Sibling Donor Transplantation Research Articles

Total Marrow and Lymphoid Irradiation [TMLI] is associated with good early outcomes in patients undergoing matched sibling donor and haplo-identical transplants for acute lymphoblastic leukemia.

Total marrow and lymphoid irradiation [TMLI] can deliver higher doses of irradiation without increased toxicity. This study evaluated TMLI and Cyclophosphamide in patients undergoing stem cell transplantation for acute lymphoblastic leukemia [ALL] . Fifty-eight patients underwent matched related, unrelated or haplo-identical donor transplant using TMLI. The graft source was PBSC in all while GVHD prophylaxis consisted of cyclosporine with methotrexate or post-transplant cyclophosphamide. The median age was 20 years [range: 5 - 49] and included 20 children. Engraftment occurred in 56 [96.5%] at median of 15 days [range: 12 - 23] with 2 early deaths. Sinusoidal obstruction syndrome [SOS] was seen in 10 patients while hemorrhagic cystitis and cardiac dysfunction occurred in 2 patients each. Cumulative incidence of grade II - IV acute GVHD was 23.6% while grade III - IV was 10.9%. Chronic GVHD was seen in 46.9% while relapse was seen in 10 patients [17.2%]. The 2-year overall survival [OS] was 65.9 ± 6.8% and 2-year disease free survival [DFS] was 59 ± 6.7%. Outcomes were compared with 52 patients who received either Cy/TBI or Flu/Bu4 for conditioning during the same period. Engraftment rates and time to engraftment were similar. Acute GVHD [p = 0.002], regimen related toxicity [p = 0.043] and Day 100 non-relapse mortality [p = 0.020] were significantly lower with TMLI. TMLI was associated with better OS [p = 0.004] and DFS [p = 0.005] for haplo-identical transplants. Better DFS was seen with TMLI in patients with high-risk disease [p = 0.007] and disease status > CR1 [p = 0.041]. The use of TMLI and cyclophosphamide is associated with good outcomes in patients undergoing HSCT for ALL especially with haploidentical stem cell transplants.

Hematopoietic stem cell transplantation activity in China 2022-2023. The proportions of peripheral blood for stem cell source continue to grow: a report from the Chinese Blood and Marrow Transplantation Registry Group.

Over past two years, a total of 39,918 hematopoietic stem cell transplantation (HSCT) cases were reported, with 18,194 and 21,714 transplants performed in 2022 and 2023, respectively. Autologous HSCT accounted for 6562 cases (31%) in 2022, while allogeneic HSCT comprised 12,632 cases (69%). In 2023, the number of allogeneic HSCTs exceeded 15,000, maintaining a 69% share. Participation in the 2022 and 2023 surveys included 193 and 212 transplantation teams, respectively, from 27 provinces, municipalities, or autonomous regions. The leading indication of HSCT was acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia, with a total of 17,421 cases. AML was the most common disease (10,339, 38%) for allogeneic HSCT, which was followed by ALL (5925 cases, 21%). Peripheral blood emerged as the primary source of stem cell grafts, utilized in 54% of matched sibling donor transplants and 77% of haploidentical donor transplants. The BuCy-based conditioning regimen was the most prevalent, used in 53% of allogeneic HSCT cases in the past two years. This survey offers a comprehensive overview of the current HSCT landscape and serves as a valuable resource for clinical practice.

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P<0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P=0.027; P=0.003; P=0.035; P=0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P<0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

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.

Risk factors and predictive model for mortality in patients undergoing allogeneic hematopoietic stem cell transplantation admitted to the intensive care unit.

Hematological malignant tumors represent a group of major diseases carrying a substantial risk to the lives of affected patients. Risk factors for mortality in critically ill patients have garnered substantial attention in recent research endeavors. The present research aimed to identify factors predicting intensive care unit (ICU) mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, the present study analyzed and compared the mortality rate between patients undergoing haploidentical hematopoietic stem cell transplantation (Haplo-SCT) and those undergoing identical sibling donor (ISD) transplantation. A total of 108 patients were included in the present research, 83 (76.9%) of whom underwent Haplo-SCT. ICU mortality was reported in 58 (53.7%) patients, with the values of 55.4 and 48.0% associated with Haplo-SCT and ISD, respectively (P=0.514). The mortality rate of patients undergoing Haplo-SCT was comparable to that of patients undergoing ISD transplantation. The present study found that reduced hemoglobin, elevated total bilirubin, elevated brain natriuretic peptide, elevated fibrinogen degradation products, need for vasoactive drugs at ICU admission, need for invasive mechanical ventilation and elevated APACHE II scores were independent risk factors for ICU mortality. Among patients presenting with 5-7 risk factors, the ICU mortality reached 100%, significantly exceeding that of other patients. The present research revealed that ICU mortality rates remain elevated among patients who underwent allo-HSCT, especially those presenting multiple risk factors. However, the outcome of patients undergoing Haplo-SCT were comparable to those of patients undergoing ISD transplants.

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.

Risk Factors for Positive Posttransplantation Measurable Residual Disease in Patients with Acute Lymphoblastic Leukemia

Background: The level of MRD before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-HSCT MRD. However, no work has been devoted to the risk factors for positive post-HSCT MRD in patients with ALL. This study evaluated the risk factors for post-HSCT MRD positivity in patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic HSCT (allo-HSCT). Methods: A total of 1683 ALL patients were enrolled. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Results: Both in total patients and in T-ALL or B-ALL, pediatric or adult, HLA-matched sibling donor transplantation or haploidentical HSCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P &amp;lt; 0.001 for all). Disease status was also a risk factor for post-HSCT MRD positivity in all patients and in the B-ALL, pediatric, or haploidentical SCT subgroups ( P =0.003; P=0.035; P =0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P&amp;lt;0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as LFS and OS. Conclusion: Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic 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.

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.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. To describe the outcome of TBD patients transplanted for marrow failure. This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Application prospect of low-dose porcine anti-thymocyte globulin in HLA-matched sibling donor transplantation

ABSTRACTObjectiveTo investigate the preventive effect of low-dose porcine anti-thymocyte globulin (P-ATG) on graft versus host disease (GVHD) in patients' donors over 40 years old or female donors undergoing HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT).MethodsThe clinical data of 30 patients received Low-dose Porcine antithymocyte globulin (P-ATG) as a part of the conditioning regimen (the P-ATG group), while the other 30 patients didn’t receive ATG (the Non-ATG group).ResultsThere was a significant difference in the incidence of aGVHD ([23.3 (10.1–39.7) %] vs [50.0 (30.8–66.5) %], P = 0.028), grade II–IV aGVHD ([16.7 (5.94–32.1) %] vs [40.0 (22.4–57.0) %], P = 0.049) and chronic GVHD (cGVHD) ([22.4 (6.03–45.1) %] vs [69.0 (43.4–84.8) %], P = 0.001) between two groups. But there was no significant difference in terms of moderate-severe cGVHD (P = 0.129), 1-year relapse rate (P = 0.742), non-relapse mortality (P = 0.237), or overall survival (P = 0.441).ConclusionThe application of low-dose P-ATG in patients/donors over 40 years old or female donors undergoing MSD-HSCT for hematological malignancy can significantly reduce the incidence of aGVHD, grade II–IV aGVHD and cGVHD, doesn’t increase the risk of relapse.

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.