). With MSD, the cumulative incidence of progression at 3 y was significantly higher at 47% (MUD 29%, HAP 29%, p&amp;lt;0.001), and non-relapse mortality (NRM) significantly lower at 12% (MUD 26%, HAP 27%, p&amp;lt;0.001). These MSD results were confirmed in multivariable analysis. Incidence of acute graft-versus-host disease (GVHD) at 180 days was lower with MSD: grades II-IV 21% (MUD 35%, HAP 38%, p&amp;lt;0.001) and grade III-IV 8% (MUD 13%, HAP 15%, p=0.05). Incidence of chronic GVHD at 2 y was comparable between MSD, MUD and HAP transplants: moderate to severe 14%, 18% and 15%, respectively, and severe 5%, 6% and 5%, respectively. Conclusions In patients aged 65 y or more, MSD/MUD HCT performed with ATG and HAP HCT performed with PTCY yielded similar survival outcomes. MSD HCT is associated with a lower acute GVHD and NRM but a higher relapse risk. Reducing the toxicity of MUD and HAP HCT may yield better results than with MSD HCT in this population. Acknowledgements: Nicole Raus, Data manager coordinator, SFGM-TC. Viviane Fossat, Secretary, SFGM-TC.

Safety and Efficacy of Azacitidine and Chidamide Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for Patients with High-Risk Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase Ⅱ Clinical Trial

Background Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the potentially curative therapy for AML, the relapse rate after HSCT is high with 30-60% for patients with high-risk AML. Maintenance therapy with efficacy and low toxicity is needed to mitigate relapse. It has been reported that histone deacetylases inhibitor chidamide exhibits anti-tumor activity against AML cells, and is able to elicit anti-tumor immune response in mouse models. However, efficacy and safety of chidamide as maintenance therapy following allo-HSCT for patients with AML have not been reported. Therefore, we designed a multicenter, single arm, phase II clinical trial for high-risk AML patients to use azacitidine combined with chidamide as maintenance therapy post allo-HSCT to prevent relapse. Methods In this multicenter, single arm, phase II clinical trial, patients aged 18-60 years with high-risk AML, defined as the European LeukemiaNet (ELN) 2017 adverse risk group, refractory, relapsed or secondary AML were given AZA and chidamide as maintenance therapy after 60 days post transplantation (NCT05270200). AZA was given at 100mg/day (days 1-5) for 6 cycles and chidamide 5mg daily (days 1-28) with a cycle of 28 days for up to 2 years. The dose of AZA was amended at 50mg/m 2/day (days 1-3) from Dec 23,2022 due to occurrence of thrombocytopenia. If PLT was below 50×10 9/L or grade 3/4 non-hematological toxicity occurs, maintenance should be interrupted or delayed until PLT count was greater than 75×10 9/L or the non-hematological toxicity resolved to ≦ grade 1. Primary objectives were safety and one year cumulative incidence of relapse. Secondary objections were relapse-free survival (RFS), overall survival (OS) and incidence of severity of acute and chronic graft-versus-host disease (GVHD). Results From February 12,2022 to June 30,2023, seven patients were enrolled, with a median age of 46 years（28-60), four patients (57%) were female. One patient (14%) received matched sibling donor transplantation, six patients (86%) received haploidentical donor transplantation. Five patients (71%) received myeloablative and 2/7 (29%) reduced intensity conditioning regimen. Six (86%) were in ELN 2017 adverse risk with three patients harboring KMT2A rearrangement, one patient with TP53 mutation, one patient with -7, one patient with RUNX1 mutation, while one patient (14%) was diagnosed as secondary AML with broad extramedullary infiltration. All but one patients entered transplant in CR, while five patients (83%) were MRD negative and one patient (17%) were positive. The baseline patient characteristics are summarized in Table1. Outcome data were updated as of June 30,2023 (Figure1). The median time to start maintenance therapy after transplantation was 77 days (range 64-80). The median follow-up time was 9.9 months, only one patient relapsed and the accumulative incidence of relapse of one year was 16.7%（95%CI,0.4%-64.1%). The relapsed patient diagnosed with MLL-AF10 rearrangement had extramedullary infiltration of left tonsil, gum and neck lymph nodes at 197 days post transplantation while bone marrow remained in MRD negative remission. AZA/chidamide were well tolerated, with no severe adverse event was recorded. Two grade 3/4 non-hematologic adverse events were observed, with one increased bilirubin due to cGVHD and one pneumonia. Two patients (29%) experienced grade4 thrombocytopenia requiring platelet transfusion. After amendment of AZA dose, no grade4 thrombocytopenia was recorded. No one discontinued treatment due to toxicity. During follow-up, none of patients had aGVHD. Three patients (43%) experienced mild or moderate cGVHD, no severe cGVHD was observed. The median OS was not reached, with six months and one year OS both of 100%. The median RFS is not reached, with six months and one year RFS of 100% and 83.3%(95%CI,35.9%-99.6%). Conclusions Preliminary results suggest that maintenance of AZA combined with chidamide post allo-HSCT in patients with high-risk AML exhibits promising efficacy and well-tolerated. Recruitment of patients with high-risk AML post allo-HSCT for this trial is ongoing. Disclosures No relevant conflicts of interest to declare.

