The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.

/pdf/the-consensus-from-the-chinese-society-of-hematology-on-40dv8mfvcn.pdf

The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update.

Background Until now, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only effective method to cure Thalassemia major. However, it has not been determined whether similar results can be obtained with the same conditioning regimen for both fully-matched and mismatched donors grafts. We hypothesized that using modified NF-08-TM conditioning regimen could achieve similar results for both fully and mismatched donors grafts. Methods This retrospective cohort study included patients with β-thalassemia major who underwent HSCT with modified NF-08-TM conditioning regimen at Guangzhou Women and Children's Medical Centre between January 2013 and January 2019. Results Among the 257 patients (172 males) included in this study, 3 had two transplantations. Totally 193 and 67 had fully-matched and mismatched donors were examined, respectively. The median follow-up was 29 months; 6-year overall survival (OS), thalassemia-free survival (TFS), graft rejection (GR) and transplantation-related mortality (TRM) were 92.08%, 90.89%, 1.24% and 8.01%, respectively. Multivariate analysis showed that human leukocyte antigen (HLA) compatibility between patient and donor was not independently associated with OS, TFS, GR or TRM. Mismatched donor graft transplantation for β-thalassemia major is associated with similar survival outcomes and incidences of complications (except for acute GVHD) to fully-matched donor graft transplantation based on modified NF-08-TM conditioning regimen. Conclusions In conclusion, based on the modified NF-08-TM regimen, certain mismatched donor transplantations for thalassemia major patients could achieve similar results as fully-matched donor transplantations.

/pdf/hematopoietic-stem-cell-transplantation-for-thalassemia-3u9egqpp4h.pdf

Hematopoietic stem cell transplantation for thalassemia major using HLA fully-matched and mismatched donor grafts

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only consolidated, potentially curative treatment for patients with transfusion-dependent thalassemia major. In the past few decades, several new approaches have reduced the toxicity of conditioning regimens and decreased the incidence of graft-versus-host disease, improving patients' outcomes and quality of life. In addition, the progressive availability of alternative stem cell sources from unrelated or haploidentical donors or umbilical cord blood has made HSCT a feasible option for an increasing number of subjects lacking an human leukocyte antigen (HLA)-identical sibling. This review provides an overview of allogeneic hematopoietic stem cell transplantation in thalassemia, reassesses current clinical results, and discusses future perspectives. 

Hematopoietic Stem Cell Transplantation in Thalassemia.

This expert opinion originally developed by a panel of the Italian Society of Thalassemias and Hemoglobinopathies (SITE), reviewed and adopted by the European Hematology Association (EHA) through the EHA Scientific Working Group on Red Cells and Iron, has been developed as priority decision-making algorithm on evidence and consensus with the aim to identify which patients with transfusion-dependent beta-thalassemia (TDT) could benefit from a gene therapy (GT) approach. Even if the wide utilized and high successful allogeneic hematopoietic stem-cell transplantation provides the possibility to cure several patients a new scenario has been opened by GT. Therefore, it is important to establish the patients setting for whom it is priority indicated, particularly in the early phase of the diffuse use outside experimental trials conducted in high selected centers. Moreover, actual price, limited availability, and resources disposal constitute a further indication to a rational and progressive approach to this innovative treatment. To elaborate this algorithm, the experience with allogeneic transplantation has been used has a predictive model. In this large worldwide experience, it has been clearly demonstrated that key for the optimal transplant outcome is optimal transfusion and chelation therapy in the years before the procedure and consequently optimal patient's clinical condition. In the document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. According to the European Medicine Agency (EMA) for the GT product, this expert opinion must be considered as a dynamic, updatable, priority-based indications for physicians taking care of TDT patients.

Selecting β-thalassemia Patients for Gene Therapy: A Decision-making Algorithm.

Cytomegalovirus (CMV) infection remains a critical cause of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), despite improvement by pre-emptive antivirus treatment. CMV-specific cytotoxic T lymphocytes (CMV-CTL) are universally used and proven well-tolerance after allo-HSCT in adult clinical trials. However, it is not comprehensively evaluated in children’s patients. Herein, we conducted a retrospective study to determine the risk factors of CMV infection and evaluation of CMV-CTL in children patients who underwent allo-HSCT. As result, a significantly poor 5-year overall survival was found in the CMV infection group (87.3 vs. 94.6%, p=0.01). Haploidentical HSCT (haplo-HSCT) was identified as an independent risk factor for CMV infection through both univariate and multivariate analyses (p<0.001, p=0.027, respectively). Furthermore, the cumulative incidence of CMV infection was statistically higher in the haplo-HSCT group compared to the HLA-matched donor group (44.2% vs. 21.6%, p<0.001). Finally, the overall response rate of CMV-CTL was 89.7% (26/29 patients) in CMV infection after allo-HSCT. We concluded that CMV infection following allo-HSCT correlated with increased mortality in children’s patients, and haplo-HSCT was an independent risk factor for CMV infection. Adoptive CMV-CTL cell therapy was safe and effective in pediatric patients with CMV infection.

