Hematopoietic cell transplantation landscape in India.

Hematopoietic cell transplantation (HCT), commonly known as Bone marrow transplantation (BMT), is a medical procedure used to treat various conditions, including blood cancers, genetic disorders, and certain autoimmune diseases. The procedure involves replacing damaged or diseased bone marrow with healthy stem cells to promote the production of new, healthy blood cells. In India, HCT has been performed for several years in specialized medical centers. India has a growing healthcare infrastructure, and many hospitals are equipped to perform these procedures. Though there are studies on HCTs done at individual transplant centers in India, a comprehensive analysis of the current landscape of HCT in the country is lacking. HCT in India has seen major advances both in the quantity and quality of HCT centers. This review article has attempted to cover the gaps of HCT in India, including its status in the Armed Forces HCT centers.

Bone marrow transplant: A two-decade single centre hematology experience.

Background: Bone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. Methods: We reviewed our BMT data since the inception of the program till Feb 2023. Results: Over 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. Conclusion: The evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of "transplant for all". Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Safety and efficacy of splenectomy in immune thrombocytopenia.

BACKGROUND: Immune Thrombocytopenia (ITP) is characterized by low platelet counts. Splenectomy has been in practice for the treatment of ITP since the early 20th century. We aimed to analyze the data of ITP patients from our hospital who underwent splenectomy and further present the long-term outcome and safety profile in these patients. METHOD: This study was a single-center, registry based study conducted at a tertiary care hospital in Northern India. Patients aged 18 years or more, who underwent splenectomy after at least one line of therapy, were included in the study. The primary outcome was the overall response rate (ORR) at one month after splenectomy. Secondary outcomes were sustained response, relapse-free survival, factors affecting the ORR, and adverse events after splenectomy. RESULTS: Forty-five patients of ITP were included in the study. Thirty-six patients underwent splenectomy in the first half (2001-2010), of the study period. The median age of the patients was 38 (19-56) years. The median duration from diagnosis to splenectomy was 1.76 (0.47-2.58) years. The median number of therapy received before splenectomy was 3 (1-6). The overall response rate (ORR) post-splenectomy at day 30 was 89.2% with 61.8% complete response (CR). The ORR was 88.5% at 1-year, with 48.8% CR. The relapse-free survival (RFS) at 5-years was 57.38% (95% Confidence Interval 40.59-71.02%), There was no effect of duration of disease, age, gender, and prior therapy received, on the ORR at one-month. At one year, the platelet response was significantly better in patients who had a CR at one-month than patients who had a partial response at one month. The relapse-free survival was better in patients who achieved CR after 1-month of splenectomy. During the median follow-up of 5.02 (1 month-20 years) years, there were five cases of overwhelming post-splenectomy infection (OPSI). There was no recorded incidence of perioperative mortality, deep vein thrombosis, or mesenteric thrombosis. DISCUSSION: Despite the variation in outcome from different studies, splenectomy gives the best possible long-term treatment-free remission amongst all the available second-line agents. It is also, one of the most financially affordable therapies. Despite advantages, the number of ITP patients undergoing splenectomy has been on the decline and largely attributable to the newer and more effective second-line therapies. There is no pre-surgery variable predicting the ORR after splenectomy. CONCLUSION: Splenectomy in ITP offers a long-term sustained response at an economical cost.

Radiographical Spectrum of High-altitude Pulmonary Edema: A Pictorial Essay.

BACKGROUND: High-altitude pulmonary edema (HAPE) is a common cause of hospitalization in high altitude areas with significant morbidity. The clinical presentation of HAPE can overlap with a broad spectrum of cardiopulmonary diseases. Also, it is associated with varied radiological manifestations mimicking other conditions and often leading to unnecessary and inappropriate treatment. PATIENTS AND METHODS: The primary aim of the study was to study the various radiological manifestations of HAPE through real-world chest radiographs. We present six different chest X-ray patterns of HAPE as a pictorial assay, at initial presentation, and after the resolution of symptoms with supplemental oxygen therapy and bed rest alone. RESULTS: HAPE can present as bilateral symmetrical perihilar opacities, bilateral symmetrical diffuse opacities, unilateral diffuse opacities, bilateral asymmetrical focal opacities, and even lobar consolidation with lower zone or less commonly upper zonal predilection. These presentations can mimic many common conditions like heart failure, acute respiratory distress syndrome, pulmonary embolism, aspiration pneumonitis, pneumonia, malignancy, and tuberculosis. CONCLUSION: A holistic clinical-radiological correlation coupled with analysis of the temporal course can help high-altitude physicians in differentiating true HAPE from its mimics. HOW TO CITE THIS ARTICLE: Yanamandra U, Vardhan V, Saxena P, Singh P, Gupta A, Mulajkar D, et al. Radiographical Spectrum of High-altitude Pulmonary Edema: A Pictorial Essay. Indian J Crit Care Med 2021;25(6):668-674.

