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Publisher Copyright: © 2020, The Author(s). 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.

Three-loci low-resolution (LR) or intermediate-resolution HLA typing is generally considered adequate in the related blood and marrow transplantation (BMT) context. However, a single high-resolution (HR) mismatch may have a similar adverse impact on BMT outcome as an LR one. We sought to determine the frequency of mismatches that may go undetected when standard typing (LR or 3-loci HR) is used compared with 6-loci HR typing for related donor compatibility testing, and to assess its impact on relevant BMT outcomes. We analyzed data from a total of 2554 6-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) HR sequence-based typing (full typing [FT]) from 754 patients, 1011 siblings, and 789 parents done at DKMS Germany (www.DKMS.de) between January 1, 2014, and June 21, 2016. We also studied 38 cases in which the family had undergone 3-loci HLA typing (standard typing [ST]). Patients were from India (70%), Pakistan (22%), and Sri Lanka (8%). The IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) was used to tease out nonpermissive DPB1 mismatches. HLA disparity–related outcomes, such as rejection and graft-versus-host disease (GVHD) were assessed in a retrospective matched-pair cohort of 50 patients (25 with ST and 25 with FT) who underwent BMT for severe thalassemia from compatible related donors. We found fully matched (either 12/12 HR matches or with a single permissive DPB1 mismatch) related donors for 285 patients (38%). Of these donors, 89% were siblings and 11% were parents. The likelihood of matching on an individual locus on LR but not on HR was found to be 5%. A total of 9 donors (3%; 7 siblings and 2 parents) who would have been considered a full match by HR typing on A, B, and DRB1 alone were not a match by extended 6-loci HR typing. Five of these 9 donors had a mismatch on C or DQB1, and 4 had a nonpermissive DPB1 mismatch. In this group, 5 donors (56%) belonged to a consanguineous family, in 2 donors (22%) there was no reported consanguinity, and in 2 donors (22%) consanguinity was unknown. We identified 18 donors (6%; 13 siblings and 5 parents) who would have been considered a 12/12 match by LR HLA typing alone but were found not to match on extended HR typing. In this group, 11 donors (61%) were from consanguineous families, 3 donors (17%) had no reported consanguinity, and in 4 donors (22%) consanguinity was unknown. Outcome analysis showed that the actuarial proportion of patients with GVHD was 4% in the FT group compared with 16% in the ST group, with log-rank P = .1952. The ST group included 2 patients with grade III-IV acute GVHD and 1 patient each with moderate and severe chronic GVHD, whereas the FT group only 1 patient with grade III acute GVHD. We conclude that even in the context of related donors, the use of LR and/or 3-loci (A, B, and DRB1) HR HLA typing might result in a sizable risk of missing a clinically relevant mismatch, which may have an adverse impact on transplantation outcomes. In the Indian subcontinent, this observation is not limited to putatively compatible parents or consanguineous families; we recommend full 6-loci HR HLA typing even for matched related BMTs.

In spite of advances in chelation therapy and screening of blood, mortality associated with the most common life-threatening noncommunicable disease of children in India, transfusion-dependent thalassemia (TDT), remains poorly defined. This study aims at estimating death rates and mortality risk factors associated with TDT. The clinical records of 1087 patients from 5 thalassemia centers in India were retrospectively analyzed from 2011 to 2018. Median patient age was 8.5 years, with 107 patients older than 18 years; 656 patients were male and 431 were female. Demographic details and clinical parameters were analyzed at presentation and at last visit. With 41 recorded deaths, actuarial survival at 26.9 years was 50%, and under-5 mortality was 7 times higher than in the general population. Patients with transfusion-transmitted infections (TTIs) had 3.4 times higher risk for death (P = .031). Serum ferritin higher than 4000 ng/dL had 4.6 times higher risk for mortality compared with ferritin lower than 1000 ng/dL (P = .00063). A hemoglobin drop lower than 2 g/dL per week had 7.7 times higher mortality risk compared with a drop of less than 1 g/dL per week (P < .0001). Social determinants (sex, economic status, and distance from center), splenectomy, and even cardiac complications were not associated with higher mortality risk. Main causes of death were infection, iron overload, TTIs, and allo-immunization. Patients who received more than 4 years of adequate care had more than 66% mortality risk reduction (P < .0001). TDT in India continues to result in high mortality. Ineffective transfusion, TTIs, and chelation continue to be the most significant risk factors. Comprehensive care in dedicated day care centers from early age is likely to improve outcomes.

