Publications by authors named "Hasmukh Jain"

38 Publications

Sequential Treatment of Arsenic Trioxide Followed by All Trans Retinoic Acid with Anthracyclines has Excellent Long-Term Cure in Acute Promyelocytic Leukemia.

Indian J Hematol Blood Transfus 2021 Jan 26;37(1):30-36. Epub 2020 Jun 26.

Department of Medical Oncology, Tata Memorial Center, Lower Parel, Mumbai, India.

Acute promyelocytic leukemia (APL) remains the most curable myeloid leukemia made feasible through effective use of two differentiating agents, all trans retinoic acid (ATRA) and arsenic trioxide (ATO) with or without chemotherapy (CT). However, early morbidity and mortality remains a problem. With the objective of reducing early death a strategy of sequential induction ATO followed by consolidation ATRA in combination with CT was adopted by our group. The long-term outcomes of patient of APL treated on this sequential approach at our center was analyzed. In this retrospective analysis of prospectively maintained database consecutive adult patients with APL irrespective of their Sanz risk group were treated using a protocol of ATO (10 mg IV infusion over 3 h daily for 45 days) in the first phase followed by ATRA (45 mg/m for 60 days) in combination with Daunorubicin (60 mg/m for 3 days × 3 cycles) in second phase. All patients received maintenance ATRA (45 m/m for 15 days every 3 months) for a period of 18 months in phase 3. Patients were monitored for cytogenetic and molecular responses after phase 1 and 2. All patients were followed up for toxicity, event free and overall survival. 131 consecutive patients were treated in this study. At a median follow up of 60 months, 84.81% patients are alive with an overall event free survival (EFS) of 77.82%. Sanz low risk patients fared better (85%) versus intermediate and high-risk patients who had a 76% EFS. Proportion of patients alive at last follow up were 100% in Sanz low risk group and 82% in intermediate and high-risk group. The sequential schedule showed excellent tolerance and toxicity profile when treating newly diagnosed APL. The long-term follow-up data shows comparable if not better survival compared with the published real-world data and this has been consistent across all risk group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12288-020-01311-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900266PMC
January 2021

Outcomes and prognostic factors in adolescents and young adults with ALL treated with a modified BFM-90 protocol.

Blood Adv 2021 Mar;5(5):1178-1193

Adult Hematolymphoid Unit.

The use of pediatrics-inspired protocols in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) results in superior survival compared with the adult protocols. Pediatrics-inspired protocols carry an increased risk of toxicity and treatment-related mortality in low resource settings, which can offset the potential benefits. We studied the outcomes and prognostic factors in the treatment of AYA ALL with a pediatrics-inspired regimen. We retrieved data regarding demographics, investigations, treatment details, and toxicities from the electronic medical records of patients diagnosed with ALL in the 15- to 25-year-old age group who were initiated on a modified Berlin-Frankfurt-Münster 90 (BFM-90) protocol between January 2013 and December 2016 at the Tata Memorial Centre. A total of 349 patients in the 15- to 25-year-old age group were treated with a modified BFM-90 protocol. The use of this pediatrics-inspired protocol resulted in a 3-year event-free survival (EFS) and overall survival (OS) of 59.4% and 61.8%, respectively. Only 15 patients underwent an allogeneic stem cell transplant. Minimal residual disease (MRD) persistence postinduction emerged as the only factor predictive of poor outcomes. A modified BFM-90 protocol is an effective and safe regimen for AYA ALL with an OS and EFS comparable to the published literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948264PMC
March 2021

Robust anti-tumor activity and low cytokine production by novel humanized anti-CD19 CAR-T cells.

Mol Cancer Ther 2021 Feb 25. Epub 2021 Feb 25.

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay

Recent studies have described the remarkable clinical outcome of anti-CD19 chimeric antigen receptor (CAR) T cells in treating B-cell malignancies. However, over 50% of patients develop life-threatening toxicities associated with cytokine release syndrome (CRS) which may limit its utilization in low-resource settings. To mitigate the toxicity, we designed a novel humanized anti-CD19 CAR-T cells by humanizing the framework region of scFv derived from a murine FMC63 mAb and combining it with CD8a transmembrane domain, 4-1BB costimulatory domain and CD3ζ signalling domain (h1CAR19-8BBζ). Docking studies followed by molecular dynamics (MD) simulation revealed that the humanized anti-CD19 scFv (h1CAR19) establishes higher binding affinity and has a flexible molecular structure with CD19 antigen compared to murine scFv (mCAR19). Ex vivo studies with CAR-T cells generated from healthy donors and patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) expressing either h1CAR19 or mCAR19 showed comparable anti-tumor activity and proliferation. More importantly, h1CAR19-8BBζ-T cells produced lower levels of cytokines (IFN-g, TNF-a upon antigen encounter and reduced the induction of IL-6 cytokine from monocytes than mCAR19-8BBζ-T cells. There was a comparable proliferation of h1CAR19-8BBζ-T cells and mCAR19-8BBζ-T cells upon repeated antigen encounter. Finally, h1CAR19-8BBζ-T cells efficiently eliminated NALM6 tumor cells in a preclinical model. In conclusion, the distinct structural modification in CAR design confers the novel humanized anti-CD19 CAR with a favorable balance of efficacy to toxicity providing a rationale to test this construct in a phase I trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0476DOI Listing
February 2021

Evaluation of cytogenetic response in CML patients with variant Philadelphia translocation.

