69 results on '"Nair, Ranjit"'
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2. Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy.
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Manzar GS, Wu SY, Dudzinski SO, Cha EE, Yoder AK, Corrigan KL, Nasr LF, Sallard G, Ahmed S, Fayad LE, Chihara D, Nair R, Westin JR, Daher M, Neelapu SS, Nastoupil LJ, Gunther JR, Pinnix CC, Dabaja BS, Strati P, and Fang PQ
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Introduction: The impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown., Methods: We retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier., Results: Fifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3)., Conclusions: Lymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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3. Outcomes and toxicities in patients with diffuse-large B cell lymphoma involving the gastrointestinal tract and digestive organs.
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Manzar GS, Cha EE, Corrigan KL, Yoder AK, Schrank BR, Nasr LF, Chihara D, Castillo LM, Nair R, Jain P, Neelapu SS, Rodriguez MA, Strati P, Nastoupil LJ, Gunther JR, Dabaja BS, Pinnix CC, Wu SY, and Fang PQ
- Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT., Methods: Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model., Results: Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI ( p =0.001), fewer chemotherapy lines ( p <0.001), early stage ( p <0.006), and CR ( p <0.001). Survival did not differ by RT receipt ( p >0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS ( p <0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles ( p <0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n =4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy., Conclusion: GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Manzar, Cha, Corrigan, Yoder, Schrank, Nasr, Chihara, Castillo, Nair, Jain, Neelapu, Rodriguez, Strati, Nastoupil, Gunther, Dabaja, Pinnix, Wu and Fang.)
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- 2024
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4. Response-Adapted Ultralow-Dose Radiation Therapy for Orbital Indolent B-Cell Lymphoma: A Phase 2 Nonrandomized Controlled Trial.
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Pinnix CC, Dabaja BS, Gunther JR, Fang PQ, Wu SY, Nastoupil LJ, Strati P, Nair R, Ahmed S, Steiner R, Westin J, Neelapu S, Rodriguez MA, Lee HJ, Wang M, Flowers C, Feng L, and Esmaeli B
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- Humans, Female, Male, Middle Aged, Aged, Adult, Aged, 80 and over, Prospective Studies, Treatment Outcome, Radiotherapy Dosage, Lymphoma, Orbital Neoplasms radiotherapy, Orbital Neoplasms mortality, Orbital Neoplasms pathology, Lymphoma, B-Cell radiotherapy, Lymphoma, B-Cell mortality, Lymphoma, B-Cell pathology
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Importance: Radiation therapy to doses of 24 to 36 Gy is currently used to treat indolent B-cell lymphoma of the ocular adnexa; however, ocular adverse effects are common., Objective: To determine if a response-adapted radiation therapy strategy will result in excellent disease outcomes while reducing orbital morbidity., Design, Setting, and Participants: This single-institution, phase 2 prospective nonrandomized controlled trial of a response-adapted strategy involved 50 evaluable patients with stage I to IV indolent B-cell lymphoma of the ocular adnexa enrolled between July 2015 and January 2021. This treatment approach was also retrospectively evaluated with a separate 55-patient cohort treated between March 2013 and October 2021. All data were analyzed between November 2021 and December 2023., Interventions: Patients were treated with ultralow-dose radiation therapy to 4 Gy in 2 fractions and assessed for response at 3-month intervals. Patients with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions to complete the response-adapted treatment., Main Outcome and Measures: The primary end point was 2-year local orbital control within the irradiated field after response-adapted therapy. Secondary end points included overall survival and complete response rate., Results: The 50 prospective patients were a median (range) of 63 (29-88) years old, and 31 (62%) were female. Among the 50 patients, 32 (64%) had mucosa-associated lymphoid tissue lymphoma, 12 (24%) had follicular lymphoma, and 6 (12%) had unclassifiable low-grade B-cell lymphoma. Thirty-one patients (62%) had stage I disease, and 36 (72%) were newly diagnosed. At a median follow-up of 37.4 (95% CI, 33.7-52.5) months, the 2-year local control rate was 89.4% (95% CI, 81.0%-98.7%), and the 2-year overall survival rate was 98.0% (95% CI, 94.1%-100%); 45 patients (90.0%; 95% CI, 78.2%-96.7%) experienced a complete response to response-adapted radiation, including 44 patients with a complete response to ultralow-dose radiation and 1 patient with a complete response after an additional 20 Gy. No local recurrences were observed among patients with a complete response to response-adapted therapy. No grade 3 or higher toxic effects were observed. In a planned subset analysis of 22 patients with newly diagnosed, untreated stage I mucosa-associated lymphoid tissue lymphoma, the 2-year local control rate was 90.7% (95% CI, 79.2%-100%), and the 2-year freedom from distant relapse rate was 95.2% (95% CI, 86.6%-100%)., Conclusion and Relevance: In this nonrandomized controlled trial, response-adapted ultralow-dose therapy for indolent orbital B-cell lymphoma resulted in reduced radiation exposure, negligible toxic effects, and excellent disease outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02494700.
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- 2024
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5. Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone followed by brentuximab vedotin consolidation in CD30-positive peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 study.
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Herrera AF, Zain J, Savage KJ, Feldman T, Brammer JE, Chen L, Puverel S, Popplewell L, Budde LE, Mei M, Hosing C, Nair R, Leslie L, Daniels S, Peters L, Forman S, Rosen S, Kwak L, and Iyer SP
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- Humans, Female, Male, Middle Aged, Adult, Aged, Consolidation Chemotherapy, Brentuximab Vedotin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Doxorubicin therapeutic use, Doxorubicin administration & dosage, Lymphoma, T-Cell, Peripheral drug therapy, Etoposide therapeutic use, Etoposide administration & dosage, Ki-1 Antigen metabolism, Prednisone therapeutic use, Prednisone administration & dosage, Prednisone adverse effects
- Abstract
Background: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes., Methods: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m
2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort., Findings: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths., Interpretation: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active., Funding: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health., Competing Interests: Declaration of interests AFH reports research funding from Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Gilead Sciences, Seattle Genetics, AstraZeneca, and ADC Therapeutics and consultancy for Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Kite Pharma/Gilead, Seattle Genetics, Karyopharm, Takeda, Tubulis, AstraZeneca, Genmab, Regeneron, Pfizer, AbbVie, Allogene Therapeutics, Adicet Bio, and Caribou Biosciences. MM reports research funding from Bristol Myers Squibb, Incyte, and Morphosys; consultancy for Novartis, Seattle Genetics, CTI Biopharma, Janssen, and EUSA Pharma; and being part of speakers' bureau for Morphosys and Seattle Genetics. CH reports consultancy for BioLineRx. KJS reports honoraria or consulting for Seagen, Bristol Myers Squibb, Janssen, and AbbVie; research funding from Bristol Myers Squibb and Roche (institutional); participation on a data and safety monitoring committee for Regeneron; and participation on a steering committee for Beigene. SP reports research funding from Acrotech, AstraZeneca, CRISPR, Innate, Legend, Merck, Myeloid, Trillium/Pfizer, and Seagen and consultancy for Acrotech, March Bio, Star, Pfizer, Salarius, and Seagen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)- Published
- 2024
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6. Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial.
