Haploidentical Hematopoietic Stem Cell Transplantation Research Articles

High infection rates and risk‐adapted prevention strategies in contemporary pediatric allogeneic hematopoietic stem cell transplantation

AbstractWith recent changes in hematopoietic stem cell transplantation (HSCT) practices, such as the increasing use of alternative donors and ex vivo T‐cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated. We retrospectively reviewed the first 100 consecutive HSCT from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. We found that the vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral, and fungal infection rates were 35.1%, 90.5%, and 9.5%, respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections (rate of bacterial, viral, and fungal infection were 19.2%, 15.4%, and 3.8%, respectively). Human herpesvirus 6 (HHV‐6) and BK virus (BKV) typically occurred early after HSCT, adenovirus (ADV) and varicella zoster virus (VZV) thereafter, and cytomegalovirus (CMV) and Epstein–Barr virus (EBV) throughout the entire 2.5‐year observation period. Ex vivo T‐cell depletion was a general risk factor for viral infection with HHV‐6 (hazard ratio [HR] = 3.03), BKV (HR = 3.36), CMV (HR = 4.45), and EBV (HR = 7.15); all p < 0.02. Cancer in second‐complete remission compared with first‐complete remission was a risk factor for bacterial infection (OR = 6.0, 95% CI = 1.12–32.2, and p = 0.037). Patients with gut graft‐versus‐host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33–114.4, and p = 0.027). The infection‐related mortality rate was 10.0%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). Collectively, our findings in pediatric patients after contemporary HSCT support both time‐dependent and risk‐adapted measures against infective complications to improve transplant outcome.

Immunodeficiency-Related Vaccine-Derived Poliovirus (iVDPV) Excretion in an Infant with Severe Combined Immune Deficiency with Spillover to a Parent.

In order to maintain the polio eradication status, it has become evident that the surveillance of cases with acute flaccid paralysis and of environmental samples must be urgently supplemented with the surveillance of poliovirus excretions among individuals with inborn errors of immunity (IEI). All children with IEI were screened for the excretion of poliovirus during a collaborative study conducted by the ICMR-National Institute of Virology, Mumbai Unit, ICMR-National Institute of Immunohaematology, and World Health Organization, India. A seven-month -old male baby who presented with persistent pneumonia and lymphopenia was found to have severe combined immune deficiency (SCID) due to a missense variant in the RAG1 gene. He had received OPV at birth and at 20 weeks. Four stool samples collected at 4 weekly intervals yielded iVDPV type 1. The child's father, an asymptomatic 32-year-old male, was also found to be excreting iVDPV. A haploidentical hematopoietic stem cell transplant was performed, but the child succumbed due to severe myocarditis and pneumonia three weeks later. We report a rare case of transmission of iVDPV from an individual with IEI to a healthy household contact, demonstrating the threat of the spread of iVDPV from persons with IEI and the necessity to develop effective antivirals.

Combination of Anti-thymocyte Globulin with Post-transplant Cyclophosphamide for GVHD Prophylaxis in Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-analysis

Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear. This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT. Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4; pooled hazard ratios (HRs) for time-to-event outcomes were obtained using a generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using the Mantel-Haenszel method. A fixed-effects model was adopted if there was no significant heterogeneity. The primary outcome is incidence of acute GVHD. Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly lower risk of grades III-IV acute GVHD (RR 0.33; 95% CI: 0.23-0.49; P < .00001) and chronic GVHD (RR 0.65; 95% CI: 0.51-0.81; P = .0002) in comparison with ATG. Further analyses suggest that ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy, but the risks of cytomegalovirus (RR 1.42; 95% CI: 1.03-1.95; P = .03) and Epstein Barr Virus (RR 3.17; 95% CI: 1.61-6.23; P = .0008) reactivation are higher when compared with PTCy. Our results suggest that the combination of ATG with PTCy for GVHD prevention in haplo-HSCT is associated with improved efficacy but higher risk of infection. Future research is required to further establish the benefits and risks of ATG/PTCy and determine the optimal dosage adjustment strategies.

Dual T-cell depletion with individually tailored anti-thymocyte globulin and attenuated dose of post-transplant cyclophosphamide in haploidentical peripheral stem cell transplantation

This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.

