16 results on '"Ghosh, Nilanjan"'
Search Results
2. Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.
- Author
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Dickinson M, Briones J, Herrera AF, González-Barca E, Ghosh N, Cordoba R, Rutherford SC, Bournazou E, Labriola-Tompkins E, Franjkovic I, Chesne E, Brouwer-Visser J, Lechner K, Brennan B, Nüesch E, DeMario M, Rüttinger D, Kornacker M, and Hutchings M
- Subjects
- Bridged Bicyclo Compounds, Heterocyclic, Humans, Neoplasm Recurrence, Local drug therapy, Rituximab therapeutic use, Sulfonamides, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2021
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3. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia.
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Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, and Karp JE
- Subjects
- Adult, Aged, Benzamides administration & dosage, Clofarabine administration & dosage, Female, Follow-Up Studies, Histone Deacetylase Inhibitors therapeutic use, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Pyridines administration & dosage, Salvage Therapy, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Lineage, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local drug therapy, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL., Experimental Design: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m
2 /day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy., Results: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined., Conclusion: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted., (Copyright © 2021. Published by Elsevier Ltd.)- Published
- 2021
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4. Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival.
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Shanmugasundaram K, Goyal S, Switchenko J, Calzada O, Churnetski MC, Kolla B, Bachanova V, Gerson JN, Barta SK, Gordon MJ, Danilov AV, Grover NS, Mathews S, Burkart M, Karmali R, Sawalha Y, Hill BT, Ghosh N, Park SI, Epperla N, Bond DA, Badar T, Blum KA, Hamadani M, Fenske TS, Malecek M, Kahl BS, Martin P, Guo J, Flowers CR, and Cohen JB
- Subjects
- Aged, Cyclophosphamide therapeutic use, Dexamethasone therapeutic use, Disease-Free Survival, Doxorubicin therapeutic use, Female, Humans, Lymphoma, Mantle-Cell mortality, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Proportional Hazards Models, Remission Induction methods, Retrospective Studies, Time-to-Treatment, Transplantation, Autologous, Vincristine therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine therapeutic use, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Mantle-Cell therapy
- Abstract
Introduction: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy., Methods: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131)., Results: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model., Conclusions: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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5. ABVD followed by BV consolidation in risk-stratified patients with limited-stage Hodgkin lymphoma.
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Park SI, Shea TC, Olajide O, Reddy NM, Budde LE, Ghosh N, Deal AM, Noe JF, and Ansell SM
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- Adult, Aged, Bleomycin, Brentuximab Vedotin, Dacarbazine therapeutic use, Doxorubicin therapeutic use, Female, Humans, Male, Middle Aged, Neoplasm Staging, Vinblastine therapeutic use, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hodgkin Disease drug therapy, Hodgkin Disease pathology
- Abstract
Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment-related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)-based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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6. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL.
- Author
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Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH, Knapp M, Delioukina M, Kingsley E, Ping J, Beaupre DM, Neuenburg JK, and Ruan J
- Subjects
- Adenine analogs & derivatives, Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Drug Administration Schedule, Female, Humans, Lenalidomide administration & dosage, Lenalidomide adverse effects, Lymphoma, Large B-Cell, Diffuse pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Piperidines, Pyrazoles administration & dosage, Pyrazoles adverse effects, Pyrimidines administration & dosage, Pyrimidines adverse effects, Rituximab administration & dosage, Rituximab adverse effects, Treatment Outcome, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lenalidomide therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Rituximab therapeutic use
- Abstract
The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m
2 intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response [CR], 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166., (© 2019 by The American Society of Hematology.)- Published
- 2019
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7. Curative potential of chemoimmunotherapy in diffuse large B cell lymphoma with hepatic and/or renal dysfunction.
- Author
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Ghosh N, Sanikommu S, Robinson M, Trivedi J, Brown T, Bose R, Park SI, Avalos BR, Copelan EA, Jacobs R, and Hu B
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Humans, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse mortality, Male, Middle Aged, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Kidney Diseases complications, Liver Diseases complications, Lymphoma, Large B-Cell, Diffuse complications, Lymphoma, Large B-Cell, Diffuse drug therapy
- Published
- 2019
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8. Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.