Asia Pac J Clin Oncol 2021 Feb 25. Epub 2021 Feb 25.

Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India.

Background And Aim: Molecular mechanism of translocation and outcome in variant chronic myeloid leukaemia (vCML) has been a topic of debate. While several cytogenetic studies suggest a low response to Imatinib Mesylate, others demonstrate a similar disease course in both classical and vCML. Besides, many studies comprehensively also link tyrosine kinase domain (TKD) mutations with aggressive clinical outcome. Thus, we aim to study the molecular mechanism of translocation, identify the third partner chromosomes and comment on the disease course and clinical outcome.

Method: We cytogenetically characterised 25 vCML cases to determine the third partner chromosome, mechanism of translocation and prognostic outcome. We also compared vCML cases with and without TKD mutation to most appropriately outline the clinical consequence and ascertain the potent cause of unresponsiveness to treatment.

Results: Third partner chromosome in variant translocation was defined by conventional and molecular cytogenetics. Although in our study most cases showed inadequate clinical response attributable to TKD mutation rather than variant translocation, we observed an inferior outcome in cases involving chromosome 5 as the third partner.

Conclusion: Thus, we conclude that characterising and reporting new cases of variant translocations, involving various different chromosomes as third partner (with different breakpoints) by cytogenetics, will lead to a better understanding of the disease. To the best of our knowledge, this kind of delineate study has not been applied to precisely comment on the prospects of cytogenetically characterised vCML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajco.13522DOI Listing
February 2021

Clinical impact of panel-based error-corrected next generation sequencing versus flow cytometry to detect measurable residual disease (MRD) in acute myeloid leukemia (AML).

Leukemia 2021 Feb 8. Epub 2021 Feb 8.

Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India.

We accrued 201 patients of adult AML treated with conventional therapy, in morphological remission, and evaluated MRD using sensitive error-corrected next generation sequencing (NGS-MRD) and multiparameter flow cytometry (FCM-MRD) at the end of induction (PI) and consolidation (PC). Nearly 71% of patients were PI NGS-MRD and 40.9% PC NGS-MRD (median VAF 0.76%). NGS-MRD patients had a significantly higher cumulative incidence of relapse (p = 0.003), inferior overall survival (p = 0.001) and relapse free survival (p < 0.001) as compared to NGS-MRD patients. NGS-MRD was predictive of inferior outcome in intermediate cytogenetic risk and demonstrated potential in favorable cytogenetic risk AML. PI NGS-MRD patients had a significantly improved survival as compared to patients who became NGS-MRD subsequently indicating that kinetics of NGS-MRD clearance was of paramount importance. NGS-MRD identified over 80% of cases identified by flow cytometry at PI time point whereas FCM identified 49.3% identified by NGS. Only a fraction of cases were NGS-MRD but FCM-MRD. NGS-MRD provided additional information of the risk of relapse when compared to FCM-MRD. We demonstrate a widely applicable, scalable NGS-MRD approach that is clinically informative and synergistic to FCM-MRD in AML treated with conventional therapies. Maximum clinical utility may be leveraged by combining FCM and NGS-MRD modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01131-6DOI Listing
February 2021

Expression of CD304/neuropilin-1 in adult b-cell lymphoblastic leukemia/lymphoma and its utility for the measurable residual disease assessment.

Int J Lab Hematol 2021 Jan 12. Epub 2021 Jan 12.

Department of Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, India.

Introduction: Many new markers are being evaluated to increase the sensitivity and applicability of multicolor flow cytometry (MFC)-based measurable residual disease (MRD) monitoring. However, most of the studies are limited to childhood B-cell lymphoblastic leukemia/lymphoma (B-ALL), and reports in adult B-ALL are extremely scarce and limited to small cohorts. We studied the expression of CD304/neuropilin-1 in a large cohort of adult B-ALL patients and evaluated its practical utility in MFC-based MRD analysis.

Methods: CD304 was studied in blasts from adult B-ALL patients and normal precursor B cells (NPBC) from non-B-ALL bone marrow samples using MFC. CD304 expression intensity and pattern were studied with normalized-mean fluorescent intensity (nMFI) and coefficient of variation of immunofluorescence (CVIF), respectively. MFC-based MRD was performed at end of induction (EOI; day-35), end of consolidation (EOC; day 78-80), and subsequent follow-up (SFU) time points.

Results: CD304 was positive in 120/214(56.07%) and was significantly associated with BCR-ABL1 fusion (P = .001). EOI-MRD and EOC-MRD were positive in 129/214(60.3%) and 50/81(61.72%), respectively. CD304 was positive in a significant percentage of EOI (48%, 62/129) and EOC (52%, 26/50) MRD-positive B-ALL samples. Its expression was retained, lost, and gained in 73.7%, 26.3%, and 11.3% of EOI-MRD and 85.7%, 14.3%, and none of EOC-MRD samples, respectively. Low-level MRD (<0.01%) was detectable in 34 of all (EOI + EOC + SFU = 189) MRD-positive samples, and CD304 was found useful in 50% of these samples.

