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Aswin Anand Pai, Ajith Mohan, Esther Sathya Bama Benjamin, Raveen Stephen Stallon Illangeswaran, Infencia Xavier Raj, Nancy Beryl Janet, Arun Kumar Arunachalam, ML Kavitha, Uday Kulkarni, Anup J Devasia, NA Fouzia, Aby Abraham, Alok Srivastava, Biju George, Vikram Mathews, Anu Korula, Poonkuzhali Balasubramanian Department of Haematology, Christian Medical College, Vellore, Tamilnadu, IndiaCorrespondence: Poonkuzhali BalasubramanianDepartment of Haematology, Christian Medical College, Vellore, Tamilnadu, IndiaEmail bpoonkuzhali@cmcvellore.ac.inPurpose: Severe myelosuppression in patients with acute lymphoblastic leukemia (ALL) undergoing 6-MP-based maintenance therapy is attributed to TPMT gene polymorphisms, which is rare in Asian populations. This study aims to evaluate the role of selected polymorphisms in NUDT15, ITPA, and MRP4 genes in addition to TPMT in predicting 6-MP intolerance during ALL maintenance therapy.Patients and Methods: We screened for the presence of NUDT15&ast;3 (c.415 C>T, rs116855232); MRP4 c.2269 C>T (rs3765534), ITPA c.94 C>A (rs1127354) polymorphisms in addition to TPMT &ast;2 (rs1800462), &ast;3A (&ast;3B and &ast;3C; rs1800460 and rs1142345) in ALL patients with documented severe neutropenia (cohort-1; n=42). These polymorphisms were then screened in a prospective cohort of ALL patients (cohort-2; n=133) and compared with 6-MP dose reduction, early/late myelotoxicity.Results: Nineteen (45%) patients in cohort-1 and 18 (14%) in cohort-2 had NUDT15 c.415 C>T variant while 4 (3%) patients in cohort-2 had TPMT&ast;3C variant. Five (12%) in cohort-1 and 30 (24%) in cohort-2 had ITPA c.94 C>A variant while 9 (22%) and 15 (12%) had MRP4 c.2269 C>T variant in cohorts-1 and 2, respectively. All in cohort-1 and 36 (27%) in cohort-2 had severe myelotoxicity. Twenty-eight patients (66.6%) in cohort-1 and 40 (30%) patients in cohort-2 had significant 6-MP dose reduction. NUDT15 c.415 C>T variant explained severe myelotoxicity in 63% and 33% in cohort 1 and 2. TPMT&ast;3C and ITPA c.94 C>A variants also explained myelotoxicity in cohort-2 (Median ANC: 376 vs 1014 mm3; p=0.04 and 776 vs 1023 mm3; p=0.04 respectively). NUDT15 c.415 C>T polymorphism explained significant myelotoxicity (507 vs 1298 mm3; p< 0.0001) in the multivariate analysis as well (β=− 0.314, p< 0.0001).Conclusion: NUDT15 c.415 C>T (15&ast;3), TPMT&ast;3C, as well as ITPA c.94 C>A and MRP4 c.2269 C>T polymorphisms explain hematotoxicities. Preemptive genotype-based (NUDT15&ast;3, TPMT, ITPA c.94 C>A) 6-MP dosing could improve the outcome after maintenance therapy.Keywords: leukemia, mercaptopurine, myelotoxicity, pharmacogenomics

To assess vitamin D status of children on long-term anticonvulsants, including the less studied widely used levetiracetam, and the potential risk factors for deficiency. Children on antiepileptic drugs (cases, n = 269) were compared with controls (n = 295) for serum biochemistry, 25OHD, parathormone (PTH), sun exposure, dietary calcium, and vitamin D intake. Cases had lower serum 25OHD [median (IQR) 18.4 (11.5–24.1) ng/mL] compared to controls [20.8 (15.4–26.2] ng/mL, p < 0.001), as well as more frequent vitamin D deficiency (25OHD < 12 ng/mL, 27.1%) and insufficiency (25OHD < 20 ng/mL, 57.6%) than did controls (11.2% and 46.1%, respectively). Significantly lower median (IQR) serum calcium [8.8 (8.1–9.4) vs. 9.2 (8.5–10.0) mg/dL], phosphorous [3.8 (3.3–4.2) vs. 4.7 (4.0–5.3) mg/dL), and higher PTH [58.4 (42.9–85.8) vs. 38.9 (24.6–55.5) pg/mL, p < 0.001 for all] and proportion of elevated alkaline phosphatase (11.2% vs. 5.1%, p < 0.01) was seen in cases versus controls. Vitamin D deficiency was present in 53.4% of children with cerebral palsy (CP) versus 19.9% in those without CP (p < 0.001). Serum 25OHD did not differ between patients on cytochrome P450 inducers versus noninducers, neither among the 3 major groups, users of carbamazepine, valproate, and levetiracetam. Logistic regression analysis showed serum 25OHD < 12 ng/mL to be independently influenced by case or control status, presence of CP, and season of sampling. Vitamin D deficiency is common with anticonvulsant therapy, especially in those having CP. In Kerala, the hot, dry season from March to May is protective.

Background Acute cutaneous graft-versus-host disease (acGVHD) following haematopoietic stem cell transplant (HSCT) is common but difficult to distinguish from other causes of rash. Plasma elafin has been proposed as a diagnostic and prognostic biomarker of skin GVHD. Aim To evaluate the role of plasma elafin as a biomarker in acGVHD in an Indian population. Methods Plasma elafin was evaluated in a prospective study of HSCT recipients, conducted over 2 years, taking measurements at baseline and at onset of skin rash after HSCT. Patients were categorized into those with GVHD rash, those with non-GVHD rash and those with no rash and the three groups were compared. Results Two hundred and sixty-one patients with a median age of 16 years (range 1–61 years) and a male predominance (175 : 86 M/F) underwent HSCT during the study period: 56 patients in the GVHD group, 49 in the non-GVHD group and 156 in the no-rash group. The median baseline elafin was similar in all three groups. At the onset of rash, median elafin level was similar between GVHD and non-GVHD rash (34 549 vs. 32 077 pg/mL; P = 0.58) and between GVHD and no rash (34 549 vs. 26 197 pg/mL; P = 0.08). A rise in elafin from baseline was significantly different between GVHD and no rash (P < 0.001) but not between GVHD and non-GVHD rash (P = 0.44). Conclusion The utility of plasma elafin as a biomarker of skin GVHD is very limited. Plasma elafin, although elevated in cutaneous GVHD, is not helpful in distinguishing between GVHD rash and other causes of rash following HSCT.

