Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

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.

Figures

Graphical abstract

Figure 1.

Study schema. (A) Trial profile. (B) Patient disposition. CR, complete response; CRu,complete response, unconfirmed; CSF, cerebrospinal fluid; EN, extranodal; f-up, follow-up; IT, intrathecal; OS, overall survival; PD, progressive disease; PET, positron emission tomography; PR, partial response; RT, radiotherapy; SD, stable disease.

Figure 2.

Survival analyses. Kaplan-Meier survival estimates for FFS (A), risk of CNS relapse (B), PFS (C), and OS (D).

Figure 3.

Subgroup analyses. Forest plot showing subgroup analysis of PFS. Ara-C, cytarabine; DPE, double-protein expressor; EN, extranodal; PS, performance status.

Figure 4.

Comparison of survival rates between LBC-04 and LBC-05 trials. Kaplan-Meier survival estimates for FFS (A), PFS (B), OS (C), and risk of CNS relapse (D) according to the LBC-04 and LBC-05 trials. (E) Forest plot showing subgroup analysis of PFS in the LBC-04 vs LBC-05 trials. In panel E, PFS in case of all patients is adjusted for aaIPI score.