Bendamustine/Rituximab is an Effective Salvage Therapy in CLL


The combination of bendamustine and rituximab induced a 12-month progression-free survival of 78.6% for patients with chronic lymphocytic leukemia, suggesting that the combination is an effective first salvage regimen.

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The combination of bendamustine (Treanda) and rituximab (Rituxan) induced a 12-month progression-free survival (PFS) of 78.6% for patients with chronic lymphocytic leukemia (CLL), suggesting that the combination is an effective first salvage regimen.1

Investigators said that patient characteristics for those who received bendamustine/rituximab closely resembled the typical CLL patient for age, performance score, and comorbidities.

&ldquo;The data presented here show that [bendamustine/rituximab] is an efficacious first salvage regimen in CLL in a real-life population, including elderly patients, patients with 2 or more comorbidities, and a creatinine clearance <70 ml/min,&rdquo; Antonio Cuneo, MD, PhD, Department of Medical Sciences, St. Anna University Hospital, Ferrara, Italy, and colleagues wrote.

&ldquo;Importantly, no significant differences in terms of OS were noted in this real-life report with respect to the survival data recently observed in clinical trials,&rdquo; investigators added.

Data from 237 adult patients treated at 35 Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) and European Research Initiative on CLL (ERIC) medical centers from 2008 to 2014 were eligible for this retrospective observational study. All patients had undergone 1 previous treatment with purine analogues and/or alkylating agents with or without monoclonal antibodies.

Median patient age was 70 years and 70.9% of patients were aged >65 years. Nearly 60% had &ge;2 comorbidities, 46.9% had a creatinine clearance of &le;70 ml/min.IGHVdata was available for 61.6% of patients and 73% of those had unmutatedIGHV. Among the 79.3% of patients with data available, 33.4% had 11q- and/or 17p13 deletion. More than a fifth (21.4%) of patients had advanced disease, defined as Rai III/IV or Binet C.

In first-line, 59% of patients were treated with chemoimmunotherapy regimens and 41% received chemotherapy. Two patients received monotherapy with rituximab or alemtuzumab (Campath). No patient in the study received first-line therapy with ibrutinib (Imbruvica) or any other novel oral agent.

Patients with HIV, active HCV or HBV infection, or Richter&rsquo;s syndrome transformation were ineligible.

All patients received second-line treatment with 70 mg/m2of bendamustine/rituximab.

PFS at 12 months from treatment initiation was the primary endpoint. Secondary endpoints included overall response rate (ORR) in the intent-to-treat (ITT) population, time to next anti-leukemic treatment (TTNT), and OS.

A total of 165 (69.6%) patients received the full course of treatment.

At a median follow-up of 37.1 months, 12-month PFS was 78.6% (95% CI, 73.5-84.1). Estimated PFS was 30.9% (95% CI, 24.8-38.5) at 30 months and 16.2% (95% CI, 10.6-24.6) at 60 months. Median overall PFS was 25 months.

In multivariate analysis, advanced stage, unmutatedIGHV, and the presence of 17p- were associated with shorter PFS. Median PFS in the 12.2% of patients with a low risk profile—mutatedIGHVand Rai stage 0 to 2without del(17p)—was 40.4 months versus 20.7 months in the rest of the cohort (P= .003).

There was no effect on PFS for age, creatinine clearance, or the presence or absence of &ge;2 comorbidities.

ORR was 82.3%. Response rate for patients with del(17p) was 69.6%, significantly lower than the 73.7% ORR for patients with del(11q) and the 82.2% ORR for patients with del(13q). ORR was also significantly better in patients with no aberrations (86.7%) or +12 (96.9%).

Median TTNT was 31.3 months and 12-month TTNT was 18.1% (95% 12.6-22.2). Median TTNT was 20.2 months for patients with del(17) versus 34.6 months for the rest of the cohort. Median TTNT was also shorter for those who received previous chemoimmunotherapy compared with those who received chemotherapy in first line (27.2 vs 40.4 months). Age and creatinine clearance had no effect on TTNT.

On multivariate analysis, only first-line chemoimmunotherapy treatment was a predictor for shorter TTNT.

Median OS was 74.5 months. OS was 92.7% at 12 months, 72.2% at 36 months, and 54% at 60 months. At 36 months, 78.2% of responders were still alive compared with 42.4% for patients who did not respond to bendamustine/rituximab. Resistant disease and advanced Binet stage were significantly associated with shorter OS in both the univariate and multivariate analyses.

Twenty-seven patients died due to infection with or without active CLL, 14 died due to CLL, 7 died due to second primary tumors, and 4 died due to Richter&rsquo;s syndrome. Cause of death was not reported for 12 patients and 9 patients died due to other causes.

A total of 72 patients discontinued treatment. Thirty-nine discontinued due to toxicity, 20 discontinued for other reasons, 7 withdrew consent, and 6 had progressive disease.

Roughly 40% of patients (n = 95) received 6 cycles of treatment without dose reduction. More than a quarter (28.9%) of patients required a >10% dose reduction of bendamustine, and 22.5% of patients needed a treatment delay.

Seventy-nine (33%) patients experienced at least 1 grade 3/4 adverse event (AE). Cytopenia (24.9%) and neutropenia, including febrile neutropenia (20.7%), were the most common grade 3/4 AEs. Sixteen patients experienced grade &ge;3 infections, including 4 (6.3%) cases of febrile neutropenia and 8 (3.4%) lung infections. One patient died of encephalitis.

Cuneo et al compared these results with findings from 95 patients treated with ibrutinib monotherapy in second-line from 2014 to 2015. The cohorts were comparable for median age, ECOG performance score, ORR to first-line treatment, and frequency of unmutatedIGHVwhen the analysis was limited to those who received chemoimmunotherapy in first line.

After excluding patients with del(17p), investigators found that 36-month OS was similar for patients treated with ibrutinib (n = 39) and the 92 patients treated with bendamustine/rituximab (63% vs 74.4%, respectively).

Investigators conducted a subanalysis of 55 patients in the bendamustine/rituximab cohort and 33 patients in the ibrutinib with intact 17p and a <36-month interval between first-line treatment and first salvage treatment. They found no significant OS difference between the groups at 3 years, with 72.6% (95% CI, 60.1-87.7) of patients in the bendamustine/rituximab group still alive compared with 59.8% (95% CI, 44.2-80.7) in the ibrutinib group (P= .19).

&ldquo;Though obvious caution must be used when interpreting data derived from different series, these data suggest that [bendamustine/rituximab] and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in CLL patients without 17p deletion managed in the real-life setting,&rdquo; the authors wrote.


Cuneo A, Follows G, Rigolin GM, et al. Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study [published online April 19, 2018].Haematologica. doi: 10.3324/haematol.2018.189837.

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