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Abstract Background The karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available. Methods We performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC). Results There were 936 patients aged 18–86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1–3% each. Conclusion The most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS.

Background: The present study is intended to evaluate the changes in upper incisor angulation, skeletal and dental parameters, soft-tissue and airway dimensions following rapid palatal expansion and maxillary protraction. Materials and Methods: Twenty class III subjects (mean age 11.3 years) were given bonded rapid maxillary expansion (RME) and facemask (FM) for 6 months. Pre- and posttreatment cephalogram were compared and dental, skeletal, soft-tissue, and airway changes were quantified. Results: The mean increase in SNA was 1.85° (P < 0.001) while SNB decreased by 1.85° (P < 0.001). Upper and lower face height increased (UFH 1.1 mm, P < 0.05; LFH 2.92 mm, P < 0.001). Upper lip moved forward (E line U/lip 1.27 mm, P < 0.001; S line U/lip 1.3 mm, P < 0.01). 1-SN decreased by 4.35° and 1-NA decreased by 4.50° with P < 0.01. Overjet improved by 3.07 mm (P < 0.001). Conclusion: RME and FM therapy resulted in maxillary forward movement; mandible rotated downward and backward; UFH and LFH increased. The upper lip exhibited forward movement, resulting in a less concave profile. Upper incisor retroclined and there was increase in overjet and no changes in airway dimensions. The upper incisors following RME and FM does not always procline; it is decided by the interaction of four factors – mesial dental movement, rotation of maxillary/occlusal plane, amount of expansion with RME (expansion effect), and reverse twin block if incorporated with FM.

Abstract The survival of leukemic cells is significantly influenced by the bone marrow microenvironment, where stromal cells play a crucial role. While there has been substantial progress in understanding the mechanisms and pathways involved in this crosstalk, limited data exist regarding the impact of leukemic cells on bone marrow stromal cells and their potential role in drug resistance. In this study, we identify that leukemic cells prime bone marrow stromal cells towards osteoblast lineage and promote drug resistance. This biased differentiation of stroma is accompanied by dysregulation of the canonical Wnt signaling pathway. Inhibition of Wnt signaling in stroma reversed the drug resistance in leukemic cells, which was further validated in leukemic mice models. This study evaluates the critical role of leukemic cells in establishing a drug-resistant niche by influencing the bone marrow stromal cells. Additionally, it highlights the potential of targeting Wnt signaling in the stroma by repurposing an anthelmintic drug to overcome the microenvironment-mediated drug resistance.

Background: Patient-reported outcomes (PROs) reflect patient perceptions of disease and treatment and are important for evaluating new therapies. Objectives: Evaluate the effects of once-daily concizumab prophylaxis on health-related quality of life (HRQoL), treatment burden, and treatment preference in males aged ≥12 years with hemophilia A/B with inhibitors. Methods: Patients enrolled in the multicenter, open-label explorer7 phase 3 study (ClinicalTrials.gov identifier: NCT04083781) were randomized to receive no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or were nonrandomly allocated to concizumab prophylaxis (arms 3 and 4). The study included questionnaires to assess patients’ perception of HRQoL (Haemophilia Quality of Life Questionnaire for Adults), treatment burden (Hemophilia Treatment Experience Measure), and treatment preference (Haemophilia Patient Preference Questionnaire). Results: The estimated treatment difference between patients receiving concizumab prophylaxis vs no prophylaxis at week 24 for Haemophilia Quality of Life Questionnaire for Adults “total score” was −22.6 points (95% CI, −42.5; −2.7), directionally favoring patients receiving concizumab prophylaxis. For Hemophilia Treatment Experience Measure “total score,” the estimated treatment difference was −19.9 points (95% CI, −34.3, −5.6) in favor of concizumab vs no prophylaxis. The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being “fewer bleeds,” “require less time,” and “less painful to inject.” Across all PROs, there were less responses collected than anticipated, limiting interpretations. Conclusion: PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis.

Background/Aims Rotational thromboelastometry (ROTEM) is a viscoelastic test that is used in patients with liver disease for guiding blood component use. This study is aimed at comparing the amount of blood products transfused and bleeding rates in patients without liver disease, who underwent therapeutic endoscopic procedures with deranged screening coagulation tests (prothrombin time [PT]; activated partial thromboplastin time [aPTT]), with and without hypocoagulable ROTEM.