Survival Outcomes of Newly Diagnosed Multiple Myeloma at a Tertiary Care Center in North India (IMAGe: 001A Study).

PURPOSE: The outcomes of patients with myeloma from developing countries are often lacking because of poor record maintenance. Publications from such settings are also limited because of the retrospective nature of the data collection. Information technology can bridge these gaps in developing countries with real-time data maintenance. We present the real-time survival data of the patients with myeloma from a tertiary care center in North India using one such indigenously built software. PATIENTS AND METHODS: These are real-time data of all patients with myeloma presenting to a tertiary care center from North India. The patient characteristics (demographics, baseline disease characteristics, risk stratification, and outcomes) were recorded contemporaneously. The survival of the study population was analyzed and grouped based on various disease characteristics at diagnosis. RESULTS: The median age of the study population (N = 696) was 65.9 (34.9-94.9) years with male predominance (65%). The median follow-up was 3.7 years (0-18.6 years) with the median overall survival (OS) not achieved. The OS of the study population at 1, 3, and 5 years was 94% (n = 558), 87.5% (n = 394), and 83.1% (n = 267), respectively. Most of the patients presented in advanced stages based on International Staging System (III:70%). On Kaplan-Meier analysis, the presence of weight loss (P = .01), renal dysfunction (P = .047), and anemia at diagnosis (P = .004) had a significant impact on survival. On Cox proportional model univariate analysis, the presence of renal dysfunction, anemia, and weight loss had the significant hazard ratio of 1.68 (1-2.82, P = .049), 3.18 (1.39-7.29, P = .0063), and 2.81 (1.22-6.42, P = .014), respectively, whereas on multivariate analysis of hypercalcemia, renal disease, anemia, and bone disease (CRAB) features, only anemia was found to have a significant hazard ratio of 2.56 (1.01-6.47, P = .046). CONCLUSION: The real-world data show OS comparable with the published western literature. Only anemia was found to have significant impact on survival. The use of such software can aid in better data-keeping in resource-constrained settings.

Summary of the Highlights of 2019 ASTCT Meeting by iNDUS BMT Group at Chennai, India.

This article summarises the main highlights of the abstracts presented at the annual meeting of American Society of Transplantation and Cellular Therapy (ASTCT). The highlights of ASTCT meeting were organised by iNDUS BMT group in Chennai, India. The purpose of the highlight meeting was to educate the students about the latest research in the field of hematopoietic stem cell transplantation and its applicability for the developing country perspective.

PRES in Pediatric HSCT: A Single-Center Experience.

Posterior reversible encephalopathy syndrome (PRES) has diverse etiologies and is closely linked to hematopoietic stem cell transplant (HSCT). Headache and seizures are the most common clinical presentations. Although near total recovery is seen in the majority of patients with appropriate management, the implications of its occurrence in the setting of an HSCT is much more than the residual neurological deficits. Graft rejection and occurrence of graft versus host disease has been reported. We analyzed retrospectively our data of 35 pediatric HSCT recipients over the last 2 years at our center. In total, 17% (n=6) patients developed PRES. Headache and seizures were the most common clinical presentations. All patients were on calcineurin inhibitors at the onset of symptoms. The median time after HSCT to the onset of PRES was 21 days. In total, 34% (n=2) patients developed residual neurological deficit. One patient died of acute graft versus host disease at a later date, and 50% (n=3) patients had graft rejection and return to transfusion dependence. The implications of PRES on HSCT outcomes are grave, and better immunosuppression transition protocols need to be developed.

Stem cell transplant in systemic sclerosis: An Indian experience.