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

Objectives:To study the clinical profile and outcomes of patients with paraproteinemic neuropathy (PPN) and to explore the utility of nerve conduction studies (NCSs) to differentiate between the demyelinating subtypes.Methods:We did a retrospective analysis of patients diagnosed with PPN between January 2010 and December 2019 in an inpatient setting. The study population consisted of patients above 16 years of age presenting with clinical features suggestive of chronic peripheral neuropathy and on evaluation was found to have PPN.Results:A total of 74 patients were identified. The patients were predominantly in the 6th decade, and the majority were males. The subtypes of PPN were monoclonal gammopathy of undetermined significance (MGUS) (45.9%), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) (24.3%), solitary plasmacytoma (17.6%), multiple myeloma (8.1%), and AL amyloidosis (4.1%). There are specific features on NCS which can help in identifying POEMS syndrome and IgM MGUS. The majority of patients with PPN tend to stabilize or improve with treatment; however, many have a severe residual disability. New terminology and classification of these entities as ‘monoclonal gammopathies of neurological significance’ can aid in early diagnosis and the development of effective treatment, to prevent residual disability.Conclusion:PPN has a heterogeneous spectrum of clinical, biochemical, and electrophysiological features. NCS can help distinguish POEMS syndrome and IgM MGUS from other demyelinating subtypes.

The standard of care for patients with acute promyelocytic leukaemia (APL) relapsing after front-line treatment with arsenic trioxide (ATO)-based regimens remains to be defined. A total of 67 patients who relapsed after receiving ATO-based up-front therapy and were also salvaged using an ATO-based regimen were evaluated. The median (range) age of patients was 28 (4-54) years. While 63/67 (94%) achieved a second molecular remission (MR) after salvage therapy, three (4·5%) died during salvage therapy. An autologous stem cell transplant (auto-SCT) was offered to all patients who achieved MR, 35/63 (55·6%) opted for auto-SCT the rest were administered an ATO + all-trans retinoic acid maintenance regimen. The mean (SD) 5-year Kaplan-Meier estimate of overall survival and event-free survival of those who received auto-SCT versus those who did not was 90·3 (5·3)% versus 58·6 (10·4)% (P = 0·004), and 87·1 (6·0)% versus 47·7 (10·3)% (P = 0·001) respectively. On multivariate analysis, failure to consolidate MR with an auto-SCT was associated with a significantly increased risk of relapse [hazard ratio (HR) 4·91, 95% confidence interval (CI) 1·56-15·41; P = 0·006]. MR induction with ATO-based regimens followed by an auto-SCT in children and young adults with relapsed APL who were treated with front-line ATO-based regimens was associated with excellent long-term survival.

Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder that is characterized by hyper absorption of plant sterols from the intestinal mucosa leading to toxic levels in the blood. Four patients of age ranging from 11 to 29 years presented to the outpatient department with clinical features of hemolytic anemia. There were no features of hypercholesterolemia in any of the patients. Peripheral smear examination of all four patients showed stomatocytes and macrothrombocytopenia. Qualitative testing for plant sterols was performed in one case. Next generation sequencing revealed a compound heterozygous mutation in ABCG5 gene (c.1222C>T and c.1255C>T) in one case and homozygous mutations in ABCG5 gene (c.727C>T), (c.332G>A (p.G111E)), (c.1222C>T) in the other three cases. Ezetimibe (10 mg/day) was administered in one case, with complete resolution of symptoms. All patients were advised a low plant sterol diet and regular monitoring of hemoglobin and lipid profile. Our cases highlight a rare but important cause of hemolytic anemia that can be suspected from careful peripheral blood examination but only conclusively established by molecular genetic diagnosis.

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1− myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation–based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Molecular detection of JAK2 mutation (V617F or exon 12) is included as a major diagnostic criterion for polycythemia vera (PV) by the WHO 2016 guidelines. JAK2 exon 12 mutations are seen in about 2–5% of JAK2V617F-negative cases of PV. Mutations in JAK2 cause constitutive activation of JAK-STAT pathway which results in variable phenotypes. PV patients with exon 12 mutations in JAK2 present characteristically with erythrocytosis. There are limited reports describing the spectrum of JAK2 exon12 mutations in myeloproliferative neoplasms (MPNs). Here, we describe the characteristics of a series of MPN patients with mutations in exon 12 of JAK2 of which two were novel variants associated with polycythemia. Interestingly, we noted two patients presenting as myelofibrosis having JAK2 exon 12 mutations.

The standard‐of‐care for patients with acute promyelocytic leukemia (APL) relapsing after upfront arsenic trioxide (ATO) therapy is not defined. The present study was undertaken to evaluate the safety of addition of bortezomib to ATO in the treatment of relapsed APL based on our previously reported preclinical data demonstrating synergy between these agents. This was an open label, nonrandomized, phase II, single‐center study. We enrolled 22 consecutive patients with relapsed APL. The median age was 26.5 years (interquartile range 17.5 to 41.5). The median time from initial diagnosis to relapse was 23.1 months (interquartile range 15.6 to 43.8). All patients achieved hematological remission at a median time of 45 days (range 40‐63). Nineteen patients were in molecular remission at the end of induction. Grade 3 adverse events occurred in eight instances with one patient requiring discontinuation of therapy for grade 3 neuropathy. Twelve (54.5%) patients underwent autologous transplantation (auto‐SCT) in molecular remission while the rest opted for maintenance therapy. The median follow‐up was 48 months (range 28‐56.3). Of the patients undergoing auto‐SCT, all except one was alive and relapse free at last follow‐up. Of the patients who opted for maintenance therapy, three developed a second relapse. For treatment of APL relapsing after upfront ATO therapy, addition of bortezomib to a standard ATO‐based salvage regimen is safe and effective. This trial was registered at http://www.clinicaltrials.gov as NCT01950611., The standard‐of‐care for patients with acute promyelocytic leukemia (APL) relapsing after upfront arsenic trioxide (ATO) therapy is not defined. In this phase II study we demonstrate the safety of adding a proteasome inhibitor with ATO in the management of relapsed APL treated with upfront ATO. We also demonstrate the efficacy of this combination and the potential for its utilization in this setting.

Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre-transplant telomere length of patients and donors, measured by quantitative real-time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26 years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft-versus-host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow-up of 37 months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR) = 0·2, P = 0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five-year overall survival was significantly better (94·9 ± 3·5% vs 65·4 ± 4·3%, P = 0·002) for donors with long (highest quartile, DTL-HQ) versus short (lower three quartiles, DTL-LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:2 pages:362-368 ispartof: location:United States status: published

Background: Drug reaction with eosinophilia and systemic symptoms is an outcome of a complex interaction between specific drugs, certain herpesviruse types and the immune system of the affected individual and is characterized by an unpredictable course and recurrent flares even after withdrawal of the offending drug and administration of systemic steroids. Aims: To identify the predictors of disease severity in drug reaction with eosinophilia and systemic symptoms. Methods: After obtaining ethical clearance from the institutional ethics committee and a written informed consent from individual study participant, the first hundred patients who required inpatient care in Government Medical College, Kozhikode with drug reaction with eosinophilia and systemic symptoms from January 1st 2011 were included in this study aimed to identify the predictors of disease severity in drug reaction with eosinophilia and systemic symptoms. Results: Male-to-female ratio of the study group was 0.8:1. The presence of atypical cells in peripheral smear and advanced age were found to be predictors of disease severity in drug reaction with eosinophilia and systemic symptoms, whereas, sex, facial erythema and edema and absolute eosinophil count were found not to be predictors of the same. Limitations: The main limitation of this study was our inability to assess the role of human leukocyte antigen (HLA) association and herpes virus reactivation in disease severity in drug reaction with eosinophilia and systemic symptoms. This study was also not designed to evaluate the response to treatment given and the mortality caused by drug reaction with eosinophilia and systemic symptoms. Conclusions: Studies on the predictors of severity in drug reaction with eosinophilia and systemic symptoms in different population groups may enable us to identify the warning signs and help to formulate the standard therapeutic guidelines.

High dose chemotherapy followed by autologous stem cell transplantation is the treatment of choice for relapsed Hodgkin lymphoma (HL). We analyzed 100 consecutive patients who underwent ASCT at our center between January 1999 and June 2019 for relapsed or refractory disease with a median age of 28 years (range: 9–65). At ASCT, 59 were in complete remission (CR) while 31 achieved partial remission (PR) and 10 had refractory disease (RD). Most had BEAM conditioning with a median infused cell dose of 4.84 × 10(6) CD 34 cells/kg. Prompt engraftment occurred in 97 patients at a median of 11 days. The day 100 transplant related mortality (TRM) was 5%. At a median of 37 months follow up, 79 patients are alive while 34 have relapsed. The 3-year event free survival (EFS) and overall survival (OS) are 62.3 ± 0.5% and 77.9 ± 4.4% respectively. The 3-year OS for patients in CR, PR and RD were 83.0 ± 5.2%, 78.4 ± 8.1% and 38.9 ± 1.7 respectively [p = 0.007] while the 3-year EFS for CR, PR and RD were 73.1 ± 6.2%, 61.3 ± 9.2% and 25.0 ± 1.5 respectively [p = 0.005]. Only disease status at time of ASCT was found to correlate with both OS and EFS. ASCT for HL is associated with good outcomes and low TRM. Disease status at ASCT impacted both OS and EFS and strategies to improve outcomes in patients with refractory disease needs to be explored.

Aim Although the fludarabine (F-araA)-treosulfan based toxicity reduced conditioning regimen has improved hematopoietic cell transplantation (HCT) outcome in patients with high-risk beta-thalassemia major (TM), rejection and regimen related toxicities (RRT) are still of major concern. This study aims to assess the role of F-araA pharmacokinetics (PK) and pharmacogenetics (PG) in a uniform cohort of patients with TM. Methods All patients with TM who receiving F-araA based regimen prior to HCT between September 2010 and 2019 were enrolled in this study. F-araA plasma levels were analyzed using LC-MS/MS. Selected polymorphisms in genes encoding for the enzymes (NT5E (Ecto-5’-nucleotidase) and DCK (Deoxycytidine kinase) involved in the metabolism of F-araA were screened. The influence of F-araA PK and PG on clinical outcomes were evaluated. Results F-araA PK showed wide inter-individual variation (27 and 19 fold in F-araA AUC and CL) which was explained by a promoter polymorphism (rs2295890) in the NT5E gene. Patients carrying the NT5E promoter variant showed no graft rejection (0% vs 7.7%, p=0.07) or Sinusoidal Obstruction Syndrome (0% Vs 19%, p=0.0007) and a trend to better EFS (87.5% vs 75.7%, p=0.1). F-araA systemic exposure was not associated with HCT outcome. Conclusion Our results suggest that the NT5E promoter polymorphism could be a predictive biomarker in F-araA based HCT setting in TM, however extensive functional studies are warranted to validate the clinical utility of this finding.

There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1–18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866–8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5–53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33–195), 130 (range:17–1012) and 147 (range:27.7–1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37–182), target ferritin level of 2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation.Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India.Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed.Results: Data on 107 patients with SAID were collated—of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness.Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

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Assessment of measurable residual disease (MRD) has emerged as a powerful prognostic tool in pediatric and adult acute lymphoblastic leukemia (ALL). In this single-centre retrospective study, we evaluated the prognostic relevance of MRD based on BCR-ABL1 copy numbers in Ph + ALL patients between 2006 and 2018. Molecular responses were evaluated at 3, 6, 9 and 12 months after the initiation of treatment. Patients who had their MRD assessed at three or more time points were categorized into MRD good risk or poor risk based on BCR-ABL1/ABL1 copy number ratio. MRD positive patients consistently showed a trend toward poor survival and on multivariate analysis, MRD poor risk patients had adverse outcomes when compared to MRD good risk patients in terms of overall (OS; p = .031) and event-free (EFS; p < .001) survival. In conclusion, molecular MRD based on BCR-ABL1 copy number ratio is an ideal prognostic indicator in Ph + ALL patients undergoing treatment.

Objectives Azathioprine (AZA) is a commonly used immunosuppressant in patients with autoimmune diseases. The toxic side effect to AZA (myelosuppression, hair loss, and oral ulcers) are highly unpredictable which can be life threatening if not identified earlier and dose adjustments made or the drug is withdrawn. Case presentation Here we report a case series of five patients with severe toxicity while on treatment with AZA for autoimmune hemolytic anemia (n=1) and Immune thrombocytopenia (n=4). The common thiopurine methyltransferase (TPMT) variants (TPMT*2, *3A, *3B) were not present in these patients. However, all these patients had the NUDT15 415C>T variant that has been reported to explain serious toxicity to thioguanine in Asian patients. Conclusions Our report suggests pre-emptive genotype-based dosing of AZA could reduce adverse toxicity and hence better outcome.

Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m2/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age 40 years (n = 28) (P = .11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P = .000). Factors affecting OS on multivariate analysis included aGVHD (P = .02) and graft failure (P = .000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.

Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/ intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR],.74; 95% confidence interval [CI],.62 to.88; P

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range

Background With the increasing incidence of multidrug-resistant (MDR) organisms and high mortality rates associated with these infections, we describe the spectrum of the major drug-resistant pathogens identified in fecal surveillance, and re-visit the use of fecal surveillance in predicting infection with these organisms post-allogeneic stem cell transplant. Methods Data from allogeneic stem cell transplant recipients with common drug-resistant strains of bacteria in fecal surveillance (Escherichia coli, Klebsiella spp., and Enterococcus spp.) were compared with recipients who did not have the same in fecal surveillance cultures. Baseline characteristics and post-transplant outcomes including similar drug resistance in blood cultures, severe sepsis, and 100-day transplant-related mortality were compared. Multivariate analysis using logistic regression model was used to determine independent predictors of outcome. Results In 232 transplants, the prevalence of common drug-resistant isolates in fecal surveillance cultures was 57.7% (134 out of 232 patients—with a single isolate in 115 and ≥2 isolates in the remaining 19 patients. A total of 164 drug-resistant isolates were obtained from 134 patients. Of the 164 isolates, 133 (81%) were positive for ESBL screening, 19 (11.5%) for carbapenem-resistant organisms (CRO) screening, 12 (7.3%) for VRE screening. Patients who had common drug-resistant pathogens detected in fecal surveillance have significantly higher subsequent blood culture positivity with drug resistance, as well as higher 100-day mortality. Factors influencing 100-day mortality included patient's age (P = .001), drug resistance positivity in blood (P < .001), drug resistance in fecal surveillance (P = .011), use of an alternate donor (other than fully matched sibling) (P < .001), GVHD grade 3-4 (P < .001), and severe sepsis (P < .001). On multivariate analysis, only use of an alternate donor (0.024), severe sepsis (P < .001), and grade 3-4 GVHD (P < .001) retained significance in predicting 100-day mortality. Conclusion Organisms resistant to 3rd generation cephalosporins are frequently seen on fecal surveillance in the pre-transplant setting and are associated with a higher incidence of drug-resistant organisms in subsequent blood cultures (not limited to the same drug resistance pattern as seen in fecal surveillance). Drug-resistant organisms in fecal surveillance are associated with poorer outcomes following allogeneic stem cell transplant and may be used as a guide to identify patients at risk of subsequently developing a drug-resistant organism in blood.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System–Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT.

Haploidentical stem cell transplantation (SCT) using post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis is a reasonable therapeutic option for patients who do not have a matched sibling donor. Between 2010 and June 2020, 257 patients underwent 269 Haploidentical transplantations, including 122 children. Indications included both malignant (56.8%) and non-malignant (43.2%) diseases. Conditioning regimens included both myeloablative (57.6%) and nonmyeloablative regimens (42.4%). Peripheral blood stem cells were the predominant graft source (96.2%). Based on the disease risk index, patients were classified into early-, intermediate-, and late-stage disease. Engraftment was seen in 205 patients (76.2%) whereas 39 (14.4%) died before engraftment and 23 (8.6%) had primary graft failure. The cumulative incidence of grade II-IV acute GVHD was 47.8% with a 23.9% incidence of grade III-IV acute GVHD. Chronic GVHD was seen in 41.9% with a 15.4% incidence of extensive chronic GVHD. More than 90% had at least 1 documented infection with a 44% incidence of bacterial, 71% viral, and 38% fungal infection. The 2-year overall survival is 40.5% ± 3.2% with a higher survival among children (48.2% ± 3.4%) compared to adults (34.2% ± 4.1%). Survival was poor with late-stage disease (23.6% ± 4.3%) compared to early- (62.5% ± 7.5%) and intermediate-stage (50.3% ± 4.3%). Factors adversely affecting survival included older age of patient (P = .007), late disease status (P = .000), nonmyeloablative conditioning regimen (P = .003), bone marrow as graft source (P = .006), presence of acute GVHD (P = .069), primary graft failure (P = .000), and presence of a documented bacterial (P = .000) and fungal infection (P = .000). On multivariate analysis, older age (P = .027), presence of acute GVHD (P = .033), documented bacterial infection (P = .000), documented fungal infection (P = .000) and primary graft failure (P = .012) continued to remain significant. Haploidentical SCT offers a reasonable chance of cure for patients with both malignant and nonmalignant hematological diseases. Strategies to reduce aGVHD and infection related mortality needs to be explored further. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.

For patients requiring allogeneic stem cell transplant, in the absence of a HLA-matched sibling, an extended donor search within the family may yield a suitable donor especially in societies with a high prevalence of consanguinity. We describe outcomes in transplants with non-sibling family donors, and compare outcomes with controls having a sibling donor transplant. Retrospective analysis of all matched related (non-sibling) donor transplants between 1995 and 2015. For comparison, appropriate age, sex and disease-matched patients were chosen from the sibling transplants (MSD) performed during the same time period (± 2 years). Comparison between the fully matched non-sibling donor cohort and age, sex and disease-matched sibling donor transplants showed a significant increase in complications in the family donor group (viral infections, acute GVHD and rejection). Event-free survival and overall survival were significantly lower in the non-sibling donor cohort, and HLA disparity (1-2 antigen) further worsened the adverse impact. Though there was a significantly lower event-free and overall survival at 3 years in the family donor cohort, this did not retain significance in the multivariate analysis. This data on allogeneic transplants using family donors showed higher complication rates and poorer outcomes. However in situations where financial constraints prevent access to matched unrelated donor sources, extended family searches may be fruitful in yielding a donor, and modifications in conditioning regimens and improvement in supportive care may help in improving the outcomes in family donor transplants.