Abstract Background Cytogenetic analysis continues to have an important role in the management of acute myeloid leukemia (AML) because it is essential for prognostication. It is also necessary to diagnose specific categories of AML and to determine the most effective form of treatment. Reports from South Asia are few because the availability of cytogenetic services is relatively limited. Methods We performed a retrospective analysis of the cytogenetic findings in adults with AML seen consecutively in a single centre in India. The results were categorised according to the 2022 World Health Organisation (WHO), International Consensus Classification (ICC) and European LeukemiaNet (ELN) classifications. Results There were 1791 patients aged 18–85 years (median age 42, 1086 males). Normal karyotypes were seen in 646 (36%) patients. The 1145 (64%) abnormal karyotypes comprised 585 (32.7%) with recurrent genetic abnormalities (RGA), 403 (22.5%) with myelodysplasia-related cytogenetic abnormalities (MRC), and 157 (8.8%) with other abnormalities. There were 567 (31.7%) patients with solitary abnormalities and 299 (16.7%) with two abnormalities. Among the 279 (15.6%) patients with ≥ 3 abnormalities, 200 (11.2%) had complex karyotypes (CK) as per the WHO/ICC and 184 (10.3%), as per the ELN definition. There were 158 (8.8%) monosomal karyotypes (MK). Patients with normal karyotypes had a higher median age (45 years) than those with abnormal karyotypes (40 years, p

Abstract Purpose Identifying persistent bacteremia early in patients with neutropenia may improve outcome. This study evaluated the role of follow-up blood cultures (FUBC) positivity in predicting outcomes among patients with neutropenia and carbapenem-resistant gram-negative bloodstream infections (CRGNBSI). Methods This retrospective cohort study conducted between December 2017 and April 2022 included patients more than 15 years old with neutropenia and CRGNBSI, who survived for ≥ 48 h, receiving appropriate antibiotic therapy and had FUBCs. Patients with polymicrobial bacteremia within 30 days were excluded. The primary outcome was 30 day mortality. Persistent bacteremia, septic shock, recovery from neutropenia, prolonged or profound neutropenia, requirement of intensive care and dialysis, and initiation of appropriate empirical therapy were also studied. Results In our study cohort of 155 patients, the 30 day mortality rate was 47.7%. Persistent bacteremia was common in our patient cohort (43.8%). Carbapenem resistant isolates identified in the study were K.pneumoniae (80%), E.coli (12.26%), P.aeruginosa (5.16%), A.baumanii (1.94%) and E.cloacae (0.65%). The median time for sending a FUBC was 2 days (IQR, 1–3 days). Patients with persistent bacteremia had higher mortality than those without (56.76% versus 32.1%; p

Hyperacute GVHD (HaGVHD) is a rare complication of hematopoietic stem cell transplantation (HSCT) occurring before engraftment, a syndrome commonly involving skin and/or gut and/or liver, with increased morbidity and mortality. Myeloablative conditioning (MAC) regimes and mismatched donor transplants have an increased risk for HaGVHD. There is a higher chance of steroid-refractoriness and chronic GVHD in those who develop HaGVHD. There is limited literature about HaGVHD, especially in the paediatric age group. This retrospective single-centre case series included five paediatric patients who underwent HSCT between 1st April 2013 and 31st July 2015 at a tertiary care centre in South India, who fulfilled the criteria for HaGVHD as per criteria by Kim et al. and whose follow up data was available. We noted their risk factors, clinical course and prognosis. There were five paediatric HaGVHD patients. The risk factors noted among them were MAC regimen in three and mismatched unrelated donor sources in three. Two had steroid-refractory disease, four went on to develop chronic GVHD and three died of GVHD or treatment-related complications. A high index of suspicion is necessary to recognize HaGVHD, especially in patients with known risk factors developing a fever with rash post-HSCT.

