ObjectivesThe study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D3 supplementation in patients newly diagnosed with chronic-phase ...chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D3 on complete haematological response (CHR) and its safety.DesignDouble-blind, placebo-controlled, exploratory randomised trial.SettingTertiary care hospital in northern India.ParticipantsTreatment-naive patients with chronic phase chronic myeloid leukaemia (n=62) aged >12 years were recruited from January 2020 to January 2021. Patients with progressive disease, pregnancy and hypercalcaemia were excluded.InterventionOral vitamin D3 supplementation (60 000 IU) or matched placebo was given once weekly for an initial 8 weeks along with imatinib after randomisation with 1:1 allocation ratio.Primary and secondary outcome measuresThe primary outcome was to compare EMR (defined as BCR-ABL1 transcript level ≤10%, international scale) at 3 months. The secondary outcomes were to compare effect of the intervention on CHR, correlation of 25(OH)2D3 levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.ResultsAt baseline, 14.5% of the patients had normal vitamin D3 levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D3 group and 21 (75%) of the placebo group (OR 1.6, 95% CI 0.37 to 7.37, p=0.4). A significant difference in vitamin D3 levels from baseline to the end of study was observed. Patients with vitamin D3 supplementation did not achieve higher CHR in comparison with placebo (OR 1.3, 95% CI 0.25 to 7.23, p=1.0). Vitamin D3 levels were not significantly correlated with BCR-ABL1 levels. No dose-limiting toxicities were observed.ConclusionVitamin D3 levels were low among patients with CML-CP in this study. Vitamin D3 supplementation with imatinib therapy did not have significant effect on EMR or CHR. Further clinical trials could be undertaken to assess the effective dosage and duration of vitamin D3 supplementation in these patients.Trial registration numberCTRI/2019/09/021164.
Abstract
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Deepak Sundriyal
Background and Objectives
The newly established medical oncology and hemato-oncology center at the All India Institute of Medical ...Sciences (AIIMS), Rishikesh, Uttarakhand, India, provided us an opportunity to audit in-hospital mortalities with a vision that the audit will serve as a standard for ceaseless improvement. Aim of the study was to initiate a vigorous process for the evaluation of all-cause mortality in patients suffering from cancer.
Methods
An audit of all in-hospital deaths that occurred during the year 2019 was performed, and comprehensive scrutiny of various parameters (demographic, clinico-pathological, therapeutic, causes of death) was done. Reviews from two independent observers sharpened the infallibility of the audit. The lacunae in the existing practices and the scope for further improvement were noted.
Results
Forty-five in-hospital deaths were registered during the study period (January–December 2019). The majority of the deaths occurred in patients with advanced stage of malignancy (
n
= 31 68.8%). Most common causes of death were progressive disease, neutropenic, and non-neutropenic sepsis. Chemotherapeutic agents, growth factors, blood components, and antibiotics were found to be used judiciously as per institutional policy. The reviewers emphasized on the use of comorbidity indexes in the treatment planning and avoiding intensive care unit referrals for patients receiving best supportive care (BSC). Emphasis was put on providing only BSC to the patients with a very limited life expectancy. Emphasis was also laid down on record of out of the hospital deaths.
Interpretation and Conclusion
The audit disclosed areas of care which require further improvement. The mortality audit exercise should become a regular part of evaluation and training for the ongoing and future quality commitment. This should impact the clinical decision making in an oncology center providing quality care to the terminally ill patients.