Conclusion: CD304 is commonly expressed in adult B-ALL and clearly distinguish B-ALL blasts from normal precursor B cells. It is a stable MRD marker and distinctly useful in the detection of MFC-based MRD monitoring, especially in high-sensitivity MRD assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijlh.13456DOI Listing
January 2021

Infection Prevalence in Adolescents and Adults With Acute Myeloid Leukemia Treated in an Indian Tertiary Care Center.

JCO Glob Oncol 2020 11;6:1684-1695

Department of Medical Oncology, Tata Memorial Hospital, affiliated to Homi Bhabha National Institute, Mumbai, India.

Purpose: Infections remain a major challenge in the treatment of acute myeloid leukemia (AML). Induction-related mortality reported in the literature is approximately < 5% in clinical trials. However, the real-world scenario is different, especially in developing countries, given the high incidence of multidrug-resistant (MDR) organisms, high incidence of fungal pneumonia at baseline, and significant delay before initiation of chemotherapy. We aimed to look at contemporary infections and infection-related mortality and analyze the patterns of infections.

Materials And Methods: This retrospective study was conducted at a large tertiary care oncology center in India. Patients with newly diagnosed AML who were older than age 15 years, considered fit for intensive therapy, and treated in the general wards of the adult hematolymphoid unit from March 1, 2014, until December 31, 2015, were included.

Results: One hundred twenty-one patients were treated during the study period. The most common presenting complaint was fever (85%). The focus of infection at presentation was found in 63% of patients, with respiratory infection being the most common (47%). MDR organisms were isolated in 55% of patients during induction from various foci. was the most common blood culture isolate (42.9%). Fungal pneumonia was diagnosed in 55% of patients during induction despite antifungal prophylaxis. Treatment-related mortality was 10.7% in all phases, with an induction mortality rate of 7.4%. Complete remission was attained in 69% of patients. Of all patients who received induction chemotherapy, 74% completed all three consolidation cycles. The 121 patients were followed up for a median period of 53 months. Four-year event-free survival was 35.8%, and 4-year overall survival was 41.5%.

Conclusion: Infections and infection-related mortality are major challenges during AML induction. Gram-negative MDR and fungal infections are particularly common in our region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/GO.20.00240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713585PMC
November 2020

COVID-19 in cancer patients on active systemic therapy - Outcomes from LMIC scenario with an emphasis on need for active treatment.

Cancer Med 2020 12 31;9(23):8747-8753. Epub 2020 Oct 31.

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India.

Background: There is limited data on outcomes in cancer patients with coronavirus disease 2019 (COVID-19) from lower middle-income countries (LMICs).

Patients And Methods: This was an observational study, conducted between 12 April and 10 June 2020 at Tata Memorial centre, Mumbai, in cancer patients undergoing systemic therapy with laboratory confirmed COVID-19. The objectives were to evaluate cumulative 30-day all-cause mortality, COVID-19 attributable mortality, factors predicting mortality, and time to viral negativity after initial diagnosis.

Results: Of the 24 660 footfalls and 7043 patients evaluated, 230 patients on active systemic therapy with a median age of 42 (1-75) years were included. COVID-19 infection severity, as per WHO criteria, was mild, moderate, and severe in 195 (85%), 11 (5%), and 24 (11%) patients, respectively. Twenty-three patients (10%) expired during follow-up, with COVID-19 attributable mortality seen in 15 patients (6.5%). There were no mortalities in the pediatric cohort of 31 (14%) patients. Advanced stage cancer being treated with palliative intent vs others [30-day mortality 24%% vs 5%, odds ratio (OR) 5.6, 95% CI 2.28-13.78, P < .001], uncontrolled cancer status vs controlled cancer (30-day mortality37.5%% vs 4%%, OR 14, 95% CI 4.46-44.16, P < .001) and severe COVID-19 vs mild COVID-19 (30-day mortality 71% vs 3%, OR 92.29, 95% CI 26.43-322.21, P < .001) were significantly associated with mortality. The median time to SARS-CoV-2 RT-PCR negativity was 17 days [interquartile range (IQR)17-28) in the cohort.

Conclusions: The mortality rates in cancer patients with COVID-19 who are receiving systemic anti-cancer therapy in LMICSs are marginally higher than that reported in unselected COVID-19 cohorts with prolonged time to viral negativity in a substantial number of patients. The pediatric cancer patients tended to have favorable outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724305PMC
December 2020

Hodgkin Lymphoma in Adolescent and Young Adults: Real-World Data from a Single Tertiary Cancer Center in India.

J Adolesc Young Adult Oncol 2020 Oct 22. Epub 2020 Oct 22.

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.