Refractory acute myeloid leukemia (AML), defined as failure of two cycles of induction therapy at diagnosis or of one cycle at relapse, represents a subgroup with poor outcomes. Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (fludarabine + cytosine + granulocyte colony-stimulating factor ± idarubicin or mitoxantrone + etoposide) followed by 1-week rest and then reduced-intensity transplant with fludarabine + melphalan. We used the same backbone for this trial (CTRI/2019/02/017505) with the addition of CD56-positive cells from a family donor infused 1 day after the completion of chemotherapy. CD56-positive selection was done using a CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany) followed by overnight incubation in autologous plasma with 2 micromolar arsenic trioxide and 500 U/mL of interleukin-2. From February 2019, 14 patients with a median age of 29 years (interquartile range [IQR]: 16.5–38.5) were enrolled in this trial. Six were females. Six had primary refractory AML while eight had relapsed refractory AML. The median CD56-cell dose infused was 46.16 × 106/kg (IQR: 25.06–70.36). One patient withdrew consent after NK cell infusion. Of the 13 patients who proceeded to transplant, five died of immediate post-transplant complications while two did not engraft but were in morphologic leukemia-free state (both subsequently died of infective complications after the second transplant). Of the remaining six patients who engrafted and survived beyond 1 month of the transplant, two developed disease relapse and died. The remaining four patients are alive and relapse free at the last follow-up (mean follow-up duration of surviving patients is 24 months). The 2-year estimated overall survival for the cohort was 28.6% ± 12.1% while the treatment-related mortality (TRM) with this approach was 38.5% ± 13.5%. Haploidentical NK cell therapy as an adjunct to transplant is safe and needs further exploration in patients with AML. For refractory AML, post-transplant NK infusion and strategies to reduce TRM while using pre-transplant NK infusion merit exploration.

Background: Hematopoietic stem cell transplantation [HSCT] is the only curative option for Fanconi Anemia (FA) patients with hematological abnormalities. Materials and Methods: This is a retrospective analysis of patients with FA who underwent a matched-related donor HSCT. Results: Sixty patients underwent 65 transplants between 1999-2021 using a fludarabine-based low-intensity conditioning regimen. The median age at transplant was 11 years (range: 3-37). Aplastic anemia (AA) was the underlying diagnosis in 55 (84.6%) while 8 (12.4%) had myelodysplastic syndrome (MDS) and 2 (3%) had acute myeloid leukemia (AML). The conditioning regimen used was fludarabine with low-dose cyclophosphamide for aplastic anemia and Fludarabine with low-dose busulfan for MDS/AML. Graft versus host disease (GVHD)prophylaxis consisted of cyclosporine and methotrexate. Peripheral blood stem cells was the predominant graft source (86.2%). Engraftment occurred in all but 1 patient. The median time to neutrophil and platelet engraftment was 13 days (range: 9-29) & 13 days (range: 5-31), respectively. Day 28 chimerism analysis showed complete chimerism in 75.4 % and mixed chimerism in 18.5%. Secondary graft failure was encountered in 7.7%. Grade II–IV acute GVHD occurred in 29.2% while Grade III-IV acute GVHD occurred in 9.2%. Chronic GVHD was seen in 58.5% and was limited in most patients. The median follow-up is 55 months [range: 2-144] & the 5-year estimated overall survival (OS) is 80.2 ± 5.1%. Secondary malignancies were noted in 4 patients. The 5-year OS was significantly higher in patients undergoing HSCT for AA (86.6 + 4.7%) as compared to MDS/AML (45.7+16.6%) (p= 0.001). Conclusion: SCT using a fully matched donor provides good outcomes with low-intensity conditioning regimens in patients with FA who have an aplastic marrow.

Introduction: The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (RARA).Methods: Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines.Results: Retinoid-X-receptor alpha (RXRA) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34+ cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IM in-vitro in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34+ cells in-vitro. In-vivo, this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of RXRA inhibited proliferation and improved sensitivity to IM in-vitro. In-vivo, RXRA OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both RXRA OE and ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells.Conclusion: Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency due to defect in various genes leading to an increase in susceptibility to skin and mucosal infection. Mutation in signal transducer and activator of transcription 1 (STAT 1) gene being the most common cause of CMC can lead to increased risk of infections, multisystem abnormalities, and malignancy. We describe a 27 year old Indian woman with clinical features of CMC including esophageal stenosis, gangrene of the finger, endocrinological and immunological abnormalities and STAT1 mutation (p.Leu407Val). She was treated with antifungals which led to symptomatic improvement.

Introduction: BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection. Methods: This retrospective case–control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology. Results: Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0–858) days. Survival was significantly lower in the cases (42.9% vs. 61%, P < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning (P = 0.04), residual disease at the time of transplant in malignant conditions (P = 0.001), lower CD34 dose (P = 0.006), presence of acute graft versus host disease (GVHD, P < 0.001), reactivation of cytomegalovirus infection (P < 0.001), and presence of bacterial urinary tract infection (UTI) (P < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD (P = 0.041), bacterial UTI (P < 0.001), and residual disease (P = 0.009) at HCT as significant risk factors for BKPyV-HC. Conclusions: Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.