Donor’s age influences outcome in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide - a single center experience

Haploidentical stem cell transplantation (haplo-SCT) using post-transplantation cyclophosphamide (post-Cy) is considered a reasonable therapeutic option for patients who lack matched donor or who urgently need transplant procedure due to high risk disease. We analyzed the results of haplo-SCT performed in years 2018–2023. Eighty one patients (46 males) at median age of 52 years underwent haplo-SCT using peripheral blood as a stem cell source in most cases. Indications included hematological malignancies (acute leukemias in 88% of cases). In 25 cases (31%) transplantation was performed in relapsed/refractory disease. Majority of patients (61%) presented with very high and high disease risk index (DRI). Conditioning regimens were as follows: nonmyeloablative − 46 cases (57%), myeloablative – in 18 (22%) and reduced intensity – 17(20%). 90% of patients engrafted. All patients received unified immunosuppressive treatment (post-Cy/TAC/MMF). Median follow-up time was 12 months The cumulative incidence of acute and chronic GVHD was 37.5% and 37.6%, respectively. Estimated 2-year overall survival (OS) was 43.1% and donor’s age was the only factor influencing survival. The 2-year progression-free survival (PFS) was 42.5%, whereas relapse incidence (RI) − 35%. The cumulative incidence of non-relapse mortality (NRM) was 44% and was mostly due to infections. Haplo-SCT is a feasible treatment option for hematological patients. Younger donor improves post-transplant survival. Strategies to reduce infection-related mortality and relapse rate remain a challenge.

Haploidentical HSCT in the Treatment of Pediatric Hematological Disorders.

Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD.

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: A Study on Behalf of the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy Group (GETH)

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed.

Reduced intensity conditioning regimen of fludarabine, busulfan, ATG based haploidentical stem cell transplantation for older or unfit patients.

Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30mg/m²/kg 6 days combined with busulfan 3.2mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2group was significantly higher than Bu3group(P = 0.045). However, the2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.

Clinical Observation on Haploid Hematopoietic Stem Cells Combined with Umbilical Cord Blood Double Transplantation for Aplastic Anaemia in Children

To explore the efficacy and safety of haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood infusion for the treatment of aplastic anaemia in children. Nine cases of children with aplastic anaemia treated with umbilical cord blood combined with haploidentical hematopoietic stem cell transplantation at the People's Hospital of Henan University of Chinese Medicine from January 1, 2021 to September 15, 2023 with a median age of 11(2-13) years and a median follow up of 18(7.5-21) months were included, and the clinical data were retrospectively analyzed. Hematopoiesis reconstitution, the incidence of graft-versus-host disease(GVHD), infections and survival of the patients were analyzed. All 9 children were successfully implanted. The median time to neutrophil and platelet implantation was 11.11±1.27 d and 12.44±3.36 d, respectively. One case developed acute gastrointestinal GVHD of degree I, which was improved after treatment, and the patient developed superficial gastritis and chronic gastrointestinal GVHD at a later stage, which is currently under clinical follow-up. Acute GVHD of II-IV degree was 0%. Hemorrhagic cystitis in 3 cases, CMV infection in 5 cases and bacterial and fungal infections in 5 cases improved with symptomatic treatment.All 9 children demonstrated complete donor chimerism within 1 month after transplantation, at two years of follow-up, all nine children survived without recurrence or development of grade II-IV GVHD, and there were no children with transplant-related deaths. Haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood transfusion for aplastic anaemia in children has a low incidence and mild degree of GVHD, with significant efficacy, and can be used as a therapeutic option for children without an HLA full donor chimeric match.

Effect of CD8+ CD28- T Cells on Acute Graft-Versus-Host Disease after Haploidentical Hematopoietic Stem Cell Transplantation