Background: The skin is the most common organ involved in acute graft-versus-host disease (GvHD). Because histopathology has limited utility in ruling out clinical mimics of acute skin GvHD, more accurate diagnostic techniques are required. Aim: To evaluate the utility of elafin expression in skin by immunohistochemistry (IHC) for accurate diagnosis of acute skin GvHD. Methods: Consecutive allogeneic haematopoietic stem cell transplant (HSCT) recipients during a 6-month period who developed rash within the first 100 days post-transplant were recruited. Skin biopsies were taken on the day the rash developed. IHC for epidermal elafin was performed and interpreted by a pathologist blinded to the histopathological diagnosis. Staining of ≥ 50% of epidermis was considered positive. Final diagnosis of the rash was assigned using clinical features supported by histopathology. The accuracy of elafin IHC in predicting the final diagnosis of acute GvHD was evaluated. Results: In total, 23 patients (20 male, 3 female; median age 16 years, range 3-53 years) with 27 episodes of skin rash were recruited. Skin rash post-HSCT occurred at a median of 20 days (range 5-45 days). A diagnosis of GvHD was made in 16 episodes (59.26%) while the remaining 11 episodes (40.74%) were judged to be non-GvHD rash. Elafin IHC was positive in all patients with GvHD. Of the 11 episodes of non-GvHD rash, elafin was negative in 8. Thus, the sensitivity and specificity of elafin IHC for predicting acute skin GvHD was 100% and 75%, respectively. Conclusion: Tissue elafin is a useful immunohistochemical marker for acute skin GvHD. However, larger studies are needed to validate these results.

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality following allogeneic stem cell transplantation (SCT). We wanted to study if the high sero-prevalence seen in our population translated into a high incidence of CMV infection following SCT. This is a retrospective analysis of patients who underwent allogeneic SCT between January 2008 and December 2012 at our centre. 475 patients underwent allogeneic SCT for malignant (46.5%) and non-malignant (53.5%) haematological disorders. 463 (97.4%) SCT recipients and 403 (84.8%) SCT donors were IgG seropositive for CMV. CMV reactivation within 100 days post SCT was seen in 174 (36.6%) at a median of 41 days (range 10–100) post SCT. Ganciclovir was used in 166 patients (95.4%) for a mean duration of 16 days (range 5–32). 157 patients (90%) responded to therapy. Sixty-six patients (42.3%) had secondary reactivation of the virus. Use of a male donor (p = 0.000), donor and recipient age > 15 (p = 0.005 and 0.000), unrelated donor (p = 0.000), degree of HLA mismatch (p = 0.000), occurrence of acute GVHD (p = 0.000) and steroid refractory acute GVHD (p = 0.026) were identified as risk factors for CMV reactivation while early neutrophil recovery (

High-dose cyclophosphamide (PTCY) after allogeneic hematopoietic cell transplantation (HSCT) has been shown to be effective in preventing graft-versus-host disease (GVHD) after HLA-matched bone marrow transplantation. We performed a phase II study of PTCY given at 50 mg/kg i.v. on days 3 and 4 as the sole GVHD prophylaxis after HSCT for severe aplastic anemia (SAA) in patients receiving granulocyte colony-stimulating factor–mobilized peripheral blood stem cell (PBSC) grafts from HLA-matched related donors after conditioning with fludarabine, CY, and single-dose total body irradiation. Thirty patients with a median age of 29 years (range, 16 to 49) were enrolled in this study. Engraftment was seen in 27 patients (90%) at a median of 16 days (range, 12 to 21) post-HSCT. None of the patients developed veno-occlusive disease of the liver or hemorrhagic cystitis. Grades II to IV acute GVHD was seen in 22% of patients with grades III to IV GVHD in 11.1%. The 2-year cumulative incidence of chronic GVHD was 22.7%. Fourteen patients (46.6%) did not require any further immunosuppression after receiving PTCY. Comparing with 2 historical cohorts of 30 patients each who received cyclosporine and methotrexate (MTX; at 15 mg/m2 [MTX15] and 10 mg/m2 [MTX10]), the incidence of grades II to IV acute GVHD was lower, albeit not significantly, with the use of PTCY (PTCY, 22.2%, vs MTX15, 37.1%, vs MTX10, 53.8%; P = .056), whereas rates of chronic GVHD were significantly reduced (PTCY, 22.7%, vs MTX15, 63.6%, vs MTX10, 76.2%; P = .013). Viral infections including cytomegalovirus were significantly higher with the use of PTCY (60%) compared with cyclosporine and MTX (MTX15, 23.3%, vs MTX10, 33.3%; P = .008). Overall survival was similar between the 3 groups. We conclude that PTCY as the sole GVHD prophylaxis is associated with low rates of acute and chronic GVHD in patients undergoing PBSC transplant for SAA using HLA-matched donors. This trial is registered at CTRI/2010/091/001480.

Purpose Limited data exist on intensifying chemotherapy regimens in the treatment of adult acute lymphoblastic leukemia (ALL) outside the setting of a clinical trial. Materials and Methods Retrospectively, data from 507 consecutive adults (age ≥ 15 years) with a diagnosis of ALL treated at our center were analyzed. Standard-risk (SR) patients were offered treatment with a modified German Multicenter ALL (GMALL) regimen, whereas high-risk (HR) patients were offered intensification of therapy with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD). Because of resource constraints, a proportion of HR patients opted to receive the same treatment regimen as used for SR patients. Results There were 344 SR patients (67.8%) and 163 HR patients (32.2%) at diagnosis. Among the HR patients, 53 (32.5%) opted to receive intensification with the HCVAD regimen. The SR cohort showed a superior 5-year event-free survival rate compared with the HR cohort (47.3% v 23.6%, respectively; P < .001). Within the HR subgroup, there was no statistically significant difference in overall survival or event-free survival between patients who received the modified GMALL regimen (n = 59) and patients who received HCVAD (n = 53). Conclusion Intensified therapy in the HR subset was associated with a significant increase in early treatment-related mortality and cost of treatment. A modified GMALL regimen was found to be cost-effective with clinical outcomes comparable to those achieved with more intensive regimens.