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Hill BT, Nastoupil L, Winter AM, Becnel MR, Cerhan JR, Habermann TM, Link BK, Maurer MJ, Fakhri B, Reddy P, Smith SD, Mukhija D, Jagadeesh D, Desai A, Alderuccio JP, Lossos IS, Mehra P, Portell CA, Goldman ML, Calzada O, Cohen JB, Hussain MJ, Ghosh N, Caimi P, Tiutan T, Martin P, Kodali A, Evens AM, and Kahl BS
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride adverse effects, Cyclophosphamide adverse effects, Disease-Free Survival, Doxorubicin administration & dosage, Doxorubicin adverse effects, Female, Humans, Lymphoma, Follicular mortality, Male, Middle Aged, Prednisone adverse effects, Retrospective Studies, Rituximab adverse effects, Survival Rate, Vincristine adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bendamustine Hydrochloride administration & dosage, Cyclophosphamide administration & dosage, Lymphoma, Follicular drug therapy, Maintenance Chemotherapy, Prednisone administration & dosage, Rituximab administration & dosage, Vincristine administration & dosage
- Abstract
Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2019
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9. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma.
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Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, Kline J, Roschewski M, LaCasce A, Collins GP, Tran T, Lynn J, Chen JY, Volkmer JP, Agoram B, Huang J, Majeti R, Weissman IL, Takimoto CH, Chao MP, and Smith SM
- Subjects
- Adult, Aged, Aged, 80 and over, Anemia chemically induced, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cell Cycle Checkpoints drug effects, Drug Resistance, Neoplasm, Female, Follow-Up Studies, Humans, Macrophages drug effects, Male, Middle Aged, Phagocytosis drug effects, Rituximab adverse effects, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, CD47 Antigen antagonists & inhibitors, Lymphoma, Follicular drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Macrophages physiology, Rituximab therapeutic use
- Abstract
Background: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically., Methods: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose., Results: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing., Conclusions: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).
- Published
- 2018
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10. R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis.
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Shah NN, Szabo A, Huntington SF, Epperla N, Reddy N, Ganguly S, Vose J, Obiozor C, Faruqi F, Kovach AE, Costa LJ, Xavier AC, Okal R, Kanate AS, Ghosh N, Kharfan-Dabaja MA, Strelec L, Hamadani M, Fenske TS, Calzada O, Cohen JB, Chavez J, and Svoboda J
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Murine-Derived adverse effects, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Cyclophosphamide adverse effects, Cyclophosphamide therapeutic use, Disease Management, Doxorubicin adverse effects, Doxorubicin therapeutic use, Etoposide adverse effects, Etoposide therapeutic use, Female, Humans, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell mortality, Male, Mediastinal Neoplasms diagnosis, Mediastinal Neoplasms mortality, Middle Aged, Neoplasm Grading, Neoplasm Staging, Prednisone adverse effects, Prednisone therapeutic use, Recurrence, Retrospective Studies, Rituximab administration & dosage, Treatment Failure, Treatment Outcome, Vincristine adverse effects, Vincristine therapeutic use, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, B-Cell drug therapy, Mediastinal Neoplasms drug therapy
- Abstract
Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R-EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment-related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment-related toxicities. At 2 years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2018
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11. The shrinking role of chemotherapy in the treatment of chronic lymphocytic leukemia.
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Jacobs RW, Awan FT, Leslie LA, Usmani SZ, and Ghosh N
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- Age Factors, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents administration & dosage, Biomarkers, Tumor antagonists & inhibitors, Disease Progression, Drug Resistance, Neoplasm, Genetic Testing, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Molecular Targeted Therapy, Prognosis, Recurrence, Signal Transduction drug effects, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Introduction: The therapeutic landscape of chronic lymphocytic leukemia (CLL) has changed significantly since the first targeted therapy, rituximab, was approved for the treatment of symptomatic patients. Areas covered: Multiple monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) that target the B-cell receptor (BCR) and BCL-2 pathways are now approved treatments for CLL patients. Recent and emerging clinical data investigating the use of targeted therapies in the treatment of CLL patients will be reviewed. The changing role of cytotoxic chemotherapy in the treatment of the CLL patient as a result of the increasing availability of novel targeted therapies will be discussed. Expert commentary: Use of novel therapies is progressively shifting much of the treatment of CLL patients towards a targeted therapeutic approach. Increasing availability of targeted agents such as SMIs will likely reduce the role of cytotoxic chemotherapy in the treatment of both front-line and relapsed/refractory CLL patients.