There is lack of consensus on management of adolescent and young adult (AYA) Hodgkin lymphoma with respect to chemotherapy approach (adult or pediatric). Hence we sought to evaluate the efficacy and safety of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) chemotherapy in AYA Hodgkin lymphoma. It is a retrospective, observational, single-center study. From January 2013 to December 2016, all consecutive patients with AYA (15-25 years, all stages) were analyzed. The primary endpoint of the study was event-free survival (EFS). Secondary endpoints were complete response rates (CR) and overall survival (OS). A total of 220 patients (70% men) with median age 20 years were evaluated. A significant proportion of patients had adverse features such as stage III/IV disease (63%), bulky disease (63%), extranodal involvement (37%), and marrow involvement (22%). After two cycles and end of therapy, 77% patients achieved complete response. Primary progressive disease was seen in 6% patients. With a median follow-up of 2.6 years, 19 (8.6%) patients relapsed, 1 patient developed second malignancy, and 6 patients died. Three-year EFS and OS were 81.3% and 97%, respectively. Bleomycin-induced lung injury was seen in 16% patients. On multivariate analysis stage at presentation, bone marrow involvement, partial response at interim positron emission tomography and International prognosis score (IPS) >3 were predictors of poor EFS. ABVD is an effective and safe regimen in AYA Hodgkin lymphoma. Advanced disease with high IPS (>3) score needs an early escalation approach to escBEACOPP regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jayao.2020.0061DOI Listing
October 2020

Over expression of brain and acute leukemia, cytoplasmic and ETS-related gene is associated with poor outcome in acute myeloid leukemia.

Hematol Oncol 2020 Dec 16;38(5):808-816. Epub 2020 Sep 16.

Department of Medical Oncology, Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, India.

The high expression of brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) has been reported to influence the outcome in acute myeloid leukemia (AML), but due to limited prospective studies, their role as prognostic factors is unclear. At diagnosis, the prognostic value of BAALC and ERG expression with respect to other cytogenetic and molecular markers was analyzed in 149 AML patients. Patients were divided into quartiles which resulted in the formation of four groups (G1-G4) based on expression values of BAALC and ERG and clinical response defined across groups. Groups with similar survival probabilities were merged together and categorized subsequently as high versus low expressers. Patients with high BAALC and ERG expression had significantly lower overall survival (OS; BAALC: p = 0.001 at 5 years 29.4% vs. 69.8%; ERG: p < 0.0001 at 5 years 4% vs. 50.4%) and disease-free survival (BAALC: p = 0.001 at 5 years 19.5% vs. 69.8%; ERG: p < 0.0001 at 5 years 4.2% vs. 47%). Patients were further stratified combining BAALC and ERG expression in an integrative prognostic risk score (IPRS). After a median follow-up of 54 months (95% CI 45-63 months) among survivors, IPRS for high versus low expressers was a significant predictor for OS (BAALC + ERG: 4% vs. 71.6%, p < 0.0001) and DFS (BAALC + ERG: 4.5% vs. 74.1%, p < 0.0001). In a multivariate model, IPRS of BAALC + ERG expression retained prognostic significance for OS (hazard ratio [HR] 2.96, 95%CI 1.91-4.59, p < 0.001) and DFS (HR 3.61, 95%CI 2.26-5.76, p < 0.001).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2800DOI Listing
December 2020

Primary diffuse large B cell lymphoma of Uterine Cervix: Treatment outcomes of a rare entity with literature review.

Cancer Rep (Hoboken) 2020 Oct 6;3(5):e1264. Epub 2020 Aug 6.

Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Homi Bhaba National Institute, Mumbai, India.

Background: Primary lymphomas involving the female genital tract are rare, and those arising from cervix are extremely uncommon. They are often misdiagnosed because of their rarity.

Methods And Cases: The treatment and clinical outcomes of the four cases treated at our institution were compared with the previously published studies. Written informed consent was taken. We highlight four cases of primary diffuse large B-cell lymphoma of cervix treated at our institution with immunochemotherapy and radiotherapy. The mean age was 50 years (range, 39-62 years). Three patients had stage I disease while one had stage II disease. All the patients were in complete remission following treatment with immunochemotherapy and radiation therapy. The average disease free survival was 20 months (range, 8-43 months). None of the patients had any local or systemic relapse.

Conclusion: These cases highlight the physicians to be aware of this entity as their management, natural history and prognosis is completely different from squamous carcinomas of the cervix. Surgery should not be attempted in these patients. Immunochemotherapy and radiotherapy results in favorable clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1264DOI Listing
October 2020

Machine learning derived genomics driven prognostication for acute myeloid leukemia with .

Leuk Lymphoma 2020 12 5;61(13):3154-3160. Epub 2020 Aug 5.

Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India.

Panel based next generation sequencing was performed on a discovery cohort of AML with . Supervised machine learning identified mutation and absence of mutations in and genes as well as a low mutation to be associated with favorable outcome. Based on this data patients were classified into favorable and poor genetic risk classes. Patients classified as poor genetic risk had a significantly lower overall survival (OS) and relapse free survival (RFS). We could validate these findings independently on a validation cohort ( = 61). Patients in the poor genetic risk group were more likely to harbor measurable residual disease. Poor genetic risk emerged as an independent risk factor predictive of inferior outcome. Using an unbiased computational approach based we provide evidence for gene panel-based testing in AML with and a framework for integration of genomic markers toward clinical decision making in this heterogeneous disease entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1798951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116445PMC
December 2020

Investigating the clinical, hematological and cytogenetic profile of endoreduplicated hypodiploids in BCP-ALL.

