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.
Small lymphocytic lymphoma (SLL) is a relatively rare B-cell non-Hodgkin lymphoma that is considered to be the tissue equivalent of the much more common entity chronic lymphocytic leukemia (CLL). ...Most patients with SLL present with indolent generalized lymphadenopathy, which has frequently been present for several years. We hereby describe an unusual case of SLL in a patient who presented with a huge swelling at the right shoulder region and a single right enlarged axillary lymph node. The other uncommon findings were the presence of peripheral blood hypereosinophilia and CD5 immunonegativity.
Introduction: Chronic myeloid leukemia (CML) is the commonest adult leukemia in India. Prognostication of newly diagnosed patients of chronic phase CML (CML-CP) is done by calculating pre-treatment ...risk scores as per Sokal and Hasford scoring systems, and patients are categorized into low-, intermediate- & high-risk groups. According to the latest NCCN guidelines, CML-CP patients with intermediate- or high-risk Sokal or Hasford score may preferentially benefit from second generation tyrosine kinase inhibitor (TKI) treatment. The two second generation TKI drugs available in India are dasatinib & nilotinib. Unfortunately, majority of CML-CP patients in India cannot afford upfront second generation TKI therapy, and generic imatinib is the mainstay of treatment even for intermediate-risk & high-risk patients. Achievement of early molecular response (EMR), defined as BCR-ABL1 (international scale, IS) ≤ 10% after 3 months of first-line TKI therapy, has emerged as one of the most important predictors of favourable long-term outcomes in CML-CP. The present study describes the rate of EMR achievement with first-line generic imatinib therapy in Sokal & Hasford intermediate- & high-risk patients.
Objectives: To study the early molecular response rates with generic imatinib therapy at 400 mg/day dose in CML-CP patients with intermediate-risk & high-risk Sokal or Hasford scores.
Methods: Our study enrolled 73 newly diagnosed CML-CP patients with intermediate- or high-risk Sokal/Hasford scores between March 2016 and March 2018. All the patients hailed from poor socio-economic background with severe financial constraint, and none of them had any medical insurance. All the patients were treated with generic imatinib mesylate 400 mg/day which was available free of cost at the hospital. None of the patients could afford dasatinib or nilotinib, despite adequate counseling & information regarding the efficacy of 2nd generation TKIs. Treatment response was monitored and defined as per European LeukemiaNet 2013 recommendations. Hematological response was assessed at 3 months for achievement of complete hematologic response (CHR). Molecular response was assessed at 3 months of first-line treatment by quantitative real-time PCR for BCR-ABL1 (IS). Complete data of 65 patients who were compliant to imatinib treatment for at least 3 months were available for analysis. Eight patients were lost to follow up.
Results: The median age of patients was 35 years (age range 17 - 72 years; 40 male). CHR was achieved in 92% patients (60 out of 65 patients). Early molecular response at 3 months (BCR-ABL1, IS) ≤ 10%) was documented in 68% (44 out of 65) patients. The range of BCR-ABL1 transcript level at 3 months was 0.01% - 10% in patients who achieved EMR. EMR was not achieved in about 60% of Sokal high-risk patients and 30% of Hasford high-risk patients.
Conclusion: The real scenario of CML treatment in developing countries with resource-constrained settings is very much different from that in the developed countries. The response rates to generic Imatinib therapy in Sokal/Hasford intermediate-risk & high-risk CML-CP patients are not impressive. There is scope for significant improvement in treatment response with upfront 2nd generation TKI therapy in intermediate- & high-risk CML-CP patients, if the drugs can be made available at affordable costs in developing countries.
No relevant conflicts of interest to declare.
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.
Display omitted
No relevant conflicts of interest to declare.
Objectives
The study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D
3
supplementation in patients newly diagnosed with chronic-phase ...chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D
3
on complete haematological response (CHR) and its safety.
Design
Double-blind, placebo-controlled, exploratory randomised trial.
Setting
Tertiary care hospital in northern India.
Participants
Treatment-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.
Intervention
Oral vitamin D
3
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 measures
The 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)2D
3
levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Results
At baseline, 14.5% of the patients had normal vitamin D
3
levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D
3
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 D
3
levels from baseline to the end of study was observed. Patients with vitamin D
3
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.
Conclusion
Vitamin D
3
levels were low among patients with CML-CP in this study. Vitamin D
3
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 D
3
supplementation in these patients.
Trial registration number
CTRI/2019/09/021164.
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