Assessment of Imatinib as a Primary Treatment of Chronic Myeloid Leukemia in Chronic Phase: a Cohort Study.

PURPOSE: The study aimed to assess the effectiveness of Imatinib in chronic myeloid leukaemia (CML) in our hospital population. In addition to identify which brand of imatinib (Gleevec/Veenat) is cost effective for CML patients and to assess the possible adverse drug reactions during the treatment for chronic myeloid leukaemia. METHODS: A non-interventional (observational), both retrospective and prospective study was carried out in the department of Medical Oncology and Haematology of our hospital. A total of 152 patients were enrolled in the study. Patients who satisfied the inclusion and exclusion criteria were selected for the study. RESULTS: Evaluation of baseline characteristics of study population (n = 152) showed predominance of males (65.1%). The mean age was 49.80 ± 16.561 years. The overall clinical outcome of the sample population, BCR ABL value responses during 3,6 and 12 months are the main indicators for the prediction of outcome in CML -CP patients. Using Independent sample t test, it was found that the difference in response to Imatinib therapy during 3,6 & 12 months were statistically significant and showed a statistically significant difference between the good and adverse outcome (p < 0.001). CONCLUSION: Our study concluded that Imatinib showed a benefit in treating the condition without any life-threatening adverse events and also the drug exhibits a complete haematological and optimal response based on European Leukaemia Net criteria during the period of study. From which, it can be concluded that imatinib appears to be a safe and well-tolerated treatment for the chronic-phase chronic myeloid leukaemia population.

Neonatal Autoimmune Lymphoproliferative Syndrome: A Case Report and A Brief Review.

The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life.

Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases.

Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n=9), including refractory and relapsed cases, and three representative cell lines expressing CD34(+)/CD38(-) stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having ~100nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML. FROM THE CLINICAL EDITOR: Through the use of a protein-vorinostat agent, exceptional single-agent activity was demonstrated against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. The studied epigenetics targeted nanomedicine approach is a promising therapeutic strategy against various French-American-British classes of acute myeloid leukemia.

Correction to: Efficacy and Safety of Biosimilar Romiplostim Versus Innovator Romiplostim in Patients with Chronic Immune Thrombocytopenia.

[This corrects the article DOI: 10.1007/s12288-022-01602-5.].

Efficacy and Safety of Biosimilar Romiplostim Versus Innovator Romiplostim in Patients with Chronic Immune Thrombocytopenia.

Romiplostim is a Food and Drug Administration (FDA)-approved therapy for immune thrombocytopenia (ITP). Biosimilar is a biological product that has no clinical meaningful difference from an existing FDA-approved reference product. It has a potential of lowering health-care-related cost. Biosimilar of romiplostim can be made available to patients with ITP at a low cost and can be beneficial in providing the best therapy. Thus, the efficacy and safety of biosimilar romiplostim (ENZ110) was compared with innovator romiplostim (Nplate) with respect to platelet response in patients with chronic ITP. This was a prospective, multicenter, randomized, and double-blind clinical trial. Patients with chronic ITP, aged 18-65 years, were enrolled in a study and were randomized to receive either ENZ110 or Nplate in a 3:1 ratio for a treatment period of 12 weeks, respectively. After completion of the treatment period, the patients were followed-up for one week to evaluate the platelet response and to monitor the adverse events (AEs). Over the duration of 12 weeks, platelet response of > 50 × 109/L was achieved in 85.3% patients treated with ENZ110 and in 75.0% patients treated with Nplate in per protocol population. In intent-to-treat population, 83.8% patients with ENZ110 and 76.9% patients with Nplate achieved a platelet response of > 50 × 109/L. In the ENZ110 group, 111 AEs were recorded in 66.7% patients, while 18 AEs were reported in 61.5% patients in the Nplate group. The study demonstrated non-inferiority with comparable efficacy and safety between biosimilar romiplostim and innovator romiplostim in patients with chronic ITP. Trial registration number and date of registration: CTRI/2019/04/018614.

Rationally designed aberrant kinase-targeted endogenous protein nanomedicine against oncogene mutated/amplified refractory chronic myeloid leukemia.

