Updated Data on Treatment With Ibrutinib and Venetoclax in Patients With CLL/SLL

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This is the longest follow-up in any CLL population. Responses are impressive with single-agent ibrutinib upfront, and the drug is generally well tolerated. Importantly, there were no late unexpected side effects.
— Susan O'Brien, MD

Long-term follow-up of treatment with ibrutinib (Imbruvica) in patients with previously untreated and treated chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) has shown high response rates that are durable. At 5 years, 89% of patients with treatment-naive and relapsed or refractory CLL/SLL achieved a complete response or partial response to ibrutinib, including some patients with high-risk disease. Just under one-third of patients (29%) treated with ibrutinib upfront achieved complete response. Patients treated earlier in the course of disease had longer progression-free survival as well.

“This is the longest follow-up in any CLL population. Responses are impressive with single-agent ibrutinib upfront, and the drug is generally well tolerated,” said lead investigator Susan O’Brien, MD, Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center, University of California Irvine Health. “Importantly, there were no late unexpected side effects.”

“These 5-year results give us confidence that both previously treated and untreated CLL/SLL patients can achieve robust and long-lasting responses with single-agent ibrutinib, with more patients developing a complete response over time,” Dr. O’Brien told listeners at the 2016 American Society of Hematology (ASH) Annual Meeting. “Our data also suggest that starting treatment with ibrutinib in CLL/SLL rather than waiting until after patients have relapsed from chemotherapy has promising clinical potential for long-term progression-free and overall survival.”

Ibrutinib is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor approved by the U.S. Food and Drug Administration (FDA) to treat patients with CLL/SLL, including those with 17p deletions, in the front-line and relapsed settings; the drug is also approved by the FDA to treat patients with mantle cell lymphoma treated with at least one prior therapy and  patients with Waldenström’s macroglobulinemia, and for marginal zone lymphoma.

Ibrutinib: PCYC Trials

The analysis Dr. O’Brien presented was based on the PCYC-1102 trial and PCYC-1103 extension study of single-agent ibrutinib.1 Two patient cohorts were followed: 31 treatment-naive patients and 101 patients with relapsed or refractory disease (24 with high-risk disease). In general, treatment-naive patients were older and had more advanced Rai stage disease, whereas those with relapsed or refractory disease were more likely to have been heavily pretreated as well as to have bulky disease and higher levels of beta-2 microglobulin.

Median time on study was 62 months for treatment-naive patients and 49 months for those with relapsed or refractory disease. Almost two-thirds of treatment-naive patients remained on therapy, compared with less than one-third of those with relapsed or refractory disease.

Clinical Trials of Ibrutinib and Venetoclax in CLL/SLL

  • At 5 years, 89% of patients with treatment-naive and relapsed or refractory CLL/SLL achieved a complete response or partial response to ibrutinib.
  • The least favorable outcome with ibrutinib was seen in patients with 17p deletion.
  • Venetoclax may be an option for high-risk patients who relapse or are refractory to ibrutinib.
  • There may still be a role for chemotherapy as upfront treatment of younger fit patients with mutated IGHV.

The overall response rate was 89% at 5 years, with 14% achieving complete response. In treatment-naive patients, the overall response rate was 87%, and the complete response rate was 29%; in patients with relapsed or refractory disease, the overall response rate was 89%, and the complete response rate was 10%.

At 5 years, progression-free survival was 92% in treatment-naive patients and 43% in those with relapsed or refractory disease. Overall survival was 92% and 57%, respectively. Median progression-free survival was not yet reached in the treatment-naive group and was 52 months in those with relapsed or refractory disease. Median overall survival was not reached in either cohort.

“We update this information annually. What is new is that median progression-free survival was 52 months in relapsed/refractory patients, and this is impressive,” revealed Dr. O’Brien.

The least favorable outcome was seen in patients with 17p deletion. Median progression-free survival was 26 months for those with 17p deletion, 55 months for those with deletion 11q, 43 months for those with unmutated immunoglobulin heavy-chain variable region (IGVH), and not reached for those with deletion 13q.

“We also have new information related to chromosomal abnormalities. Median progression-free survival in the group with 11q deletion is 55 months, better than you get with FCR [fludarabine, cyclophosphamide, rituximab (Rituxan)] upfront,” she stated. “Ibrutinib is less effective in the 17p-deleted group but still substantially better than chemoimmunotherapy in that subset,” Dr. O’Brien continued. “However, for patients not at high risk, defined as deleted 17p or 11q, median progression-free survival has still not been reached in the relapsed population.”

Results also showed a dropoff related to the number of prior therapies a patient received. Median progression-free survival was 63 months for those with relapsed or refractory disease treated with 1 to 2 prior regimens, 59 months for those treated with 3 prior regimens, and 39 months for those treated with 4 or more prior regimens.

Among all patients, the rate of grade 3 or higher treatment-related adverse events was highest in the first year of treatment and decreased over time, with the exception of hypertension, reported Dr. O’Brien. The most frequent grade 3 or higher adverse events were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (8%).