To investigate the effect of CD8+ CD28- T cells on acute graft-versus-host disease(aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT). The relationship between absolute count of CD8+ CD28- T cells and aGVHD in 60 patients with malignant hematological diseases was retrospectively analyzed after haplo-HSCT, and the differences in the incidence rate of chronic graft-versus host disease(cGVHD), infection and prognosis between different CD8+ CD28- T absolute cells count groups were compared. aGVHD occurred in 40 of 60 patients after haplo-HSCT, with an incidence rate of 66.67%. The median occurrence time of aGVHD was 32.5(20-100) days. At 30 days after the transplantation, the absolute count of CD8+ CD28- T cells of aGVHD group was significantly lower than that of non-aGVHD group (P =0.03). Thus the absolute count of CD8+ CD28- T cells at 30 days after transplantation can be used to predict the occurrence of aGVHD to some extent. At 30 days after transplantation, the incidence rate of aGVHD in the low cell count group (CD8+ CD28- T cells absolute count < 0.06/μl) was significantly higher than that in the high cell count group (CD8+ CD28- T cells absolute count ≥0.06/μl,P =0.011). Multivariate Cox regression analysis further confirmed that the absolute count of CD8+ CD28-T cells at 30 days after transplantation was an independent risk factor for aGVHD, and the risk of aGVHD in the low cell count group was 2.222 times higher than that in the high cell count group (P =0.015). The incidence of cGVHD, fungal infection, EBV infection and CMV infection were not significantly different between the two groups with different CD8+ CD28- T cells absolute count. The overall survival, non-recurrent mortality and relapse rates were not significantly different between different CD8+ CD28- T cells absolute count groups. Patients with delayed CD8+ CD28- T cells reconstitution after haplo-HSCT are more likely to develop aGVHD, and the absolute count of CD8+ CD28- T cells can be used to predict the incidence of aGVHD to some extent. The absolute count of CD8+ CD28- T cells after haplo-HSCT was not associated with cGVHD, fungal infection, EBV infection, and CMV infection, and was also not significantly associated with the prognosis after transplantation.

Successful Treatment of Severe Steroid-Resistant Engraftment Syndrome Following Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Emapalumab: A Case Report

Successful Treatment of Severe Steroid-Resistant Engraftment Syndrome Following Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Emapalumab: A Case Report

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

The impact of donor human leukocyte antigen-Bw4 allele on natural killer cell reconstitution and transplant-related mortality in haploidentical transplantation

Objective: To investigate the impact of donor human leukocyte antigen (HLA) -Bw4 expression on natural killer (NK) cell reconstitution and transplant outcomes in recipients undergoing haploidentical hematopoietic stem cell transplantation (HSCT) from maternal or related donors without ex vivo T-cell depletion. Methods: This study prospectively enrolled 32 patients who received T-replete haploidentical HSCT from maternal or collateral donors (cohort 1) to evaluate the facilitating effect of donor HLA-Bw4 expression on NK cell reconstitution. Furthermore, a retrospective analysis was conducted on 278 patients who underwent T-replete haploidentical HSCT from maternal or collateral donors (cohort 2) to analyze the impact of donor HLA-Bw4 expression on HSCT outcomes. Thus, a comparison was made between the effects of donor HLA-Bw4 expression on HSCT outcomes in patients receiving or not receiving post-transplant cyclophosphamide (PT-Cy) conditioning. Results: Donors expressing HLA-Bw4 alleles facilitated NK cell reconstitution and functional recovery, which remained unaffected by PT-Cy. Donors with HLA-Bw4 expression were associated with reduced transplant-related mortality (TRM), particularly mortality related to infections. The use of PT-Cy did not impact the ability of donor HLA-Bw4 to decrease TRM. Conclusion: In haploidentical HSCT from maternal or related donors without ex vivo T-cell depletion, the presence of donor HLA-Bw4 expression promotes rapid NK cell reconstitution and functional recovery and is significantly associated with lower TRM, especially infection-related mortality. These findings underscore the clinical significance of donor HLA-Bw4 expression in patients who underwent HSCT. Hence, the consideration of donor HLA-Bw4 in recipient selection and HSCT strategies holds important clinical implications.

Real-World Challenges of Haplo-Identical Hematopoietic Stem Cell Transplant in a Developing Country: A Single Center Experience.

Hematopoietic stem cell transplant (HSCT) is potentially, the sole curative option for many malignant and non-malignant hematological disorders. Finding a human leukocyte antigen (HLA) compatible donor remains one of the limiting factors, hampering the utilization of HSCT. However, the introduction of post-transplant cyclophosphamide (PTCy) has improved the outcomes of haploidentical transplants making it a suitable option for patients lacking HLA-compatible donors. We collected data from 44 patients who underwent haplo-identical allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) from the year 2015 to 2022. The diseases were divided into three categories, i.e., bone marrow failure (BMF) syndromes, hematological malignancies (HM) and miscellaneous (Misc) groups. Median age at transplant was 18 (01-39) years. Transplant indications included aplastic anemia (AA) in 21 (47.7%) cases, 15 (34.1%) HM, and eight (18.2%) cases falling in the Misc groups. A maximum number of graft failures occurred in the BMF group; primary graft failure in 07 (33.3%) cases and secondary graft failure in four (19%) cases, (p-value < 0.05). Acute graft versus host disease (aGVHD) grade II-IV occurred in nine (20.5%) cases while chronic graft versus host disease (cGVHD) occurred in 10 (22.7%) cases. Cytomegalovirus (CMV) reactivation was seen in 31 (70.5%) cases. Maximum CMV reactivation was seen in HM group 13 (86.6%) cases, (p-value < 0.05) as compared to BMF (71.4%) and Misc groups (37.5%). Post-transplant cyclophosphamide (PTCy) based regimens, early neutrophil engraftment, and patients with GVHD had better survival outcomes (p-value < 0.05) overall survival (OS), and relapse-free survival (RFS). and GVHD-free relapse-free survival (GFRS) were significantly better in cases with early neutrophil engraftment. OS of the study cohort was 50% while disease-free survival (DFS) and GFRS were 45.5% and 36.4%, respectively.

