Higher Bortezomib Doses Linked to Longer OS in MCL

Tadeusz Robak, MD, PhD

Patients with newly diagnosed mantle cell lymphoma (MCL) assigned to frontline chemotherapy had a survival advantage when they were able to receiver higher dose intensities of bortezomib (Velcade), according to findings published in Leukemia & Lymphoma.

In posthoc analysis from the randomized, phase III LYM-3002 study, the 4-year overall survival (OS) rate was 79.5% for patients ineligible for stem cell transplantation (SCT) assigned to ≥4.6 mg/m2 of bortezomib per cycle compared with 57.1% for patients who received a lower dose intensity (hazard ratio [HR], 0.38; P = .003). In multivariate analysis adjusted for potential confounding patient and disease characteristics, dose intensity remained the most significant predictor of OS (HR, 0.40; 95% CI, 0.20-0.78; P = .008).

Patients with newly diagnosed MCL who were not candidates for SCT were assigned to ≥4.6 mg/m2 of bortezomib (n = 93) or <4.6 mg/m2 bortezomib (n = 88) for at least 6 cycles. All patients received first-Line chemotherapy with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP).

Bortezomib dose modifications were based on previously established toxicities or new toxicities observed at any time. Bortezomib was withheld in patients experiencing grade ≥3 neutropenia with fever, grade 4 neutropenia >7 days, a platelet count <10,000 cells/L, or any grade ≥3 nonhematologic toxicity determined to be related to bortezomib.

For nonhematologic toxicities, bortezomib was held for up to 2 weeks until resolution to grade 2. For hematologic toxicities, bortezomib was held for up to 2 weeks until absolute neutrophil count was ≥750 cells/L and platelet count was ≥25,000 cells/L. Bortezomib was discontinued permanently if toxicities were not resolved, as per the above after dose withholding. If toxicities were resolved, bortezomib dose was reduced by approximately 25%.

Patients in the lower-intensity arm were older on average (69 vs 60 years) and more patients in that arm were older than 60 years (83% vs 54%). Investigators added that there were slight imbalances between the 2 groups in terms of gender, race, age, performance status, IPI score and proportion of patients with elevated LDH.

In the lower-intensity group, 16% of doses were withheld due to adverse events (AEs), most frequently neutropenia (69%), leukopenia (24%) and thrombocytopenia (23%). Doses were withheld less often due to AEs in the higher dose intensity group, at 4%, with similar AEs being responsible: neutropenia (68%), leukopenia (24%) and thrombocytopenia (19%).

After automatic backward selection for the most significant covariates—bortezomib dose intensity, baseline ECOG performance status, and baseline LDH level—dose intensity remained the strongest predictor of OS of all the variables considered in the final model (HR, 0.38; 95% CI, 0.20-0.71; P = .003).

For baseline ECOG performance status (1 vs >1), the HR in the final model was 0.43 (95% CI, 0.20-0.95; P = .037); for baseline LDH level (normal vs above normal limits), the HR was 0.50 (95% CI, 0.26-0.97; P = .041). There was a stronger association between bortezomib dose intensity and OS than between the components of MIPI (age, WBC count, LDH level, ECOG performance status) or disease stage.

Investigators observed a clear trend for prolonged progression-free survival (PFS) in the higher-intensity group in univariate analysis, but the difference was not statistically significant (HR, 0.78; 95% CI, 0.51-1.20; P = .2528). Median PFS was 35.2 months (95% CI, 20.6-49.7) for the higher-intensity arm compared with 19.9 months (95% CI, 13.9-45.6) in the lower-intensity group.

“As PFS appeared to be less strongly influenced by bortezomib dose intensity, further analyses focused on OS using a multivariate approach to account for the imbalances in baseline and disease characteristics between the higher and lower dose intensity groups,” first author Tadeusz Robak, MD, PhD, Copernicus Memorial Hospital, Medical University of Lodz, Poland, and coinvestigators wrote.

The researchers noted fewer grade ≥3 AEs in the higher dose intensity group compared with the lower dose intensity group (83.9% vs 98.9%). Hematologic toxicities were the most frequently reported AEs in both groups.

Amelia A. Langston, MD, professor and executive chair, department of hematology and medical oncology, Emory University Medical School, and medical director, bone marrow and stem cell transplant program, Emory Winship Cancer Institute, reviewed the data for OncLive. She said the study pointed to the importance of bortezomib as a therapy and showed that, as might be expected, patients who are able to receive more treatment have superior outcomes. However, the results raise more questions than they answer.

“This is not unlike other studies that have been done in a variety of cancer types examining the ability to deliver the planned therapy as a predictor of outcome. In almost every study where that’s been done, the outcome has been the same—the people who were able to get full-dose therapy, or something approaching full-dose therapy, did better than the people who did not,” she said. “But does that mean that the people who couldn’t get full dose therapy where just sicker and were destined to do poorly or does it mean that the delivery of chemotherapy is important in terms of being able to cure the disease? I think it means both things.”

Langston went on to say, “There are 2 categories of toxicities that there were rules around in the study. One was neuropathy and in most regimens, that’s the most common toxicity we see and the most debilitating. But most of the patients in this study were held or not dose reduced for neuropathy. They were held or dose-reduced for hematologic toxicity. It raises the question about whether or not future studies should try to be more aggressive about managing patients’ hematologic toxicity without bortezomib dose reduction.”

Robak T, Huang H, Jun J, et al. Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study [published online June 5, 2017]. Leuk Lymphoma. doi: 10.1080/10428194.2017.1321750.