- Published
- 2016
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12. Tandem Transplantations in Lymphoma--Best of Both Worlds.
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Ghosh N
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- Female, Humans, Male, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Lymphoma mortality, Lymphoma therapy, Stem Cell Transplantation
- Published
- 2015
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13. Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma.
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Noonan KA, Ghosh N, Rudraraju L, Bui M, and Borrello I
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- Carbolines pharmacology, Clarithromycin administration & dosage, Dexamethasone administration & dosage, Humans, Immune Tolerance drug effects, Immunologic Factors administration & dosage, Interleukin-4 Receptor alpha Subunit immunology, Lenalidomide, Male, Middle Aged, Multiple Myeloma immunology, Myeloid Cells drug effects, Myeloid Cells immunology, Phosphodiesterase 5 Inhibitors pharmacology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tadalafil, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carbolines therapeutic use, Multiple Myeloma drug therapy, Phosphodiesterase 5 Inhibitors therapeutic use
- Abstract
Myeloid-derived suppressor cells (MDSC) play a significant role in tumor-induced immune suppression. Targeting their function could improve antitumor therapies. Previously, we demonstrated that phosphodiesterase 5 (PDE5) inhibition in MDSCs augmented antitumor immunity in murine models. Here, we show how the addition of the PDE5 inhibitor, tadalafil, in a patient with end-stage relapsed/refractory multiple myeloma reduced MDSC function and generated a dramatic and durable antimyeloma immune and clinical response. Strategies targeting MDSC function with PDE5 inhibitors represent a novel approach that can augment the efficacy of tumor-directed therapies., (©2014 American Association for Cancer Research.)
- Published
- 2014
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14. Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.
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Ghosh N, Tucker N, Zahurak M, Wozney J, Borrello I, and Huff CA
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Dexamethasone administration & dosage, Female, Humans, Lenalidomide, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Remission Induction, Retrospective Studies, Survival Analysis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Clarithromycin therapeutic use, Drug Resistance, Neoplasm drug effects, Multiple Myeloma drug therapy
- Abstract
The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1-8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1-13.6 months) and the median duration of response was 6.9 months (range 3-52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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15. Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma.
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Ghosh N, Ye X, Ferguson A, Huff CA, and Borrello I
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Boronic Acids administration & dosage, Boronic Acids adverse effects, Bortezomib, Drug Administration Schedule, Epidemiologic Methods, Female, Humans, Male, Middle Aged, Multiple Myeloma pathology, Neoplasm Staging, Peripheral Nervous System Diseases chemically induced, Pyrazines administration & dosage, Pyrazines adverse effects, Thalidomide administration & dosage, Thalidomide adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Abstract
Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1·3 mg/m(2) on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81·5% with 25·8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16·8 months (95% confidence interval 8·7-21·6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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16. Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma
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Ghosh, Nilanjan, Tucker, Noah, Zahurak, Marianna, Wozney, Jocelyn, Borrello, Ivan, and Huff, Carol Ann
- Subjects
Adult ,Aged, 80 and over ,Male ,Remission Induction ,Antineoplastic Agents ,Middle Aged ,Survival Analysis ,Article ,Dexamethasone ,Thalidomide ,Treatment Outcome ,Drug Resistance, Neoplasm ,Clarithromycin ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Multiple Myeloma ,Lenalidomide ,Aged ,Retrospective Studies - Abstract
The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1-8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1-13.6 months) and the median duration of response was 6.9 months (range 3-52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses.
- Published
- 2014
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