Haploidentical Hematopoietic Stem Cell Transplantation for Paediatric Patients with X-linked Lymphoproliferative Syndrome.

The aim of this study was to investigate the prognostic factors of haploid hematopoietic stem cell transplantation in the treatment of X-linked lymphoproliferative syndrome. Seven children with X-linked lymphoproliferative syndrome diagnosed by XIAP gene analysis were enrolled. The conditioning regimens were tolerated in all seven patients, and the median time of neutrophil engraftment was 10 days (8-13 days), and that of platelet engraftment was 21 days (14-24 days). STR-PCR analysis on the peripheral blood cells showed complete donor origins. Four cases developed Grade I acute graft versus host disease (aGVHD), one developed Grade III aGVHD (intestinal tract), and two cases had limited chronic GVHD. Four cases had cytomegalovirus (CMV) reactivation, and two cases had Epstein-Barr virus (EBV) reactivation. One case was diagnosed as pneumocystosis, and thrombotic microangiopathy (TMA) occurred in three cases. During the follow-up period (median time of 42 months), one patient died of TMA and six patients survived. Statistical analysis showed that the status of disease remission and the positive result of virus in blood before transplantation were independent prognostic factors. Haplo-HSCT might be a curative option for children with refractory X-linked lymphoproliferative syndrome. Low-intensity conditioning regimens may reduce transplant-related mortality and improve overall survival.

Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis

BackgroundPatients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear.MethodsWe tested a novel “all-in-one” strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored.ResultsAfter CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease–negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100).ConclusionsOur findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.)

Comparison of upfront haploidentical hematopoietic stem cell transplantation and salvage haploidentical hematopoietic stem cell transplantation after immunosuppressive therapy in children with acquired severe aplastic anemia - a multicenter study.

For children with severe aplastic anemia, if the first immunosuppressive therapy (IST) fails, it is not recommended to choose a second IST. Therefore, for patients without matched sibling donor (MSD) and matched unrelated donor (MUD), haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) can be chosen as a salvage treatment. This article aims to explore the comparison between upfront Haplo-HSCT and salvage Haplo-HSCT after IST. 29 patients received salvage Haplo-HSCT, and 50 patients received upfront Haplo-HSCT. The two groups received Bu (Busulfan, 3.2mg/kg/d*2d on days -9 to-8), CY (Cyclophosphamide, 60mg/kg/d*2d on days -4 to-3), Flu (fludarabine, 40mg/m2/d*5d on days -9 to -5) and rabbit ATG (Anti-thymocyte globulin, total dose 10mg/kg divided into days -4 to -2). The OS of the salvage Haplo-HSCT group showed no difference to the upfront Haplo-HSCT group (80.2 ± 8.0% vs. 88.7 ± 4.8%, p=0.37). The FFS of the salvage Haplo-HSCT group also showed no difference to the frontline Haplo-HSCT group (75 ± 8.2% vs. 84.9 ± 5.3%, p=0.27). There was no significant difference in the incidence of other complications after transplantation between the two groups, except for thrombotic microangiopathy (TMA). In the grouping analysis by graft source, the incidence of II-IV aGVHD in patients using PBSC ± BM+UCB was lower than that in the PBSC ± BM group (p=0.010). Upfront Haplo-HSCT and salvage Haplo-HSCT after IST in children with acquired severe aplastic anemia have similar survival outcomes. However, the risk of TMA increases after salvage Haplo-HSCT. This article provides some reference value for the treatment selection of patients. In addition, co-transplantation of umbilical cord blood may reduce the incidence of GVHD.

Immune reconstitution in children after haploidentical haematopoietic stem cell transplantation.