Bone marrow transplant: A two-decade single centre hematology experience

BackgroundBone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. MethodsWe reviewed our BMT data since the inception of the program till Feb 2023. ResultsOver 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. ConclusionThe evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of “transplant for all”. Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Developing an Allogeneic Hematopoietic Progenitor Cell Transplant Service in a Resource-Limited Country: Challenges and Outcomes.

Introduction Allogeneic stem cell transplant has curative potential for many hematological disorders. Building an allogeneic hematopoietic progenitor cell transplant (HPCT) unit requires huge investment, infrastructure, equipment, medical supplies, and training of health care professionals. The key objective of this study is to share our experience of developing an allogeneic HPCT service at our tertiary care cancer hospital in a low-middle-income country. In addition, this study presents the outcomes of the first 30 allogeneic HPCTs done at our center. Methods This retrospective observational study included adult patients 18 years old or older with hematological malignancies who underwent allogeneic HPCT between July 2019 and April 2023 at Shaukat Khanum Memorial Cancer Hospital and Research Centre. Result Of the 30 patients, 24 underwent matched sibling donor (MSD) transplants in which a myeloablative-conditioning regimen (MAC) was used in 19, and a reduced conditioning regimen (RIC) was used in one. Of the six haploidentical-related donor transplants, four received MAC, and two received RIC. The median recipient age at HPCT was 23 and 21 years for MSD and Haplo-related donor transplants, respectively. The median follow-up duration was 12 months (Range: 10 days - 33 months). The overall survival rate at one yearwas 71.3% among all allogeneic stem cell transplant patients, whereas the disease-free survival rate at one yearwas 63.7%. In the acute lymphoblastic leukemia group, the disease-free survival rate at one year post allograft was 51.5%, while in the acute myeloid leukemia group, it was 78.7%. Conclusion This study demonstrates the successful development of an allogeneic bone marrow transplant unit at our hospital despite significant financial constraints. This has allowed us to provide a potentially curative and life-saving treatment to a substantial number of cancer patients. The bone marrow transplant outcomes of this study are comparable to those reported by international bone marrow transplant registries.

Choosing Between Older Matched Sibling Donor and Younger Matched Unrelated Donor in Allogeneic Hematopoietic Cell Transplantation: Comparison of Clinical Outcomes in Acute Myeloid Leukemia and Myelodysplastic Syndrome