Introduction: BK Polyomavirus induced Haemorrhagic Cystitis (BKPyV-HC), a well-recognised complication following Haematopoietic Cell Transplantation (HCT), is associated with increased organ dysfunction and mortality. The treatment is a multipronged strategy which includes manipulating immunosuppression and antiviral therapy along with newer advances of virus specific cellular therapy. Cidofovir is a nucleotide analogue of Cytosine that is effective against many Deoxyribonucleic Acid (DNA) viruses and its use has been limited in the past because of cost and toxicity. Aim: To capture real world data on the use of cidofovir in BKPyVHC, post HCT especially with regard to dosage, efficacy, toxicity and predictors of response to therapy. The study compared the efficacy and safety of the innovator molecule of cidofovir with Generic versions. Materials and Methods: This study was a retrospective cohort of 67 patients, who were diagnosed with BKPyV-HC post haematopoietic stem cell transplant, and were treated with cidofovir. The study was conducted at a tertiary care centre at Vellore, Tamil Nadu, India, between 2015 and 2021. BKPyV Polymerase Chain Reaction (PCR) was checked in urine routinely in alternate donor transplants, and if there were typical lower urinary tract symptoms or haematuria in any other transplant setting. Treatment with cidofovir (initially innovator and subsequently generic) was as per physician’s discretion. The descriptive data were reported as means with Standard Deviation (SD) or frequencies with percentages as appropriate. Results: Total 985 patients underwent Allogeneic HCT during the study period, of which 67 had BKPyV-HC and were treated with cidofovir (47 with Innovator molecule, 20 with Generic molecule). There was clinical resolution in 47 (70.1%) and mortality in 32 (47.8%) of the cohort. On univariate analysis, risk factors associated with mortality were an absence of clinical resolution (p9×106/Kg (p=0.029), partial remission of malignancy at the time of transplant (p=0.001), ≤3 doses of cidofovir used (p=0.036), BK log value >log 7 at the time of stopping cidofovir (p=0.021) and toxicity with cidofovir (p=0.036). However, only the absence of clinical resolution was significantly associated (p

Abstract Early complications post hematopoietic stem cell transplantation (HSCT) such as sinusoidal obstruction syndrome (SOS) and graft versus host disease (GVHD) can be life threatening. Although several biomarkers have been identified to correlate with these complications and their response to treatment, these are yet to be used in clinical practice. Here, we evaluated circulating endothelial cells (CECs) (n = 26) and plasma biomarkers (ST2, REG3α, VCAM1, ICAM1, TIM3) (N = 210) at early time points, to determine their association with early complications post‐HSCT. Elevated CEC counts at the end of conditioning was associated with GVHD, indicating endothelial damage during HSCT. Plasma levels of REG3α, VCAM1, ICAM1, and TIM3 on day 14 (D14) and D14 ICAM1 and D28 ST2 were significantly higher in patients with SOS and aGVHD, respectively. Upon sub‐group analysis, D28 ST2, D14/D28 REG3α, and D14 ICAM1 levels were significantly higher in patients with gastrointestinal GVHD, while D28 ST2 was higher in those with skin/liver GVHD. High ST2 levels on D28 was significantly associated with non‐relapse mortality (NRM) and overall survival. Our results suggest that elevated ST2 levels on D28 could predict the likelihood of developing aGVHD and could influence NRM and OS.

Abstract 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 www.clinicaltrials.gov as NCT01950611.

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.

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.

Allogeneic stem cell transplantation (allo-SCT) is the only currently available curative treatment for thalassemia major. Since it was first done in 1981, several thousand patients have benefited from it and it is now possible to offer this treatment in different parts of the world with good results. With better risk stratification and supportive care, the results of allo-SCT are now very good even in high risk patients who have significant iron overload related organ dysfunction. The improvements have mainly been in the conditioning strategies with less toxic myeloablation and management of the complications of SCT. However, several challenges remain. Transplant related complications still cause significant morbidity and mortality. There is data to show that the results of transplantation as best if done in well transfused and chelated patients

Purpose: There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods: We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results: Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively (P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% (P = .003) and 63.8 ± 6.4% versus 32.3 ± 7.9% (P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion: In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