Immune reconstitution (IR) kinetics of paediatric patients underwent haploidentical haematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCy) have not been extensively studied. We compared IR patterns of children receiving HSCT from haploidentical (n = 92) and HLA-matched donors (n = 36), and analysed risk factors for viral infection in these patients. We prospectively measured lymphocyte subset numbers before HSCT and at 1, 3, 6 and 12 months after HSCT. Blood cytomegalovirus (CMV), Epstein-Barr virus, adenovirus, BK virus (BKV) and urine adenovirus and BKV viral loads were measured at designated time points. The median numbers of total T and T helper cells at 1 month were significantly lower in the haploidentical group compared with the HLA-matched group. Haploidentical HSCT recipients had significantly lower median numbers of several T cell subsets and B cells for 1 year after HSCT. The median NK cell count of the haploidentical group was lower at 1 month. BKV haemorrhagic cystitis, blood CMV and urine adenovirus reactivation were more frequently found in the haploidentical group. Post-haploidentical HSCT patients receiving anti-T lymphocyte globulin (ATG) had significantly lower median numbers of total T cells (at 1 month) and T helper cells (at 6 and 12 months) and higher rate of blood BKV reactivation compared with those without ATG. Paediatric patients who undergo haploidentical HSCT with PTCy are likely to have delayed IR and an increased risk of viral reactivation/infection compared with HLA-matched HSCT. The addition of ATG to PTCy delayed T cell recovery and increased risk of BKV reactivation.

Production of donor-derived cytotoxic T lymphocytes with potent anti-leukemia activity for adoptive immunotherapy in high-risk pediatric patients given haploidentical hematopoietic stem cell transplantation

Background aimsSomatic cell therapy based on the infusion of donor-derived cytotoxic T lymphocytes (CTL) able to recognize patients’ leukemia blasts (LB) is a promising approach to control leukemia relapse after allogeneic HSCT. The success of this approach strongly depends on the ex vivo generation of high-quality donor-derived anti-leukemia CTL in compliance with Good Manufacturing Practices (GMP). We previously described a procedure for generating large numbers of donor-derived anti-leukemia CTL through stimulation of CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with apoptotic LB in the presence of interleukin (IL)-12, IL-7 and IL-15. Here we report that the use of IFN-DC and the addition of IFNα2b during the priming phase significantly improve the generation of an efficient anti-leukemia T cells response in vitro. MethodsUsing this approach, 20 high-risk pediatric patients given haploidentical HSCT for high-risk acute leukemia were enrolled and 51 batches of advanced therapy medical products (ATMP), anti-leukemia CTL, were produced. ResultsQuality controls demonstrated that all batches were sterile, free of mycoplasma and conformed to acceptable endotoxin levels. Genotype analysis confirmed the molecular identity of the ATMP based on the starting biological material used for their production. The majority of ATMP were CD3+/CD8+ cells, with a memory/terminal activated phenotype, including T-central memory populations. ATMP were viable after thawing, and most ATMP batches displayed efficient capacity to lyse patients’ LB and to secrete interferon-γ and tumor necrosis factor-α. ConclusionsThese results demonstrated that our protocol is highly reproducible and allows the generation of large numbers of immunologically safe and functional anti-leukemia CTL with a high level of standardization.

Post-Transplant Cyclophosphamide versus Anti-Thymocyte Globulin in Patients with Hematological Malignancies Treated with Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical and Matched Unrelated Donors: A Real-Life Experience.

Background: Post-transplant cyclophosphamide (PTCY) is widely used as graft versus host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplant (HSCT) recipients, with reported clinical benefits in patients who underwent transplant from a matched unrelated donor (MUD). However, real-life data on clinical efficacy and safety of PTCY in haploidentical and MUD transplantations are still poor. Methods: In our real-life retrospective observational study, we included a total of 40 consecutive adult patients who underwent haploidentical or MUD HSCT for various hematological malignancies and who received PTCY (n = 24) or ATG (n = 16) as GvHD prophylaxis at Hematology Units from hospitals of Salerno and Avellino, Italy, and clinical outcomes were compared. Results: We showed protective effects of PTCY against disease relapse with the relapse rate after transplantation of 16% versus 50% in the ATG arm (p = 0.02). All-cause mortality was lower (36% vs. 75%; p = 0.02) and the 2-year overall survival was slightly superior in patients administered PTCY (61% vs. 42%; p = 0.26). Conclusions: We support the use of PTCY, even in a real-life setting; however, the optimization of this protocol should be further investigated to better balance relapse prevention and GvHD prophylaxis.