Autologous Stem Cell Transplantation in Adult Hodgkin Lymphoma at a Tertiary Care Center in India: Analysis of Outcomes and Prognostic Factors.

High-dose chemotherapy and autologous stem cell transplant (ASCT) is the standard of care treatment in relapsed/refractory Hodgkin lymphoma (rrHL). Published long-term follow-up data concerning this modality from the Indian subcontinent is lacking. In this retrospective study, the data on adults (> 16 years) with biopsy-confirmed rrHL who were autografted from 1 January 2000 to 31 December 2021 at our transplant unit were analyzed. Progression-free survival (PFS) was defined as time from transplant to disease progression or death due to any cause. Overall survival (OS) was determined from date of transplant to date of death due to any cause. Overall, 134 patients with Hodgkin lymphoma underwent ASCT. At a median follow-up of 38.2 (range, 0.1-240) months, 5 years PFS was 45.3% (95% CI 35.4-54.4). The probability of OS at 5 years was 60.5% (95% CI 49.6-69.6). Eleven (8.2%) patients suffered transplant-related mortality by 100 days. Post-transplant persistent disease, pre-transplant serum hypoalbuminemia (< 3.5 g/dl) and chemo-resistance (< PR after last salvage regimen) of tumour at transplant were independent prognostic factors associated with worse PFS in multivariable analysis. Likewise, age ≥ 30 years, ECOG performance status ≥ 1 and residual disease after transplantation correlated with inferior OS. Long-term outcomes of rrHL patients undergoing ASCT in India match those from the developed world in the era of peripheral blood stem cell transplantation. Pre-transplant performance status, chemo-sensitivity of disease, serum albumin and post-transplant remission status determined survival in our cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01690-x.

Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic.

Introduction: Breast cancer is the most common cancer among Indian females. There is limited data on germline profiling of breast cancer patients from India. Objective: The objective of the current study was to analyse the frequency and spectrum of germline variant profiles and clinicopathological characteristics of breast cancer patients referred to our Familial Cancer Clinic (FCC). Materials and methods: It is a single-centre audit of patients with a confirmed diagnosis of breast carcinoma referred to our FCC from January 2017 to 2020. All patients underwent pretest counselling. Genetic testing was done by multigene panel testing by next-generation sequencing along with reflex multiplication ligation-dependent probe amplification for BRCA1 and 2. The variants were classified based on American College of Medical Genetics guidelines. Demographic and clinicopathological details were extracted from the case record files. Results: One hundred and fifty-five patients were referred to the FCC and underwent pretest counselling. A total of 99 (63.9%) patients underwent genetic testing. Among them, 62 patients (62/99 = 62.6%) had a germline variant. A pathogenic/likely pathogenic (P/LP) germline variant was identified in 41 (41.4%) of the patients who underwent testing. Additional variants of unknown significance (VUS) were identified in seven patients who also carried a P/LP variant. VUS alone was detected in 21 patients (21/99 = 21.2%). Among the P/LP pathogenic variants (PV), BRCA 1 PV were seen in 27 patients (65.8%), BRCA 2 variants in 7 patients (17.1%), ATM variants in 3 patients (7.3%) and RAD51, TP53, CHEK2 and HMMR in 1 patient each. Variants were significantly more common in patients with a family history (FH) of malignancy than those without FH (58.5% versus 29.5%; p = 0.013). Age and triple-negative histology were not found to be significantly associated with the occurrence of P/LP PVs. Conclusion: We report a 41% P/LP variant rate in our selected cohort of breast cancer patients, with variants in BRCA constituting 83% and non-BRCA gene variants constituting 17%.

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Dexamethasone-free antiemetic strategy for highly emetogenic chemotherapy: safety and efficacy-pilot study.

OBJECTIVES: Dexamethasone sparing strategies have shown success. The feasibility of a dexamethasone-free antiemetic strategy remains undetermined. A prospective, single-arm, pilot study was planned to determine the efficacy of an olanzapine-based, dexamethasone-free, three-drug antiemetic regimen. METHODS: Chemotherapy naïve, adult patients (≥18 years) who received ondansetron, aprepitant and olanzapine during the first cycle of highly emetogenic chemotherapy were enrolled. The primary endpoint was the rate of complete response (CR: no vomiting and no use of rescue medications) during the overall period (0-120 hours). RESULTS: Out of the total of 101 patients enrolled, most were women (82%) and received anthracycline cyclophosphamide (73%) combination therapy. The rate of CR for the overall period was 65% (95% CI 55.2% to 74.5%). The rate of CR for the acute and delayed period was 79% (95% CI 70% to 86.7%) and 76% (95% CI 66.7% to 84.1%). The rate of nausea control rates for the acute, delayed and overall periods were 34%, 29% and 24%, respectively. The grade I, II and III sedation rates over the 5 days were 8%, 5% and 1%, respectively. CONCLUSIONS: The dexamethasone-free antiemetic strategy showed modest efficacy with low incidence of clinically significant somnolence. There is a need to prospectively investigate the role of dexamethasone in the era of newer potent antiemetics in a randomised fashion. TRIAL REGISTRATION NUMBER: CTRI/2021/07/034813.