Natural killer cells (NK) contribute significantly to eradication of cancer cells, and there is increased interest in strategies to enhance it’s efficacy. Therapeutic agents used in the treatment of cancer can impact the immune system in a quantitative and qualitative manner. In this study, we evaluated the impact of arsenic trioxide (ATO) used in the management of acute promyelocytic leukemia (APL) on NK cell reconstitution and function. In patients with APL treated with single agent ATO, there was a significant delay in the reconstitution of circulating NK cells to reach median normal levels from the time of diagnosis (655 days for NK cells vs 145 and 265 days for T cells and B cells, respectively). In vitro experiments demonstrated that ATO significantly reduced the CD34 hematopoietic stem cell (HSC) differentiation to NK cells. Additional experimental data demonstrate that CD34+ sorted cells when exposed to ATO lead to a significant decrease in the expression of IKZF2, ETS1, and TOX transcription factors involved in NK cell differentiation and maturation. In contrast, exposure of NK cells and leukemic cells to low doses of ATO modulates NK cell receptors and malignant cell ligand profile in a direction that enhances NK cell mediated cytolytic activity. We have demonstrated that NK cytolytic activity toward NB4 cell line when exposed to ATO was significantly higher when compared with controls. We also validated this beneficial effect in a mouse model of APL were the median survival with ATO alone and ATO + NK was 44 days (range: 33–46) vs 54 days (range: 52–75). In conclusion, ATO has a differential quantitative and qualitative effect on NK cell activity. This information can potentially be exploited in the management of leukemia.

Introduction: Hairy cell leukemia (HCL) is a B-cell non-Hodgkin lymphoma with distinct clinical, morphological and immunophenotypic features; however, there are many other B-cell lymphomas, which closely mimic HCL. Accurate diagnosis of HCL is important as treatment with 2-chloro-2′-deoxyadenosine (cladribine) is associated with >80% chance of complete cure. The recent description of BRAF p.V600E mutations in almost all HCL cases in various studies has not only improved the pathogenetic understanding of this entity but also increased the diagnostic accuracy of this disorder. Aim: The aim of the study was to standardize a molecular test for diagnosis of HCL and compare with standard established morphological, cytochemical and immunophenotypic parameters for HCL diagnosis. Materials and Methods: The incidence of this mutation was sought in 20 patients with either classical HCL or HCL variant (HCLv) by Sanger sequencing and allele-specific polymerase chain reaction. BRAF p.V600E mutation was present in all HCL cases and absent in the only HCLv case. Results: A high degree of correlation was noted between the presence of BRAF p.V600E and established diagnostic criteria in 20/20 patients with HCL/HCLv. Our data supports the observation that this mutation is present in all cases of HCL and is absent in HCLv. Hence, detection of the BRAF p. V600E mutation can be a useful adjunct in the diagnostic algorithm.

Background : Chronic myelogenous leukemia (CML) is characterised by the t(9;22)(q34;q11.2) which results in the formation of the BCR/ABL1 fusion gene. Occasionally, the t(9;22) may be associated with submicroscopic deletions of chromosomes 9 and/or 22 which appear to be associated with a worse prognosis. Three or four-way variant t(9;22) may also occur. All these changes as well as gain of the Philadelphia chromosome which represents disease progression can be detected by fluorescence in situ hybridization (FISH) analysis. FISH analysis at presentation is used to determine the number of cells with BCR/ABL1 fusion and establish whether the patterns are typical or atypical. Response to therapy can then be monitored by serial testing. Patients and Methods : The study group consisted of all patients diagnosed or suspected to have CML who had interphase FISH analysis at presentation on peripheral blood/bone marrow using a commercially available BCR/ABL1 dual colour, dual fusion probe. The study was performed at a tertiary hospital in India between 2004 and 2010. Results: There were 1076 diagnostic samples which were positive for BCR/ABL1 fusion. Typical dual fusion signals (two fusions, one red and one green, 2F1R1G) were seen in 801 cases (74 %). Atypical signal patterns were seen in 275 cases (26%). These were: 1F1R2G (4%), 1F2R1G (2.5%) and 1F1R1G (11%) representing deletions of the derivative 9 involving chromosome 9 sequences, chromosome 22 sequences, or both respectively; 3F1R1G (6.5%) usually representing gain of an additional Philadelphia chromosome and 1F2R2G (1%) representing a three- or four-way variant translocation. More than one signal pattern was seen in 1%. Conclusions: Our findings were similar to the literature with respect to the distribution of signal patterns except that we had a lower number of patients with variant translocations. While each signal pattern is typically associated with a particular abnormality, there can be more than one explanation for each pattern. Hence, metaphase FISH analysis is the "gold standard" for the interpretation of signal patterns.

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.

Improving clinical outcomes among high risk Class III β thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 ± 7.3 Vs. 39.4 ± 6.8%; P = 0.002 and 77.8 ± 8.8 Vs. 32.4 ± 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients.