Ten-Year Outcomes after CAR T-Cell Therapy for B-Cell Lymphomas
After 10 years one third of the heavily pretreated lymphoma patients who had CAR-T therapy stayed disease free.
Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial
Author(s): Prof Georg Lenz, MD1; Prof Marek Trněný, MD2; John M Burke, MD3; Prof Grzegorz S Nowakowski, MD4; Prof Christopher P Fox, MD5; Annalisa Chiappella, MD6; Johannes Duell, MD7; Young Woo Jeon, MD8; Prof Chan Y Cheah, MD9; Jason Westin, MD10; Joseph Z Ye, MD11; Priscilla B Caguioa, MD12; David Belada, MD13; Ho-Jin Shin, MD14; Prof Sung Yong Oh, MD15; Sandy Amorim, MD16; Matthew Ku, MBBS17; Heidi Mocikova, MD18; Javier López Jiménez, MD19; Prof Gianluca Gaidano, MD20; Andreas Rosenwald, MD21; Roberto Chiarle, MD22,23; Philomena Colucci, DO24; Sonia Ioannidis, PhD25; Lulu Cheng, PhD24; Umberto Vitolo, MD26;
Source: DOI: 10.1016/S0140-6736(26)00866-4
Dr. Maen Hussein's Thoughts
Progression-free survival was improved in the tafa-len-R-CHOP group vs the R-CHOP with 2-year progression-free survival rates of 71·1vs 62·9% toxicity was higher with tafa-len-R-CHOP with a higher rate of fatal treatment-emergent adverse events, but more overall deaths the RCHOP arm. It is early to add Len taf because of toxicity esp with OS survival and deep response data being immature.
BACKGROUND
Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone). We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas.
METHODS
frontMIND is a phase 3, randomised, double-blind, placebo-controlled study conducted 298 centres in North America, South America, Europe, and the Asia–Pacific region. Patients aged 18–80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m2 intravenous on day 1, cyclophosphamide 750 mg/m2 intravenous on day 1, doxorubicin 50 mg/m2 intravenous on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1–5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1–10), while those in the R-CHOP group received matching placebos. The primary endpoint was investigator-assessed progression-free survival (defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treat population; safety was included as a secondary endpoint among all patients who received least one dose of study treatment. The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling.
FINDINGS
Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group. the time of primary analysis (median follow-up 35·2 months [95% CI 35·0–35·4]), progression-free survival was improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio [HR] 0·75 [95% CI 0·59–0·96]; p=0·0194), with 2-year progression-free survival rates of 71·1% (66·3–75·4) with tafa-len-R-CHOP versus 62·9% (57·9–67·5) with R-CHOP. Interim HR for overall survival was 0·85 (0·63–1·14). The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 [87%] of 443) than with R-CHOP (340 [76%] of 447). Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 [6%]) than with R-CHOP (17 [4%]). However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 [19%] vs 97 [22%]). Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 [16%] of 443) and R-CHOP group (66 [15%] of 447).
INTERPRETATION
Progression-free survival was significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide. Overall survival data are immature; follow-up is ongoing. Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survival benefit observed with tafa-len-R-CHOP. Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL.
Author Affiliations
1Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany; 2First Faculty of Medicine, Charles University, Prague, Czechia; 3Sarah Cannon Research Institute Rocky Mountain Cancer Centers, Aurora, CO, United States of America; 4Division of Hematology, Mayo Clinic, Rochester, MN, United States of America; 5School of Medicine, University of Nottingham, and Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom of Great Britain and Northern Ireland (the); 6Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology, Milan, Italy; 7Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; 8Department of Hematology, Yeouido St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of); 9Hollywood Private Hospital and University of Western Australia, Nedlands, WA, Australia; 10MD Anderson Cancer Center, Houston, TX, United States of America; 11American Oncology Network, Vista Oncology Division, Olympia, WA, United States of America; 12St Luke's Medical Center, Quezon, Philippines; 13Department of Internal Medicine-Haematology, Charles University, Hospital and Faculty of Medicine, Hradec Králové, Czechia; 14Division of Hematology-Oncology, Department of Internal Medicine, Research Institute of Medical Science, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea (the Republic of); 15Division of Hematology-Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea (the Republic of); 16Department of Hematology and Cellular Therapy, Hôpital Saint Vincent de Paul, Lille, France; 17Department of Haematology, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia; 18Department of Hematology, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czechia; 19Department of Haematology and Hemotherapy, Hospital Ramón y Cajal, Universidad Alcalá Henares, IRYCIS, Madrid, Spain; 20Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità, Novara, Italy; 21Institute of Pathology, University of Würzburg, Würzburg, Germany; 22Division of Diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy; 23Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy; 24Incyte Corporation, Wilmington, DE, United States of America; 25Incyte Biosciences International Sàrl, Morges, Switzerland; 26Candiolo Cancer Institute, FPO-IRCCS Candiolo, Turin, ItalyRelated Articles
Mosunetuzumab Plus Polatuzumab Vedotin in Transplant-Ineligible Refractory/Relapsed Large B-Cell Lymphoma: Primary Results of the Phase III SUNMO Trial
Median progression-free survival (PFS) was significantly longer with mosunetuzumab plus polatuzumab vedotin (Mosun-Pola) than with R-GemOx (11.5 months vs 3.8 months). The overall response rate (ORR) was significantly higher with Mosun-Pola compared with R-GemOx (70% vs 40%; P < .0001), with complete response rates of 51% and 24%, respectively. Cytokine release syndrome (CRS) occurred in fewer than 5% of patients.
Five-Year Outcomes of the POLARIX Study Comparing Pola-R-CHP and R-CHOP in Patients With Diffuse Large B-Cell Lymphoma
Another update demonstrated the superiority of polatuzumab vedotin plus R-CHOP (Pola-R-CHOP) over R-CHOP alone, with improved progression-free survival (PFS) (64% vs 59%). Overall survival (OS) was not statistically significant; however, the hazard ratio was 0.85, with greater benefit observed in high-risk patients.
Remission Assessment by Circulating Tumor DNA in Large B-Cell Lymphoma
Minimal residual disease (MRD) testing after two cycles of therapy and at the end of treatment predicted 2-year progression-free survival (PFS) (96% in MRD-negative patients vs 67% in MRD-positive patients). MRD status was more predictive of treatment outcomes than radiographic imaging in this patient population.
Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma
The ECHELON-3 study showed BV + Len + R is an active and (relatively) tolerable in the rrDLBCL patient group. Interestingly, patients did not have to be CD30+ to see a benefit.