Introduction: Next-generation sequencing (NGS) elucidates the diffuse large B-cell lymphoma (DLBCL) genetic characteristics by finding recurrent and novel somatic mutations. This observational study ...attempted to create an NGS panel with a focus on identifying novel somatic mutations which could have potential clinical and therapeutic implications. This panel was created to look for mutations in 133 genes chosen on basis of a literature review and it was used to sequence the tumor DNA of 20 DLBCL patients after a centralized histopathologic review.Methods: The study included 20 patients having DLBCL. The quality and quantity of tumor cells were accessed by H&E staining and correlated with histopathology and Immunohistochemistry (IHC) status. Patients were grouped as ABC (activated B-cell), PMBL (primary mediastinal large B-cell lymphoma), and other or unclassified subtypes. The lymphoma panel of 133 was designed on targeted sequencing of multiple genes for the coding regions through NGS. The libraries were prepared and sequenced using the Illumina platform. The alignment of obtained sequences was performed using Burrows-Wheeler Aligner and identification of somatic mutations was done using LoFreq (version 2) variant caller. The mutations were annotated using an annotation pipeline (VariMAT). Previously published literature and databases were used for the annotation of clinically relevant mutations. The common variants were filtered for reporting based on the presence in various population databases (1000G, ExAC, EVS, 1000Japanese, dbSNP, UK10K, MedVarDb). A custom read-depth-based algorithm was used to determine CNV (Copy Number Variants) from targeted sequencing experiments. Rare CNVs were detected using a comparison of the test data read-depths with the matched reference dataset. Reportable mutations were prioritized and prepared based on AMP-ASCO-CAP (Association for Molecular Pathology-American Society of Clinical Oncology-College of American Pathologists), WHO guidelines, and also based on annotation metrics from OncoMD (a knowledge base of genomic alterations).Results: The informativity of the panel was 95 percent. NOTCH 1 was the most frequently mutated gene in 16.1% of patients followed by 12.9% who had ARID1A mutations. MYD88 and TP53 mutations were detected in 9.6% of the patient while 6.4% of patients had CSF3R mutations. NOTCH 1 and TP 53 are the most frequently reported gene in the middle age group (40-60). Mutation in MYD88 is reported in every age group. MYD88 (51%) is the most common mutation in ABC subtypes of DLBCL, followed by NOTCH 1 (44%) and SOCS 1 (33%) according to our findings. NOTCH 1 mutations are frequent in ABC and PMBL subtypes. Closer investigation reveals missense mutation is the most frequent mutation observed in the total cohort targeting 68.4% followed by frameshift deletion reported in 26.3%. Six novel variants have been discovered in this study.Conclusions: This study demonstrates the high yield of information in DLBCL using the NGS Lymphoma panel. Results also highlight the molecular heterogeneity of DLBCL subtypes which indicates the need for further studies to make the results of the NGS more clinically relevant.
Candida bloodstream infection is the major cause of increased morbidity and mortality (20–49%) in hospitalized patients in both paediatric and adult age groups. Due to the increase in the number of ...immunocompromised patients, other important species such as Trichosporon asahii and Debaryomyces hansenii are emerging. One such organism, Wickerhamomyces anomalous, previously known as Pichia anomala (teleomorph stages of several Candida species), is increasingly being reported as a cause of fungemia in neonatal intensive care units and is now increasingly being reported in a lot of immunosuppressive conditions such as interstitial lung disease, endocarditis, enteritis, corticosteroids, and chemotherapy uptake. Though this yeast is ubiquitous in nature, systemic infections from isolated cases and sporadic outbreaks with high mortality have been reported in ICUs, which emphasize the importance to consider this fungus within the diagnostic possibilities. Here, we report a case of catheter-related bloodstream infection (CRBSI) caused by W. anomalus in a leukemic immunosuppressed patient who was successfully treated by early detection and treatment of this emerging fungus.
Hematopoietic stem cell transplants (HSCTs) are increasingly being offered to patients in India for various conditions. The Indian Stem Cell Transplant Registry shows that a total of 2533 transplants ...were done in India in 2019.
An epidemiological descriptive cross-sectional survey (55 questions) of centers providing HSCT in India was planned to analyze variations in policies and practices regarding HSCT graft manipulation (i.e., plasma reduction, red blood cell RBC depletion and cryopreservation). A total of 63 of 102 centers responded to the survey (response rate, 61.7%), mostly from the northern part of India (27 of 63 42.8%).