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Gurumurthi A, Chin CK, Feng L, Fowler NH, Strati P, Hagemeister FB, Fayad LE, Westin JR, Obi C, Arafat J, Nair R, Steiner RE, Neelapu SS, Flowers CR, and Nastoupil LJ
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Background: Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma., Methods: In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669., Findings: Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95)., Interpretation: Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted., Funding: Genentech and an MD Anderson Core grant., Competing Interests: AG: Received honorarium for participation in advisory board for Kite Pharma. CKC: has received honorarium for participation in advisory boards with Kite/Gilead. LF: No competing interests. NF: has received research support from Celgene for undertaking the preclinical and clinical trials of lenalidomide. PS: consultancy for Kite, a Gilead Company, Roche-Genentech, Hutchinson MediPharma, ADC Therapeutics, Incyte Morphosis and TG Therapeutics; research funding from Sobi Pharmaceuticals, AstraZeneca-Acerta, ALX Oncology, and ADC Therapeutics. Research: Salary support from the Leukemia Lymphoma Society Scholar in Clinical Research Career Development Program, the Sabin Fellowship Award, and by Gilead Scholar in Clinical Research Award. FJH: No competing interests. LEF: No competing interests. JRW: Consulting and Research Funding—BMS ADC Therapeutics, AstraZeneca, Genentech, Kite, Janssen, Kymera, Merck, Morphosys/Incyte, Novartis. Consulting: Abbvie, GenMab, Regeneron, and SeaGen. CO: No competing interests. JA: No competing interests. RN: Consulting–Abbvie, Incyte. Honorarium for Educational Events—AstraZeneca, ScienciaCME, MedPage, Curio Science. Travel Support for Attending Meetings–Viracta Therapeutics, Inc. Studio E.R. Congressi s.r.l. World Health Communications, Ltd. RES: Grants–Seagen, BMS, GSK and Rafael Pharmaceuticals. SSN—has received research support from Kite/Gilead, Cellectis, Poseida, Merk, Acerta, Karus, BMS, Unum Therapeutics, Allogene, and Precision Biosciences; served as consultant and advisory board member for Kite/Gliead, Celgene, Novartis, Unum Therapeutics, Pfizer, Merck, Precision Biosciences, Cell Medica, Incyte, Allogene, Calibr, and Legend Biotech; has patents related to cell therapy. CF: Consultant: Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Foresight Diagnostics, Genentech/Roche, Genmab, Gilead, Karyopharm, N-Power Medicine, Pharmacyclics/Janssen, SeaGen, Spectrum. Stock Options: Foresight Diagnostics, N-Power MedicineResearch Funding: 4D, Abbvie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, Leukemia and Lymphoma Sociery, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research. LJN: has received honorarium for participation in advisory boards/consulting from Abbvie, ADC Therapeutics, BMS/Celgene, Caribou Biosciences, Daiichi Sankyo, Epizyme, Genentech/Roche, Genmab, Janssen, Incyte, Ipsen, Novartis, and Takeda; research support from BMS/Celgene, Caribou Biosciences, Daiichi Sankyo, Epizyme, Genentech/Roche, Genmab, Gilead/Kite, IGM Biosciences, Ipsen, Janssen, Novartis, and Takeda., (© 2024 The Authors.)
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- 2024
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7. Radiotherapy in the treatment of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.
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Wu SY, Damron EP, Xu J, Fang PQ, Dai J, Nair R, Malpica Castillo LE, Fayad LE, Torres-Cabala CA, Medeiros LJ, Vega F, Miranda RN, Duvic M, Pinnix CC, Dabaja BS, Iyer SP, Huen AO, and Gunther JR
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Background: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD) is an increasingly recognized entity with heterogeneous management strategies that may include radiotherapy., Objective: Our aim was to characterize treatment options for PCSM-LPD, with a focus on the role of radiotherapy., Methods: This is a retrospective review of 46 patients seen in the Cutaneous Lymphoma Program at the University of Texas MD Anderson Cancer Center, with a clinicopathologic review consistent with PCSM-LPD. All patients were biopsied and underwent observation, topical/intralesional steroids, and/or radiotherapy. Patients were confirmed to have residual disease prior to radiotherapy., Results: All patients achieved a complete response (CR). Sixteen patients (35%) received focal radiotherapy, with a CR in 15 (94%). The CR rate following ultra-low-dose radiotherapy (4 Gy in 1-2 fractions) was 92%. There was no grade 3 toxicity after radiotherapy. Thirty patients were managed without radiotherapy, with excision and observation or steroids., Conclusion: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder has excellent outcomes, and management strategies may include observation following biopsy, steroids, or radiation. Ultra-low-dose radiotherapy results in excellent outcomes with limited toxicity and is effective for persistent lesions after steroidal therapy., (© 2024 the International Society of Dermatology.)
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- 2024
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8. Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: a single-centre, pilot trial.
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Gunther JR, Xu J, Bhutani MS, Strati P, Fang PQ, Wu SY, Dabaja BS, Dong W, Bhosale PR, Flowers CR, Nair R, Malpica Castillo L, Fayad L, Iyer SP, Parmer S, Wang M, Lee HJ, Samaniego F, Westin J, Ahmed S, Nze CC, Jain P, Neelapu SS, Rodriguez MA, Chihara D, Nastoupil LJ, and Pinnix CC
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- Humans, Male, Female, Middle Aged, Aged, Pilot Projects, Adult, Prospective Studies, Treatment Outcome, Aged, 80 and over, Lymphoma, B-Cell, Marginal Zone radiotherapy, Stomach Neoplasms radiotherapy, Stomach Neoplasms pathology, Radiotherapy Dosage
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Background: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach., Methods: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total dose of 4 Gy in two fractions. Patients with a complete response to 4 Gy via endoscopy and imaging at 3-4 months were observed; patients with a partial response were re-evaluated in 6-9 months. Residual disease at 9-13 months or stable or progressive disease at any time required additional treatment with 20 Gy. The primary endpoint was gastric complete response at 1 year (second evaluation timepoint) after 4 Gy treatment. All analyses were performed as intention to treat. This trial is registered at ClinicalTrials.gov (NCT03680586) and is complete and closed to enrolment., Findings: Between March 27, 2019, and Oct 12, 2021, we enrolled 24 eligible patients. The median age of participants was 67 years (IQR 58-74; range 40-85); 15 (63%) were female and nine (37%) male; 18 (75%) were White, four (17%) Asian, and two (8%) Hispanic; 20 (83%) had stage I disease, one (4%) stage II, and three (13%) stage IV. Median follow-up time was 36 months (IQR 26-42). 20 patients (83%) had a complete response to 4 Gy (16 at 3-4 months, four at 9-13 months); two patients received 20 Gy for symptomatic stable disease at 3-4 months and two for residual disease at 9-13 months; all had a complete response. The 3-year local control rate was 96% (95% CI 88-100), with one local relapse at 14 months after 4 Gy radiotherapy salvaged successfully with 20 Gy. One patient with stage IV disease had a distant relapse. The most common adverse events were grade 1 nausea (nine [38%] of 24 patients who received 4 Gy and two [50%] of four patients who received 20 Gy) and grade 1 abdominal pain (five [21%] of 24 and zero of four, respectively). No grade 3 or worse adverse events were noted, including no treatment-related deaths., Interpretation: Most patients had a complete response after 4 Gy radiotherapy; all who required an additional 20 Gy had a complete response within 12 months. This response-adapted strategy could be used to select patients who would benefit from additional radiotherapy and spare others potential associated toxicity., Funding: National Cancer Institute., Competing Interests: Declarations of interests CCP has received research support from Merck. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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9. Efficacy and safety of brexucabtagene autoleucel CAR T-cell therapy with BTK inhibitors in the treatment of relapsed mantle cell lymphoma with central nervous system involvement.
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Lionel AC, Gurumurthi A, Fetooh A, Eldaya R, Ahmed S, Iyer SP, Nastoupil LJ, Westin J, Nair R, Fayad L, Malpica L, Tummala S, Flowers C, Neelapu SS, Wang ML, and Jain P
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- Humans, Treatment Outcome, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Aged, Receptors, Chimeric Antigen, Female, Combined Modality Therapy, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell therapy, Lymphoma, Mantle-Cell pathology, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Central Nervous System Neoplasms therapy, Central Nervous System Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects
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- 2024
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10. Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.
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Jallouk AP, Kui N, Sun R, Westin JR, Steiner RE, Nair R, Nastoupil LJ, Fayad LE, Zaki AA, Hawkins M, Adkins S, Noorani M, Das K, Henderson J, Shpall EJ, Kebriaei P, Ramdial J, Flowers CR, Neelapu SS, Ahmed S, and Strati P
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- Humans, Male, Female, Adolescent, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Progression-Free Survival, Lymphocyte Depletion adverse effects, Treatment Delay, Lymphoma, B-Cell mortality, Lymphoma, B-Cell therapy, Immunotherapy, Adoptive
- Abstract
Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (P=0.006), lower platelets (P=0.004), lower hemoglobin (P<0.001) and higher C-reactive protein (P=0.001) than those with on-time infusion. Patients with delayed infusion had lower day 30 overall response rates (59.0% vs. 79.4%; P=0.008) and shorter median progression-free survival (PFS) (3.5 vs. 8.2 months; P=0.002) and overall survival (7.8 vs. 26.4 months; P=0.046) than those with on-time infusion. The association with PFS was maintained on multivariate analysis. There was also an association between extent of delay and survival, with shorter median PFS in patients who had delays of 2-5 days (1.8 vs. 8.2 months; P=0.001) and >5 days (4.6 vs. 8.2 months; P=0.036), but not 1 day (5.7 vs. 8.2 months; P=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; P=0.015). Levels of pro-inflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.
- Published
- 2024
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11. Native Aortic Valve Endocarditis Secondary to Gastric Antral Vascular Ectasia Manipulation During Endoscopic Argon Plasma Coagulation.