Blood Cells Mol Dis 2020 11 11;85:102465. Epub 2020 Jul 11.

Department of Medical Oncology, Tata Memorial Hospital (TMH), Parel, Mumbai, India; Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India.

Ploidy, besides known translocations in lymphoblasts, is a strong predictor of prognosis in B- cell progenitor acute lymphoblastic leukemia (BCP-ALL). While hyperdiploidy with >50 chromosomes shows a favourable outcome, hypodiploidy with <45 chromosomes have a dismal clinical outcome. However, there exists a small subset where both the hypodiploid and hyperdiploid clones are apparent either by cytogenetics or flow cytometry and are defined partially masked hypodiploids or mosaics based on the percentage of clonal population. These patients are essentially hypodiploids, and show the hyperdiploid clone as a consequence of endoreduplication of the primary hypodiploid clone- A phenomenon of successive replication of genome without mitosis (cytokinesis) resulting in increased ploidy. In the current study, we present the complete clinical, hematological and cytogenetic profile of 11 such newly diagnosed mosaics or partially masked hypodiploid BCP-ALL cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2020.102465DOI Listing
November 2020

Outcomes of T-lymphoblastic lymphoma treated with pediatric ALL-like protocol.

Indian J Cancer 2020 Jul-Sep;57(3):262-266

Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.

Background: The management of T-lymphoblastic lymphoma (T-LBL) in adults poses uncertainties, including optimal chemotherapy regimen, need for radiotherapy, and the benefit of stem cell transplant. This retrospective case series investigated the efficacy of the pediatric BFM-90 regimen in adult patients and evaluated the role of early response assessment by positron emission tomography with computed tomography (PET-CT) in predicting outcomes.

Methods: Patients aged 15 years or older with T-LBL diagnosed at Tata Memorial Hospital, Mumbai, India were given chemotherapy according to the European BFM-90 protocol (n = 38). The patients were evaluated for early response by interim PET-CT, post-induction and monitored for toxicity and long-term outcomes.

Results: Thirty-eight consecutive patients (median age 23.5 years) were analyzed. After a median follow-up of 33.5 (1-77) months, following induction, 35 out of 38 patients (92.1%) had achieved complete response (CR) on PET-CT. Thirty (78.9%) patients treated according to BFM-90 were alive in first remission. Three-year event-free survival for those with CR on PET-CT was 78%, against no survivors for those who remained PET-positive.

Conclusion: This study demonstrates the feasibility and efficacy of BFM-90 approach in adults with T-LBL. We found an early PET response to be highly predictive of outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijc.IJC_616_18DOI Listing
December 2020

Frontline Therapy of Chronic Lymphocytic Leukemia: Changing Treatment Paradigm.

Curr Hematol Malig Rep 2020 06;15(3):168-176

Adult Hematolymphoid Unit, Tata Memorial Centre, Affiliated to Homi Bhabha National University, E Borges Road, Mumbai, 400 012, Maharashtra, India.

Purpose Of Review: The treatment landscape of treatment-naive chronic lymphocytic leukemia (TN-CLL) is rapidly evolving. As more and more new drugs and combinations are becoming part of therapeutic armamentarium, it becomes highly pertinent to understand the evidence for each of the treatment options to select the right drug for the right patient. We summarize the recent data of the available frontline treatment options.

Recent Findings: The novel agents can overcome adverse biological attributes and provide long-term disease control. MRD may become a reliable surrogate for survival in the evaluation of future therapies. FCR still remains one of the best options in a young fit CLL with mutated IGVH. Long-term follow-up data of ibrutinib confirm its efficacy and safety in both high-risk and elderly TN-CLL patients. A combination of venetoclax with obinutuzumab has provided the hope of fixed-duration therapy and the potential for functional cure in TN-CLL. Several other trials testing the efficacy of other targeted agents and the optimal sequencing approaches are underway. Chemoimmunotherapy holds its ground as an effective treatment in the IGVH-mutated CLL. The targeted agents either singly or in combination have become standard of care in many subsets of TN-CLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11899-020-00580-7DOI Listing
June 2020

Flow cytometric evaluation of CD38 expression levels in the newly diagnosed T-cell acute lymphoblastic leukemia and the effect of chemotherapy on its expression in measurable residual disease, refractory disease and relapsed disease: an implication for anti-CD38 immunotherapy.

J Immunother Cancer 2020 05;8(1)

Hematopathology Laboratory, Tata Memorial Centre, Navi Mumbai, Maharashtra, India.