Introduction: Continued quality improvement systems are necessary not only to maintain minimum quality standards, but also contribute to improved outcomes (Snowden et al. 2017; Hashmi et al. 2017). In-spite of its importance, the implementation of a functional Quality Management System (QMS) in the routine daily activity oh health professionals may be a challenge, especially in resource limited settings (Hashmi et al. 2017). Methodology: BMTPlus is an information and communication technology (Agarwal et al. 2014) platform that has been used for knowledge management by Sankalp-People Tree Centre for Paediatric BMT, Bangalore (PTH) from July 2015 and Sankalp-CIMS Centre for Paediatric BMT, Ahmedabad (CIMS) from March 2017. BMTPlus brings together all aspects of transplant data management including clinical data management, personal records and QMS. The usage of these tools which directly relate to the continued quality improvement process was reviewed. Clinical outcomes for patients who underwent transplant for thalassemia in these centres from matched related donors were summarised using R statistical package (version 3.5.x) as an indicator of the effectiveness of the continued quality improvement process. Results: Table 1 summarises the program information, utilisation of various quality management-related records, staff turnover, outcomes and costs. Information technology-driven QMS provided the unique advantage of being able to audit all the data instead of sample data sets and thus widening the potential to detect issues. The inventory management and prescriptions system was audited in 2019 at PTH and the findings are that there were only 3 events in 4 years where important drugs/supplies came close to a critical shortage. Automated treatment plan imports contributed to 2 of the 1570 drug orders being detected with inaccuracies (0.13%). The PTH BMT service has been using BMTPlus for auto submission of data to CIBMTR; data audit in July 2019 showed that 92% of the 1263 due forms were successfully submitted. CIMS is catching up with 39% forms submitted so far. The impact of this quality improvement system on clinical outcomes of the program was measured on 172 successive first matched related transplants (103 from PTH and 69 from CIMS) upto April 15 2019. Outcomes were compared across 3 successive transplant protocols, all patients were transplanted at-least 100 days prior to this analysis. Both overall and disease-free survival improved significantly from protocol 1 to 3, i.e. from 88% to 100% (p = 0.002) and from 77% to 98% (p < 0.0001) respectively. Transplant-related mortality and rejection significantly dropped from 10% to 0% (p = 0.01) and from 22% to 3% (p < 0.0001) respectively. The outcomes achieved at this lower-middle income centre compared favourably with the 96.9% day-100 survival reported in USA for thalassemia ("U.S. Patient Survival Report" 2017). Progressively improved outcomes and good utilisation of quality management features were seen in spite of the fact that PTH had an attrition rate as high as 44% for physicians and 78% for nurses while in CIMS this was 74% and 57% respectively. The impact of quality management on the cost and sustainability of the program can be seen from the cost of the transplants. Though the programs experienced a 10% increase in operational costs on a year on year basis, the ongoing quality improvements led to fewer complications and cost escalations as a result of which the program at PTH and CIMS continue to offer matched-related transplants at USD 12.500 and USD 13.300 respectively which was the bundled cost set at the beginning of the programs in July-2015 and March-2017 respectively. Thanks to the use of online platform, only one quality/data manager is the only additional resource specific to continued quality improvement, quality assurance, outcome reporting and participation in international registries. Conclusion: Information and communication technology enabled comprehensive knowledge management and facilitated continuous quality improvement. This contributed to the delivery of cost-efficient and effective transplantations with progressively improving outcomes, which finally are at par with the best centres in the world in spite of the challenges of high staff turnover. Disclosures No relevant conflicts of interest to declare.