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Nair R, Elsaygh J, Zaher A, Fragner M, and Perk G
- Abstract
Gastric antral vascular ectasia (GAVE) is an uncommon cause of upper gastrointestinal (GI) bleeds. Due to the high vascularity of the region, transient bacteremia due to manipulation of the GI tract can very rarely cause the translocation of bacteria. We present a rare case in which endoscopic manipulation to treat GAVE led to native valve infective endocarditis (IE). Our patient had a prior history of GAVE and presented with worsening dizziness and shortness of breath (SOB). After an esophagogastroduodenoscopy (EGD) and subsequent argon plasma coagulation (APC) for active preantral bleeding, the patient was noted to have repeated fevers, a new cardiac murmur, and positive blood cultures for Staphylococcus epidermidis , leading to a diagnosis of native infective endocarditis. With high clinical suspicion and early recognition of a new cardiac murmur, a transesophageal echocardiogram (TEE) was key in identifying vegetation. This case highlights the importance of combining history, a physical exam, and diagnostic lab tests and imaging to identify endocarditis. Management included two months of intravenous (IV) vancomycin and repeat TEE for close monitoring of vegetation improvement., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Nair et al.)
- Published
- 2024
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12. Real-world analysis of safety and efficacy of CAR T-cell therapy in lymphoma patients with decreased kidney function.
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Mamlouk O, Strati P, Feng L, Sun R, Ayers A, Steiner RE, Nair R, Flowers C, Ramdial JL, Saini N, Srour SA, Champlin RE, Kebriaei P, Nastoupil LJ, Rodriguez MA, Shpall EJ, Nieto Y, Westin J, Neelapu SS, Mandayam S, and Ahmed S
- Subjects
- Humans, T-Lymphocytes, Kidney, Antigens, CD19, Immunotherapy, Adoptive adverse effects, Lymphoma therapy
- Published
- 2024
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13. Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma.
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Steiner RE, Hwang SR, Khurana A, Habermann TM, Epperla N, Annunzio K, Allen PB, Baird K, Paulino D, Alderuccio JP, Lossos IS, David K, Evens AM, Pandya K, Bair SM, Kamdar M, Ba Aqeel S, Torka P, Lynch R, Smith S, Feng L, Noorani M, Ahmed S, Nair R, Vega F, Wu S, Fang P, Pinnix CC, Gunther JR, Dabaja BS, and Lee HJ
- Subjects
- Humans, Adult, Brentuximab Vedotin therapeutic use, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bleomycin adverse effects, Hodgkin Disease therapy
- Abstract
In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV., (© 2023 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
- 2023
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14. A phase 1 study of prophylactic anakinra to mitigate ICANS in patients with large B-cell lymphoma.
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Strati P, Jallouk A, Deng Q, Li X, Feng L, Sun R, Adkins S, Johncy S, Cain T, Steiner RE, Ahmed S, Chihara D, Fayad LE, Iyer SP, Horowitz S, Nastoupil LJ, Nair R, Hassan A, Daoud TE, Hawkins M, Rodriguez MA, Shpall EJ, Ramdial JL, Kebriaei P, Hong DS, Westin JR, Neelapu SS, and Green MR
- Subjects
- Humans, Immunotherapy, Adoptive, Interleukin 1 Receptor Antagonist Protein therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy
- Published
- 2023
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15. Capnocytophaga canimorsus Infection in a 38-Year-Old Male after a Dog Bite.
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Ahsen A, Korsun P, Albahra F, Nair R, and Tariq Z
- Abstract
Here, we present a unique case of a 38-year-old male with a history of alcohol use disorder and multiple sexual partners, who presented with fulminant sepsis with shock, multiorgan failure, and livedo racemosa after a dog bite the week prior. The patient was intubated on arrival and was started on vasopressors and antibiotics. Eventually, the patient's clinical status improved, and he was transferred out of the intensive care unit. Blood cultures tested positive for oxidase-positive Gram-negative rods two days after collection, and species identification showed Capnocytophaga canimorsus ., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Ahmad Ahsen et al.)
- Published
- 2023
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16. Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells.
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Strati P, Li X, Deng Q, Marques-Piubelli ML, Henderson J, Watson G, Deaton L, Cain T, Yang H, Ravanmehr V, Fayad LE, Iyer SP, Nastoupil LJ, Hagemeister FB, Parra ER, Saini N, Takahashi K, Fowler NH, Westin JR, Steiner RE, Nair R, Flowers CR, Wang L, Ahmed S, Al-Atrash G, Vega F, Neelapu SS, and Green MR
- Subjects
- Humans, Immunotherapy, Adoptive, Bone Marrow, CD8-Positive T-Lymphocytes, Antigens, CD19, Interferon-gamma, Receptors, Chimeric Antigen, Lymphoma, B-Cell
- Abstract
Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1
hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia., Competing Interests: Declaration of interests M.R.G. reports research funding from Sanofi, Kite/Gilead, Abbvie, and Allogene; consulting for Abbvie; honoraria/consulting fees from Tessa Therapeutics, Monte Rosa Therapeutics, Daiichi Sankyo, and Abbvie; and stock ownership of KDAc Therapeutics. S.S.N. received research support from Kite/Gilead, BMS, Cellectis, Poseida, Allogene, Unum Therapeutics, Precision Biosciences, and Adicet Bio; served as Advisory Board Member/Consultant for Kite/Gilead, Merck, Novartis, Sellas Life Sciences, Athenex, Allogene, Incyte, Adicet Bio, BMS, Legend Biotech, Bluebird Bio, Fosun Kite, Sana Biotechnology, Caribou, Astellas Pharma, Morphosys, Janssen, Chimagen, ImmunoACT, and Orna Therapeutics; has received royalty income from Takeda Pharmaceuticals; has stock options from Longbow Immunotherapy, Inc; and has intellectual property related to cell therapy. P.S. received research support from Sobi, AstraZeneca/Acerta, ALX Oncology, and ADC Therapeutics; and served as Advisory Board Member/Consultant for Kite/Gilead, Roche/Genentech, Incyte/Morphosys, ADC Therapeutics, TG Therapeutics, Hutchinson/MediPharma, and AstraZeneca/Acerta. R.N. reports speakership for Incyte. J.R.W. reports consulting for Kite/Gilead, BMS, Novartis, Genentech/Roche, AstraZeneca, Morphosys/Incyte, Janssen, ADC Therapeutics, Calithera, Kymera, Merck, MonteRosa, SeaGen, and Abbvie; and research funding from Kite/Gilead, BMS, Novartis, Genentech/Roche, AstraZeneca, Morphosys/Incyte, Janssen, ADC Therapeutics, Calithera, and Kymera. S.A. reports research funding from Seattle Genetics, Merck, Xencor, Chimagen, and Tessa Therapeutics; advisory board membership or consulting for Tessa Therapeutic’s, Chimagen, ADC Therapeutics, and KITE/Gilead; and data safety monitoring board membership for Myeloid Therapeutics. L.J.N. reports honoraria for participation on advisory boards from ADC Therapeutics, Atara, BMS, Caribou Biosciences, Epizyme, Genentech, Genmab, Gilead/Kite, Janssen, Morphosys, Novartis, and Takeda; research support from BMS, Caribou Biosciences, Epizyme, Genentech, Genmab, Gilead/Kite, Janssen, IGM Biosciences, Novartis, and Takeda; and serves on a DSMB for DeNovo, Genentech, MEI, and Takeda. C.R.F. reports consulting for Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Foresight Diagnostics, Genentech/Roche, Genmab, Gilead, Karyopharm, N-Power Medicine, Pharmacyclics/Janssen, SeaGen, and Spectrum; research funding from 4D, Abbvie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, and Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research; and stock ownership in Foresight Diagnostics, N-Power Medicine. F.V. reports research funding from Allogene and Geron corporation; and honoraria from i3Health, Elsevier, America Registry of Pathology, Society of Hematology Oncology, and CRISP Therapeutics. K.T. reports consulting for Symbio Pharaceuticals and honoraria from Mission Bio. R.E.S. reports research funding from SeaGen, BMS, GSK, and Rafael Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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17. Safety of Concurrent Radiation Therapy With Brentuximab Vedotin in the Treatment of Lymphoma.