Deregulated protein kinases play a very critical role in tumorigenesis, metastasis, and drug resistance of cancer. Although molecularly targeted small molecule kinase inhibitors (SMI) are effective against many types of cancer, point mutations in the kinase domain impart drug resistance, a major challenge in the clinic. A classic example is chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in the early chronic phase of the disease, but failed in the advanced stages due to amplification of oncogene or point mutations in the drug-binding site of kinase domain. Here, by identifying critical molecular pathways responsible for the drug-resistance in refractory CML patient samples and a model cell line, we have rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly activated secondary kinase in the oncogenic network. Molecular diagnosis revealed that, in addition to point mutations and amplification of oncogenic BCR-ABL kinase, relapsed/refractory patients exhibited significant activation of STAT5 signaling with correlative overexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we have developed a human serum albumin (HSA) based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface conjugated the same with holo-transferrin (Tf) ligands for TfR specific delivery. This dual-targeted "transferrin conjugated albumin bound sorafenib" nanomedicine (Tf-nAlb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with average size of ∼150 nm and drug encapsulation efficiency of ∼74%. TfR specific uptake and enhanced antileukemic activity of the nanomedicine was found maximum in the most drug resistant patient sample having the highest level of STAT5 and TfR expression, thereby confirming the accuracy of our rational design and potential of dual-targeting approach. The nanomedicine induced downregulation of key survival pathways such as pSTAT5 and antiapoptotic protein MCL-1 was demonstrated using immunoblotting. This study reveals that, by implementing molecular diagnosis, personalized nanomedicines can be rationally designed and nanoengineered by imparting therapeutic functionality to endogenous proteins to overcome clinically important challenges like molecular drug resistance.

Role of myeloid derived suppressor cells in sepsis.

Sepsis is a serious and menacing organ dysfunction that occur due to dysregulated response of the host towards the infection. This organ dysfunction may lead to sepsis with intense cellular, metabolic and circulatory dysregulation, multiple organ failure and high mortality. Lymphopenia is observed in two-third of sepsis patients and a significant depletion of lymphocytes occurs in non-survivors compared to sepsis survivors. Myeloid derived suppressor cells (MDSCs) gave new insights into sepsis-associated lymphopenia. If MDSC expansion and its tissue-infiltration persist, it can induce significant pathophysiology including lymphopenia, host immunosuppression and immune-paralysis that contributes to worsened patient outcomes. This review focuses on MDSCs and its subsets, the role of MDSCs in infection, sepsis and septic shock.

Interactome based identification and validation of prefoldin 5-α for prognosing CNS leukemia in B-ALL patients.

We report here the identification and validation of prefoldin 5-alpha (PFDN5-α) for the first time as prognostic biomarker for prediction of central nervous system (CNS) leukemia of B cell acute lymphoblastic leukemia (B-ALL) origin. Since cerebrospinal fluid (CSF) cytology being the gold standard of diagnosis for CNS leukemia with poor sensitivity, mandatory prophylactic intrathecal chemotherapy is administered irrespective of patients develop CNS leukemia. Thus, using interactome studies, we identified PFDN5-α as a prognostic biomarker for predicting CNS leukemia by interacting lymphoblastic proteins and CSF from B-ALL patients using far-western clinical proteomics approach. Validation by both western and ELISA methods confirmed our results. For further clinical translation, we performed Receiver Operating Characteristic (ROC) curve analysis generated from CNS +ve (n = 25) and -ve (n = 40) CSF samples from B-ALL patients and identified PFDN5-α-CSF reactivity cut-off value as 0.456. Values below 0.456 indicate the patient is at risk of developing CNS leukemia and suggestive of having intrathecal chemotherapy. Further flow cytometry validation for CNS leukemia positivity revealed that with increasing blast cells, a decrease in PFDN5-α-CSF reactivity confirming ELISA based PFDN5α-CSF reactivity assay. Predicting CNS leukemia development risk by ELISA based PFDN5-α-CSF reactivity assay could have potential in the clinical management of CNS leukemia.

A quality improvement initiative to improve the appropriateness of candidemia management by the implementation of a comprehensive candidemia care bundle at a tertiary care hospital in South India: Results of a quasi-experimental study.

ABSTRACT: Management of candidemia in developing countries like India encounters laxity in appropriate clinical management and challenges in terms of healthcare capacity, despite its association with high morbidity and mortality. Our study aims to evaluate the impact of a comprehensive candidemia care bundle implementation on appropriateness of therapy and major clinical outcomes.The single-center, quasi-experimental study conducted at a south Indian tertiary care center included adult patients diagnosed with candidemia. Following a retrospective review of candidemia patients of the pre-implementation period (January 2013-December 2015), the hospital antifungal stewardship team instituted a clinical pharmacist driven comprehensive candidemia care bundle for candidemia patients during the post-implementation period (October 2017-2019) and its impact on appropriateness of antifungal prescriptions and inpatient mortality was evaluated.The study included 175 patients with candidemia, comprising of 103 patients in the pre-implementation period and 72 patients in the post-implementation period. Appropriateness of antifungal prescriptions rose to 65% during post-implementation period from 30% observed in pre-implementation phase (P = .0005). The inhospital mortality rate reduced from 40% in the pre-implementation phase to 36% in the post-implementation phase, recording a 10% reduction over 2 years post-implementation (P = .26). No significant difference was observed in terms length of stay (P = .17).Our study demonstrates the successful implementation of an antifungal stewardship led comprehensive care bundle in a low middle income countries setting. The results of our study will have profound implications in improving the appropriateness of management of candidemia and feasibility of scaling up to wider settings could be explored.