Paul M. Barr, MD

Paul M. Barr, MD

Ibrutinib: RESONATE-2 Trial

A separate presentation focused on updated findings from the pivotal phase III RESONATE-2 trial of ibrutinib as first-line therapy for patients 65 years and older with CLL/SLL.2 The lead investigator was Paul M. Barr, MD, of the James P. Wilmot Cancer Center, University of Rochester Medical Center, New York.

This multicenter, randomized, open-label study enrolled 269 treatment-naive patients from the United States, European Union, and other countries. Patients were randomized to receive ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity or chlorambucil on days 1 and 15 of a 28-day cycle for up to 12 cycles.

At a median follow-up of 29 months, ibrutinib reduced the risk of disease progression or death by 88% compared with chlorambucil. At 24 months, progression-free survival was 89% in the ibrutinib group and 34% in the chlorambucil group (P < .0001).

Updated investigator-assessed overall response rate was 92% with ibrutinib and 36% with chlorambucil. Over time, more patients achieved a complete response with ibrutinib (15% at 24 months up to 18% at 29 months).

Safety findings were consistent with those reported in other studies of ibrutinib.

Richard Furman, MD

Richard Furman, MD

What’s Next for Poor-Risk Patients?

“These promising long-term data support the use of ibrutinib in all CLL patients,” said Richard Furman, MD, Director of CLL Research at Weill Cornell Medicine–New York Presbyterian Hospital. Dr. Furman was a coauthor on the abstract Dr. O’Brien presented.

“We can have confidence that single-agent ibrutinib is perhaps the only therapy that most CLL will require. The relapsed/refractory patients with 11q and 17p deletions, with 5-year progression-free survival of 33 and 19% respectively, do require an alternate treatment strategy. Emerging data suggest that venetoclax may be useful in those patients with 17p deletion who relapse. Additional strategies, such as the addition of venetoclax to ibrutinib, are designed for these patients who require more than just ibrutinib alone,” according to Dr Furman.

Jeffrey Jones, MD

Jeffrey Jones, MD

Venetoclax: M14-032 Study

A separate study suggested that venetoclax (Venclexta) has encouraging activity in patients with CLL who relapse or are refractory to ibrutinib or idelalisib (Zydelig). At the ASH Annual Meeting, lead author Jeffrey Jones, MD, of The Ohio State University, Columbus, reported the interim results of M14-032, an ongoing phase II open-label study of venetoclax.3 He presented data on the first 43 patients treated in arm A (previously treated with ibrutinib) and 21 patients in arm B (previously treated with idelalisib). Dr. Furman was a coauthor on this study.

“This is the first prospective trial to demonstrate high rates of durable responses, including minimal residual disease [MRD] negativity in patients progressing after B-cell receptor pathway antagonists,” Dr. Jones stated.

A total of 49% of patients in arm A and 10% of patients in arm B had 17p deletion. A total of 33 patients received both ibrutinib and idelalisib. All patients were treated with venetoclax, a selective small-molecule inhibitor of Bcl-2, escalated from 20 mg during week 1 to 400 mg at week 5 and onward.

Venetoclax carries the risk of tumor-lysis syndrome, so all patients received prophylaxis with uric acid–lowering agents and hydration starting at least 72 hours prior to initiation of venetoclax. Patients with a high tumor burden were hospitalized for the first and second doses of venetoclax, and all patients were monitored closely.

The overall response rate by independent review committee was 70% in arm A and 62% in arm B. These findings were driven mainly by partial response, which was achieved in 67% and 62%, respectively. At 12 months, median duration of response, progression-free survival, and overall survival had not yet been reached in either arm. Estimated 12-month progression-free survival for all patients was 80%. Of 31 samples tested, 14 (45%) were minimal residual disease–negative between weeks 24 and 48.

No clinical case of tumor-lysis syndrome has occurred thus far. All patients had at least one adverse event; 83% had grade 3 or 4 adverse events, including neutropenia, thrombocytopenia, anemia, decreased white blood cell count, febrile neutropenia, and pneumonia. Serious adverse events occurred in 53%.

Cytopenias were managed by dose adjustments and/or supportive care. ■

Disclosure: The ibrutinib studies were sponsored by Pharmacyclics, and the venetoclax study was sponsored by AbbVie. Dr. O’Brien has consulted and received honoraria from AbbVie, Janssen, and Pharmacyclics as well as research funding from Pharmacyclics. Dr. Barr has consulted for AbbVie and Pharmacyclics as well as received research funding from AbbVie and Pharmacyclics. Dr. Furman has received honoraria and served as a consultant for AbbVie, Genentech, and Pharmacyclics. Dr. Jones has served as a consultant and received research funding from AbbVie, and received honoraria from AbbVie.


1. O’Brien SM, Furman RF, Coutre SE, et al: Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia. 2016 ASH Annual Meeting. Abstract 233. Presented December 3, 2016.

2. Barr PM, Robak T, Owen CJ, et al: Updated efficacy and safety from the phase 3 RESONATE-2 study: Ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. 2016 ASH Annual Meeting. Abstract 234. Presented December 3, 2016.

3. Jones J, Choi MY, Mato AR, et al: Venetoclax monotherapy for patients with chronic lymphocytic leukemia who relapsed after or were refractory to ibrutinib or idelalisib. 2016 ASH Annual Meeting. Abstract 637. Presented December 5, 2016.