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Wu SY, Fang PQ, Wang EB, Ahmed S, Duvic M, Jain P, Castillo LEM, Nair R, Steiner RE, Strati P, Huen AO, Iyer SP, Pinnix CC, Dabaja BS, and Gunther JR
- Abstract
Purpose: Purpose: Radiation therapy (RT) and the antibody-drug conjugate brentuximab vedotin (BV) are standard-of-care treatment options for patients with certain B and T-cell lymphomas; however, there are limited data exploring the safety of concurrent BV and RT (BVRT)., Methods and Materials: We performed a single institutional retrospective review of 44 patients who received BVRT., Results: Twenty percent of patients (9/44) developed new grade 2 or higher (G2+) hematologic toxicity (HT) after BVRT, which was associated with radiation dose (median dose of 35 Gy in those with new G2+ HT compared with 15 Gy in those without; P < .001). Acute G2+ elevation in aspartate transaminase or alanine transaminase level was associated with administration of concurrent chemotherapy with BVRT (57% vs 21%; P = .047) but was not associated with any RT factors. Local control (LC) was achieved in 24 of 42 patients (57%) with available follow-up. Ten patients (23%) proceeded to stem cell transplant or cellular therapy after BVRT at a median of 48 days (interquartile range, 27-188 days). At last follow-up, 10 patients (23%) remained without evidence of disease., Conclusions: Our analysis demonstrates that the combination of BV and RT is well tolerated, though care should be taken during RT planning to reduce the risk of HT. This combination can be considered for patients in need of both local and systemic disease control., (© 2023 The Author(s).)
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- 2023
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18. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.
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Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, Schubert ML, Mor U, Fante MA, Schmidt S, Hayase E, Hayase T, Rohrbach R, Chang CC, McDaniel L, Flores I, Gaiser R, Edinger M, Wolff D, Heidenreich M, Strati P, Nair R, Chihara D, Fayad LE, Ahmed S, Iyer SP, Steiner RE, Jain P, Nastoupil LJ, Westin J, Arora R, Wang ML, Turner J, Menges M, Hidalgo-Vargas M, Reid K, Dreger P, Schmitt A, Müller-Tidow C, Locke FL, Davila ML, Champlin RE, Flowers CR, Shpall EJ, Poeck H, Neelapu SS, Schmitt M, Subklewe M, Jain MD, Jenq RR, and Elinav E
- Subjects
- Humans, Immunotherapy, Immunotherapy, Adoptive adverse effects, T-Lymphocytes, Antigens, CD19, Receptors, Chimeric Antigen, Gastrointestinal Microbiome genetics, Lymphoma, B-Cell
- Abstract
Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
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19. PD-L1 + macrophages are associated with favorable features in primary mediastinal (thymic) large B-cell lymphoma.
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Steiner RE, Parra ER, Vega F, Feng L, Westin JR, Neelapu SS, Strati P, Green MR, Flowers CR, Solis LM, Wistuba II, Ahmed S, Nair R, Hagemeister FB, Noorani M, and Marques-Piubelli ML
- Abstract
Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients who had disease relapse, were included in the analysis. At a median follow-up time of 32.2 months, the median progression-free and overall survival durations were not reached. Our findings suggest that a high density of PD-L1
+ macrophages is associated with favorable features, such as early disease stage and the absence of B-symptoms, and indicate that a high percentage of PD-L1+ macrophages and high densities of CD30+ PD-L1+ cells and CD30+ cells might be associated with a lower risk of relapse within 12 months of therapy initiation. Further studies are needed to develop a biomarker signature predictive of treatment response with therapeutic consequences for patients with newly diagnosed PMBCL., (© 2023. The Author(s).)- Published
- 2023
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20. Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma.
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Westin J, Davis RE, Feng L, Hagemeister F, Steiner R, Lee HJ, Fayad L, Nastoupil L, Ahmed S, Rodriguez A, Fanale M, Samaniego F, Iyer SP, Nair R, Oki Y, Fowler N, Wang M, Ma MCJ, Vega F, McDonnell T, Pinnix C, Griffith D, Lu Y, Tewari S, Sun R, Scott DW, Flowers CR, Neelapu S, and Green MR
- Subjects
- Humans, Middle Aged, Aged, Rituximab, Lenalidomide, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide, Piperidines therapeutic use, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Purpose: Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset., Methods: We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m
2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed., Results: The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively., Conclusion: Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.- Published
- 2023
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21. Positron emission tomography derived metrics in relapsed or refractory large B-cell lymphoma with residual disease before autologous stem cell transplant.
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Cherng HJ, Xu G, Feng L, Steiner R, Fayad L, Strati P, Nair R, Nastoupil LJ, Lee HJ, Neelapu SS, Flowers CR, Rodriguez M, Wang M, Hagemeister F, Pinnix CC, Ramdial J, Srour S, Nieto Y, Rezvani K, Champlin R, Kebriaei P, Westin J, Macapinlac HA, Shpall E, and Ahmed S
- Subjects
- Humans, Retrospective Studies, Transplantation, Autologous, Positron-Emission Tomography methods, Stem Cell Transplantation, Prognosis, Fluorodeoxyglucose F18, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Large B-Cell, Diffuse diagnostic imaging, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A
18 F-fluorodeoxyglucose positron emission tomography (PET) scan after salvage chemotherapy is used to assess response and eligibility for ASCT, but metrics for chemosensitivity in patients with residual disease are not well defined. We performed a single-centre retrospective analysis of 92 patients with a partial response or stable disease after salvage chemotherapy for rrLBCL who received ASCT to investigate PET-derived parameters and their prognostic utility. The Deauville 5-point Scale (D-5PS) score, maximum standardised uptake value (SUVmax ), total metabolic tumour volume (TMTV), and total lesion glycolysis (TLG) were calculated from the post-salvage/pre-ASCT PET scan. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 40% and 54% respectively. A D-5PS score of 5 (p = 0.0082, hazard ratio [HR] 2.09), high SUVmax (p = 0.0015, HR 2.48), TMTV (p = 0.035, HR 1.83) and TLG (p = 0.0036, HR 2.27) were associated with inferior PFS. A D-5PS score of 5 (p = 0.030, HR 1.98) and high SUVmax (p = 0.0025, HR 2.55) were associated with inferior OS. PET-derived parameters may help prognosticate outcomes after ASCT in patients with rrLBCL with residual disease after salvage chemotherapy., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2023
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22. A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma.
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Fahrmann JF, Saini NY, Chia-Chi C, Irajizad E, Strati P, Nair R, Fayad LE, Ahmed S, Lee HJ, Iyer S, Steiner R, Vykoukal J, Wu R, Dennison JB, Nastoupil L, Jain P, Wang M, Green M, Westin J, Blumenberg V, Davila M, Champlin R, Shpall EJ, Kebriaei P, Flowers CR, Jain M, Jenq R, Stein-Thoeringer CK, Subklewe M, Neelapu SS, and Hanash S
- Subjects
- Humans, Polyamines, Antigens, CD19, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL., Competing Interests: Declaration of interests An Invention Disclosure Report related to findings reported herein has been submitted to the University of Texas. M.S. has received industry research support from Amgen, Gilead, Miltenyi Biotec, Morphosys, Roche, and Seattle Genetics and has served as a consultant/advisor to Amgen, BMS, Celgene, Gilead, Pfizer, Novartis, and Roche. She sits on the advisory boards of Amgen, Celgene, Gilead, Janssen, Novartis, Pfizer, and Seattle Genetics and serves on the speakers' bureau at Amgen, Celgene, Gilead, Janssen, and Pfizer. N.Y.S. has intellectual property rights in the field of cellular immunotherapy and microbiome. S.S.N. received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Bluebird Bio, and Unum Therapeutics; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; royalties from Takeda Pharmaceuticals; and has intellectual property rights related to cell therapy. M.G. reports research funding from Sanofi, Kite/Gilead, Abbvie, and Allogene, honoraria from Tessa Therapeutics and Daiichi Sankyo, and stock ownership of KDAc Therapeutics. P.S. received research support from Astrazeneca-Acerta and from ALX Oncology and is a consultant for Roche-Genentech and Hutchinson MediPharma. S.S.N. has received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics, and Bluebird Bio; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; and patents, royalties, or other intellectual property from Takeda Pharmaceuticals., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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23. Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy.
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Strati P, Jallouk AP, Sun R, Choi J, Das K, Cherng HJ, Ahmed S, Lee HJ, Iyer SP, Nair R, Nastoupil LJ, Steiner RE, Huff CD, Yu Y, Mistry H, Pulsifer B, Noorani M, Saini N, Shpall EJ, Kebriaei P, Flowers CR, Westin JR, Hildebrandt MAT, and Neelapu SS
- Subjects
- Humans, Antigens, CD19, Neoplasm Recurrence, Local drug therapy, Leukapheresis, Lymphocytes pathology, Immunotherapy, Adoptive adverse effects, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 10
9 /L (range, 0.01-2.75 × 109 /L) and was significantly higher in patients who achieved complete response (p = 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2-0.8, p = 0.007). Low DLIx was independently associated with shorter progression-free (p = 0.02) and overall survival (p = 0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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24. Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma.