Therapeutic potential of [177Lu]Lu-DOTAGA-FAPi dimers in metastatic breast cancer patients with limited treatment options: efficacy and safety assessment.

PURPOSE: The upregulation of fibroblast activation protein (FAP) expression has been observed in various cancers, including metastatic breast carcinoma, prompting research into small molecule inhibitors for both diagnostic and therapeutic purposes. While the diagnostic value of PET/CT imaging using 68 Ga- or 18F-labelled FAPi-monomers in breast cancer diagnosis is well-established, there is a significant need for therapeutic analogs. This retrospective study aimed to assess the safety and effectiveness of [177Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage breast cancer who had previously undergone [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans to confirm the expression of FAP. MATERIALS AND METHODS: Between November 2020 and March 2023, a compassionate treatment approach was utilized to administer [177Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy to heavily pretreated patients with advanced breast cancer. Nineteen patients (18 females, 1 male) with metastatic breast cancer participated in the study, with an average age of 44.6 ± 10.7 years. The therapy was administered at intervals of 8 to 12 weeks, and the median follow-up duration was 14 months. The primary objective of the study was to assess molecular response using [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans, with response evaluation based on the PERCIST criteria. Secondary endpoints included overall survival (OS), progression-free survival (PFS), clinical response assessment, and safety evaluation using CTCAE v5.0 guidelines. RESULTS: A total of 65 cycles were administered, with a mean cumulative activity of 19 ± 5.7 GBq (510 ± 154 mCi) ranging from 11 to 33.3 GBq (300 to 900 mCi) of [177Lu]Lu-DOTAGA.FAPi dimer. The number of cycles ranged from 2 to 6, with a median of 3 cycles. The treatment protocol consisted of different numbers of cycles administered to the patients: specifically, two cycles were given to five patients, three cycles to nine patients, four cycles to one patient, and six cycles to four patients. Most patients had invasive/infiltrative ductal carcinoma (94.7%), while a small percentage had invasive lobular carcinoma (5.3%). All patients had bone metastases, and five of them also had liver involvement, while seven had brain metastases. Response assessment using [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans showed that 25% of the 16 patients evaluated had partial remission, while 37.5% exhibited disease progression. According to the VAS response criteria, 26.3% achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. The clinical disease control rate was promising, with 95% of patients achieving disease control. The clinical objective response rate was 84%. The median follow-up period was 14 months. At the time of analysis, the median overall survival was 12 months, and the median progression-free survival was 8.5 months. Notably, no severe hematological, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study. CONCLUSION: The findings suggest that [177Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [177Lu]Lu-DOTAGA.FAPi dimer treatment demonstrated promising efficacy in patients with advanced breast cancer, as indicated by high disease control rates, favorable response outcomes, and acceptable safety profile. Further research and longer follow-up are warranted to assess long-term outcomes and validate these findings.

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY.

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

Whole exome sequencing identifies novel variants of PIK3CA and validation of hotspot mutation by droplet digital PCR in breast cancer among Indian population.

BACKGROUND: Breast cancer (BC) is the most common malignancy with very high incidence and relatively high mortality in women. The PIK3CA gene plays a pivotal role in the pathogenicity of breast cancer. Despite this, the mutational status of all exons except exons 9 and 20 still remains unknown. METHODS: This study uses the whole exome sequencing (WES) based approach to identify somatic PIK3CA mutations in Indian BC cohorts. The resultant hotspot mutations were validated by droplet digital PCR (ddPCR). Further, molecular dynamics (MD) simulation was applied to elucidate the conformational and functional effects of hotspot position on PIK3CA protein. RESULTS: In our cohort, PIK3CA showed a 44.4% somatic mutation rate and was among the top mutated genes. The mutations of PIK3CA were confined in Exons 5, 9, 11, 18, and 20, whereas the maximum number of mutations lies within exons 9 and 20. A total of 9 variants were found in our study, of which 2 were novel mutations observed on exons 9 (p.H554L) and 11 (p.S629P). However, H1047R was the hotspot mutation at exon 20 (20%). In tumor tissues, there was a considerable difference between copy number of wild-type and H1047R mutant was detected by ddPCR. Significant structural and conformational changes were observed during MD simulation, induced due to point mutation at H1047R/L position. CONCLUSIONS: The current study provides a comprehensive view of novel as well as reported single nucleotide variants (SNVs) in PIK3CA gene associated with Indian breast cancer cases. The mutation status of H1047R/L could serve as a prognostic value in terms of selecting targeted therapy in BC.

Bilateral Breast Cancer: Clinical Profile and Management.

There is paucity of literature regarding the demography, histopathology, management, and outcomes of bilateral breast cancer (BBC). We present our experience of treating 127 BBC with multimodality management. An audit of prospectively maintained computerized breast cancer database of the department of surgical oncology at a tertiary care center was performed. Demography, clinical profile, molecular sub-types, treatment patterns, and outcomes were analyzed. A total 127 patients presented with BBC between 1992 and 2019. Ninety-four had metachronous (MBBC) and 33 had synchronous breast cancer (SBBC). Most contralateral breast cancer (CBC) patients had early-stage breast cancer in comparison to the index side cancer (37% vs 32%). Ninety-four patients underwent bilateral mastectomy and only 18 patients underwent bilateral breast conservation. Seventy-one patients undergoing BCS and surgery for LABC were given postoperative radiotherapy. All patients received adjuvant chemo- and/or hormonal therapy both for index and CBC based on the stage and hormone receptor status. Thirty-three percent of patients had either locoregional or distant relapse. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) of the entire cohort were 86.6% and 68.4% respectively. There was no difference in the OS and DFS between SBBC and MBBC. The incidence of BBC is expected to increase with effective diagnostic and therapeutic interventions and improving survival. Patients require individualized treatment planning in a multidisciplinary treatment setting.

Posttransplant lymphoproliferative disorder in a heart transplant recipient: a case report.

Malignancy in heart transplant recipients is a grave complication. Post-transplant lymphoproliferative disorder (PTLD) is the second most common tumour in adults and commonest in children. The incidence varies with the transplanted organ from 1 to 2% following kidney transplantation to as high as 10% following thoracic organ transplantation due to different immunosuppression intensity. PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissue to frank malignancy with aggressive behaviour (lymphoma). Epstein-Barr virus (EBV) infection and prolonged immunosuppressant therapy are implicated in the pathogenesis of PTLD. The incidence of PTLD varies from 2.6% at 1 year to 28% at 10 years post-transplant. Seronegativity for EBV in recipients with seropositive donors increases the risk of PTLD in recipients. The majority of early-onset PTLDs (85%) are of B-cell origin and associated with EBV. Timely and accurate diagnosis with histological examination of lymphoid tissue is essential for early intervention. Reduction of immunosuppressive therapy (IST) and rituximab usually are effective in remission of PTLD. In resistant cases, chemotherapy is given with or without rituximab. Adoptive T-cell transfer represents a promising therapeutic approach. Early PTLD respond well to lowering immunosuppression and has a favourable prognosis compared to late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse. One out of 40 heart transplant recipients followed up in our centre developed PTLD. He was treated to remission and we describe this case here.

Neoadjuvant chemotherapy with or without anthracyclines in combination with single HER2-targeted therapy in HER2-positive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with human epidermal growth factor receptor 2 (HER2) blockade is the preferred approach for treating early and locally advanced HER2-positive breast cancer. There is a lack of robust data comparing pathological complete response (pCR) and survival outcomes in anthracycline-free and anthracycline-containing regimens with single HER2-targeted therapy. OBJECTIVES: The present study retrospectively evaluated pCR between two groups: Single HER2-targeted therapy with and without anthracycline. METHODS: A total of 215 HER2-positive female breast cancer patients were analyzed who received eitheranthracycline-containing EC-TH (epirubicin and cyclophosphamide, followed by docetaxel and trastuzumab)oranthracycline-free TCH [docetaxel, carboplatin and trastuzumab]. Univariate and multivariate analyses identified prognostic factors for survival and pCR.Kaplan Meier survival curvesdetermined disease-free survival(DFS) and overall survival (OS). RESULTS: Baseline characteristics were comparable in both treatment groups. The pCR rate was 30.8% in the anthracycline-containing EC-TH group and 40.9% in the anthracycline-free TCH group; p = 0.140. Disease-free survival at 3 years (65.8% vs. 58.4%) and 5 years (49.2% vs. 55.2%) was similar between EC-TH and TCH groups, respectively (log-rank p = 0.550). Three-year (95.5% vs. 92.5%) and five-year (84.4% vs. 80.8%) OSwere also comparable between both groups (log-rank p = 0.485). The anthracycline-containing EC-TH group had a higher incidence of febrile neutropenia (6.4%. vs. 3.6%) and cardiac adverse events (7.7% vs. 4.4%) than the anthracycline-free TCH group. CONCLUSION: Neoadjuvant anthracycline-free chemotherapy has similar pCR and survival outcomeswith favourable cardiac and non-cardiac adverse effect profiles compared with anthracycline-containing chemotherapy.

Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis.

Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.

Splenic Lymphomas: A Tertiary Care Center Experience and Review of Literature.

Primary splenic lymphomas are rare with the majority of lymphomas in spleen being secondary to an extra-splenic lymphoma. We aimed to analyze the epidemiological profile of the splenic lymphoma and review the literature. This was a retrospective study including all splenectomies and splenic biopsies from 2015 to September 2021. All the cases were retrieved from Department of Pathology. Detailed histopathological, clinical and demographic evaluation was done. All the lymphomas were classified according to WHO 2016 classification. A total of 714 splenectomies were performed for a variety of benign causes, as part of tumor resections and for the diagnosis of lymphoma. Few core biopsies were also included. A total of 33 lymphomas diagnosed in the spleen, primary splenic lymphomas constituted 84.84% (n = 28) of the cohort with 5 (15.15%) having the primary site elsewhere. The primary splenic lymphomas constituted 0.28% of all the lymphomas arising at various sites. Adult population (19-65 years) formed the bulk (78.78%) with a slight male preponderance. Splenic marginal zone lymphomas (n = 15, 45.45%) comprised of major proportion of cases followed by primary splenic diffuse large B-cell lymphoma (n = 4, 12.12%). Splenectomy was the main course of treatment for SMZL with a good overall outcome, with chemotherapy ± radiotherapy forming the mainstay in other lymphomas. Lymphomas in spleen can be infiltrative or a primary, hence proper clinic-radiological and pathological evaluation is required. Appropriate management is guided by the precise and detailed evaluation by the pathologist, requiring understanding of the same.

Bone health in breast cancer.

Early breast cancer is among the most common cancers worldwide. Recent advances continue to improve outcomes and increase long-term survivorship. However, therapeutic modalities are deleterious for patients' bone health. While antiresorptive therapy may partially negate this, consequent reduction in rates of fragility fractures remains unproven. Selective prescription of bisphosphonates or denosumab may be an amicable middle ground. Recent evidence also suggests a possible role of osteoclast inhibitors as adjuvant therapy, but the evidence is modest at best. In this narrative clinical review, we explore the impact of various adjuvant modalities on bone mineral density and fragility fracture rates of early breast cancer survivors. We also review optimal patient selection for antiresorptive agents, their impact on rates of fragility fractures, and the possible role of these agents as adjuvant therapy.

Follicular Helper T-Cell-derived Nodal Lymphomas: Study of Histomorphologic, Immunophenotypic, Clinical, and RHOA G17V Mutational Profile.

The study was designed to review the demographic, clinical, and pathologic characteristics of follicular helper T cells (TFH)-derived nodal PTCL in India including angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma (PTCL) with follicular helper T cell phenotype (P-TFH), and follicular T-cell lymphoma with additional immunohistochemistry (IHC) and RHOAG17V mutational analysis, as well as their impact on survival. This retrospective study included 88 cases of PTCL that were reclassified using IHC for TFH markers (PD1, ICOS, BCL6, and CD10) and dendritic-meshwork markers (CD21, CD23). Cases of TFH cell origin were evaluated for RHOAG17V mutation using Sanger sequencing and amplification-refractory mutation system-polymerase chain reaction (PCR) (validated using cloning and quantitative PCR) with detailed clinicopathologic correlation. Extensive re-evaluation with added IHC panel resulted in a total of 19 cases being reclassified, and the final subtypes were AITL (37 cases, 42%), PTCL-not otherwise specified (44, 50%), P-TFH (6, 7%), and follicular T-cell lymphoma (1, 1%). The presence of at least 2 TFH markers (>20% immunopositivity) determined the TFH origin. AITL patients tended to be male and showed increased presence of B-symptoms and hepatosplenomegaly. Histomorphology revealed that 92% of AITL cases had pattern 3 involvement. Sanger sequencing with conventional PCR did not yield any mutation, while RHOAG17V was detected by amplification-refractory mutation system-PCR in AITL (51%, P =0.027) and P-TFH (17%), which was validated with cloning followed by sequencing. Cases of RHOAG17V-mutant AITL had a worse Eastern Cooperative Oncology Group performance status initially but fared better in terms of overall outcome ( P =0.029). Although not specific for AITL, RHOAG17V mutation shows an association with diagnosis and requires sensitive methods for detection due to low-tumor burden. The mutant status of AITL could have prognostic implications and translational relevance.

