Rituximab/Bendamustine Combo Demonstrates Promising Results in Fludarabine-Ineligible CLL

According to results from the MABLE trial, the combination of rituximab (Rituxan) plus bendamustine (Treanda; R-B) demonstrated significant value as a frontline treatment option for fludarabine-ineligible patients with chronic lymphocytic leukemia (CLL).

The standard treatment for patients with CLL is combination rituximab plus fludarabine and cyclophosphamide. However, many patients are deemed unfit to receive fludarabine, leaving only chemotherapy options of bendamustine and chlorambucil. The MABLE trial sought to find an alternative treatment option for patients with CLL that are ineligible for standard treatment.

MABLE, a randomized, open-label, multicenter phase IIIb trial, investigated the efficacy and safety with treatment regimens of R-B or rituximab plus chlorambucil (R-Clb). The results were compared to the current treatment option for this patient population, obinutuzumab (Gazyva) plus chlorambucil (G-Clb).

A total of 357 fludarabine-ineligible patients with CLL were recruited for the trial, of which 355 were enrolled. The study was conducted from February 23, 2010, to March 31, 2014.

Treatment-naïve patients were randomized to receive either R-B (n=121) or R-Clb (n=120) every 4 weeks for 6 cycles. Investigators also looked at those patients who were previously treated, wherein 57 patients were randomized to the R-B arm and 59 to the R-Clb arm for second-line treatments. Notably, 95 (27%) patients withdrew from treatment during the study.

Rituximab (375 mg/m²) was administered on day 1 of cycle 1, followed by a dose of 500 mg/m²on day 1 of cycles 2-6. In the R-B arm, bendamustine was administered at 90 mg/m²in the frontline or 70 mg/m²in the second-line on days 1 and 2 of each cycle, while chlorambucil (10 mg/m²) was administered daily for each cycle in the R-Clb arm.

If patients in the R-Clb arm did not achieve complete response after cycle 6, they continued treatment for at least 6 more cycles or until complete response was reached.

The primary endpoint of this trial was complete response rate (ORR), based on a bone marrow biopsy in firstline patients. Progression-free survival (PFS), overall survival (OS), minimal residual disease, and safety were included as secondary endpoints. Safety was based on adverse events (AEs) which were monitored throughout the study.

Ninety-two (76.7%) patients in the R-B arm and 97 (80.8%) patients in the R-Clb arm completed 6 cycles of rituximab, while 92 (76.7%) versus 57 (47.5%) completed six cycles of bendamustine and chlorambucil, respectively. Also, 6 (5.0%) patients in the R-B arm and 2 (1.7%) patients in the R-Clb arm received a dose reduction or delay in treatment due to treatment-emergent toxicities.

Median follow-up was 23.5 months in the R-B arm and 23.3 months in the R-Clb arm. In the frontline group, 29 (24%) patients in the R-B arm achieved complete response, compared to 11 (9%) patients in the R-Clb arm.

Investigators noted ORRs in the R-B and R-Clb arms at 91% versus 86%, respectively (P= .304). Stable disease was found in 3% of the R-B arm and 6% of the R-Clb arm. Progressive disease was also found in 3% at the end of treatment of R-B and 2% of R-Clb.

There was a statistically significant difference in PFS of 10 months between the R-B and R-CLb arms (39.6 vs. 29.9 months, respectively) (HR= 0.523; 95% CI, 0.339-0.806;P= .003). However, median OS was not statistically different, recorded at 43.8 months for R-B and not reached for R-Clb (HR= .975; 95% CI, 0.505-1.880;P= .939)

Regarding the AEs found in this study, authors wrote, “Safety profiles were similar for rituximab plus chlorambucil and rituximab plus bendamustine, with no new or clinically relevant safety signals, and events were as expected for CLL patients receiving immunochemotherapy.”

Neutropenia was the most common in both R-B and R-Clb (56% vs .49%, respectively). Of AEs recorded by the System Organ Class (SOC), the R-B arm experienced more SOC ‘skin and subcutaneous tissue disorders’ (36% vs. 23% in the R-Clb arm), as well as a higher rate of incidence of rash (16% vs. 5%).

A higher rate of grade 3 or higher AEs was recorded for R-B (75%) compared to R-Clb (64%). SOC ‘blood and lymphatic system disorders’ were found in 56% versus 47%, serious AEs in 41% versus 32%, and SOC ‘infections and infestations’ in 19% versus 8%, for R-B and R-Clb arms, respectively.

Rituximab-related AEs were experienced in 81% of patients in the R-B arm and 73% in the R-Clb arm, leading to discontinuation in 18% R-B versus 11% R-Clb.

Sixty-five patients had CLL-related deaths, of which 30 (17%) were from the R-B arm and 35 (20%) from R-Clb. In AE-related deaths, 4 per arm were caused by infection, 1 per arm by acute myeloid leukemia or myelodysplastic syndrome, 1 in R-Clb from other neoplasm, and 11 in R-B versus 8 in R-Clb from other causes.

While ORRs were similar in both arms, it was higher in treatment-naïve patients in the R-Clb arm. However, the PFS in that group of patients was over 10 months lower than treatment-naïve patients in the R-B arm. Treatment regimens for the R-B arm found double PFS results compared to the previous CLL11 trial (29.9 vs. 15.4 months, respectively).

Median OS was not reached in previous studies, nor was it significantly different in the MABLE trial. Safety profiles, though were found similar for R-B and R-Clb, and AEs were similar to those expected for immunochemotherapy treatments. The grade 3 or higher AEs were slightly higher in the R-B arm, mostly due to a higher rate of infections and infestations.

Compared to previous studies of G-Clb, response rates were lower in R-Clb, while PFS was also recorded at lower rates. However, R-B demonstrated comparative responses to G-Clb for treatment-naïve patients with CLL.

“Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible CLL patients,” the study authors wrote. Due to the economic burden and availability issues found with new agents, R-B can be a useful option for the frontline treatment of patients with CLL.

Reference:

A. Michallet, M. Aktan, W. Hiddemann, et al. Rituximab Plus Bendamustine Or Chlorambucil For Chronic Lymphocytic Leukemia: Primary Analysis Of The Randomized, Open-Label MABLE Study.HaematologicaApril 2018 103: 698-706; Doi:10.3324/haematol.2017.170480