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Saini NY, Swoboda DM, Greenbaum U, Ma J, Patel RD, Devashish K, Das K, Tanner MR, Strati P, Nair R, Fayad L, Ahmed S, Lee HJ, Iyer SP, Steiner R, Jain N, Nastoupil L, Loghavi S, Tang G, Bassett RL, Jain P, Wang M, Westin JR, Green MR, Sallman DA, Padron E, Davila ML, Locke FL, Champlin RE, Garcia-Manero G, Shpall EJ, Kebriaei P, Flowers CR, Jain MD, Wang F, Futreal AP, Gillis N, Neelapu SS, and Takahashi K
- Subjects
- Antigens, CD19 adverse effects, Biological Products, Clonal Hematopoiesis, Humans, Immunotherapy, Adoptive adverse effects, Receptors, Antigen, T-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics, Neurotoxicity Syndromes epidemiology
- Abstract
To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028]., Significance: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369., (©2022 American Association for Cancer Research.)
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- 2022
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25. Risk assessment with low-pass whole-genome sequencing of cell-free DNA before CD19 CAR T-cell therapy for large B-cell lymphoma.
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Cherng HJ, Sun R, Sugg B, Irwin R, Yang H, Le CC, Deng Q, Fayad L, Fowler NH, Parmar S, Steiner R, Hagemeister F, Nair R, Lee HJ, Rodriguez M, Samaniego F, Iyer SP, Flowers CR, Wang L, Nastoupil LJ, Neelapu SS, Ahmed S, Strati P, Green MR, and Westin J
- Subjects
- Antigens, CD19, Humans, Risk Assessment, Cell-Free Nucleic Acids, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .0026; hazard ratio, 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most highly associated with poor outcomes, leading to inferior PFS (P < .0001; hazard ratio, 3.49) and OS (P = .0027; hazard ratio, 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated lactate dehydrogenase and >1 extranodal site), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials., (© 2022 by The American Society of Hematology.)
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- 2022
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26. Second malignancies in patients with Hodgkin's Lymphoma: Half a century of experience.
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Shbib Dabaja B, Boyce-Fappiano D, Dong W, Damron E, Fang P, Gunther J, Rodriguez MA, Strati P, Steiner R, Nair R, Lee H, Abou Yehia Z, Shihadeh F, Pinnix C, and Ng AK
- Abstract
Purpose: Therapeutic improvements for Hodgkin's Lymphoma (HL) has resulted in excellent survival outcomes. Thus, patients are increasing susceptible to developing secondary malignancy (SM) a feared iatrogenic complication., Materials & Methods: We evaluated the SM risk in a cohort of patients with HL treated over a 50-year period. In total, 1653 patients were treated for HL from 1956 to 2009 at a tertiary-cancer-center. A cumulative incidence function was used to quantify SM risk and the Fine and Gray competing risk model was used to identify disease and treatment related correlates., Results: Two-hundred-ninety patients (19%) developed SMs. Paradoxically, SM risk was higher in the modern era with 20-year cumulative incidence rates of 11.1%, 11.9%, 17% and 21.8%, for patients treated <1970, 1971-1986, 1986-1995 and 1996-2009, respectively. We hypothesized that the disproportionately high rate of early deaths in the early era may skew the assessment of SM risks, a much-delayed event. When the analysis was restricted to patients with early-stage favorable HL treated >1980, we found a reversal of the trend, especially on the risk of solid tumor, with a hazard ratio of 0.57 (p = 0.0651) in patients treated after 1996., Conclusion: Our findings highlight the limitations of comparing the risk of a late event between groups with disparate rates of early deaths, despite the use of a competing risk model. When partially corrected for, patients treated in the more recent time period experienced a lower solid tumor risk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2022
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27. Day 30 SUVmax predicts progression in patients with lymphoma achieving PR/SD after CAR T-cell therapy.
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Al Zaki A, Feng L, Watson G, Ahmed SA, Mistry H, Nastoupil LJ, Hawkins M, Nair R, Iyer SP, Lee HJ, Steiner RE, Flowers CR, Shpall EJ, Kebriaei P, Neelapu SS, Westin JR, and Strati P
- Subjects
- Antigens, CD19, Humans, Progression-Free Survival, Retrospective Studies, Immunotherapy, Adoptive methods, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
About 70% of patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel) and who achieve a partial response (PR) or stable disease (SD) on the day 30 (D30) positron emission tomography (PET)-computed tomography (CT) scan progress; however, the factors that are predictive of progression are unknown. This a retrospective study of patients with LBCL who were treated with axi-cel at MD Anderson Cancer Center between January of 2018 and February of 2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to a complete response (CR). Among 95 patients with a D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day -5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (P = .05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was a lower maximum standardized uptake volume (SUVmax; P < .001); all patients with D30 SUVmax ≥ 10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed between patients who converted from D30 PR/SD to subsequent CR and those who had been in CR since D30 (P = .19). Novel predictive and prognostic markers based on tissue biopsy and noninvasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease., (© 2022 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.)
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- 2022
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28. Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.
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Nieto Y, Gruschkus S, Valdez BC, Jones RB, Anderlini P, Hosing C, Popat U, Qazilbash M, Kebriaei P, Alousi A, Saini N, Srour S, Rezvani K, Ramdial J, Barnett M, Gulbis A, Shigle TL, Ahmed S, Iyer S, Lee H, Nair R, Parmar S, Steiner R, Dabaja B, Pinnix C, Gunther J, Cuglievan B, Mahadeo K, Khazal S, Chuang H, Champlin R, Shpall EJ, and Andersson BS
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Brentuximab Vedotin, Humans, Neoplasm Recurrence, Local pathology, Retrospective Studies, Hodgkin Disease diagnosis, Hodgkin Disease drug therapy
- Abstract
High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.
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- 2022
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29. Perioperative Anticoagulation Management.
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Briete LD, Towers WF, Bone R, Nair R, Steck M, Cutshall BT, and Shah SP
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- Humans, Risk Assessment, Risk Factors, Anticoagulants therapeutic use, Perioperative Care methods
- Abstract
Management of anticoagulation in individuals undergoing operative procedures is a complex situation. Each case should be assessed individually with proper risk assessment, monitoring, and plan for perioperative and postoperative anticoagulation. Clinical evidence for the management of these patients is relatively scarce, and clinicians are often assessing each individual case with minimal guidance. This review provides nurses with a summary of available literature on the assessment, laboratory monitoring, timing of adjusting anticoagulation, and bridging prior to procedures. In addition to general perioperative anticoagulation management, this review discusses perioperative management in special populations and provides a summary on principles when anticoagulation should be resumed following a procedure., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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30. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.
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Wang ML, Jain P, Zhao S, Lee HJ, Nastoupil L, Fayad L, Ok CY, Kanagal-Shamanna R, Hill HA, Yao Y, Hagemeister FB, Westin JR, Fowler N, Samaniego F, Steiner R, Nair R, Iyer SP, Navsaria L, Badillo M, Feng L, Xuelin H, Nogueras Gonzalez GM, Xu G, Wagner-Bartak N, Thirumurthi S, Santos D, Tang G, Lin P, Wang SA, Jorgensen J, Yin CC, Li S, Patel KP, Vega F, Medeiros LJ, Flowers CR, and Wang L
- Subjects
- Adenine analogs & derivatives, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide, Cytarabine, Doxorubicin, Humans, Methotrexate, Middle Aged, Piperidines, Rituximab, Treatment Outcome, Vincristine, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell pathology, Lymphopenia chemically induced, Thrombocytopenia chemically induced
- Abstract
Background: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma., Methods: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m
2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620., Findings: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related., Interpretation: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma., Funding: Pharmacyclics, Janssen., Competing Interests: Declaration of interests MLW reports consultancy for InnoCare, Loxo Oncology, Juno, Oncternal, CStone, AstraZeneca, Janssen, VelosBio, Pharmacyclics, Genentech, and Bayer Healthcare; research funding from Pharmacyclics, Janssen, AstraZeneca, Celgene, Loxo Oncology, Kite Pharma, Juno, BioInvent, VelosBio, Acerta Pharma, Oncternal, Verastem, Molecular Templates, Lilly, and Innocare; and honoraria from Janssen, Acerta Pharma, OMI, Physicians Education Resources, Dava Oncology, CAHON, Hebei Cancer Prevention Federation, Clinical Care Options, Mumbai Hematology Group, Anticancer Association, and Newbridge Pharmaceuticals. PJ reports consultancy for Incyte, Eli Lilly, Aptitude Health, and Kite Pharma; research funding from Kite and AstraZeneca; and honoraria from Aptitude Health. FV reports research funding and support from National Cancer Institute, CRISP Therapeutics, and Geron Corporation; and honoraria from i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and Society of Hematology Oncology. CRF has consulted for Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Epizyme, Genentech–Roche, Gilead, Karyopharm, MEI Pharmaceuticals, Pharmacyclics–Janssen, and Spectrum in the past 3 years; and reports research funding in the past 12 months from Abbvie, Acerta, Celgene, Gilead, Genentech–Roche, Janssen Pharmaceutical, Millennium–Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, CPRIT, Eastern Cooperative Oncology Group, National Cancer Institute, and V Foundation. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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31. A prospective study on early PET/CT scans during the first cycle of salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma.