Randomized double-blind, placebo-controlled study of oral gabapentin for prevention of neuropathy in patients receiving paclitaxel.

BACKGROUND: Peripheral neuropathy is a common dose-limiting side effect of paclitaxel. To date, there is no effective strategy to prevent paclitaxel-induced peripheral neuropathy. A recent small phase II study demonstrated the potential role of oral gabapentin in this setting. This phase III study is aimed to assess the efficacy of oral gabapentin in preventing paclitaxel-induced neuropathy. OBJECTIVE: To compare the efficacy of oral gabapentin with placebo in preventing clinically significant peripheral neuropathy (NCI CTCAEv5.0 grade 2 or higher) in patients receiving paclitaxel. METHODS: This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial. The primary outcome is the development of grade 2 or higher chemotherapy-induced peripheral neuropathy. Secondary outcomes include any grade neuropathy, the percentage change in sensory nerve conduction velocities in peripheral nerves, time to development of any grade neuropathy, paclitaxel dose reductions and delays due to peripheral neuropathy, patient-reported outcomes, adverse events, and adherence to oral therapy. A total of 136 patients receiving paclitaxel will be randomly allocated (stratified by weekly vs. non-weekly administration) to receive either oral gabapentin or placebo till three weeks after the last dose of chemotherapy or occurrence of the primary outcome. CONCLUSION: This study aims to find if oral gabapentin reduces the incidence of grade 2 or higher chemotherapy-induced peripheral neuropathy in patients receiving paclitaxel. TRIAL REGISTRATION: The trial is registered prospectively with the Clinical Trials Registry of India (CTRI/2022/02/040030) on April 4, 2022.

Safety and Efficacy of Bendamustine and Rituximab (BR) Regimen in Indian Chronic Lymphocytic Leukaemia Patients.

We investigated the safety and efficacy of bendamustine-rituximab (BR) in previously untreated symptomatic and advanced CLL patients, as there is no data available on BR from the Indian subcontinent.This retrospective study included 120 consecutive treatment naïve patients with CLL without del (17p), who were registered at the Department of Medical Oncology, AIIMS between January 2010 and July 2018. Bendamustine was given at a dose of 90 mg/m2 on days 1 and 2, combined with rituximab 375 mg/m2 rituximab on day 1, every 28 days for up to 6 courses. Event-free survival (EFS) was defined as the date of treatment to date of relapse, disease progression, or death due to any cause.The median age was 57 years (range: 30-75 years). As per the clinical Rai stage, 30 (25%) patients were in stage II, 42 (35%) were in stage III and 48 (40%) were in stage IV. ZAP70 was positive (> 20%) in 50%, CD 38 was positive (> 30%) in 33%, and CD49d was positive (> 30%) in 49% of cases. Beta-2 microglobulin (B2M) was elevated (≥ 3.5 mg/L) in 80% of cases. Fifty-five cases (50%, n = 110) were IGHV mutated. The mean number of cycles was 5 (1-6). The overall response rate (ORR) seen with BR was 90% and complete response was 45%. Median progression-free survival was 24 months with a median follow-up period of 29 months. Haemoglobin (< 10 g/dL), elevated B2 M, unmutated IGHV had a statistically significant adverse impact on EFS on univariate analysis but on multivariate analysis, only IGHV mutation status was found to had significance on EFS. The median EFS was 27 months in IGHV mutated versus 18 months in IGHV unmutated-CLL patients (p = 0.001). Grade 3/4 neutropenia, thrombocytopenia, anemia, and infections were observed in 30.6%, 8%, and 12% respectively. The most common non-hematological toxicity was skin rash which was grade 1/2 in 24 (20%) cases and grade 3/4 in 12 (10%) cases. This is the largest study from India to demonstrate the safety and efficacy of BR in symptomatic CLL patients. BR is an effective and safe regimen in the first-line treatment of CLL. Unmutated-CLL patients have inferior EFS than mutated-CLL patients. Skin toxicity was the most common adverse effect seen in our population which was observed in around one-third of cases.

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.