Low Dose Prophylaxis in Hemophilia Care.

Hemophilia is an inherited bleeding disorder which causes impaired blood clotting. The severity of disease depends on the type of Hemophilia, level of clotting factor concentrate (CFC), phenotypic heterogeneity and the development of inhibitors. The currently accepted standard of care of this disease is prophylaxis therapy (PT) with CFC. Prophylaxis therapy for Hemophilia is given in developed countries for the last few decades. On the contrary, episodic therapy (ET) is still the mode of treatment in middle and low income countries. ET is documented to have several potential risks such as increased bleeding rate, disability due to haemarthrosis, poor quality of life and increased chances of mortality. Several studies conducted in developed countries have confirmed the clinical efficacy of PT in Hemophilia treatment. Currently, there exist several challenges for implementation of this effective treatment in resource poor nations. Low dose prophylaxis (LDP) has been developed as a solution to minimize these challenges and to provide better care for subjects with Hemophilia from low resource countries. The impact of LDP was evaluated by several recent studies and the reported clinical outcomes seem to suggest an optimistic future for this line of therapy. Several themes related to Hemophilia care like inhibitor development, tolerance, pharmacokinetics of CFCs and cost-benefit analysis of different prophylaxis regimens are currently understood poorly. These distinct elements are highly relevant to assess the actual benefits of LDP regimen in a global scale.

Extracellular Trap by Blood Cells: Clinical Implications.

BACKGROUND: Extracellular trap formation (ETosis) by various blood cells has been reported. This trap contains DNA, histones and granular proteins which can elicit an innate immune response by entrapping microorganisms. The trap thus formed has been reported to have an involvement in various pathogenic conditions as well. This review focusses on the trap formation by different blood cells, the immune response associated with trap formation and also its role in various clinical conditions. METHOD: An extensive literature survey on ETosis by blood cells from 2003 to 2019 has been done. After going through the literature throughly, in this review we focuses on the trap formation by different blood cell types such as neutrophils, macrophages, eosinophils, basophils, mast cells, plasmacytoid dentritic cells, and monocytes. The mechanism with which it releases trap, the immune response it elicits and ultimately its involvement in various pathogenic conditions are described here. This article extensively covered all the above aspects and finally comprehends in nutshell the various stimuli that are currently known in trigerring the ETosis, its effect and ultimately its role in disease process. RESULTS: A clarity about the extracellular trap formation by various blood cells, mechanism of ETosis, role of Etosis in microbial invasion and in various pathogenic situations by various blood cells have been described here. CONCLUSION: The current understanding about the process of ETosis and its effects has been extensively described here. Along with lot of favourable outcomes, the process of ETosis will lead to lot of pathogenic situations including thrombosis, tumour metastasis and sepsis. Current understanding about ETosis is limited. Indepth understanding of ETosis may have great therapeutic potential in the diagnosis, guiding of therapy and prognostication in various pathogenic situations including infectious conditions, autoimmune disorders and tumors.

Intermediate Dose Prophylaxis in Adults with Haemophilia: A Clinical Audit from a Resource Limited Setting.

To address the scarcity of real world data on adult prophylaxis from developing world, a short term intermediate dose prophylaxis in adult haemophilia A patients was initiated. A total of eight patients aged > 18 years with moderate/severe haemophilia A were given an average dose of 23 IU/kg recombinant factor VIII (rFVIII) concentrate twice weekly for 2 months. A clinical audit was done on completion of four months. The mean age of the participants was 31.63 (± 6.98) years. The mean bleed rate during two months of episodic versus prophylactic regimen was 5.13 versus 0.63 (p = 0.01) and that of work days lost, hospital visits for hemophilia care were 30.63 (± 24.69) versus zero days, 20.63 (± 16.19) versus zero days respectively. The mean of factor VIII consumed during prophylaxis was 13,500 IU/month (i.e., 23 IU/kg/dose).The median time gap between prophylactic infusion to trough level was 67.50 h (60-74 h) and the median trough level observed was 2.50% (range 1-5%). The results of our clinical audit show that Intermediate dose prophylaxis with rFVIII concentrates in young adult patients with moderate/severe haemophilia A appears to be effective in reducing the frequency of bleeds.

Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients.

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases (n = 69; 49%), hematology (n = 68; 48%), and others (n = 41; 29%). BCT was performed in 57% (n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% (n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome.

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.

Clinical characteristics and treatment outcomes of primary autoimmune hemolytic anemia: a single center study from South India.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is a less recognized, potentially fatal condition. There is a scarcity of data on clinicoserological characteristics and response to therapy concerning this disease from South India. METHODS: Data for 33 patients with primary AIHA recorded from July 2009 to June 2015 were retrospectively analyzed for clinical presentation, response to frontline therapy, durability of response, time to next treatment (TTNT), and response to second-line agents. RESULTS: The median follow-up period was 50 months. Among 33 patients, 48% of the cases were warm autoimmune hemolytic anemia (WAIHA), 46% were cold agglutinin disease (CAD), and 6% were atypical. Three-fourth of patients had severe anemia (<8 g/dL hemoglobin [Hb]) at onset; younger patients (age <40 yr) had more severe anemia. All of the patients who required treatment received oral prednisolone at 1.5 mg/kg/d as a frontline therapy, and the response rate was 90% (62% complete response [CR] and 28% partial response [PR]). The overall response to corticosteroids in WAIHA and CAD was 87% and 92%, respectively. The median corticosteroid duration was 14 months, and 50% of the patients required second-line agents. Fourteen patients received azathioprine as a second-line agent, and 11 of these patients responded well, with half of them not requiring a third agent. Four patients developed severe infections (pneumonia, sepsis, and soft tissue abscess) and two had life-threatening venous thrombosis. One case of death was recorded. CONCLUSION: AIHA is a heterogeneous disease that requires care by physicians experienced in treating these patients.

Carbimazole-induced agranulocytosis.

UNLABELLED: A 47 year old lady with hyperthyroidism for past 1½ years was initially on Carbimazole 20 mg orally then changed to 30 mg (during Hysterectomy) but was taking 10 mg for last 1 year. She had intermittent fever with severe B/L bifrontal headache since 3 weeks. Routine investigations showed anaemia, neutropenia, leucopenia and CRP elevation. Peripheral smear showed normocytic normochromic anaemia with Rouleaux formation, leucopenia with 2% atypical cells and mild thrombocytosis. Widal test, RA factor (Rheumatoid factor) test, Ig M (Immunoglobulin M) dengue, Ig M Lepto, TORCH infections (Toxoplasmosis, Other (Syphilis, varicella-zoster, parvovirus B19), Cytomegalovirus and Herpes infections), ANA (Antinuclear antibody) screen cANCA (Cytoplasmic antineutrophil cytoplasmic antibodies) and pANCA (Perinuclear Anti-Neutrophil Cytoplasmic Antibodies) tests were negative. Bone marrow aspiration showed normo to hypercellular marrow with 15% atypical cells and plasma cells. Multiple myeloma workup was done. Carbimazole was withheld. CONCLUSION: Drug induced agranulocytosis occurs with in 1-2 months of taking the antithyroid medication but onset delayed by 1½ year. De-challenge resulted normalization of blood parameters.

Protein Nanomedicine Exerts Cytotoxicity toward CD34+ CD38- CD123+ Leukemic Stem Cells.

The efficacy of protein-vorinostat nanomedicine (NV) is demonstrated in leukemic stem cells (LSC) isolated from refractory acute myeloid leukemia (AML) patient samples, where it successfully ablated both CD34+ CD38- CD123+ LSC and non-LSC "leukemic blast" compartments, without inducing myelosuppression or hemotoxicity. Besides, NV also exerted excellent synergistic lethality against leukemic bone marrow cells (BMC) at lower concentrations (0.1 µM) in combination with DNA methyltransferase (DNMT) inhibitor, decitabine. Considering the extermination of resilient LSC and synergism with decitabine, NV shows promise for clinical translation in the setting of a more tolerable and effective epigenetic targeted therapy for leukemia.

Salmonella Typhimurium pneumonia in a patient with multiple myeloma.

Pneumonia due to non-typhoidal Salmonella is a rarely reported entity. A fatal case of Salmonella pneumonia is reported here where Salmonella Typhimurium was isolated from the endotracheal aspirate and blood culture.