Background: Recently, anti-CD38 monoclonal antibody (Mab) therapy has become a focus of attention as an additional/alternative option for many hematological neoplasms including T-cell acute lymphoblastic leukemia (T-ALL). It has been shown that antitumor efficacy of anti-CD38-Mab depends on the level of CD38 expression on tumor cells. Reports on CD38 expression in T-ALL are scarce, and data on the effect of cytotoxic chemotherapy on CD38 expression are limited to very few samples. Moreover, it lacks entirely in refractory disease and in adult T-ALL. We report the flow cytometric evaluation of CD38 expression in T-ALL blasts at diagnosis and the effect of cytotoxic chemotherapy on its expression in measurable residual disease (MRD), refractory disease (MRD≥5%), and relapsed disease in a large cohort of T-ALL.

Methods: The study included 347 samples (188 diagnostic, 100 MRD, 24 refractory and 35 relapse samples) from 196 (children: 85; adolescents/adults: 111) patients with T-ALL. CD38-positive blasts percentages (CD38-PBPs) and expression-intensity (mean fluorescent intensity, CD38-MFI) were studied using multicolor flow cytometry (MFC). MFC-based MRD was performed at the end-of-induction (EOI-MRD, day 30-35) and end-of-consolidation (EOC-MRD, day 78-85) subsequent follow-up (SFU-MRD) points.

Results: Patients were classified into early thymic precursor subtype of T-ALL (ETPALL, 54/188, 28.7%), and non-ETPALL (134/188, 71.3%). Of 188, EOI-MRD assessment was available in 152, EOC-MRD was available in 96 and SFU-MRD was available in 14 patients. CD38 was found positive in 97.9% (184/188) of diagnostic, 88.7% (110/124) MRD (including 24-refractory) and 82.9% (29/35) relapsed samples. Median (95% CI) of CD38-PBPs/MFI in diagnostic, MRD, refractory, and relapsed T-ALL samples were, respectively, 85.9% (82.10%-89.91%)/4.2 (3.88-4.47), 74.0% (58.87%-83.88%)/4.6 (3.67-6.81), 79.6% (65.25%-96.11%)/4.6 (3.33-8.47) and 85.2% (74.48%-93.01%)/5.6 (4.14-8.99). No significant difference was noted in CD38 expression between pediatric versus adult and patients with ETPALL versus non-ETPALL. No change was observed in CD38-MFI between diagnostic versus MRD and diagnostic versus relapsed paired samples. However, we noticed a mild drop in the CD38-PBPs in MRD samples compared with the diagnostic samples (p=0.016).

Conclusion: We report an in-depth analysis of CD38 expression in a large cohort of T-ALL at diagnosis, during chemotherapy, and at relapse. Our data demonstrated that CD38 is robustly expressed in T-ALL blasts with a little effect of cytotoxic chemotherapy making it a potentially effective target for antiCD38-Mab therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-000630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247386PMC
May 2020

Symptomatic intracranial Rosai-Dorfman disease in the suprasellar region treated with conformal radiotherapy - A report of two cases and literature review.

Neurol India 2020 Mar-Apr;68(2):489-492

Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India.

Intracranial Rosai-Dorfman Destombes (RDD) disease is a rare entity. Lesions can lead to cranial nerve palsies and visual loss, especially in suprasellar location. Resection is considered to be definitive treatment; however, complete excision is difficult to achieve in view of the close proximity of critical structures. Radiotherapy (RT) is sometimes used for refractory or progressive disease for local tumor control and amelioration of symptoms. We report two patients with suprasellar RDD's with progressive symptoms treated with conformal RT after subtotal excision. These patients were treated with high precision conformal techniques to a dose of 45 Gy with significant and durable improvement in vision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0028-3886.284371DOI Listing
March 2021

The Th9 Axis Reduces the Oxidative Stress and Promotes the Survival of Malignant T Cells in Cutaneous T-Cell Lymphoma Patients.

Mol Cancer Res 2020 04 29;18(4):657-668. Epub 2020 Jan 29.

Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3 T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. IMPLICATIONS: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-19-0894DOI Listing
April 2020

Utility of Immunophenotypic Measurable Residual Disease in Adult Acute Myeloid Leukemia-Real-World Context.

Front Oncol 2019 13;9:450. Epub 2019 Jun 13.

Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Mumbai, India.

One of the mainstays of chemotherapy in acute myeloid leukemia (AML) is induction with a goal to achieve morphological complete remission (CR). However, not all patients by this remission criterion achieve long-term remission and a subset relapse. This relapse is explained by the presence of measurable residual disease (MRD). We accrued 451 consecutive patients of adult AML (from March 2012 to December 2017) after informed consent. All patients received standard chemotherapy. MRD testing was done at post-induction and, if feasible, post-consolidation using 8- and later 10-color FCM. Analysis of MRD was done using a combination of difference from normal and leukemia-associated immunophenotype approaches. Conventional karyotyping and FISH were done as per standard recommendations, and patients were classified into favorable, intermediate, and poor cytogenetic risk groups. The presence of -ITD, , and mutations was detected by a fragment length analysis-based assay. As compared to Western data, our cohort of patients was younger with a median age of 35 years. There were 62 induction deaths in this cohort (13.7%), and 77 patients (17.1%) were not in morphological remission. The median follow-up was 26.0 months. Poor-risk cytogenetics and the presence of -ITD were significantly associated with inferior outcome. The presence of post-induction MRD assessment was significantly associated with adverse outcome with respect to OS ( = 0.01) as well as RFS ( = 0.004). Among established genetic subgroups, detection of MRD in intermediate cytogenetic and mutated groups was also highly predictive of inferior outcome. On multivariate analysis, immunophenotypic MRD at the end of induction and -ITD emerged as independent prognostic factors predictive for outcome. This is the first data from a resource-constrained real-world setting demonstrating the utility of AML MRD as well as long-term outcome of AML. Our data is in agreement with other studies that determination of MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post-remission strategies in AML and should be incorporated into routine treatment algorithms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584962PMC
June 2019

