Frontline CLL Therapy: Changes in Paradigm

Kanti R. Rai, MD

Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) with the addition of options such as the tyrosine kinase inhibitor (TKI) ibrutinib, the monoclonal antibody obinutuzumab, and the BCL2 inhibitor venetoclax. “These drugs have led to excellent responses across all CLL groups. Combinations are currently under clinical trials,” said Kanti R. Rai, MD, at the 21st Annual International Congress on Hematologic Malignancies, being held February 23–25 in Sunny Isles, Florida.

 -Interviewed by Mark L. Fuerst

Cancer Network: What are the specific therapeutic advances in CLL?

Dr. Rai: BCR signaling kinases of therapeutic relevance have been identified that promote CLL cell survival and proliferation. These include the BTK inhibitor ibrutinib and the P3K inhibitor idelalisib. Also, venetoclax inhibits cell death by inhibiting BCL2.

Cancer Network: How has the treatment paradigm changed?

Dr. Rai: Clinical trials are now in progress with novel TKIs, both alone and in combination with rituximab/obinutuzumab/ofatumumab. TKIs offer big hope for the elderly, physically unfit patients with CLL, and patients with high-risk prognosis, such as del17p or mutated TP53.

Frontline ibrutinib in patients age 65 years or older leads to a high overall response rate (ORR) with some complete responses (CR). Few patients have grade 3/4 diarrhea, atrial fibrillation, or major bleeding. Progression-free survival (PFS) at 18 months is 90% and overall survival (OS) at 24 months is 98%. And the vast majority of patients continue on ibrutinib.

Cancer Network: What is the advantage of using ibrutinib in patients with TP53/del17p?

Dr. Rai: Studies show high ORR and good 24-month PFS and OS with grade 3 or worse adverse events that are manageable.

Cancer Network: What are the results with frontline 5-year follow-up with Ibrutinib?

Dr. Rai: In one study, the ORR was 84% and CR was 29% in untreated patients. Median PFS has not reached for all untreated patients, and 92% patients were estimated to be alive at 60 months.

Cancer Network: What are the concerns with Ibrutinib?

Dr. Rai: CR rates are lower compared to chemoimmunotherapy. Adverse effects include bleeding risk, atrial fibrillation, and severe infections. Marrow clearance of CLL cells is infrequent. There are BTK and non-BTK mutations and clonal evolution. Patients who transform or progress on ibrutinib have poor outcome.

Cancer Network: What is the promise of a combination of ibrutinib with rituximab in high-risk CLL?

Dr. Rai: This combination in high-risk CLL achieves a high partial response and good CR and is well-tolerated. At 4-year follow-up, about one-quarter of patients achieve CR with a median PFS of 45 months.

Cancer Network: What is the value of venetoclax in CLL?

Dr. Rai: This selective, potent, orally bioavailable BCL2 inhibitor leads to an ORR around 80% and high CR rate. Tumor lysis syndrome may develop in some patients. Grade 3/4 adverse events include neutropenia, infection, anemia, and thrombocytopenia. Venetoclax induces minimal residual disease-negative CRs, which is a major advantage over ibrutinib.

Cancer Network: How would you select frontline treatment regimens in 2017?

Dr. Rai: For patients with symptomatic disease (any stage) over age 70 years, I would choose obinutuzumab with chlorambucil, ibrutinib, or idelalisib-rituximab; or a reduced dose of BR (bendamustine and rituximab )/FCR (fludarabine, cyclophosphamide, and rituximab) or standard dose if the patient is physically fit.

For patients with del17p, ibrutinib as a single agent or refer to a clinical trial.

For patients without del17p, for young patients, choose either FCR or ibrutinib, and discuss the pros and cons; for less fit patients, choose ibrutinib with/without an anti-CD20 monoclonal antibody, obinutuzumab with chlorambucil, or refer to clinical trials.