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Cherng HJ, Chuang HH, Steiner R, Fayad L, Strati P, Nair R, Hagemeister F, Nastoupil LJ, Lee HJ, Neelapu SS, Flowers CR, Samaniego F, Rodriguez M, Macapinlac HA, Feng L, and Westin J
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Fluorodeoxyglucose F18, Humans, Pilot Projects, Prospective Studies, Salvage Therapy, Lymphoma, Large B-Cell, Diffuse diagnostic imaging, Lymphoma, Large B-Cell, Diffuse drug therapy, Positron Emission Tomography Computed Tomography
- Abstract
Many patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) will not respond to platinum-containing salvage chemotherapy. Predicting treatment failure earlier could help clinicians minimize chemotherapy toxicities for non-responders in favor of other treatments. We conducted a pilot study where 2 early PET/CTs were obtained on days 4 (D4) and 21 (D21) of cycle 1 (C1) of salvage therapy for DLBCL. Twenty-five patients were enrolled and have evaluable data. Ten (40%) had an unplanned therapy change after C1 and before end-of-treatment (EOT) evaluation due to treatment failure on early PET/CT as interpreted by the treating physician. Early PET/CT response at D4 or D21 was not associated with EOT response in evaluable patients. Disease specific survival was longer for patients with a persistent response on both D4 and D21 ( p = 0.042). Early PET/CT may predict salvage chemotherapy failure and could inform future clinical trials investigating early therapy change to non-chemotherapy treatments.
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- 2022
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32. Prognostic value of disease distribution in secondary central nervous system diffuse large B cell lymphoma treated with radiation therapy.
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Al Feghali KA, Fang P, Gule-Monroe M, Milgrom S, Khoury JD, Gunther JR, Sheu T, Nair R, Ahmed S, Steiner R, Strati P, Shpall EJ, Nieto YL, Hosing C, Nastoupil LJ, Westin JR, Neelapu SS, Fowler N, Flowers C, Pinnix CC, and Dabaja BS
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Central Nervous System, Humans, Neoplasm Recurrence, Local, Prognosis, Retrospective Studies, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
This study aimed to assess the prognostic value of baseline disease distribution for patients with the secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy and radiation (RT). 44 patients with secondary CNS DLBCL were reviewed. Twenty patients had leptomeningeal disease (LMD), and 24 had localized/targetable disease (LTD). Of 8 patients who received stem cell transplantation (SCT) after RT, 6 had LTD with a complete or partial response after RT. Median time to CNS relapse after RT was 10.1 months; 3/24 patients with LTD and 5/15 with LMD had CNS relapse. The median overall survival (OS) was 8 and 20 months for patients with LMD and LTD, respectively ( p = 0.20). On multivariable analysis, LTD, receipt of SCT, and response after RT were associated with better OS and CNS-disease-free survival. Patients with localized secondary CNS DLBCL may benefit from RT serving as a bridge to SCT.
- Published
- 2021
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33. BCL-W expression associates with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified.
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Marques-Piubelli ML, Solis LM, Parra ER, Castillo LM, Gouni S, Nair R, Chihara D, Konopleva M, Wistuba II, Iyer SP, Vega F, and Strati P
- Subjects
- Adult, Aged, Aged, 80 and over, Apoptosis Regulatory Proteins analysis, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, T-Cell, Peripheral epidemiology, Lymphoma, T-Cell, Peripheral pathology, Male, Middle Aged, Survival Analysis, Young Adult, Apoptosis Regulatory Proteins genetics, Lymphoma, T-Cell, Peripheral genetics
- Published
- 2021
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34. CRP and ferritin in addition to the EASIX score predict CAR-T-related toxicity.
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Greenbaum U, Strati P, Saliba RM, Torres J, Rondon G, Nieto Y, Hosing C, Srour SA, Westin J, Fayad LE, Lee HJ, Iyer SP, Nair R, Nastoupil LJ, Parmar S, Rodriguez MA, Samaniego F, Steiner RE, Wang M, Pinnix CC, Flowers CR, Tummala S, Ramdial JL, Yalniz FF, Hawkins M, Rezvani K, Champlin RE, Shpall EJ, Neelapu SS, Kebriaei P, and Ahmed S
- Subjects
- Cytokine Release Syndrome, Ferritins, Humans, Hematopoietic Stem Cell Transplantation, Lymphoma, Large B-Cell, Diffuse, Receptors, Chimeric Antigen
- Abstract
The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration., (© 2021 by The American Society of Hematology.)
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- 2021
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35. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma.
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Strati P, Ahmed S, Furqan F, Fayad LE, Lee HJ, Iyer SP, Nair R, Nastoupil LJ, Parmar S, Rodriguez MA, Samaniego F, Steiner RE, Wang M, Pinnix CC, Horowitz SB, Feng L, Sun R, Claussen CM, Hawkins MC, Johnson NA, Singh P, Mistry H, Johncy S, Adkins S, Kebriaei P, Shpall EJ, Green MR, Flowers CR, Westin J, and Neelapu SS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Male, Middle Aged, Retrospective Studies, Survival Rate, Adrenal Cortex Hormones administration & dosage, Dexamethasone administration & dosage, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy-associated toxicities., (© 2021 by The American Society of Hematology.)
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- 2021
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36. The impact of cell-of-origin, MYC/Bcl-2 dual expression and MYC rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy.
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Augustyn A, Medeiros LJ, Ludmir EB, Gunther J, Fang P, Li S, Ok CY, Bankston ME, Verma V, Pasalic D, Ahmed S, Nastoupil LJ, Westin JR, Strati P, Neelapu SS, Nair R, Steiner RE, Iyer SP, Rodriguez A, Fayad LE, Flowers CR, Dabaja BS, and Pinnix CC
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Humans, Neoplasm Recurrence, Local genetics, Prognosis, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-6 genetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse therapy, Proto-Oncogene Proteins c-myc genetics
- Abstract
We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 - 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.
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- 2021
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37. Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.
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Zhang S, Jiang VC, Han G, Hao D, Lian J, Liu Y, Cai Q, Zhang R, McIntosh J, Wang R, Dang M, Dai E, Wang Y, Santos D, Badillo M, Leeming A, Chen Z, Hartig K, Bigcal J, Zhou J, Kanagal-Shamanna R, Ok CY, Lee H, Steiner RE, Zhang J, Song X, Nair R, Ahmed S, Rodriquez A, Thirumurthi S, Jain P, Wagner-Bartak N, Hill H, Nomie K, Flowers C, Futreal A, Wang L, and Wang M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis genetics, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Humans, Imidazoles pharmacology, Lymphoma, Mantle-Cell diagnostic imaging, Lymphoma, Mantle-Cell drug therapy, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Naphthoquinones pharmacology, Positron Emission Tomography Computed Tomography methods, Sequence Analysis, RNA methods, Xenograft Model Antitumor Assays methods, Mice, Drug Resistance, Neoplasm genetics, Gene Expression Profiling methods, Genetic Heterogeneity, Lymphoma, Mantle-Cell genetics, Single-Cell Analysis methods, Tumor Microenvironment genetics
- Abstract
The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.
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- 2021
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38. Safety of CAR T-cell therapy in kidney transplant recipients.
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Mamlouk O, Nair R, Iyer SP, Edwards A, Neelapu SS, Steiner RE, Adkins SA, Hawkins M, Saini N, Devashish K, Strati P, Mandayam S, and Ahmed S
- Subjects
- Adult, Graft Rejection etiology, Graft Rejection pathology, Humans, Lymphoma, Large B-Cell, Diffuse pathology, Male, Prognosis, Graft Rejection therapy, Immunotherapy, Adoptive methods, Kidney Transplantation adverse effects, Lymphoma, Large B-Cell, Diffuse therapy, Transplant Recipients
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- 2021
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39. Outcomes of relapsed mantle cell lymphoma patients after discontinuing acalabrutinib.
