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Chemoimmunotherapy combination remains standard of care in frontline treatment of advanced CLL
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Fludarabine, cyclophosphamide and rituximab prolonged PFS compared with rituximab and bendamustine and should remain the standard of care for the frontline treatment of patients with advanced chronic lymphocytic leukemia, according to results of the international phase 3 CLL10 study.
However, the bendamustine (Treanda, Teva) and rituximab (Rituxan; Genentech, Biogen) combination is associated with less toxicity.
The use of fludarabine, cyclophosphamide and rituximab has become the standard of care in the frontline setting for physically fit patients with CLL. However, studies have shown the combination results in severe hematotoxicity in 56% of patients, and severe infections in 25% of patients.
Because the combination of bendamustine and rituximab yielded positive results in a phase 2 study of patients with CLL, Barbara Eichhorst, MD, associate professor in the department of internal medicine and the Center of Integrated Oncology at University of Cologne in Germany, and colleagues hypothesized that first-line treatment with this combination might confer similar efficacy, but less toxicity, than the standard of care.
Researchers conducted an open-label phase 3 noninferiority study, designed to evaluate 2-year PFS in 564 treatment-naive, fit patients (aged 33 to 81 years) with CLL, who did not have deletion 17p.
Researchers randomly assigned 282 patients to receive six cycles of IV fludarabine (25 mg/m² per day) and cyclophosphamide (250 mg/m² per day) for the first 3 days of each cycle, and 279 patients to receive IV bendamustine (90 mg/m² per day) for the first 2 days of each cycle. All patients also received 375 mg/m² IV rituximab on day 0 of cycle 1 and then 500 mg/m² on day 1 of the next five cycles.
Median follow-up was 37.1 months (31-45.5).
Early treatment discontinuations within the first three cycles occurred more often in the triple combination group (13% vs. 11%); however, the rate of dose reductions was the same in both groups (52%).
Patients treated with bendamustine and rituximab demonstrated shorter median PFS compared with patients who received standard therapy (41.7 vs. 55.2 months; HR = 1.64; 90.4% CI, 1.31-2.01).
“As the upper limit of the 90.4% CI was greater than 1.39, the null hypothesis for the corresponding noninferiority hypothesis was not rejected,” Eichhorst and colleagues wrote.
More patients assigned the triplet achieved complete response (40% vs. 31%; P = 0.034). When evaluating patients with available samples, more patient assigned the triple combination also achieved minimal residual disease (74% vs. 63%; P = .029).
Safety analysis demonstrated grade 3 or grade 4 adverse events occurred more frequently in patients who received the triple combination — including severe neutropenia (84% vs. 59%) and the severe infections (39% vs. 25%).
The frequency of infectious complications with the triple combination increased in patients aged older than 65 years old.
“The question is if high minimal residual disease negativity rates are still needed for long-term disease control in the era of new targeted treatment options, in which excellent disease control can be achieved with persistent lymphocytosis,” the researchers wrote. “Similarly, it remains to be investigated whether chemoimmunotherapy can be replaced by chemotherapy-free combinations including BCL2 or kinase inhibitors.”
This study added valuable contributions to use of personalized medicine in CLL, Adrian Wiestner, MD, PhD, senior investigator at the laboratory of lymphoid malignancies at the NHLBI, wrote in an accompanying editorial.
“The large group of patients with intermediate risk factors might not find ready-made answers in these data,” he wrote. “But the CLL10 study provides information for nuanced discussions about treatment choices tailored to treatment goals, risk–benefit considerations, financial constraints, and personal preferences.” – by Kristie L. Kahl
Disclosures: Eichhorst reports honoraria and research funding from Roche and Mundipharma. Please see the full study for a list of all other researchers’ relevant financial disclosures. Wiestner reports grants from Acerta Pharma and Pharmacyclics.
Perspective
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Kanti R. Rai
From an optimist’s point of view, we should be happy that — in chronic lymphocytic leukemia — we have several regimens available that are effective and have gone through vigorous clinical testing. The current times are truly exciting and increasingly more promising for achieving better control of CLL than had been possible just a few years ago.
The German CLL Study Group (GCLLSG) deserves our congratulations for having led several very important studies, all of which have been definitive and large randomized trials. Its now-famous CLL8 trial provided proof that the addition of rituximab (Rituxan; Genentech, Biogen) to fludarabine plus cyclophosphamide (FCR) compared with fludarabine plus cyclophosphamide alone significantly improved outcomes for patients.
CLL8 provided a solid confirmation to the earlier data from Keating and colleagues at The University of Texas MD Anderson Cancer Center, and the trial became the basis for FDA approval of the FCR regimen. Keating and colleagues recently reported that many of their FCR–treated patients with CLL who had good prognostic markers — such as mutated IGVH — have had very long PFS and might even be considered to have been cured of their CLL.
The trial by Eichhorst and colleagues — a prospective randomized comparison of FCR vs bendamustine and rituximab (BR) — had been undertaken to prove noninferiority of BR compared with FCR for frontline therapy of CLL. The study succeeded in demonstrating noninferiority.
The fact remains that FCR emerged as significantly more effective. PFS was longer for the younger age group. For patients aged older than 65, PFS was not significantly different between the two regimens. Although overall response rates were identical, complete remission rates were superior with FCR (40% vs. 31%). These results certainly keep BR alive compared with FCR as a frontline therapy — especially for elderly patients with CLL, because severe neutropenia is more likely with FCR than with BR.
The study by Eichhorst and colleagues was conducted from 2008 to 2011. Since then, we have witnessed the emergence of at least two additional major FDA–approved therapies for previously untreated CLL. One is the combination of chlorambucil and obinutuzumab (Gazyva, Genentech), an anti-CD20 monoclonal antibody. The other is ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton’s tyrosine kinase inhibitor. Thus, today’s physician truly has several choices available for frontline therapy of CLL.
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