The choice between an older matched sibling donor (MSD) and a younger matched unrelated donor (MUD) in allogeneic hematopoietic cell transplantation (HCT) remains a subject of ongoing debate. In this single-center retrospective study of 377 patients who received peripheral blood stem cell (PBSC) transplants for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), we compared outcomes of 85 patients who received grafts from MSDs age >60 years and 292 patients who received grafts from MUDs age <30 years. Compared to recipients of MSD transplants, recipients of MUD transplants were younger and more likely to receive dual T cell depletion (TCD), a higher CD34+ cell dose, and a fresh graft. Recipients of MSD transplants were maintained on immunosuppressive therapy longer than those who received MUD grafts. We found no differences in overall survival, relapse-free survival, graft-versus-host disease (GVHD)-free and relapse-free survival, nonrelapse mortality, relapse, engraftment, graft failure, and acute GVHD between recipients of MSD grafts and recipients of MUD grafts. We report a higher 30-day incidence, but not 1-year incidence, of bloodstream infections among recipients of MUD transplants compared to subjects who received their grafts from a MSD. The incidence of moderate-severe chronic GVHD was higher in MSD graft recipients compared with MUD graft recipients in univariate analysis, but not in multivariate analysis. Although this difference could reflect the greater use of dual TCD, known to be associated with very low rates of chronic GVHD in MUD transplant recipients, the incidence of moderate-severe chronic GVHD was no different between MSD and MUD transplant recipients following propensity score matching, suggesting that other variables could be responsible. Taken together, our data suggest that in patients with AML or MDS who receive PBSC transplants, such factors as convenience, ease of access, and costs should be considered when selecting an older MSD over a younger MUD.

Haploidentical transplants deliver equal outcomes to matched sibling transplants: a propensity score-matched analysis

The success of allogeneic hematopoietic stem cell transplant for hematological malignancies is heavily dependent on the availability of suitable donors. Haploidentical donor (HID) and matched sibling donor (MSD) are two important donor options providing faster and easier sources of stem cells, however, due to confounding factors present in most retrospective studies, the validity of comparing outcomes between these two donor types remains uncertain. We conducted a post-hoc analysis of a prospective clinical trial (trial registration: Chinese Clinical Trial Registry; #ChiCTR-OCH-12002490; registered 22 February 2012; https://www.chictr.org.cn/showproj.aspx?proj=7061) to compare outcomes of HID versus MSD peripheral blood stem cell-derived transplants in patients with hematologic malignancies between 2015 and 2022. All HID-receiving patients had antithymocyte globulin-based conditioning. Propensity score matching was employed to minimize potential confounding factors between the two cohorts. A total of 1060 patients were initially reviewed and then 663 patients were ultimately included in the analysis after propensity score matching. The overall survival, relapse-free survival, non-relapse mortality rate and cumulative incidence of relapse were similar between HID and MSD cohorts. Subgroup analysis revealed that patients with positive measurable residual disease in first complete remission may have better overall survival with an HID transplant. The present demonstrated that haploidentical transplants can provide outcomes comparable to conventional MSD transplants, and HID should be recommended as one of the optimal donor choices for patients with positive measurable residual disease in first complete remission.

Post-transplantation cyclophosphamide combined with tacrolimus and low-dose post-engraftment anti-thymoglobulin as GVHD prophylaxis for patients undergoing peripheral blood stem cell transplantation from haploidentical family donor: A single center analysis.

Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.

Haematopoietic stem cell transplantation for hepatitis-associated aplastic anaemia and non-hepatitis-associated aplastic anaemia: Apropensity score-matched analysis.

To validate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in hepatitis-associated aplastic anaemia (HAAA) patients, we reviewed 260 patients who underwent HSCT for acquired aplastic anaemia and eventually included 30 HAAA patients and 90 non-HAAA patients using propensity score matching. In the HAAA group, the estimated 5-year overall survival rate (75.8% vs. 86.5%, p = 0.409), failure-free survival (FFS) rate (74.0% vs. 83.2%, p = 0.485), graft-versus-host disease (GVHD)-free FFS rate (61.2% vs. 67.6%, p = 0.669) after HSCT were slightly lower but not statistically significant than those in the non-HAAA group. Both groups did not significantly differ in engraftment, post-transplant severe infection, cytomegalovirus (CMV) or Epstein-Barr virus viraemia, or GVHD incidences. The patterns of immune reconstitution were broadly consistent between the two groups. When stratifying HAAA patients according to donor type, no significant differences in survival, transplant-related mortality, or GVHD cumulative incidences were observed. CMV viraemia (68.7% vs 8.3%, p = 0.009) occurred more commonly in haploidentical donor (HID) transplants than in matched sibling donor transplants. However, early CMV disease incidence (5.6% vs. 0.0%, p = 1.000) was low. Overall, the post-transplant outcomes of HAAA patients were comparable to those of non-HAAA patients after balancing potential confounders, and HID-HSCT can offer an alternative curative option for HAAA.