AIM: To prospectively evaluate long term outcomes in a cohort of patients with Systemic sclerosis treated with Hematopoietic stem cell transplant (HSCT). METHOD: This is a prospective observational study of four SSc patients who underwent HSCT at a tertiary care center in India between 2008-2012. The selection criteria included young individuals with rapidly progressive disease and at least one major organ involvement. We used granulocyte colony-stimulating factor for peripheral blood stem cell mobilization, pre-transplant conditioning with fludarabine, cyclophosphamide and rabbit anti-thymocyte globulin followed by re-infusion of autologous stem cells as per standard institute protocol. RESULTS: A total of four patients (one male and three females) underwent autologous HSCT for SSc. Patients had heterogeneous disease manifestations including severe Raynaud's phenomenon with vasculopathic ulcers, gastrointestinal problems and mild interstitial lung disease (ILD). Patients were followed up for a mean duration of 7 years. There was significant sustained improvement in skin score, vasculopathy and gastrointestinal manifestations. Interstitial lung disease did not show any deterioration. The quality of life indices showed remarkable improvement in all subjects. No complications related to transplant were noted. CONCLUSION: In absence of an effective pharmacotherapy for SSc, autologous HSCT has a huge potential in management of cutaneous and internal organ manifestations.

Derivation of human iPSC line NCCSi002-A from umbilical cord blood (UCB) CD34+cells of donor from Indian ethnicity.

We discuss the reprogramming of CD34+ cells isolated from UCB of a healthy female child of Indian ethnicity. The CD34+cells were nucleofected using episomal vectors expressing Oct4, Sox2, L-Myc, Klf4, Lin28 and p53DD (negative mutation in p53). The colonies were stained for alkaline phosphatase and evaluated for pluripotency marker expression by PCR, immunofluorescence and flow-cytometry. The safety of cells was confirmed by absence of plasmid in subsequent passages by PCR. G-banded karyotype demonstrated a stable genome. The ability of tri-lineage differentiation was confirmed by specific marker expression by immunofluorescence invitro and teratoma formation invivo.

Acute Radiation-Induced Changes in Sprague-Dawley Rat Submandibular Glands: A Histomorphometric Analysis.

BACKGROUND: Radiation-induced xerostomia is a distressing clinical condition that starts appearing from the initial stages of radiotherapy in head and neck cancer patients. Though submandibular glands contribute to maximum of the "resting salivary" secretions, most of the acute xerostomia experiments so far reported have been on animal parotid glands. Therefore, we assessed and quantified the histologic changes in submandibular glands of Sprague-Dawley (SD) rats using histomorphometry, 24 hours after radiation. METHODS: Three SD rats were given single-dose radiation of 15 Gray from a gamma cobalt-60 irradiator. Same number of non-radiated animals was the controls. Animals were sacrificed at 24 hours followed by histopathology and histomorphometry of submandibular glands, where the mean values were analyzed by Student's t-test. RESULTS: Irradiated submandibular glands showed highly significant reduction in acinar area (53%: 77.16±5.05% to 36.55±4.90%) and acinar size (87%: 3,447.53 ± 461.03 mm2 to 428.25 ± 75.22 mm2) with concomitant increase in inter-acinar space (3.46 ± 0.67 mm to 10.08 ± 0.60 mm). Acini nuclei displayed anisonucleosis, poikilonucleosis and pyknosis. "Serous acini" had marked morphologic changes, with fluid accumulation between cells, generalized cytoplasmic vacuolation and vascular congestion, while "mucous acini" largely retained cell architecture. Similarly, ductal cells and nuclei also did not show apparent differences. This demonstrated radiosensitivity variations among different submandibular gland cell types. CONCLUSION: Evaluation of acute submandibular acinar cell dysfunctions has helped in quantifying the histologic elements, which mainly contribute to the resting salivary secretions. Findings would aid in future research of radioprotector drugs, salivary glandular regeneration modalities and in devising prudent radiotherapy protocols to address radiation-induced xerostomia.

Single Dose Preemptive Plerixafor for Stem Cell Mobilization for ASCT After Lenalidomide Based Therapy in Multiple Myeloma: Impact in Resource Limited Setting.