Background & objectives: Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin's lymphomas (NHLs), with universally poor outcome. This study was undertaken to provide data on demographics and outcomes of patients with PTCL who underwent treatment in a single tertiary care centre in southern India. Methods: Retrospective study was done on all patients (age ≥18 yr) diagnosed with PTCL from January 2007 to December 2012. The diagnosis of PTCL was made according to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Results: A total of 244 adult patients were diagnosed with PTCL (non-cutaneous). The most common subtype was PTCL-not otherwise specified (35.7%), followed by anaplastic large cell lymphoma (ALCL), ALK negative (21.3%), natural killer/T cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), ALCL, ALK positive, hepatosplenic T cell lymphoma (HSTCL) and adult T cell leukaemia/lymphoma followed in frequency with 13.1, 11.5, 8.6, 8.2 and 1.6 per cent cases, respectively. The three-year Kaplan-Meier overall survival (OS) and event-free survival (EFS) for the patients who received chemotherapy (n=122) were 33.8±5.0 and 29.3±4.7 per cent, respectively. Various prognostic indices developed for T cell lymphomas were found to be useful. Interpretation & conclusions: Except for ALCL, ALK positive, all other PTCLs showed poor long-term outcome with CHOP-based chemotherapy. Novel therapies are needed to improve the outcome.

Objectives: The primary objective of the study was to assess the association between central aortic blood pressure indices and coronary artery disease (CAD) in patients undergoing elective angiography and the secondary objective was to study whether any association exists between central aortic pressure indices and the incidence of major adverse cardiovascular events (MACE) in the same patients during a 6-month follow-up period. Methods: We conducted a prospective observational study in consecutive patients undergoing coronary angiography. Central and peripheral pressures were invasively recorded and CAD was classified into obstructive and nonobstructive group. CAD severity was graded using the Gensini score and patients were divided into tertiles. Patients were followed up, and the role of central aortic pressure indices in the prediction of cardiovascular events was analyzed. Results: A total of 623 patients were enrolled. Central pulsatility was found to be most closely associated with severity of CAD by univariate analysis, with age, sex, and smoking status being important predictors of pulsatility. A positive correlation was found between the central and peripheral mean and pulse pressures. No significant association was noted between the central aortic pressures and MACE on short-term follow-up. Conclusions: Of the various central aortic pressure indices studied, central pulsatility was found to be most closely associated with the severity of CAD.

Allogeneic stem cell transplantation (SCT) is a curative treatment for beta-thalassemia major. The Pesaro risk stratification classifies patients with thalassemia into three groups (class I, II, and III) to predict the transplant-related mortality (TRM) and graft rejection after myeloablative conditioning with busulfan and cyclophosphamide. However, in developing countries, where inadequate chelation therapy prior to transplant is common, most patients would fall under the class III category. There is heterogeneity in the clinical outcomes in this group. Hence, our center introduced a further refinement in this risk stratification, identifying a subset of "class III high risk" as those with age greater than or equal to 7 years and liver size > 5cm (Mathews V et al. BBMT 2007). Subsequently, we showed that the use of a conditioning regimen containing thiotepa, treosulfan, and fludarabine (TTF) along with a peripheral blood stem cell graft led to improved outcomes in this subset with a reduction in early TRM from 46% (with busulfan-cyclophosphamide) to 13% (Mathews V et al. PLoS One 2013). There is still a need to identify predictors of poor clinical outcomes to optimize further the clinical outcomes of these class III high-risk thalassemia patients. Endothelial activation and stress index (EASIX) is a simple biomarker calculated using lactate dehydrogenase, creatinine, and platelet counts. EASIX has been shown to be predictive of overall survival in various settings like GVHD following reduced-intensity transplants for malignancies in adults, veno-occlusive disease, and nonrelapse mortality following SCT (Luft T et al. Lancet Haem 2017; Jiang S et al. Haematologica 2021; Luft T et al. BMT 2020). Here, we evaluated the role of EASIX (measured before conditioning therapy) as a biomarker in predicting early TRM in patients with thalassemia major who have undergone SCT with a uniform conditioning regimen using TTF at our center. During the study period from January 2012 to December 2019, 281 patients with thalassemia major underwent SCT with a uniform TTF protocol at our center. The median age was nine years (range 1 to 25 years). One hundred and nine (38.8%) were females. As per Pesaro classification (with Vellore modification), three (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. The stem cell donors were matched sibling (n=218, 77.6%), matched related non-sibling (n=23, 8.2%), or matched unrelated donors (n=40, 14.2%). The stem cell donor was HLA matched in all cases except 21 (7.5%), wherein there was a mismatch at one locus. Five (1.8%) had a bone marrow graft, while others had peripheral blood stem cell grafts. Thirty-eight (13.5%) patients had transplant-related mortality by day 100 (TRM100). The median follow-up of the cohort was 31 months (range 0 to 103 months). EASIX score pre-transplant was available for 184 (65.5%) patients. There was no difference in the rate of TRM100 in patients where EASIX was available compared to those where EASIX was not available (14.7% versus 11.3%, p 0.47). Also, there was no difference in overall mortality rate in patients where EASIX was available compared to those where EASIX was not available (21.2% versus 17.5%, p 0.53). Among patients with TRM100 vis-à-vis those who did not, the median EASIX score was significantly higher (1.09 versus 0.75, p 0.008). We then plotted a receiver operating characteristics (ROC) curve for predicting TRM100 using the EASIX score. The area under the curve was 0.661 (Figure 1a). A cut-off of 0.85 for the EASIX score had a 70.4% sensitivity and 62% specificity for predicting TRM100. The TRM100 for patients with EASIX above 0.85 was significantly higher than those with EASIX less than 0.85 (24.4% versus 7.5%, p 0.003). On multivariable logistic regression analysis, the factors independently predicting TRM100 were pre-transplant EASIX score, pre-transplant ferritin, unrelated donor source, and chimerism at day 60 (Figure 1b). In patients with thalassemia major undergoing SCT using a uniform TTF conditioning, EASIX score measured pre-transplant can identify patients at greater risk for Day100 TRM. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

BACKGROUND Urinary tract infection is a common problem in children. Early diagnosis and prompt treatment is very important for preventing its complications like renal parenchymal disease. Emergence of multidrug-resistant bacteria has made treatment of urinary tract infection a challenge in children. The aim of the study is to determine the clinico-bacteriological profile of urinary tract infections in children and resistance pattern of uropathogens. MATERIALS AND METHODS A cross-sectional study was conducted in children ≤12 years with suspected urinary tract infections from October 2011 to February 2012 in a tertiary care centre. Urine samples were collected for urinalysis and culture. Antibiotic susceptibility test was performed as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS Out of 550 children studied significant bacteriuria detected in 90 (16.4%) cases. Males constituted 60% and females 40%. Infants (31.2%), 1-5 years (35.5%) and 5-12 years (33.3%) were the age distribution. Fever was present in 93.4% and specific urinary symptoms in 48.9% children. Blood culture was positive in 4.8%. E. coli (57.8%), Klebsiella spp. (22.3%), Proteus (6.7%), Pseudomonas spp. (6.7%), Enterobacter (4.4%) and methicillin-resistant staphylococcus aureus (2.2%) were the uropathogens. Multidrug-resistant isolates were 65.6%. Sensitivity and specificity of pyuria was 71.2% and 76.6%, respectively. CONCLUSION Urinary tract infection should be ruled out in all febrile children with no obvious focus of infection. MDR uropathogens should be considered while initiating treatment in children with UTI.

G6PD deficiency is a monogenic, X-linked genetic defect with a worldwide prevalence of around 400 million people and an overall prevalence of 8.5% in India. Hemolytic anemia is encountered in only a small proportion of patients with G6PD variants and is usually triggered by some exogenous agent. Although G6PD deficiency was reported in India more than 50 years ago, there are very few studies on molecular characterization and phenotypic correlation in G6PD deficient patients. We aimed to study the epidemiology and correlate the phenotypic expression with molecular genotypes in symptomatic G6PD deficient patients. All symptomatic hemolytic anaemia patients with a possible etiology of G6PD deficiency based on the clinical, hematological and biochemical parameters and reduced G6PD enzyme levels were included in this study. Molecular analysis of the G6PD gene was done by direct Sanger sequencing. From a total of 38 patients with hemolytic anemia suspected for G6PD deficiency, 24 patients had reduced G6PD enzyme levels and were included for the molecular analysis and mutations in the G6PD gene were identified in 21 of them (83.3%). The different mutations identified in our study include 6 patients with c.131C > G (G6PD Orissa), 3 patients with c.563C > T (G6PD Mediterranean), two patients with c.825G > T (G6PD Bangkok), one patient each with c.208T > C (G6PD Namouru), c.487G > A (G6PD Mahidol), c.949G > A (G6PD Kerala-Kalyan), c.100 G > A (G6PD Chatham), c.1178C > G (G6PD Nashville), c.1361 G > A (G6PD Andalus) and 4 patients with novel mutations (2 patients with c.1186C > T and 1 patient each with c.1288-2A > T and c.1372C > T. No disease causing genetic variants were identified in the other three cases. Co-inheritance of other red cell and hemoglobin disorders can modify the clinical phenotype of G6PD patients and the diagnostic accuracy can be improved by molecular characterization of the variant. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12288-019-01205-7) contains supplementary material, which is available to authorized users.

We studied 1110 children, adolescents and young adults with β thalassemia major transplanted with grafts from HLA-matched relative (n=677; 61%), HLA-mismatched relative (n=78; 7%), HLA-matched unrelated (n=252; 23%) and HLA-mismatched unrelated (n=103; 9%) donors in 2000 - 2016. The median age at transplantation was 6 years (range Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy; Chimerix, Inc.: Membership on an entity's Board of Directors or advisory committees. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Arsenic trioxide (ATO)-based regimens are the standard of care for treating acute promyelocytic leukaemia (APL) and have replaced chemotherapy-based approaches. However, the cost of "patented" ATO is prohibitive because of patent rights. "Generic" ATO has been used in a few countries, but its implications for health resource utilization (HRU) and cost of treatment are unknown. We hypothesized that treating APL patients using generic ATO (APL-ATO) will be cost effective compared to the chemotherapy-based regimen (APL-CT). In a single-centre retrospective study, we used a bottom-up costing method to compare the direct medical cost of treatment and HRU between APL-ATO and APL-CT. These costs and the survival and relapse probabilities were imputed in a three-state Markov decision model to estimate the cost effectiveness of APL-ATO compared to APL-CT. The mean cost of treatment for APL-ATO (n = 30, $8500 ± 2078) was significantly less than for APL-CT (n = 30, $22 600 ± 5528) (P < 0·001). APL-ATO reduced hospitalization, antibiotic and antifungal usage (P < 0·001). In the Markov model, five-year treatment costs were significantly lower for APL-ATO ($11 131) than for APL-CT ($17 926) (P < 0·001). Treatment cost and health resource utilization were significantly lower for generic ATO-treated APL patients compared to the chemotherapy-based regimen.

We performed a prospective multi-centre observational study to understand the incidence of IFI in patients with AML in India with use of anti-fungal prophylaxis. All patients with AML receiving either induction chemotherapy or salvage chemotherapy between November 2014 and February 2016 were included in this prospective observational study from 10 Indian centres. IFI was defined as per the revised EORTC-MSG criteria. Data on type of chemotherapy used, type of anti-fungal prophylaxis used, time to neutrophil recovery, incidence of IFI and survival were collected. Two hundred patients (118 male and 82 females) with a median age of 35 years (range: 2–66) were recruited. One hundred and eighty-six (93%) had newly diagnosed acute myeloid leukemia (AML) while 14 (7%) had relapsed disease. IFI occurred in 53 patients (26.5%) with proven or probable IFI occurring in 17 (8.5%). Use of posaconazole prophylaxis (p = 0.027) was the only factor found to be associated with a reduced incidence of IFI. The overall survival (OS) at 6 weeks and 3 months respectively was similar among patients who had IFI (83.0 ± 5.2%; 81.0 ± 5.4%) as compared to those without IFI (84.4 + 3.0%; 81.4 ± 3.2%). This prospective study reveals a high incidence of IFI in patients undergoing chemotherapy for AML in India. The use of posaconazole prophylaxis was associated with a significantly lower incidence of IFI. Optimal strategies to prevent IFI need to be studied.

Treatment of Hodgkin lymphoma (HL) has evolved with risk-stratified therapy based on PET-CT scan at multiple timepoints. In a resource constraint setting even a single PET-CT scan ($400) is inaccessible to many patients, who are re-assessed with only clinical examination, abdominal ultrasonogram and/or x-ray (C/U/X) ($10). To compare clinical outcomes in patients with HL who have had suboptimal imaging after completion of chemotherapy for HL, with those who had a CT or PET-CT, 283 patients were treated for HL from 2011 to 2015, and 268 patients completed six cycles of ABVD therapy with response assessment modality by CT/PET in 185 patients and by C/U/X in 83. There was no difference in the number of patients with advanced (64·1% vs. 61·1%; P = 0·650) or bulk disease (8·1% vs. 7·2%). A significantly higher number of patients in the CT/PET group received IFRT (25·4% vs. 7·7%; P = 0·0005). The three-year overall survival and progression-free survival of all treated patients (n = 283) was 83·5 ± 2·3% and 76·7 ± 2·6% respectively [median follow-up 36 months (range 2-93)]. At three years, the overall relapse-free survival (RFS) was 80·1 ± 2·5%, with RFS of 77 ± 3·2% vs. 85 ± 4·0% in the CT/PET group and C/U/X groups respectively (P = 0·349). There was no difference in RFS between the two groups either in early-stage disease (88·1 ± 4·6% vs. 91·8 ± 5·6%; P = 0·671) or late-stage disease (73·9 ± 4·8% vs. 81·3 ± 6·0%; P = 0·747). The only significant factor adversely affecting RFS was advanced disease (P = 0·004). Factors not affecting RFS were age (P = 0·763), sex (P = 0·925), bulk disease (P = 0·889) and imaging modality (P = 0·352). There was no difference in relapse rates between patients who had suboptimal imaging compared to those who had a PET/CT. It is possible to use these basic imaging modalities when resources are a constraint, with acceptable outcomes.

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma among adults, although it also affects the young and the elderly. DLBCL is treated with a chimeric monoclonal antibody against CD20, a B cell surface protein, named rituximab, in combination with a multidrug chemotherapeutic regimen. However, owing to its high cost, rituximab cannot be afforded by patients in developing or underdeveloped countries. In such cases, biosimilars of rituximab have been used instead of rituximab, with equivalent efficacy. In this single center, retrospective, observational study, we have compared patient outcomes such complete response (CR), partial response (PR), and overall response rate (ORR) in a cohort of 152 patients in an Indian hospital, who were treated either with innovator rituximab or Reditux, a biosimilar. We observed that the ORRs of both groups (88% in innnovator group and 82% in biosimilar group) were comparable. There was no statistically significant difference between the two groups in terms of CR (p = 0.353), PR (p = 0.42), ORR (p = 0.23), unfavorable responses, and stable or progressive disease (p = 0.42). The number of patients who died due to complications were few, and there was no significant difference between the two groups. The differences in the 3-year event-free survival and overall survival were not statistically significant. Biosimilar rituximab can suitably and safely replace the innovator rituximab for treatment of diffuse large B cell lymphoma.

Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.

Background: Substance use disorder and alcohol dependence in particular, is a major mental health problem. Many persons with alcohol dependence also suffer from a comorbid psychiatric illness, particularly depression. Depressive disorders when undiagnosed or untreated can contribute to the severity of dependence and also increase the risk of suicide. Aims and objectives: (1) To identify the prevalence of depression among alcohol dependent patients. (2) To describe the association between comorbid depression and the severity of alcohol dependence. Methodology: All consenting patients in the age group of 18-60 years who attended the de-addiction clinic were included in the study. Socio-demographic data and clinical history of those who met the inclusion criteria were recorded. Diagnosis was made using MINI-PLUS according to the ICD-10 diagnostic criteria. Severity of alcohol dependence was rated using Severity of Alcohol Dependence Questionnaire (SADQ) and depression with Hamilton Depression Rating Scale (HAM-D). Results: Seventy men participated in the study. Major depressive disorder was diagnosed in 22 (31.4%) of the subjects. Severity of alcohol dependence was assessed to be moderate in 70% of individuals. A significant association was noticed for the severity of alcoholism and severity of depression. Conclusion: Alcohol dependent individuals show a high rate of comorbid depression. The severity of alcoholism and severity of depression are statistically related.

BACKGROUND Regular monitoring of serum iron parameters is helpful for assessing the severity of alcoholic liver disease. Assessment of serum iron parameters are used for screening hereditary haemochromatosis in chronic liver disease. Serum iron parameters in chronic liver disease have not been clearly described in most of the studies. The aim of this study was to assess the serum iron, Total Iron Binding Capacity (TIBC), transferrin saturation and ferritin levels in common chronic liver disease like alcoholic cirrhosis, cryptogenic cirrhosis, chronic hepatitis C and chronic hepatitis B. MATERIALS AND METHODS 110 consecutive patients with chronic liver disease admitted to the Gastroenterology Department, Government Medical College, Kozhikode were selected for the study. The categories of chronic liver disease included in our study were alcoholic cirrhosis (Group I, n = 40), cryptogenic cirrhosis (Group II, n = 30), chronic hepatitis C (Group III, n = 20) and chronic hepatitis B (Group IV, n = 20). Serum iron, ferritin, total iron binding capacity and transferrin saturation were estimated in the fasting sample. Statistical Analysis- Analysis was performed using nonparametric Kruskal-Wallis and Bonferroni test to assess statistical significance of difference of continuous variables among and between groups, respectively. The results were considered statistically significant at the level of p

Aims The aims of the study were to study the demographical and clinicopathological characteristics of patients presenting with heart failure and evaluate the 1 year outcomes and to identify risk predictors if any. Methods and results A prospective observational study was conducted in consecutive patients of systolic heart failure. The study was divided into two parts—an initial 6 month enrolment phase followed up for 1 year for major adverse cardiovascular events. All patients were treated according to the Institutional Heart Failure Protocol. Demographical and clinicopathophysiological characteristics were studied, and results were analysed. A total of 143 patients were enrolled. The mean age of subjects was 56.4 years with male subjects constituting almost two-thirds of the study population. The commonest aetiology of heart failure was ischemic with valvular heart disease being the commonest cause of non-ischemic heart failure. Bendopnea, a recently described symptom of heart failure, was found in a significant number of subjects. By univariate analysis, male sex (P = 0.042) and cardiomegaly (P = 0.035) were predictors of rehospitalization, whereas the univariate predictors of mortality were ischemic aetiology (P = 0.000), age > 50 years (P = 0.007), hypertension (P = 0.012), worsening NYHA class (P = 0.003), diabetes mellitus (P = 0.009), and hypokalaemia (P = 0.006). Multivariate analysis performed showed age > 50 years [P = 0.007; OR (CI) = 13.547 (2.034–90.238)], NYHA class [P = 0.002; OR (CI) = 32.300 (3.733–276.532)], and hypokalaemia [P = 0.031; OR (CI) = 7.524 (1.208–46.862)] as significant predictors of mortality during long-term follow-up. Conclusions The study will definitely help us to throw more light in identifying risk predictors of heart failure and help in improving clinical outcomes.