- Recently presented at the Annual Meeting of the American Society of Hematology (ASH), two phase III studies, co-authored by VHIO investigators, assessed the efficacy and safety of novel treatment approaches for the management of B-cell lymphomas.
- Results of the phase III POLARIX trial point to a modified treatment approach for previously untreated diffuse large B-cell lymphoma.
- The POLARIX investigators reported a higher progression-free survival in patients who were assigned to receive adjusted therapy with an antibody-drug conjugate.
- The BELINDA phase III trial compared the efficacy of second-line T-cell immunotherapy vs. standard care in aggressive B-cell non-Hodgkin lymphoma.
- The investigators showed similar outcomes of patients treated with tisagenlecleucel compared with standard of care. Further studies are warranted to establish which patients may benefit most from each treatment strategy.
Barcelona, December 23, 2021. During this month’s in-person and virtual Annual Meeting of the American Society of Hematology (ASH), 11-14 December, 2021 (Atlanta, GA, USA), the results of two phase III international studies in B-Cell Lymphoma, co-authored by VHIO clinical investigators, were presented, debated and discussed. Reflective of their relevance and promise in ultimately improving outcomes for this patient population, the findings from both studies published simultaneously in The New England Journal of Medicine (NEJM) (1), (2).
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer and the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about 30% of B-cell NHL, with an estimated 8,500 new cases each year in Europe alone. For over two decades standard therapy for DLBCL has been the combination of monoclonal antibody rituximab with chemotherapeutics cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
While this first-line therapy has significantly improved outcomes for this patient population, with a cure rate of 60%, the remaining 40% of patients either fail to respond to initial treatment, or ultimately suffer disease recurrence, with limited salvage treatments available. Important research efforts aimed at more successfully managing and treating these patients have failed to translate in meaningful improvements. Identifying and developing alternative and more effective therapeutic strategies for non-responders to R-CHOP represents an important, unmet clinical need.
Standard R-CHOP combination vs. modified regimen with antibody-drug conjugate, polatuzumab vedotin
Spearhead by Hervé Tilly, Professor of Hematology, University of Rouen (France), the double-blind, placebo-controlled international phase III POLARIX trial was designed to evaluate a modified regimen of R-CHOP (pola-R-CHP) switching chemotherapy vincristine with the antibody-drug conjugate (ADC) polatuzumab vedotin, versus standard R-CHOP, in DLBCL patients with previously untreated intermediate or high-risk disease.
The POLARIX investigators, including Pau Abrisqueta, Clinical Research Coordinator of VHIO’s Experimental Hematology Group, directed by Francesc Bosch, reported positive findings showing that the novel pola-R-CHP combination with the ADC targeting CD79b, reduced the risk of disease progression, relapse or death, compared with those patients who received standard R-CHOP. These results published in parallel in The New England Journal of Medicine (NEJM) (1).
“Our positive findings point to a more effective treatment approach for patients with previously untreated intermediate or high-risk diffuse large B-cell lymphoma. Since the CD79b protein is found expressed in the majority of B cells, it constitutes a major target for drug development,” said Pau Abrisqueta, co-author of this present study.
He continued, “By specifically binding to tumor cells, this antibody selectively releases chemotherapy into the cells and thus potentiates the treatment of these patients.”
The POLARIX study included 879 patients, with 440 randomized to receive the modified pola-R-CHP regimen, and 439 assigned to the R-CHOP group. After a median follow-up of 28 months, first data shows that the percentage of patients surviving without disease progression was higher in those receiving the modified combination with ADC polatuzumab vedotin, than in those receiving standard treatment, 76.7% vs. 70.2% respectively. The risk of disease progression, relapse or death was 27% lower among those patients who received the modified pola-R-CHP combination.
“While the increase in progression-free survival between the groups at follow-up is by no means radical, our data is encouraging since no other alternative therapeutic strategy to-date has succeeded in improving outcomes from treatment with standard R-CHOP. Further, the modified regimen does not show increased toxicity,” observed Pau Abrisqueta.
He concluded, “We believe that our results could ultimately lead to a shift in the front-line standard of care for DLBCL patients. Longer follow-up will hopefully show that this new combination translates into increased overall survival of these patients.”
T-cell immunotherapy as second-line therapy for aggressive lymphoma
Patients suffering from aggressive diffuse large B-cell lymphoma (DLBCL) whose disease is refractory to or relapses within 12 months after first-line treatment have a poor prognosis. Improving outcomes for these patients remains a substantial clinical challenge.
Standard second-line options currently include immunochemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) in those patients having a response. More than half of these patients however, will not receive HSCT owing to the failure of therapy to sufficiently reduce tumor burden.
One of the most promising, emerging treatments an increasing number of tumor types including lymphoma is CAR T-cell therapy. The CD19-directed T-cell immunotherapy, tisagenlecleucel, has been approved as third-line therapy for DLBCL. Various clinical studies, including the BELINDA international, randomized phase III trial, are assessing its efficacy as second-line treatment for aggressive lymphoma.
Led by Michael R. Bishop, Director of the David and Etta Jonas Center for Cellular Therapy, University of Chicago (Chicago, IL, USA), the BELINDA Investigators, including VHIO’s Pere Barba, compared the efficacy and safety of tisagenlecleucel with current standard-care in the context of second-line therapy, results of which were also presented at the ASH Annual Meeting 2021 and published simultaneously in NEJM (2), accompanied by a related Editorial (3).
“Our study was designed with the expectation that tisagelecleucel would achieve a superior response compared with current second-line standard-care treatment, particularly in patients whose disease was refractory to chemotherapy,” said Pere Barba, Hematologist and Lead Investigator of VHIO’s Experimental Hematology Group (PI: Francesc Bosch), Vall d’Hebron Barcelona Hospital Campus, and a fourth author of this study .
“While second-line treatment with this CD19-directed T-cell immunotherapy did not show greater efficacy compared to standard salvage therapy in this trial, our findings are relevant since they will contribute to better defining second-line therapy for patients with B-cell lymphomas. Further studies are warranted to assess which patients may benefit most from each treatment approach,” concluded Pere Barba.
- Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2021 Dec 14. doi: 10.1056/NEJMoa2115304. Epub ahead of print. PMID: 34904799.
- Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2021 Dec 14. doi: 10.1056/NEJMoa2116596. Epub ahead of print. PMID: 34904798.
- Roschewski M, Longo DL, Wilson WH. CAR T-Cell Therapy for Large B-Cell Lymphoma – Who, When, and How? N Engl J Med. 2021 Dec 14. doi: 10.1056/NEJMe2118899. Epub ahead of print. PMID: 34904797.