Peripheral blood stem cell mobilization with cytokines for autologous stem cell transplant in multiple myeloma is adversely affected by initial induction therapy consisting of either Lenalidomide or cytotoxic drugs, with failure rates of up to 45%. The use of Plerixafor with G-CSF for PBSC mobilisation significantly improves the chances of a successful mobilization. Plerixafor is a costly therapy and increases the overall costs of ASCT which can affect the number of patients being taken up for ASCT in resource limited settings. We prospectively studied the impact of single dose preemptive Plerixafor for PBSC mobilization in patients with prior Lenalidomide exposure. 26 patients who had received Lenalidomide based induction protocol underwent PBSC mobilisation during the study period with G-CSF 10 µg/kg/day SC for 4 days and single dose preemptive Plerixafor 240 µg/kg SC stat 11 h before the scheduled PB stem cell harvest on D5, based on a D4 PB CD34+ counts of <20/µL. A median of 07 cycles of Lenalidomide based combination therapy was used for induction therapy prior to ASCT. 84% patients underwent successful mobilization with one sitting of stem cell harvest post a single dose of Inj Plerixafor. 7.6% patients failed to mobilise the predefined minimum cell dose of CD34 and could not be taken up for ASCT. The median CD34% of the harvest bag sample was 0.33% (0.1-0.97%). Injection site erythema (34%), paresthesia's (34%) and nausea (30%) were the commonest adverse events reported post Inj Plerixafor. We did a real-world cost analysis for a resource limited setting for PBSC mobilization and found significant cost savings for the preemptive Plerixafor group.

Guidelines for medical management of nuclear/radiation emergencies.

Management of victim of radiation injury poses a wide spectrum of challenges to the health care provider starting with the evaluation of the damage, the kind of hospitalization and treatment and the regular monitoring of the patient. Undesirable clinical outcomes are probable if prodromal stage evolves rapidly and is severe. Critical systems like neurovascular, gastrointestinal, haematopoietic and cutaneous are afflicted in Acute Radiation Syndrome. Three main elements which are essential for assessment of prognosis and selection of treatment are vomiting onset time, kinetics of depletion of lymphocyte, and chromosome abnormalities. Larger incidents warrant, a well-structured national response system. Health care institutions must develop protocols to respond to radiation exposure related emergencies in tandem with the local response teams. Multidisciplinary approach between clinical specialists, nursing staff and psychological experts is of critical significance. External decontamination, estimation of dose and fluid and electrolyte replacements form part of support therapy. Reverse isolation, antacids, H2 blockers, use of reverse barrier nursing and prophylactic antimicrobials are part of the treatment plan. Patients with severe bone marrow damage will require blood products support. Increased recovery of neutrophils in radiationaccident victims is the rationale for the use of Colony Stimulating Factors. New directions are under evaluation which includes novel cytokine therapies like interleukin-7, keratinocyte growth factor, and thrombopoietin or its analogues. The final decision regarding allogenic haematopoietic stem cell transplant should be considered after considering the irradiation source, particularity of the situations or circumstances, associated injuries and disease.

Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction--MI3 Trial.

BACKGROUND & OBJECTIVES: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 10 [8] autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy. METHODS: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI). RESULTS: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 10 [8] (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study. INTERPRETATION & CONCLUSIONS: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.

Anaphylactic Shock Secondary to Intravenous Iron Sucrose in Chronic Kidney Disease.

Intravenous (IV) iron is an essential component of therapy of anemia of chronic kidney disease (CKD). We present a rare case in which iron sucrose was infused to a patient of CKD and resulted in severe anaphylaxis and cardiac arrest minutes after starting the infusion. He was aggressively resuscitated with adrenaline and other measures following which he recovered. The use of parenteral iron is associated with several adverse drug reactions (ADR) which were seen with preparations like iron dextran but became rare with the use of newer safe preparations like iron sucrose or gluconate. The ADR can be mild or can have severe life threatening features like syncope, cardiac arrhythmias, seizures, bronchospasm and rarely cardio respiratory arrest like in our case. Iron sucrose is generally given as a IV infusion of 100-200 mg over 15-30 min and has a very low rate of ADR even with higher doses or bolus injections. But still necessary precautions and appropriate monitoring must be done in all patients. The patients who are allergic to iron sucrose may be treated with other safer preparations or by desensitisation techniques.

Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma.

Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up.

Megaloblastic anemia presenting with massive reversible splenomegaly.