Introduction: An assessment of morbidity and mortality caused by transfusion dependent thalassemia in India has never really been done despite thalassemia being the most prevalent life threatening non-communicable disorder of childhood. There is little structured understanding identifying the key risk factors feeding into research and policy making for effective management of thalassemia. With an estimated 10,000-12,000 children born with thalassemia each year in India, in addition to increasing focus on early pregnancy targeted screening, it seems critical to increase our understanding of risk factors associated with early mortality and morbidity. This is also relevant to family counselling about management options. Methodology: A retrospective analysis of mortality key risk factors in patients suffering from thalassemia major from 5 thalassemia day care centres in India was carried out. This included a total of 1,087 patients (656 males and 431 females with a median age of 8.6 years) enrolled for care between 1 Jan 2010 - 31 Oct 2018 at these centres. These centres were set up by a non-profit organization in collaboration with blood banks and /hospital facilities with the objective to provide comprehensive thalassemia care; A common web-based application was employed (ThalCare™). This system was used to track information associated with treatment including disease history at enrolment, demographic data and follow-up information. All analyses were performed with R Statistical software (3.5.2). Survival analysis was done from the age at presentation to the centre till October 2018. The reasons for mortality were categorized. Overall survival was also separately analyzed for patients in their 1st,2nd, 3rd or subsequent decades of life. The Cnaan and Ryan approach was used as patients entered and left the study cohort (left censored and right truncated data) and observation began only at enrolment and not at disease onset Results: The median age at enrolment was 5.4 years and the median follow up at the centre was 2.5 years. A total of 86 patients were cured by bone marrow transplantation (BMT), 13 of them moved to other centres for care and 41 patients died during the study period (28 males and 13 females). The median age at death was 15.4 years. Actuarial survival at 26.9 years of age was 50% (Figure 1) and under-five mortality was 7 times higher than the general population. Patients with transfusion-transmitted infections (TTI) had 3.4 times higher risk of death (p=0.031). Serum ferritin >4,000 ng/dL was associated with 4.6 times higher risk of mortality compared to ferritin 2 gm/dL/week had 7.7 times higher mortality risk compared to 2 gm/week (hazard ratio 5.58 ,p=0.0007) and lack of attention towards care for possible prevention from TTI (hazard ratio 2.86, p=0.0004) are factors independently associated with high mortality. Table 2 shows that in patients born after the year 2,000 overall survival is 85.2% compared to 29.4% for patients born earlier. Main causes of death were infection, iron overload, TTIs, and alloimmunization; In a quarter of patients the cause of death was unknown (Figure 2). Patients who received more than 4 years of adequate care had more than 66% mortality risk reduction (p Conclusion: Comprehensive care right from an early age at dedicated management centres is key to improving life expectancy of thalassemia patients in India. Optimizing blood transfusion, intensifying chelation and preventing TTIs seem particularly important. Sustained efforts in these areas coupled with increased prevention and access to safe BMT will ease the burden for both families and public healthcare. Disclosures No relevant conflicts of interest to declare.

Bone marrow transplantation (BMT) may cure and normalize health-related quality of life in over 80% of low-risk children with severe thalassemias (ST). Partially matched-related (haploidentical) transplants (Haplo) with the use of post-BMT cyclophosphamide as GVHD/rejection prophylaxis (PTCy) is an established safe and simple approach allowing BMT to be accessible to virtually all candidates even in settings with limited resources where most children with ST live. However, the experience with Haplo-PTCy in ST is still limited, particularly in terms of factors predictive of rejection, a complication relevant to ST patients because of multiple transfusions and immunocompetence. This study assessed a group of 22 patients with ST with a median age of 4.7 years (range 1.5 to 13.5), all with low-risk features, defined as liver size ≤ 2 cm from costal margin, who underwent Haplo-PTCy BMT between March 2017 and August 2018 in 2 centers in India, the South East Asia Institute for Thalassemia in Jaipur (16 cases) and the People Tree Hospital in Bangalore (6 patients). All received partially matched grafts, 5 from the father and 17 from the mother with a uniform regimen modified from Anurathapan et al. BMT 2016 (outlined in Fig. 1). G-CSF-primed bone marrow was used for all patients with a median cell dose of 16.2 nucleated cells/Kg (range 12.1 to 59.2). At a median follow up of 6.4 months (range 1.8 to 19.1) actuarial overall survival is 86%, thalassemia-free survival 72%, transplant-related mortality 9% and rejection 26%. One death was unrelated to BMT. Donor-Specific Antibodies (DSA) status was known in 21 patients, 4 patients (19%) were DSA+ (MFI > 2.000) and all but one rejected, interestingly, the DSA+ patient who engrafted had a GVH set up (donor HLA-A homozygous). Of 17 DSA− patients 3 rejected and all had a HVG set up, i.e. the recipient was homozygous for one or more HLA specificities while the donor was not: One was DRB1, one A & DPB1 (permissive), and one DRB1 & DQB1 homozygous. No rejections were observed in the absence of DSA-positivity or a HVG set up, so that actuarial rejection proportion went from 63% in DSA+ HVG+ patients to 0 in DSA− HVG− ones (log rank P=0.0023) (see Fig 2). All 15 patients who engrafted had complete donor chimerism and 9 (60%) developed acute GVHD, 8 grade I-II and one grade IV, this patent died of GVHD, interestingly he had a strong GVH set up (father donor A & C homozygous). CMV reactivation occurred in 3 engrafted patients (20%), other relevant complications included one macrophage activation syndrome who responded to steroids, one BK virus infection with severe late hemorrhagic cystitis, renal failure and death. In conclusion, in addition to DSA status, also HVG vs. GVH HLA set up might be relevant in the context of Haplo-PTCy for non-malignant conditions.

Aims: The compliance of safety and quality parameters laid out by national and international guidelines in outdoor blood donation camps has not been studied in India. Our study aimed at identifying, monitoring, analyzing, and developing preventive strategies for several key parameters associated with the quality and safety of outdoor voluntary blood donation camps (VBDC). Settings: The study covered a total of 424 VBDCs at various locations in Bengaluru, Karnataka (South India) from 2009 to 2013. Seven government hospitals based blood banks, three private hospitals based blood banks and two voluntary standalone blood banks participated in the VBDCs included in the study. Materials and Methods: At the onset, the quality and safety standards to be followed were discussed and agreed upon. During the study, noncompliance (NC) to the agreed upon standards were recorded and shared. Periodic trainings were also organized to help minimize NC. Results: One or more instances of NC in 73% of the VBDCs. Highest NC were observed associated with punctuality (34%), wearing gloves (16%), hemoglobin (Hb) estimation (11%) and donor screening and selection other than Hb check (8-9%). Conclusion: For all 16 parameters under study, significant NC was observed. As a whole private hospital based blood banks were more noncompliant. The high degree of NC to matters relating to quality and safety in VBDCs is high and warrants for urgent attention and further study. Our study also shows that regular monitoring and systematic and strategic intervention can decrease the rate of NC.

BACKGROUND Successful models of information and communication technology (ICT) applied to cost-effective delivery of quality care in low- and middle-income countries (LMIC) are an increasing necessity. Severe thalassemia is one of the most common life-threatening noncommunicable diseases of children globally. OBJECTIVE The aim was to study the impact of ICT on quality of care for severe thalassemia patients in LMIC. METHODS A total of 1110 patients with severe thalassemia from five centers in India were followed over a 1-year period. The impact of consistent use of a Web-based platform designed to assist comprehensive management of severe thalassemia (ThalCare) on key indicators of quality of care such as minimum (pretransfusion) hemoglobin, serum ferritin, liver size, and spleen size were assessed. RESULTS Overall improvements in initial hemoglobin, ferritin, and liver and spleen size were significant (P CONCLUSIONS Implementation of computer-assisted treatment planning and performance assessment consistently and positively impacted indexes reflecting effective delivery of care to patients suffering from severe thalassemia in LMIC.

Background: Successful models of information and communication technology (ICT) applied to cost-effective delivery of quality care in low- and middle-income countries (LMIC) are an increasing necessity. Severe thalassemia is one of the most common life-threatening noncommunicable diseases of children globally. Objective: The aim was to study the impact of ICT on quality of care for severe thalassemia patients in LMIC. Methods: A total of 1110 patients with severe thalassemia from five centers in India were followed over a 1-year period. The impact of consistent use of a Web-based platform designed to assist comprehensive management of severe thalassemia (ThalCare) on key indicators of quality of care such as minimum (pretransfusion) hemoglobin, serum ferritin, liver size, and spleen size were assessed. Results: Overall improvements in initial hemoglobin, ferritin, and liver and spleen size were significant (P

Rejection of paternal vs maternal fully matched bone marrow grafts in children with thalassemia

Introduction: Complications associated with blood donation significantly lower odds of subsequent donations. The aim of the study is to assess the prevalence of complications related to blood donation, identify the influencing factors, and come up with suggestions for minimizing discomfort to donors and making outdoor voluntary blood donation camps safer. Materials and Methods: This study covered 181 blood donation camps organized by Sankalp India Foundation where 16 blood banks participated from 01-04-2011 to 01-08-2014 in Karnataka. Uniform protocols for donor selection, predonation preparation, counseling, postdonation care, and refreshments were used. The postdonation complications were recorded on a form immediately, after they were observed. Results: We observed 995 (3.2%) complications in 30,928 whole blood donations. Of these 884 (2.86%) mild, 77 (0.25%) moderate, and 5 (0.02%) severe complications were observed. Local symptoms (blood outside vessels, pain, and allergy) contributed 1.0%, and generalized symptoms (vasovagal reaction) contributed 2.2% to all the complications. Conclusion: We observed 322 complications for every 10,000 donations. Since 27 out of every 10000 experience moderate and severe complication, the readiness to manage complications is crucial. Women donors, young donors, and donors with a lower weight are at a significantly greater risk of experiencing complications, highlighting the need for specific guidelines for the management of higher risk donor groups. Complications varied significantly between various blood banks. Predonation hydration was effective in limiting complications with generalized symptoms. We recommend a robust donor hemovigilance program for voluntary blood donation for monitoring complications and enable assessment of effectiveness and implementation of appropriate interventions.