Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis
Sirpa Leppä, Judit Jørgensen, Anne Tierens, Leo Meriranta, Ingunn Østlie, Peter de Nully Brown, Unn-Merete Fagerli, Thomas Stauffer Larsen, Susanna Mannisto, Lars Munksgaard, Martin Maisenhölder, Kaija Vasala, Peter Meyer, Mats Jerkeman, Magnus Björkholm, Øystein Fluge, Sirkku Jyrkkiö, Knut Liestøl, Elisabeth Ralfkiaer, Signe Spetalen, Klaus Beiske, Marja-Liisa Karjalainen-Lindsberg, Harald Holte, Sirpa Leppä, Judit Jørgensen, Anne Tierens, Leo Meriranta, Ingunn Østlie, Peter de Nully Brown, Unn-Merete Fagerli, Thomas Stauffer Larsen, Susanna Mannisto, Lars Munksgaard, Martin Maisenhölder, Kaija Vasala, Peter Meyer, Mats Jerkeman, Magnus Björkholm, Øystein Fluge, Sirkku Jyrkkiö, Knut Liestøl, Elisabeth Ralfkiaer, Signe Spetalen, Klaus Beiske, Marja-Liisa Karjalainen-Lindsberg, Harald Holte
Abstract
Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.
Conflict of interest statement
Conflict-of-interest disclosure: S.L. reports research funding from Mundipharma and Amgen during the conduct of the study; and honoraria and research funding from Celgene, Roche, Takeda, Bayer, and Janssen-Cilag outside the submitted work. J.J. reports personal fees from Roche and Gilead outside the submitted work. H.H. reports research funding from Mundipharma and Amgen during the conduct of the study; and participation in advisory boards for Novartis, Gilead, Roche, Nordic Nanovector, and Takeda. The remaining authors declare no competing financial interests.
© 2020 by The American Society of Hematology.
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Source: PubMed