Megaloblastic anemia (MA) is a common disorder with varied manifestations. It generally results in mild to moderate splenomegaly which is due to sequestration of macrocytic erythrocytes in spleen. Massive splenomegaly is generally seen in infections, myeloproliferative diseases, neoplasms, storage disorders or hematological conditions; but is not heard of and has rarely been reported in MA. We discuss a case of massive splenomegaly who presented with symptomatic anemia and was found to have MA. He was extensive evaluated for all other causes of massive splenomegaly which was normal. Further, after a therapeutic trial of MA he showed a regression in spleen size confirming that the massive splenomegaly was attributable to MA.

Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial.

BACKGROUND AND PURPOSE: Pilot studies have suggested benefit from intravenous administration of bone marrow mononuclear stem cells (BMSCs) in stroke. We explored the efficacy and safety of autologous BMSCs in subacute ischemic stroke. METHODS: This was a phase II, multicenter, parallel group, randomized trial with blinded outcome assessment that included 120 patients. Patients with subacute ischemic stroke were randomly assigned to the arm that received intravenous infusion of autologous BMSCs or to control arm. Coprimary clinical efficacy outcomes were Barthel Index score and modified Rankin scale at day 180. Secondary outcomes were change in infarct volume, National Institute of Health Stroke Scale (NIHSS) at day 90 and 180. Main safety outcomes were adverse events, any new area of (18)fluorodeoxyglucose positron emission tomography uptake in any body part over 365 days. RESULTS: Fifty-eight patients received a mean of 280.75 million BMSCs at median of 18.5 days after stroke onset. There was no significant difference between BMSCs arm and control arm in the Barthel Index score (63.1 versus 63.6; P=0.92), modified Rankin scale shift analysis (P=0.53) or score >3 (47.5% versus 49.2%; P=0.85), NIHSS score (6.3 versus 7.0; P=0.53), change in infarct volume (-11.1 versus -7.36; P=0.63) at day 180. Adverse events were also similar in the 2 arms, and no patient showed any new area of (18)fluorodeoxyglucose uptake. CONCLUSIONS: With the methods used, results of this hitherto first randomized controlled trial indicate that intravenous infusion of BMSCs is safe, but there is no beneficial effect of treatment on stroke outcome. CLINICAL TRIAL REGISTRATION: URLs: http://ctri.nic.in/Clinicaltrials and http://www.clinicaltrials.gov. Unique identifiers: CTRI-ROVCTRI/2008/091/0004 and NCT0150177.

Monitoring of response to therapy with imatinib mesylate in Chronic Myeloid Leukemia in chronic phase (CML-CP).

BACKGROUND: The BCR-ABL tyrosine kinase is a well validated therapeutic target in Chronic Myeloid Leukemia (CML). Imatinib mesylate (IM), a tyrosine kinase inhibitor is highly effective in the treatment of chronic phase CML. BCR - ABL transcripts have been well established as a molecular marker to document response to therapy in CML. Periodic monitoring of this marker helps in evolving therapeutic strategies with IM and also in diagnosing early relapse. This study was undertaken to monitor therapeutic response to IM in CML in chronic phase (CML-CP) by assessing BCR-ABL by real time quantitative PCR (RQ-PCR) techniques and to determine the effectiveness of the Indian generic IM. METHODS: One hundred consecutive patients of CML in chronic phase (CML-CP) were treated with an Indian generic of IM. Eighty-five patients were evaluable at 12 months of therapy. At entry, diagnosis of CML-CP was confirmed by FISH and RQ-PCR. Response to therapy was monitored by assessing BCR-ABL levels by RQ-PCR at 6 and 12 months of therapy. Regular follow up of patients was done to evaluate the safety profile of IM used in these patients. RESULTS: Complete hematological response (CHR) rates at 3, 6, 9 and 12 months were 92%, 94%, 100% and 100% respectively. The total molecular response at 12 months was 43.52% of which complete molecular response (CMR) was noted in 17.64% and major molecular response (MMR) was observed in 25.88%. A cumulative survival probability of 0.8 was observed. CONCLUSION: The Indian generic molecule of IM is effective in the treatment of CML-CP. The cost of Indian generic molecule is less than Rs. 10,000 per month there by making this affordable for large number of CML-CP patients in India.