The majority of responding centers reported performing >50 HSCTs annually (n = 24 38%), and 92% (58 of 63) performed stem cell collections from a pediatric donor/patient (age <18 years). A total of 56 of 63 responding centers indicated that they did product manipulations involving cryopreservation (n = 45), plasma reduction (n = 42) and RBC depletion (n = 28). Cryopreservation was primarily done by blood centers (27 of 45 60%), with dimethyl sulfoxide (DMSO) being the primary constituent, used most commonly at a concentration of 5-10% (28 of 45 centers). Dump freezing was most commonly used (27 of 45) with a -80°C deep freezer. A 7-aminoactinomycin D based viability assessment was also most commonly used (30 of 45). Thawing of the product was done mainly at the bedside (30 of 45) using a wet-type thawer (36 of 45), and washing of DMSO was done by a few centers (seven of 45). Plasma reduction and RBC depletion were primarily done for ABO incompatibility at blood centers.
This survey demonstrates the lack of standardization and uniformity in the minimal manipulation of hematopoietic stem cell grafts in centers supporting HSCT in India. This work also highlights the need for more studies and country-specific recommendations to establish best practices.
Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. The survival rates in pediatric ALL have improved to 80-90% in high-income countries, where the goal of current ...risk-adapted treatment protocols is to minimize treatment-related mortality. In contrast, cure/survival rates are still lower in low-income countries, due to combined effect of disease-related factors, high incidence of treatment abandonment, higher rates of relapse, & higher treatment-related mortality. The Berlin-Frankfurt-Münster (BFM) protocol versions are commonly used for treatment of pediatric ALL in many centers. There is no published data on treatment outcomes with ALL IC-BFM 2009 protocol in pediatric ALL in India.
Objective: The study aims to evaluate the treatment outcomes in Indian pediatric ALL/LBL patients treated with ALL IC-BFM 2009 protocol under severe resource-limited settings, in terms of morphological complete remission (CR), minimal residual disease (MRD) status, and disease-free survival.
Methods: Our study enrolled 25 newly diagnosed pediatric ALL/LBL patients (age ≤18 years) between February 2018 & June 2019. Induction chemotherapy was initiated as per ALL IC-BFM 2009 protocol after obtaining informed consent. Risk stratification was done as per protocol into standard risk (SR), intermediate risk (IR), and high risk (HR) groups, based on age, baseline leukocyte count, cytogenetics & molecular study findings, day 8 steroid response (peripheral blood absolute blast count), bone marrow MRD by flowcytometry on day 15, and bone marrow morphological response on days 15 & 33 of induction phase. Additional imaging was done to assess response in LBL patients. Central nervous system (CNS)-directed therapy with intrathecal chemotherapy was administered as per protocol. Post-induction therapy consisted of an augmented early intensification phase, risk-adapted consolidation therapy phase, a delayed intensification (reinduction) phase, & maintenance phase. Therapeutic cranial radiation (18 Gy) was administered only to patients with documented CNS leukemia.
Results: Of the total 25 patients, 17 had B-ALL, six had T-ALL & two had T-LBL. Median age of patients was 9 years (2-18 years), with 11 boys & 14 girls. All the patients had BCR-ABL negative disease; three patients had t(12;21)(p13;q22)/ETV6-RUNX1. Seven patients (28%) had hyperleukocytosis (leukocyte count >1,00,000/µL) and two patients had CNS leukemia at presentation. Nine out of the 25 patients (36%) were in high risk group as per criteria. Eight patients (32%) had poor steroid response on day 8 of induction (PB blasts ≥ 1000/µL). Six patients had M3 marrow on day 15 (>25% blasts in marrow). Day 15 bone marrow MRD was <0.1% in 13 patients (52%), >0.1% in 7 patients (28%) and could not be done in 5 patients (including the two T-LBL patients). Twenty-three out of 25 patients (92%) achieved morphological CR (marrow blasts <5%) on day 33. There were two deaths in induction; both patients were not in CR as per day 33 bone marrow morphology criteria. One B-ALL patient in HR group died of early medullary relapse. The remaining 22 patients are in CR & doing well on follow up, and four of them have started maintenance phase therapy. The results are summarized in Table 1.
Conclusion: Our preliminary results with ALL IC-BFM 2009 treatment protocol in Indian pediatric ALL/LBL patients are encouraging, with 92% complete remission rate, 88% disease-free survival and manageable treatment-related toxicity in spite of severe resource constraints. Long-term follow up & enrollment of higher number of patients is planned.
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No relevant conflicts of interest to declare.
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