Ibrutinib Regimens in Older Patients with Untreated CLL.

N Engl J Med 2019 04;380(17):1679

Tata Memorial Centre, Mumbai, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc1901284DOI Listing
April 2019

A phase III randomized controlled trial of radiation dose optimization in non-Hodgkin lymphoma-diffuse large B-cell lymphoma (DOBL study): Study protocol and design.

Cancer Rep (Hoboken) 2019 04 14;2(2):e1161. Epub 2019 Feb 14.

Department of Hemato Oncology, Tata Memorial Hospital, Homi Bhaba National Institute, Mumbai, India.

Background: Radiation therapy for diffuse large B-cell lymphoma (DLBCL) has shown improvement in progression free survival. There is uncertainty about the optimal radiation dose, with heterogeneous doses being used, ranging from 30 to 55 Gy. This trial tests the efficacy of using reduced radiation dose in DLBCL without compromising on long-term outcomes.

Aims: The primary aim is to assess the noninferiority, as assessed by 2-year event free survival (EFS), of a dose de-escalated dose (36 Gy) for DLBCL as compared with a standard dose (45 Gy).

Methods: The Dose Optimization in B cell Lymphomas (DOBL) study is a randomized phase-III noninferiority trial in a uniform cohort of DLBCL patients receiving immunochemotherapy (R-CHOP). Patients with stages I to IV of DLBCL eligible for radiotherapy (RT) after completion of at least four cycles of R-CHOP will be included in the study. Patients will be randomized to standard RT dose of 45 Gy in 25 fractions or reduced dose of 36 Gy in 20 fractions using involved site radiotherapy (ISRT) technique. It is a noninferiority design using a 7% noninferiority margin with a hazard ratio of 1.3, α of 0.05, and β of 0.80. A total of 760 patients will be accrued. Two-year EFS is the primary outcome measure that will be studied. The experimental arm will be stopped and switched over to control arm if on interim analysis, 25% events occur in the experimental arm.

Discussion: The study is designed to test the noninferiority of radiation dose de-escalation in a uniform cohort of patients diagnosed with DLBCL and treated with R-CHOP regimen in the post-positron emission tomography (PET) era. The trial is rigorously designed and is straightforward to implement. It is statistically powered to answer if reducing the radiation doses does not compromise the clinical outcome in the given patient cohort. This trial will effectively set the standards in radiotherapy doses for DLBCL in the contemporary era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1161DOI Listing
April 2019

Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in mutated acute myeloid leukemia.

Oncotarget 2018 Nov 27;9(93):36613-36624. Epub 2018 Nov 27.

Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India.

Detection of measurable residual disease (MRD) by mutation specific techniques has prognostic relevance in mutated AML ( AML). However, the clinical utility of next generation sequencing (NGS) to detect MRD in AML remains unproven. We analysed the clinical significance of monitoring MRD using ultradeep NGS (NGS-MRD) and flow cytometry (FCM-MRD) in 137 samples obtained from 83 patients of AML at the end of induction (PI) and consolidation (PC). We could monitor 12 different types of mutations at a sensitivity of 0.001% using NGS-MRD. We demonstrated a significant correlation between NGS-MRD and real time quantitative PCR (RQ-PCR). Based upon a one log reduction between PI and PC time points we could classify patients as NGS-MRD positive (<1log reduction) or negative (>1log reduction). NGS-MRD, FCM-MRD as well as mutations were predictive of inferior overall survival (OS) and relapse free survival (RFS). On a multivariate analysis NGS-MRD emerged as an independent, most important prognostic factor predictive of inferior OS (hazard ratio, 3.64; 95% confidence interval [CI] 1.58 to 8.37) and RFS (hazard ratio, 4.8; 95% CI:2.24 to 10.28). We establish that DNA based NGS MRD is a highly useful test for prediction of relapse and survival in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290958PMC
November 2018

A rare case of hepatosplenic γδ T-cell lymphoma expressing CD19 with ring chromosome 7 and trisomy 8.

Cancer Genet 2018 12 19;228-229:17-20. Epub 2018 Jul 19.

Hematopathology Department, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Sector-22, Kharghar, CCE building, Navi Mumbai 410210, India.

