This month, in a Letter to the Editor of the British Journal of Haematology, Alexey V. Danilov from the Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA, and colleagues reported findings of a phase I dose-ranging study of bendamustine and rituximab (BR) in patients with Chronic Lymphocytic Leukemia (CLL) with comorbidities.
Patients were eligible if they had previously untreated (n=5) or Relapsed/Refractory (R/R; n=2) CLL with a Cumulative Illness Rating Scale (CIRS) score of ≥7, one or more grade 3 comorbidities (“severe”), and met International Working Group CLL 2008 criteria for treatment requirement.
A standard 3 + 3 dose escalation design was implemented. Bendamustine was administered at 45mg/m2 on days 1 and 2 of 28 day cycles for up to 6 cycles. Rituximab was administered at 375mg/m2 in cycle 1 and at 500mg/m2 in cycles 2–6). Dose escalation to 70mg/m2, or de-escalation to 25mg/m2 if Dose-Limiting Toxicities (DLT) occurred, was planned for bendamustine.
The primary outcome measures included treatment-related toxicity and identification of the Maximum Tolerated Dose (MTD), defined as the dose cohort above which ≥2/6 patients experienced DLTs. Seven patients were treated in the phase I portion of the study. The dose escalation phase was completed and one patients was enrolled in the expansion cohort; however, slow accrual caused this study to be closed at this point. This Letter to the Editor included results from the dose escalation portion of the study.
- Male = 6/7 pts; median age = 71 years (range, 65–77)
- Median time since diagnosis: previously untreated = 2 years; R/R = 8 years
- Median CIRS score = 9
- Most common grade 3–4 comorbidities were hypertension (n=4; required ≥2 drugs), diabetes (n=4; HbA1c >7% or complications), and renal (n=2)
- Cohort 1 (n=3) - bendamustine 45mg/m2
- All pts completed 6 cycles of therapy with minimal toxicities
- Dose reductions not required in 2/3 pts
- Third patient required reduction to 35mg/m2 due to sustained grade 3 neutropenia in third cycle
- Cohort 2 (n=4) - bendamustine 70mg/m2
- Two pts experienced DLTs: grade 4 infection and persistent grade 3 neutropenia
- One patient completed 6 cycles after dose reduction to 45mg/m2
- Three pts discontinued therapy early due to toxicities
- Bendamustine at 45mg/m2 determined as the MTD
- ORR in evaluable pts = 83.3% (5/6); ORR in all pts = 71.4%
- Pts who achieved CR/Nodular PR (nPR) received a median cumulative dose of 500mg/m2 bendamustine (around 42mg/m2 per dose) with the remaining pts receiving 280mg/m2 (P = 0.19)
- Median follow-up = 30 months (range, 20–34); 6/7 pts are alive
- Estimated 2-year EFS = 71.4% (95% CI, 25.8–92.0%); one patient experienced PD and was successfully treated with ibrutinib, and one patient passed away
The authors stated that their phase I study identified BR at 45mg/m2 at the MTD in patients with CLL and significant comorbidities. In most evaluable patients, efficacy was demonstrated despite markedly reduced exposure to bendamustine; patients were exposed to doses around 30% less than those used in solid cancer trials. The group emphasize that their findings indicate that a dose reduction for BR is required in this population; however, larger studies are required to confirm this finding. Lastly, the authors conclude that CIRS presents as a potential tool in guiding choice and/or dose of treatment in CLL patients.