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Jain P, Kanagal-Shamanna R, Zhang S, Ok CY, Navsaria L, Nastoupil L, Lee HJ, Tang G, Yin CC, Badillo M, Nair R, Li S, Patel KM, Flowers C, Vega F, Wang L, and Wang ML
- Subjects
- Antineoplastic Agents adverse effects, Benzamides adverse effects, Combined Modality Therapy, Disease Progression, Drug Substitution, Follow-Up Studies, Humans, Immunotherapy, Adoptive, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell therapy, Mutation, Protein Kinase Inhibitors adverse effects, Pyrazines adverse effects, Recurrence, Salvage Therapy, Sample Size, Treatment Outcome, Exome Sequencing, Withholding Treatment, Antineoplastic Agents therapeutic use, Benzamides therapeutic use, Lymphoma, Mantle-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazines therapeutic use
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- 2021
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40. Acute leucoencephalomyelopathy and quadriparesis after CAR T-cell therapy.
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Nair R, Drillet G, Lhomme F, Le Bras A, Michel L, Rossi J, Sherman M, Xue A, Kerber A, Jittapiromsak N, Chi L, Tummala S, Neelapu SS, and Houot R
- Subjects
- Humans, Immunotherapy, Adoptive, Quadriplegia etiology, Quadriplegia therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Chimeric Antigen genetics
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- 2021
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41. A Prospective Trial of Radiation Therapy Efficacy and Toxicity for Localized Mucosa-associated Lymphoid Tissue (MALT) Lymphoma.
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Fang P, Gunther JR, Pinnix CC, Dong W, Strati P, Nastoupil LJ, Steiner RE, Ahmed S, Damron EP, Fowler N, Nair R, Westin JR, Neelapu S, Ha CS, and Dabaja BS
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Head and Neck Neoplasms pathology, Head and Neck Neoplasms radiotherapy, Helicobacter Infections drug therapy, Helicobacter pylori, Humans, Kaplan-Meier Estimate, Lymphoma, B-Cell, Marginal Zone pathology, Male, Middle Aged, Orbital Neoplasms pathology, Orbital Neoplasms radiotherapy, Progression-Free Survival, Prospective Studies, Radiation Injuries pathology, Radiotherapy Dosage, Recurrence, Skin Neoplasms pathology, Skin Neoplasms radiotherapy, Stomach Neoplasms pathology, Stomach Neoplasms radiotherapy, Time Factors, Treatment Outcome, Lymphoma, B-Cell, Marginal Zone radiotherapy
- Abstract
Purpose: We report the long-term results of a prospective trial conducted to determine the efficacy and safety of radiation therapy (RT) alone in treating localized mucosa-associated lymphoid tissue (MALT) lymphoma., Methods and Materials: Patients with localized MALT lymphoma were eligible and treated with involved field RT to doses of 24 to 39.6 Gy. Relapse-free survival (RFS) was the primary endpoint. Kaplan-Meier analysis was used to estimate RFS, progression-free survival (PFS), and overall survival (OS) defined from time of study entry. Preplanned subgroup analyses were performed based on site of involvement., Results: From 2000 to 2012, 75 patients were accrued; 73 received protocol-specified RT. Median follow-up was 9.8 years. Thirty-four patients had gastric MALT, 17 orbital, 13 head and neck nonorbit, 4 skin, and 5 disease of other sites. Thirteen of 34 patients with gastric MALT were Helicobacter pylori positive at the time of initial diagnosis and underwent 1 to 3 courses of triple antibiotic therapy. All gastric MALT patients had documented persistent MALT without H. pylori on endoscopy before enrollment in the study. All patients achieved a complete response with a median time of 3 months. Eleven patients (15%) had disease relapse, 9 of which were at sites outside the RT field with median time to progression of 38.3 months. Median PFS was 17.5 years, and median RFS and OS were not reached. The 10-year relapse-free rate was 83% (95% confidence interval [CI], 74%-93%). The 10-year PFS rate was 71% (95% CI, 60%-84%). The 10-year OS rate was 86% (95% CI, 77%-96%). RFS, PFS, and OS did not differ by disease site (P = .17, .43, and .50, respectively). All relapses were successfully salvaged. One patient developed metastatic gastric adenocarcinoma and was found to also have recurrent MALT on biopsy. Otherwise, all relapsed patients were alive without evidence of disease at last follow-up, and no patient died of MALT lymphoma. Sixty-seven patients (92%) experienced acute toxicity during radiation, all of which were grade 1 and 2, with only 1 grade 3 toxicity. Twenty-two patients (30%) experienced late toxicity, with only 1 grade 3 toxicity., Conclusions: This prospective study confirms that RT for MALT lymphoma provides excellent long-term RFS with acceptable rates of toxicity. Current efforts are focused on RT de-escalation in an effort to further avoid treatment-related morbidity. CLINICALTRIALS.GOV: NCT04465162., (Copyright © 2020. Published by Elsevier Inc.)
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- 2021
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42. CAR T Cells.
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Nair R and Westin J
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- Humans, T-Lymphocytes, Immunotherapy, Adoptive, Neoplasms drug therapy
- Abstract
In 1891, Dr. William B. Coley, an American surgeon, made a compelling observation that immune system can be triggered to shrink tumors. The quest to exploit the power of immunotherapy however was forestalled by an era of chemotherapy that ensued. During World War II, the accidental sinking of a US naval ship led to a group of sailors developing pancytopenia due to poisoning from mustard gas (nitrogen mustard). The observation prompted wide-scale screening of these chemical compounds with cytotoxic potential; further clinical trials led to the first Food and Drug Administration (FDA) approval of a chemotherapy drug, nitrogen mustard. Immunotherapy field took further impetus, not until the last two decades, due to our deeper understanding of the immune system and the cellular and molecular pathways leading to tumor development. Two groundbreaking therapies which have shown great promise in this field involve "taking the breaks off" and "pushing the pedal" of the immune system. These therapies, namely, immune checkpoint inhibitors and adoptive cell therapy, respectively, have been successful in a variety of malignancies, while the former mostly in solid tumors and the latter in hematological malignancies., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2021
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43. A Rare Case of C3 Glomerulonephritis Presenting as Pulmonary Renal Syndrome.
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Mederos G, Patel H, Hapuarachchi M, Nair R, Ciobanu D, and Madhrira M
- Abstract
Description C3 glomerulonephritis (C3GN) is a rare disease that falls under the umbrella of C3 glomerulopathy (C3G). Classic manifestations of C3G include acute renal failure, proteinuria, and hematuria. In some cases, extrarenal manifestations can include ocular drusen. Until recent reports, C3G manifesting with pulmonary symptoms has not been reported. In this report, we describe a patient that initially presented with hemoptysis and acute renal failure, eventually leading to a diagnosis of pulmonary renal syndrome. Renal biopsy showed C3GN. The patient's symptoms improved with pulse dose steroids, plasmapheresis and mycophenolate mofetil. C3G presenting with pulmonary symptoms is rare. Further research is needed to understand the mechanism of complement deposition in the lung parenchyma and to determine a standard therapy to treat these patients. Clinicians should be aware of the potential pulmonary manifestations that can be caused by C3GN., Competing Interests: Conflicts of Interest The authors declare they have no conflicts of interest., (© 2020 HCA Physician Services, Inc. d/b/a Emerald Medical Education.)
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- 2020
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44. Angioimmunoblastic T-cell lymphoma associated with immune checkpoint inhibitor treatment.
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Duke TC, Nair R, Torres-Cabala C, Amaria RN, Keiser E, Miranda R, Iyer SP, and Heberton M
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- 2020
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45. Assessment of Radiation Doses Delivered to Organs at Risk Among Patients With Early-Stage Favorable Hodgkin Lymphoma Treated With Contemporary Radiation Therapy.
