Setting up and sustaining blood and marrow transplant services for children in middle-income economies: an experience-driven position paper on behalf of the EBMT PDWP.

Severe blood disorders and cancer are the leading cause of death and disability from noncommunicable diseases in the global pediatric population and a major financial burden. The most frequent of these conditions, namely sickle cell disease and severe thalassemia, are highly curable by blood or bone marrow transplantation (BMT) which can restore a normal health-related quality of life and be cost-effective. This position paper summarizes critical issues in extending global access to BMT based on ground experience in the start-up of several BMT units in middle-income countries (MICs) across South-East Asia and the Middle East where close to 700 allogeneic BMTs have been performed over a 10-year period. Basic requirements in terms of support systems, equipment, and consumables are summarized keeping in mind WHO's model essential lists and recommendations. BMT unit setup and maintenance costs are summarized as well as those per transplant. Low-risk BMT is feasible and safe in MICs with outcomes comparable to high-income countries but at a fraction of the cost. This report might be of assistance to health care institutions in MICs interested in developing hematopoietic stem cell transplantation services and strengthening context appropriate tertiary care and higher medical education.

Splenomegaly May Increase the Risk of Rejection in Low-Risk Matched Related Donor Transplant for Thalassemia, This Risk Can Be Partially Overcome by Additional Immunosuppression during Conditioning.

Severe thalassemia syndromes (ST) are highly curable by bone marrow transplant (BMT), but rejection may still occur. We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol. In this study, we compared rejection rates between patients with and without splenomegaly in 189 consecutive low-risk ST transplants across 2 sequential conditioning regimens: regimen A (August 2013 to December 2016): busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg), and anti-thymocyte globulin (ATG) (Genzyme (Sanofi, Paris, France) 4 mg/kg or Fresenius (Grafalon, Neovii Biotech GmbH, Gräfelfing Germany) 16 mg/kg on days -12 to -10), and regimen B: same backbone as regimen A except fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and/or sex-mismatched transplants (January 2017 to September 2018). Compared with regimen A, in regimen B, both overall rejection rates (RRs) (16% versus 6.5%, P = .023) and treatment-related mortality (TRM) (9.9% versus 2.8%, P = .038) improved significantly. By Cox regression analysis, the improvement in RR between the 2 protocols was particularly significant in patients with splenomegaly (RR 54.5% versus 6.5%, P = .00015; TRM 18.2% versus 6.5%, P = .25) (hazard ratio, 4.13; confidence interval, 1.61 to 10.6; P = .003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG-Busulfan- Cyclophosphamide (ATG-Bu-Cy) protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

ATG vs thiotepa with busulfan and cyclophosphamide in matched-related bone marrow transplantation for thalassemia.

Matched-related bone marrow transplantation (BMT) may cure >80% of low-risk children with severe thalassemia (ST). Very long-term follow-up studies have shown how the standard busulfan-cyclophosphamide (BuCy) regimen may be associated with normalization of health-related quality of life, no second malignancies in the absence of chronic graft-versus-host disease, and fertility preservation in many patients. However, because BuCy may be associated with high rejection rates, some centers incorporate thiotepa (Tt) in busulfan- or treosulfan-based regimens, a combination that may increase the risk of permanent infertility. This study retrospectively compares matched-related BMT outcomes in 2 groups of low-risk ST patients conditioned with either Tt or anti-thymocyte globulin (ATG) in addition to BuCy. A total of 81 consecutive first BMTs were performed in 5 collaborating startup BMT centers in the Indian subcontinent between January 2009 and January 2016; 30 patients were transplanted after conditioning with Tt-BuCy between January 2009 and July 2013, whereas between August 2013 and January 2016, 51 patients received ATG-BuCy. All patients were <15 years and had no hepatomegaly (liver ≤2 cm from costal margin). Actuarial overall survival in the Tt-BuCy and ATG-BuCy groups was 87% and 94% and thalassemia-free survival was 80% and 85% at a median follow-up of 37 and 17 months, respectively, with no significant differences by log-rank statistics. Substituting Tt with ATG in the standard BuCy context seems safe and effective and may decrease transplant-related mortality. Higher fertility rates are expected for patients who received ATG-BuCy.

Remission of microangiopathy in transplanted thalassemic child.

Transplant associated thrombotic microangiopathy is a severe complication of Hematopoeitic stem cell transplantation. Although there is agreement in terms of diagnostic criteria, treatment options are not clarified yet. We present a patient aged 2.6 years who developed transplant associated thrombotic microangiopathy after allogeneic bone marrow transplantation and to discuss both risk factors and possible spontaneous remission of transplant associated thrombotic microangiopathy.

A prospective international cooperative information technology platform built using open-source tools for improving the access to and safety of bone marrow transplantation in low- and middle-income countries.

Jagriti Innovations developed a collaboration tool in partnership with the Cure2Children Foundation that has been used by health professionals in Italy, Pakistan, and India for the collaborative management of patients undergoing bone marrow transplantation (BMT) for thalassemia major since August 2008. This online open-access database covers data recording, analyzing, and reporting besides enabling knowledge exchange, telemedicine, capacity building, and quality assurance. As of February 2014, over 2400 patients have been registered and 112 BMTs have been performed with outcomes comparable to international standards, but at a fraction of the cost. This approach avoids medical emigration and contributes to local healthcare strengthening and competitiveness. This paper presents the experience and clinical outcomes associated with the use of this platform built using open-source tools and focusing on a locally pertinent tertiary care procedure-BMT.