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.

Long-term survivors demonstrate superior quality of life after haploidentical stem cell transplantation to matched sibling donor transplantation

BackgroundIt has been well-documented that haplo-identical hematopoietic stem cell transplantation (HID-HSCT) can provide outcomes comparable to conventional matched sibling donor (MSD) HSCT, however, little is known about the effects on quality of life (QoL) in long-term survivors. This study is to investigate the differences in longitudinal performance of QoL between HID and MSD HSCT using a comprehensive assessment system.MethodsThis prospective study enrolled consecutive patients who had received allogenic-HSCT (allo-HSCT) between January 2018 and December 2019 in our center. All patients were informed to complete QoL questionnaires including the Mos 36-Item Short-Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, version 4), using an online applet, before transplantation and at scheduled time points after transplantation. The linear mixed-effects model was used to analyze the variation trend of different dimensions of both SF-36 and FACT-BMT with different follow-up times.ResultsOf the 425 participants, recipients of HID and MSD who survived more than 1 year (n = 230) were included in the final analysis of QoL (median age [range]: 36, [15, 66]). The 3 year overall survival (OS) of HID and MSD was 82.42% and 86.46%, respectively. QoL was assessed using both SF-36 and FACT-BMT and there was longitudinal recovery with clinical significance in the cohort. Compared to MSD-HSCT patients, HID-HSCT recipients demonstrated superior QoL performance in some subscales describing physical and mental wellness. Specifically, the difference in physical performance is more remarkable using FACT-BMT whereas that in mental wellness is more significant using SF36. In the subsequent stratified analysis, patients with a history of aGVHD or CMV reactivation demonstrated inferior QoL.ConclusionsLong-term survivors of HID HSCT achieved better QoL in some sub-scales compared to MSD HSCT. In addition, SF-36 and FACT-BMT demonstrated different performance thus combination of both improved capacity of the evaluation system.

Organ function indications and potential improvements following curative therapy for sickle cell disease.

Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen-matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the "cure" with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.

Cytomegalovirus infection is associated with rapid NK differentiation and reduced incidence of relapse in HLA matched sibling donor transplant patients.

The effect of cytomegalovirus (CMV) infection on leukemia relapse and the potential mechanism remains controversial. In this retrospective study, we evaluated the association among CMV infection, NK reconstitution and clinical outcomes in consecutive patients with hematologic malignancy who underwent HLA matched sibling donor transplantation (MST). In total, 228 patients were enrolled in the study between January 2010 and December 2011. The cumulative incidence of CMV infection on day 100 post-HSCT was 13.6 ± 4.9%. The probabilities of OS and DFS were 45.4% vs. 71.7% (P = 0.004) and 43.9% vs. 64.2% (P = 0.050) in the patients with CMV infection and without CMV infection, respectively. The cumulative incidence of treatment-related mortality (TRM) and relapse at 5 years was 48.6 ± 9.6% vs. 11.5 ± 2.9% (P < 0.001) and 6.2 ± 4.3% vs. 29.2 ± 3.9% (P = 0.024) in the patients with CMV infection and without CMV infection, respectively. In the multivariate analysis, CMV infection was associated with higher TRM, lower OS, and lower DFS. In addition, we found that CMV infection may promote the recovery of the absolute number of NK cells and promote the differentiation of NK cells post-MST. In conclusion, CMV infection may promote the recovery and differentiation of NK cells and was correlated with a lower relapse rate post-MST.

