Promising Results in CLL for Frontline Ibrutinib Plus Chemoimmunotherapy

Matthew S. Davids, MD

Adding ibrutinib (Imbruvica) to a standard frontline chemoimmunotherapy for chronic lymphocytic leukemia (CLL) induced negative minimum residual disease (MRD) status in bone marrow for 83% of patients, according to results from preliminary clinical study.¹

In findings presented at the 2017 ASH Annual Meeting, the high rate of MRD negativity held up across all risk categories of CLL. Thirteen of 35 patients (37%) had complete response in association with MRD negativity.

“The rate of best bone marrow MRD negativity is higher than any prior regimen for frontline therapy across CLL risk groups,” said Matthew S. Davids, MD, associate director of the CLL center at Dana-Farber Cancer Institute in Boston. “Responses deepen over time in both IGHV-mutated and unmutated patients, suggesting that ibrutinib maintenance is beneficial. Correlative studies are ongoing, and an expansion cohort is now accruing to explore discontinuation in patients who are bone marrow MRD negative after two years of ibrutinib maintenance.”

Toxicity was consistent with known toxicities of ibrutinib and the fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy regimen used in the study.

The background of the study included evidence of FCR’s potential to induce a cure in IGHV-mutated CLL. Previously released results from an 800-patient randomized trial showed significant improvement in overall survival and progression-free survival with FCR as compared with FC, which was associated with an 86-month median overall survival.² Ibrutinib has demonstrated good tolerability and consistent activity in CLL irrespective of IGHV status.

The prior randomized trial showed a significant association between bone marrow MRD status and overall survival, suggesting that achievement of MRD negativity is a prerequisite for cure, said Davids.

A small case series showed that ibrutinib given with chemoimmunotherapy for relapsed/refractory CLL was active and well tolerated. All three patients treated with ibrutinib and FCR (iFCR) had durable complete responses, two of which were associated with MRD negativity.³

“We hypothesized that iFCR would increase the rate of complete response with bone marrow negativity,” said Davids. “Our goal is to increase the curative potential of FCR for younger, fit CLL patients, including those with high-risk disease markers.”

The accumulation of data led to a phase II evaluation of iFCR in 35 younger, fit patients with untreated CLL. The primary endpoint was the rate of complete response with bone marrow MRD negativity 2 months after completion of FCR.

The treatment protocol began with a week of 420 mg ibrutinib daily, followed by iFCR, with standard doses of FCR, for a maximum of 6 cycles. Patients then received ibrutinib maintenance therapy until disease progression or development of unacceptable toxicity. Patients were evaluated for response after 3 cycles of iFCR, then 2 months after the last dose of FCR (primary endpoint), and every 6 months thereafter.

The 35 patients had a median age of 55. Genetic profiling showed 4 patients had del(17p), 9 had del(11q), 6 had trisomy 12, 17 had del(13q), and 5 patients had normal genetics. Two-thirds of the patients did not have IGHV mutations. Davids said 60% of the patients had Rai stage III/IV disease at enrollment.

Efficacy data showed that iFCR induced objective responses in all 35 patients. Fourteen patients (40%) had complete response with or without hematologic recovery at the primary endpoint assessment. That number increased to 63% as best response. Davids reported that 37% of patients attained complete response with bone marrow negativity at the primary endpoint assessment, increasing to 57% at best response assessment.

The regimen induced bone marrow negativity ion 28 of 35 patients (77%) at the primary assessment, increasing to a maximum of 83% (29 of 35) at best response assessment.

The median time to best response was 95 days. Davids noted that 20 of 22 patients (91%) who attained complete response were also MRD negativity for bone marrow, as were nine of 13 patients who had partial responses.

Thirty-one patients initiated ibrutinib maintenance after FCR. After a median follow-up of 21 months, no patient died or had disease progression.

On the basis of the promising initial findings, investigators initiated a 50-patient expansion trial. Based on results from the 35-patient study, investigtors made several protocol modifications. Patients who are MRD negative in bone marrow will be taken off treatment after 2 years of ibrutinib maintenance, patients who convert to MRD positive after discontinuation will resume ibrutinib treatment and patients with del(17p) will be excluded.

Enrollment in the expansion study began in April, and 30 patients accrued since then. Davids said five patients opted to discontinue ibrutinib, and none has recurred.

References

1. Davids MS, Kim HT, Brander DM, et al. A multicenter, phase ii study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 496.
2. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-215.
3. Brown JR, Barrients JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125:2915-2922.