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Pinnix CC, Gunther JR, Fang P, Bankston ME, Milgrom SA, Boyce D, Lee HJ, Nair R, Steiner R, Strati P, Ahmed S, Iyer SP, Westin J, Parmar S, Rodriguez MA, Nastoupil L, Neelapu S, Flowers C, and Dabaja BS
- Subjects
- Adult, Bleomycin administration & dosage, Combined Modality Therapy methods, Dacarbazine administration & dosage, Disease-Free Survival, Dose-Response Relationship, Radiation, Doxorubicin administration & dosage, Female, Humans, Kaplan-Meier Estimate, Male, Neoplasm Staging, Positron Emission Tomography Computed Tomography methods, Vinblastine administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hodgkin Disease drug therapy, Hodgkin Disease pathology, Hodgkin Disease radiotherapy, Long Term Adverse Effects etiology, Long Term Adverse Effects prevention & control, Organs at Risk pathology, Organs at Risk radiation effects, Radiation Dosage, Radiotherapy methods
- Abstract
Importance: Response-adapted randomized trials have used positron emission tomography-computed tomography to attempt to identify patients with early-stage favorable Hodgkin lymphoma (ESFHL) who could be treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) without radiation therapy (RT). While maximal efficacy is demonstrated with combined modality therapy, RT is often omitted in fear of late adverse effects; however, the application of modern RT could limit these toxic effects., Objective: To determine the radiation doses delivered to organs at risk with modern involved-site RT among patients with ESFHL treated with 20 Gy after 2 cycles of ABVD., Design, Setting, and Participants: This case series included 42 adult patients with ESFHL (according to the German Hodgkin Study Group criteria) who were treated between 2010 and 2019, achieved complete response by positron emission tomography-computed tomography (1-3 on 5-point scale) following 2 cycles of ABVD, and then received consolidative RT. The study was conducted at a single comprehensive cancer center., Exposures: 2 cycles of chemotherapy followed by 20-Gy involved-site RT., Main Outcomes and Measures: The medical records of patients with ESFHL were examined. Organs at risk were contoured, and doses were calculated. Progression-free survival, defined from date of diagnosis to disease progression, relapse, or death, and overall survival were estimated using the Kaplan-Meier method., Results: The cohort comprised 42 patients with ESFHL (median [range] age at diagnosis, 35 [18-74] years; 18 [43%] women; 24 [57%] with stage II disease). At a median follow-up of 44.6 (95% CI, 27.6-61.6) months, the 3-year progression-free survival and overall survival rates were 91.2% (95% CI, 74.9%-97.1%) and 97.0% (95% CI, 80.4%-99.6%), respectively. The mean heart dose was less than 5 Gy (mean, 0.8 Gy; SD, 1.5 Gy; range, 0-4.8 Gy) in all patients. The mean (SD) breast dose for both breasts was 0.1 (0.2) Gy (left breast range, 0-1.0 Gy; right breast range, 0-0.9 Gy)., Conclusions and Relevance: In this study, combined modality therapy with 2 cycles of ABVD and 20 Gy for ESFHL was highly effective and avoided excess doses to organs at risk, which may limit long-term toxic effects.
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- 2020
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46. Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma.
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Strati P, Nastoupil LJ, Westin J, Fayad LE, Ahmed S, Fowler NH, Hagemeister FB, Lee HJ, Iyer SP, Nair R, Parmar S, Rodriguez MA, Samaniego F, Steiner RE, Wang M, Pinnix CC, Adkins S, Claussen CM, Martinez CS, Hawkins MC, Johnson NA, Singh P, Mistry HE, Horowitz S, George S, Feng L, Kebriaei P, Shpall EJ, Neelapu SS, Tummala S, and Chi TL
- Subjects
- Antigens, CD19 therapeutic use, Biological Products, Humans, Immunotherapy, Adoptive, Neurotoxicity Syndromes diagnostic imaging, Neurotoxicity Syndromes etiology, Posterior Leukoencephalopathy Syndrome
- Abstract
Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients., (© 2020 by The American Society of Hematology.)
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- 2020
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47. Interleukin-6 receptor antagonist therapy to treat SARS-CoV-2 driven inflammatory syndrome in a kidney transplant recipient.
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Allam SR, Dao A, Madhrira MM, Antiporta PB, Nair RR, Guiteau JJ, and Reyad AI
- Subjects
- Aged, Biomarkers, COVID-19, Coronavirus Infections diagnostic imaging, Female, Humans, Inflammation drug therapy, Kidney Transplantation, Pandemics, Pneumonia, Viral diagnostic imaging, SARS-CoV-2, Transplant Recipients, Antibodies, Monoclonal, Humanized therapeutic use, Betacoronavirus, Coronavirus Infections drug therapy, Pneumonia, Viral drug therapy, Receptors, Interleukin-6 antagonists & inhibitors
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- 2020
- Full Text
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48. Imaging Surveillance of Limited-stage Classic Hodgkin Lymphoma Patients After PET-CT-documented First Remission.
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Glober G, Gunther J, Fang P, Milgrom S, Korivi BR, Jensen CT, Wagner-Bartak NA, Ahmed S, Lee HJ, Nair R, Steiner R, Parmar S, Iyer S, Westin J, Fayad L, Rodriguez MA, Neelapu S, Nastoupil L, Flowers CR, Dabaja BS, and Pinnix CC
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Hodgkin Disease mortality, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Progression-Free Survival, Young Adult, Hodgkin Disease diagnostic imaging, Positron Emission Tomography Computed Tomography methods
- Abstract
Introduction: Early stage Hodgkin lymphoma (ESHL) is highly curable; however, 10% to 15% of patients experience relapse. We examined the utilization of follow-up imaging for patients with ESHL who achieved a metabolic complete response after upfront therapy., Materials and Methods: The records of adult patients treated at a single institution between 2003 and 2014 were reviewed. Positron emission tomography-computed tomography (PET-CT) and CT scan frequency was quantified during the 2 years following treatment and subsequent visits beyond 2 years., Results: The study cohort contained 179 patients. The median age was 31 years; bulky disease was present in 30%. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or AVD (doxorubicin, vinblastine, and dacarbazine) was given in 97%; 75% received radiation therapy. At a median follow-up of 6.9 years, the 5-year progression-free and overall survival rates were 93.7% and 98.1%, respectively. Relapse occurred in 5% (n = 9) of patients at a median of 9.1 months (range, 4.6-27.2 months) from therapy. Two patients presented with symptoms prompting imaging in follow-up. Within 2 years after therapy, 376 PET-CT scans and 3325 CT scans were performed, yielding an average of 2.1 PET-CTs and 18.6 CTs per patient. Of the initial 179 patients, 113 had follow-up conducted beyond 2 years post-therapy; an average of 2.7 PET-CTs and 33.2 CTs were performed. In the 2-year post-therapy period, 463 scans were performed per relapse detected., Conclusion: In this cohort of patients with ESHL who responded completely to frontline therapy, the relapse rate was low. Routine imaging surveillance lacks clinical benefit in this patient population., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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49. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma.
- Author
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Pinnix CC, Gunther JR, Dabaja BS, Strati P, Fang P, Hawkins MC, Adkins S, Westin J, Ahmed S, Fayad L, Lee HJ, Nair R, Steiner RE, Iyer SP, Rodriguez MA, Wang M, Flowers C, Neelapu SS, and Nastoupil LJ
- Subjects
- Antigens, CD19 therapeutic use, Biological Products, Humans, Survival Rate, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
The impact of bridging therapy (BT) administered between leukapheresis and chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is unclear. We evaluated the influence of BT (systemic therapy [ST], radiation therapy [RT], or combined-modality therapy [CMT]) on outcomes of 148 LBCL patients who underwent leukapheresis for planned axicabtagene ciloleucel (axi-cel) infusion. The 55% (n = 81) of patients who received BT were more likely to have international prognostic index (IPI) score ≥3 (P ≤ .01), bulky disease (P = .01), and elevated lactate dehydrogenase (LDH; P ≤ .01). The 1-year progression-free (PFS) and overall survival (OS) rates were 40% and 65% in non-BT patients vs 21% and 48% in BT patients (P = .01 and .05, respectively). Twenty-four patients (16%) did not receive axi-cel, most commonly because of lymphoma progression (88%), despite 80% (n = 19) receiving BT. Among 124 patients who received axi-cel, 50% (n = 62) received BT with ST (n = 45), RT (n = 11), or CMT (n = 6); 1-year PFS and OS rates were not significantly different between BT and non-BT cohorts (P = .06 and .21, respectively). There was no difference in proportion of patients with IPI ≥3, limited-stage disease, or elevated LDH between ST, RT, and CMT groups. Compared with non-BT patients, 1-year PFS was inferior for ST-bridged patients (P = .01). RT-bridged patients had improved PFS compared with ST-bridged patients (P = .05). Despite the poor prognosis associated with requiring BT, RT can be an effective bridging strategy. Future studies are necessary to identify strategies that may improve access to CAR T-cell therapy and outcomes., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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50. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma.
- Author
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Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Watson G, Horowitz SB, Brown ART, Do B, Rodriguez MA, Nair R, Shpall EJ, Green MR, Neelapu SS, and Westin JR
- Subjects
- Humans, Immunotherapy, Adoptive, Interleukin 1 Receptor Antagonist Protein, Treatment Outcome, Lymphoma, B-Cell, Receptors, Chimeric Antigen
- Published
- 2020
- Full Text
- View/download PDF
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