Post-Transplantation Cyclophosphamide Combined with Tacrolimus and Low-Dose Post-Engraftment Anti-Thymoglobulin As Gvhd Prophylaxis for Patients Undergoing Peripheral Blood Stem Cell Transplantation from Haplo Donors: A Single Center Analysis

Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and GVHD and relapse-free survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Fifty-three patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. The median follow-up was 397 (range, 191~762) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 9.4±4.1%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 1-year chronic GVHD and moderate-to-severe chronic GVHD were 18.9±5.4% and 7.5±3.7%, respectively. The non-relapse mortality at day+100 and 1 year were 9.4±4.4% and 11.3±4.4%, respectively. The cumulative incidence of relapse at 1 year was 3.8±2.7%. The 1-year probability of DFS and OS were 84.5% (95%CI, 75.2~95.0%) and 88.7% (95% CI, 80.5~97.6%), respectively. The 1-year GRFS was estimated as 75.0% (95%CI, 64.1~87.8%). Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved T-Cell Chimerism and Successful Withdrawal of Immunosuppression after Non-Myeloablative Stem Cell Transplantation for Sickle Cell Disease with Azathioprine/Hydroxyurea Preconditioning Added to Alemtuzumab/TBI Conditioning

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adult SCD patients, myeloablative conditioning is associated with significant toxicity, primarily because of cumulative organ damage. Recently, matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) showed promising outcomes in adult SCD patients. This chemotherapy-free regimen, typically resulting in mixed chimerism, is associated with mild toxicity with no reports of graft-versus-host disease (GvHD). Despite mixed chimerism, the red blood cell (RBC) phenotype is completely donor-derived. However, in a large series, 13% of patients experienced graft failure. Another 8.2% of patients could not stop their immunosuppression (sirolimus) after one year, because of low donor T-cell chimerism (<50%). Reported mean donor T-cell chimerism at 12-months post-transplantation was 48% (Br J Haematol. 2021 Feb;192(4): 761-768). We hypothesized, that the addition of azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI conditioning regimen will reduce the risk of graft failure and improve donor T-cell chimerism, enabling successful withdrawal of sirolimus in all patients. Aim: To investigate the effects of adding azathioprine/hydroxyurea preconditioning to alemtuzumab/TBI conditioning on donor chimerism levels and the occurrence of graft failure in adult SCD patients receiving non-myeloablative MSD-HSCT. Methods: Adult SCD patients with an available HLA-identical sibling donor were eligible for this treatment. All patients received three months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd preconditioning. After exchange transfusion (target HbS <30%), conditioning with alemtuzumab 1mg/kg total dose and 3Gy TBI started on day -7, followed by unmanipulated peripheral hematopoietic stem cell infusion on day 0. Sirolimus as GvHD and rejection prophylaxis started on day -1. Results: Twenty SCD patients (median age 26 (range 19-49) years) were transplanted with a median follow-up of 24.5 months (range 1-52 months). Patient and transplant characteristics are shown in Table 1. Median donor myeloid and T-cell chimerism of engrafted patients was 100% (range 87-100%) and 68.5% (range 37-89%) at 12-months post-transplantation and 94% (range 86-100%) and 78.5% (range 68-88%) at 18-months post-transplantation, respectively (Figure 1). These donor T-cell chimerism percentages are higher than previously reported with alemtuzumab/TBI conditioning only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Importantly, all patients with a follow-up of ≥ 12 months (n=12) could successfully taper and stop sirolimus without decreases in donor chimerism. One year estimated disease-free survival and overall survival were 94.7%. and 93.3%, respectively. One patient (5%) experienced graft failure without autologous regeneration and subsequently died after a series of complications, including EBV reactivation, post-transplantation lymphoproliferative disease, and systemic aspergillosis. Acute gastrointestinal GvHD grade 2 occurred in one patient (5%) and resolved quickly after treatment with prednisolone. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI resulted in improved donor T-cell 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% and were able to stop immunosuppressives as scheduled. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal