Frontline Ibrutinib/Chemoimmunotherapy Induces Deep Response in Young CLL Patients

A combination of ibrutinib plus standard chemoimmunotherapy induces deep responses in a relatively high-risk group of previously untreated, young chronic lymphocytic leukemia (CLL) patients, according to a new study.

Standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) provides prolonged disease-free survival for many CLL patients with mutated IGHV, however, those with unmutated IGHV typically have less durable responses.

“FCR has curative potential, but bone marrow minimal residual disease (MRD)-negativity is likely a prerequisite,” said lead author Matthew S. Davids, MD of the Dana-Farber Cancer Institute in Boston. Complete response (CR) with bone marrow MRD-negativity is only achieved in about 20% of patients, he noted.

Davids reported on the results of an ongoing multicenter phase II study (abstract 496) of the Bruton tyrosine kinase inhibitor ibrutinib plus FCR as frontline treatment for 35 evaluable young, fit CLL patients at the American Society of Hematology (ASH) Annual Meeting, held December 9–12 in Atlanta.

Patients (median age, 55 years) received ibrutinib 420 mg daily monotherapy for 7 days, followed by combination FCR for up to 6 cycles. Responders continued on ibrutinib maintenance for at least 2 years. They also received antimicrobial prophylaxis and growth factor support.

About two-thirds of the patients had unmutated IGVH, and 60% advanced Rai stage.

The overall response rate was 100%, including 63% patients with best response of CR/CR with incomplete marrow recovery. The CR rate with bone marrow MRD-negativity at 2 months post-FCR was 37%, which increased to a best rate of 57% with post-FCR ibrutinib maintenance. Best rate of bone marrow MRD-negativity by flow was 83%.

“Response deepened over time in both IGHV mutated and unmutated patients, suggesting that ibrutinib maintenance is beneficial,” said Davids.

With a median follow-up of 21 months, all patients are alive, and 86% remain on treatment, he said. Two bone marrow MRD-negative patients elected to discontinue ibrutinib, two patients who discontinued ibrutinib due to toxicity (grade 3 pneumatosis intestinalis and grade 3 transaminitis), and one patient with del(17p) who achieved MRD-positive partial response elected to pursue allogeneic stem cell transplant.

Toxicities were comparable to ibrutinib and FCR individually. Grade 3/4 hematologic toxicity included neutropenia 29%, thrombocytopenia 26%, and anemia 6%. Non-hematologic toxicities occurring in more than 15% of patients included nausea (71%), bruising (43%), rash (43%), fatigue (37%), and diarrhea (26%).

Grade 3 serious adverse events were infrequent and included pneumonia, febrile neutropenia, atrial fibrillation, transaminitis, pneumatosis intestinalis, anaplasmosis infection, and appendicitis. Six patients experienced grade 3 or higher infection.

One patient with febrile neutropenia had ibrutinib dose reduction, and 18% of patients had at least one dose reduction of chemoimmunotherapy.

In conclusion, Davids said: “The rate of best bone marrow MRD-negativity of 83% is higher than any prior regimen in frontline therapy across CLL risk types. High rates of bone marrow MRD-negativity have been observed even in higher-risk CLL, such as unmutated IGHV. Neutropenia and infection were likely mitigated by mandatory G-CSF and antimicrobial prophylaxis.”

An expansion cohort is now accruing to explore discontinuation in patients who are bone marrow MRD-negative after 2 years of ibrutinib maintenance.