Hepatosplenic T-cell lymphoma (HSTL) is a rare subtype of peripheral T-cell lymphoma predominantly seen in young males. This disease presents with isolated hepatosplenomegaly and thrombocytopenia with sinusoidal infiltration of liver and sinusal infiltration of spleen. Immunophenotype shows positivity for CD3, CD7, TCRγδ or TCRαβ, CD38 and double negative for CD4, CD8, TdT, CD5, and CD56. Isochromosome 7q with or without trisomy 8 is seen in HSTL. Recently, ring chromosome 7 has also been identified as a new abnormality. We describe the clinical, immunophenotypic and cytogenetic analysis in a 24-year-old woman. We present an unusual case of TCRγδ positive T-cell lymphoma with aberrant expression of CD19, which is a B-cell lymphoid marker, with amplification of 7q region and subsequent formation of ring chromosome 7 and trisomy 8. This is the second case of HSTL, positive for CD19 and first case presenting with ring chromosome 7 and trisomy 8 in a CD19 positive HSTL which is a rare finding in T-cell lymphoma and needs to be explored further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2018.06.003DOI Listing
December 2018

mutation in hairy cell leukemia: A single-center experience.

Indian J Pathol Microbiol 2018 Oct-Dec;61(4):532-536

Molecular Division, Tata Memorial Centre, Hematopathology Laboratory, Mumbai, Maharashtra, India.

Background: BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes.

Aims: To determine the prevalence of BRAFV600E in HCL from our center and derive clinicopathological correlation, if any.

Materials And Methods: A 9-year retrospective analysis of 46 consecutive cases of HCL diagnosed on morphology and immunophenotyping was done. Stained smears were used as samples for amplification refractory mutation system polymerase-chain reaction using fluorescent primers for mutation detection.

Results: BRAFV600E mutation was detected in 41/46 patients (89.1%) while absent in control samples of chronic lymphocytic leukemia. Cases mimicking HCL-variant clinically or immunophenotypically too showed the presence of this mutation. HCL with mutated BRAF presented at a younger age. No statistical difference in blood counts, tumor load, and immunophenotype patterns existed among BRAF mutated and unmutated group. Nine patients (45%) with mutated BRAF had residual disease following treatment with cladribine.

Conclusion: BRAFV600E mutation analysis has a definitive role in the diagnosis of HCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/IJPM.IJPM_484_16DOI Listing
February 2019

Long term clinical outcomes of adult hematolymphoid malignancies treated at Tata Memorial Hospital: An institutional audit.

Indian J Cancer 2018 Jan-Mar;55(1):9-15

Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India.

Introduction: There is paucity of data from India about the outcomes of patients with various hematological malignancies. Since its formation in 2009, the adult hematolymphoid disease management group of the Tata Memorial Centre is dedicated to the treatment of hematological malignancies alone. In this report, we present the outcomes of patients treated at our centre over a 5 year period for various haematological malignancies in both transplant and non-transplant setting.

Methods: This is a retrospective analysis of all patients registered in adult hematolymphoid disease management group between 1st January 2010 to 31st December 2014. Patients not treated at our centre were excluded from survival analysis. The cut off date for survival analysis was 31st January 2016.

Results: Overall, 1869, 3633 and 544 patients with acute leukemias, various lymphomas and myeloma respectively were registered at our centre from 1st January 2010 to 31st December 2014. Of these, 1178 (63%), 3091 (85%) and 454 (83%) respectively received treatment at our centre. The cumulative probability of 5 year overall survival for patients with acute leukemias, Hodgkin's lymphoma, non-Hodgkin lymphoma and myeloma treated at our centre is 40%, 85%, 78% and 40% respectively. Four hundred and fifteen stem cell transplants were done between 14th November 2007 to 31st December 2014 with 46% being allogeneic and 54% being autologous. The 5 year overall survival of patients with allogenic and autologous transplant was 52% and 63% respectively.

Conclusions: This is the largest single centre data on outcomes of various haematological malignancies from India. This real world data identifies areas which need further attention to improve outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijc.IJC_656_17DOI Listing
November 2018

Molecular Heterogeneity in Acute Promyelocytic Leukemia - a Single Center Experience from India.

Mediterr J Hematol Infect Dis 2018 1;10(1):e2018002. Epub 2018 Jan 1.

Hematopathology laboratory, Department of Pathology, Tata Memorial Centre, Mumbai.

Atypical breakpoints and variant APL cases involving alternative chromosomal aberrations are seen in a small subset of acute promyelocytic leukemia (APL) patients. Over seven different partner genes for RARA have been described. Although rare, these variants prove to be a diagnostic challenge and require a combination of advanced cytogenetic and molecular techniques for accurate characterization. Heterogeneity occurs not only at the molecular level but also at clinico-pathological level influencing treatment response and outcome. In this case series, we describe the molecular heterogeneity of APL with a focus on seven variant APL cases from a single tertiary cancer center in India over a period of two and a half years. We discuss five cases with fusion and two novel variants, including a Bcr3 variant involving fusion of exon4 and exon3 with an additional 40 nucleotides originating from intron2, another involving exon 6 of and exon 3 of with addition of 126 nucleotides, which mapped to the central portion of intron 2. To the best of our knowledge, this is the first case series of this kind from India.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4084/MJHID.2018.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760075PMC
January 2018