/pdf/features-of-cytomegalovirus-infection-and-evaluation-of-9eez00ae.pdf

Features of cytomegalovirus infection and evaluation of cytomegalovirus-specific T cells therapy in children’s patients following allogeneic hematopoietic stem cell transplantation: A retrospective single-center study

To the Editor: Hematopoietic stem cell transplant (HSCT) can cure thalassemia major (TM), but only 30% of the patients have a matched sibling donor. Alternative donors, including unrelated donors, cord blood, and parental donors, have continuously improved the results of HSCT in leukemia in the last decades. Therefore, HSCT from alternative donors were gradually applied to thalassemia. Our previous encouraging single-center results of the “the NF-08-TM” protocol in unrelated donor transplant in TM patients have published in Blood in 2012. Considering the limitations of our single-center study, we subsequently carried out a multicenter collaboration using the NF-08-TM protocol. Here we report the long-term results from the multi-center study. A total of 486 consecutive HSCT from four pediatric centers in China between July 2011 and June 2016 using the NF-08-TM protocol were analyzed. The ratio of male to female was 309 to 177 with a median age of 6 years (range, 2-23 years). Most patients were classified in group two according to the criteria of the NF-08-TM protocol. Patients were classified into two groups according to human leukocyte antigen (HLA-A,HLA-B, HLA-C and HLA-DRB1) matching, that is,10/10 matched group (n = 428, 88.1%) and 9/10 (n = 58, 11.9%). One hundred and nine-three patients underwent sibling donor HSCT (190 matches and three mismatches); 212 unrelated donor HSCT (173 matches and 39 mismatches), 35 parent donor HSCT (19 matches and 16 mismatches) and 46 sibling cord blood transplants (all matched). Except for cord blood transplant, peripheral blood stem cells were used as a stem cell source in the current cohort. A constant mononuclear cell dose (8.0 × 10/kg) was given to all patients regardless of CD3+ and CD34+ cell dose. All 497 patients received the NF-08-TM protocol, but the target of busulfan plasma steady-state concentration were 500-800 ug/L instead of 300-600 ug/L and doses were adjusted based on PK parameters. Sirolimus and tacrolimus were more often used since 2014. Among the 486 HSCTs with the median follow-up time of 56 months (range,28-93 months), overall survival (OS), thalassemiafree survival (TFS), graft rejection (GR) and transplant related mortality (TRM) were 94.7%, 93.3%, 2.8% and 5.3% (Figure 1), respectively. The corresponding outcomes for sibling donor HSCT (n = 193) were 97.4%, 97.4%, 1% and 2.4% (Figure S1A, see supplement, same below); for unrelated donor HSCT (n = 212) were 92%, 88.9%, 4.9% and 8% (Figure S1B); for parent donor HSCT (n = 35) were 94.3%, 94.3%, 0% and 5.7% (Figure S1C); and for cord blood transplant (n = 46) were 97.8%, 95.3%, 2.6% and 2.2% (Figure S1D), respectively. The results in mismatched unrelated donor HSCT were worse than matched sibling donor HSCT. The corresponding OS, TFS and TRM for mismatched unrelated donor HSCT vs (vs) matched sibling donor HSCT were 84.6% vs 97.4%(P = .001), 82.1% vs 97.4% (P = <.001) (Figure S2A) and 15.4% vs 2.6% (P = .001) (Figure S2B). The OS, TFS, TRM and GR for matched and mismatched unrelated donor HSCT were 93.6% vs 84.6% (P = .058, Figure S2C), 90.4% vs 82.1% (P = .089, Figure S2D), 4.4% vs 15.4% (P = .058, Figure S2E), and 4.8% vs 5.3% (P = .744, Figure S2F), respectively. The incidence of grade II-IV acute graft vs host disease (aGVHD), grade III-IV aGVHD, mild chronic GVHD (cGVHD), and moderate/ severe cGVHD in the current cohort was 11.1%, 5.1%, 4.2%, and 1.7%, respectively. When compared with matched sibling donor HSCT, grade II-IV GVHD in matched unrelated donor HSCT was more common (18% vs 5.4%, P = .008) (Figure S3A).Matched unrelated donor HSCT also had more aGVHD than matched parent donor HSCT (23.6% vs 0%, P = .046) (Figure S3B).When compared with matched sibling donor HSCT, the incidence of grade II-IV aGVHD and moderate/severe cGVHD was higher in mismatched unrelated donor HSCT (5.4% vs 25.9%, P = .000) (Figure S3C) and 3.9% vs 18.4%, P = .000) (Figure S3D), respectively. More moderate/severe cGVHD occurred in mismatched unrelated donor HSCT than matched unrelated donor HSCT (18.4% vs 6.9%, P = .018).The cumulative incidence of hemorrhagic cystitis and venous occlusive disease in the entire cohort was 9.1% and 1.4%, respectively, and no statistically difference was found in both by donor-groups. In the current multi-center large-sample study, we observed the consistent outcomes with those published in 2012 and the more than 90% long-term TFS when using the NF-08-TM protocol in HSCT for TM patients, regardless of donor family relationships. Such results are encouraging, particularly in countries with limited resources per capita, insurance deficiency, blood-product shortage, or high prevalence of irregular transfusion and chelation due to economic reasons. Another notable fact is that most of the patients in the current study might be classified as unfavorable class II-III with Pesaro classification because of irregular iron-chelation, even though we did not routinely Received: 28 February 2020 Revised: 28 July 2020 Accepted: 28 July 2020

Long-term results of the NF-08-TM protocol in stem cell transplant for patients with thalassemia major: A multi-center large-sample study.

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Long-term results of the NF-08-TM protocol in stem cell transplant for patients with thalassemia major: A multi-center large-sample study.