Ibrutinib-Chemoimmunotherapy Combo Adds to CLL Therapy

In chronic lymphocytic leukemia (CLL), combining two effective treatments enhances their clinical activity, according to early study results published recently in Blood.

Treatment-naive CLL patients will generally show good response to their first round of therapy, but relapse is very common and requires subsequent treatment. Pairing ibrutinib, a selective inhibitor of Bruton’s tyrosine kinase (BTK), with conventional chemoimmunotherapy (CIT) improved response rates and led to longer remission.

Because single-agent ibrutinib has demonstrated good tolerability in previous studies, lead author Jennifer Brown, MD, PhD, and colleagues sought to combine the agent with the two most standard CIT regimens with the goal of achieving more prolonged disease control.

“The safety and efficacy observed in this study suggest that the addition of ibrutinib may substantially enhance the clinical benefit of standard CIT treatments for patients with CLL or small lymphocytic leukemia,” Dr. Brown, from the Dana-Farber Cancer Institute in Boston, noted.

Dr. Brown and colleagues enrolled relapsed/refractory CLL/SLL patients into two parallel cohorts: a bendamustine and rituximab (BR) with ibrutinib group (n=30) or a fludarabine, cyclophosphamide, and rituximab (FCR) with ibrutinib group (n=3). Enrollment to the FCR-ibrutinib arm closed early due to a lack of fludarabine-naïve patients.

Eligible patients had between one and three prior treatment regimens for a confirmed diagnosis of either CLL or SLL. All patients received ibrutinib (420 mg, once daily) after their CIT (a maximum of six cycles) on each day of a 28-day therapy cycle. Treatment continued until disease progression or unacceptable toxicity. Ibrutinib monotherapy could continue indefinitely until progression or unacceptable toxicity.

There were no incidents of prolonged hematologic toxicity starting in cycle 1, or a grade ≥3 thrombocytopenia lasting for ≥8 weeks (the study’s primary endpoint).

“Treatment-related lymphocytosis was less frequent and less pronounced when ibrutinib was administered in combination with BR than as monotherapy,” the researchers noted. In addition, they found hematologic improvement in the majority of patients who were cytopenic at baseline.

After a median treatment duration of 15.7 months, the objective response rate, one of the phase 1b study’s secondary clinical endpoints, was 93.3% (n = 28) for patients in the ibrutinib-BR cohort. Five patients (16.7%) achieved a complete response, and 20 (66.7%) achieved a partial response.

When Dr. Brown and investigators included data from the extended follow-up (a median of 3 years), the rate of complete response increased to 40 percent (12 patients), with 14 patients (46.7%) achieving a partial response and two patients (6.7%) achieving a nodular partial response.

A majority of patients in the ibrutinib-BR cohort remained progression-free at 12 months (86.3%), as well as at 24 months (78.6%) and 36 months (70.3%).

Rates of treatment-emergent adverse events were similar to those observed when ibrutinib or BR were administered individually; the majority of these events were designated as grade 1 or 2 by the researchers. “The adverse event profile of ibrutinib in this population is pretty similar to what was seen previously,” Dr. Brown told ASH Clinical News. “Typical issues included diarrhea, fatigue, nausea, arthralgia, and ecchymosis, as well as a small risk of more significant bleeding and atrial fibrillation.”

In the FCR cohort, the ORR response rate was 100 percent – but this only accounted for three patients, the investigators noted. All three patients were able to complete six cycles of FCR with only one serious adverse event (gastritis with gastrointestinal bleeding requiring hospitalization).

Commenting on the FCR cohort, Dr. Brown explained that “our ongoing study has almost reached the safety pause at 10 patients. Thus far, there have been no issues and the study is proceeding well.”

Compared with other BTK inhibitors, such as CC-292 or ONO-4059, the safety profile of ibrutinib held its own in treatment, she added. “With CC-292, the safety profile was fairly similar; there was less ecchymosis, bleeding, and atrial fibrillation than with ibrutinib, but CC-292 has been given to many fewer patients than ibrutinib,” Dr. Brown said. “The reported number of patients who have received ONO-4059 is, in my opinion, too small to compare, but again, the safety profile looks roughly similar to ibrutinib.”


Brown J, Barrientos J, Barr P, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 March 9. [Epub ahead of print.]