Small-molecule inhibitors, especially ibrutinib (Imbruvica) and idelalisib (Zydelig), have greatly changed the outlook for patients with chronic lymphocytic leukemia. William G. Wierda, MD, PhD, Professor and Center Medical Director in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, discussed the optimal use of these agents and previewed others that are poised to further impact the treatment of chronic lymphocytic leukemia (CLL), at the National Comprehensive Cancer Network’s 10th Annual Congress on Hematologic Malignancies, held in San Francisco.
The Bruton’s tyrosine kinase inhibitor brutinib, the PI3 kinase inhibitor idelalisib, and others in development (including Syk inhibitors) target B-cell receptor signaling in CLL. The hypothesis is that CLL cells receive stimulation from their micro-environment through the B-cell receptor and other surface receptors. When this signal for activation is blocked with the small-molecule signaling inhibitors, the cells undergo apoptosis and die.
Standards of Care, for Now
Dr. Wierda first reminded listeners about the standards of care for certain CLL patient populations, summarizing the key points.
For untreated patients without an indication for treatment—even those deemed to have high-risk disease—observation is recommended. “For patients with high-risk features, we are tempted to start treatment, but we really should not,” he said. “Even for patients with 17p deletion, we can identify a subgroup of those who have a relatively indolent course who can probably go for years without needing treatment.”
In initiating first-line therapy, clinicians should evaluate patients based on age and chromosome abnormalities found with fluorescence in situ hybridization (FISH). For patients who are young and fit, chemoimmunotherapy is the standard of care, and FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) is the model regimen. For the elderly (> 65 years), data support the use of chlorambucil (Leukeran) plus an anti-CD20 monoclonal antibody; bendamustine (Treanda) plus rituximab can be used for fit elderly patients able to tolerate chemoimmunotherapy. For patients with del(17p), first-line ibrutinib is the standard of care.
In the salvage setting, for patients with active disease, ibrutinib is standard of care, and for relapsed patients who might otherwise receive rituximab, idelalisib (given with rituximab) is indicated. For patients with Richter’s transformation, intensive chemoimmunotherapy and stem cell transplant are the first options, with planning for allogeneic stem-cell transplant if possible.
“For Richter’s, we use intensive chemoimmunotherapy and try to get the patient to transplant. There is no standard-of-care regimen. This patient ultimately needs transplant,” he indicated.
Ibrutinib Data
In long-term follow-up of the phase II PCYC-1102/1103 trial of ibrutinib monotherapy in treatment-naive patients (n = 31) and those with relapsed/refractory disease (n = 101), response rates have reached 90%.1 Owing to the durability of these responses, median progression-free survival has not been reached in either group, except for relapsed/refractory patients with del(17p), whose estimated median progression-free survival was 28 months. Overall survival at 30 months was 97% for treatment-naive and 80% for relapsed/refractory groups (66% for patients with 17p deletion), and estimated median survival has not been reached.
“Patients lacking del(17p) or del(11q) are doing exceptionally well on ibrutinib, with 90% progression-free at 30 months,” Dr. Wierda noted.
Results of the large, randomized phase III RESONATE-2 trial will be presented at the 2015 American Society of Hematology Annual Meeting in December. RESONATE-2 treated patients aged 65 and older with front-line chlorambucil or ibrutinib. Positive results are expected for ibrutinib (as indicated by press release), perhaps paving the way for the label to be expanded into upfront use, Dr. Wierda said.
Long-term follow-up data indicate that after approximately 30 months of treatment, ibrutinib-treated patients begin to show an increase in disease progression on ibrutinib as well as several associated features, including Bcl-6 abnormalities, complex karyotype, and refractoriness to fludarabine. In a multivariable survival analysis of patients from MD Anderson, hazard ratios (HRs) were significant for fludarabine refractoriness (HR = 6.4) and complex karyotype (HR = 5.7).2
The emergence of activating mutations has been observed in some patients with progressive disease, “but mutations are not the whole story” in the development of resistance, he added.
Toxicities that are not uncommon with ibrutinib include neutropenia and thrombocytopenia which are likely more disease-related; the nonhematologic toxicities to watch for are atrial fibrillation and severe bleeding; each occurs in about 5% of ibrutinib recipients. Dr. Wierda cautioned against using this drug in patients taking warfarin. Age and number of prior treatments have been associated with discontinuation due to toxicity.
Ibrutinib is being evaluated in combination with other agents, but no such regimen has yet appeared to be impressive, he said.
“Personally, I am excited about combining ibrutinib with venetoclax—drugs that seem to have complementary mechanisms of action,” he commented. Venetoclax is an investigational oral Bcl-2 inhibitor with potent monotherapy activity. It has produced complete remissions in patients with relapsed/refractory CLL and del(17p), including complete responses that are negative for minimal residual disease (see below).
A number of other Bruton’s tyrosine kinase inhibitors are in development in this setting, including ACP-196, BGB-3111, and ONO-4059.
Idelalisib
The PI3 kinase inhibitor idelalisib is approved for relapsed CLL in patients appropriate for rituximab monotherapy, based on improved overall survival (in all risk categories) compared to rituximab monotherapy. Median progression-free survival was reported at 19.4 months for idelalisib plus rituximab, vs 7.3 months for rituximab alone.3
Idelalisib plus rituximab was similarly effective in patients who were IGHV gene–mutated vs nonmutated and those with and without del(17p). The regimen also demonstrated efficacy in relapsed CLL with del(17p) and del(11q).
Toxicities include elevated liver function tests (which usually occur early and are typically not treatment-limiting) and gastrointestinal side effects (eg, colitis). Pneumonitis, which can be treatment-limiting, can also occur.
“Depending on the severity of the [liver function test] elevation, you can reduce the dose, hold the drug, and continue when the patient improves,” he advised. “As for colitis, some patients develop this early, and it is not necessarily treatment-limiting. You can usually get them through this by holding the drug and restarting at a lower dose. If it’s colitis that occurs after about 6 months of treatment, in my experience this is more severe, can be more difficult to manage, and may be treatment-limiting.”
Other PI3 kinase inhibitors in clinical trials include duvelisib, AMG319, TGR-1202, GS-9820, and SAR245408, which are being studied alone and in combination with a number of drugs, such as ofatumumab (Arzerra), obinutuzumab (Gazyva), ibrutinib, and pembrolizumab (Keytruda).
“There are fewer ongoing novel combination trials with idelalisib than with ibrutinib, but there are a number of strategies,” he added. “As with ibrutinib, it is difficult at this point to identify a clear combination that will be a significant advance yet [over idelalisib plus rituximab].”
Venetoclax
The Bcl-2 inhibitor venetoclax is in phase III trials. In a study of 78 CLL patients reported last year by Seymour et al, responses were observed in 77% of patients, including complete responses in 23%.4 Response rates were consistent across subgroups with del(17p), fludarabine refractoriness, and IGHV-unmutated disease.
Dr. Wierda explained that the Bcl-2 family of proteins regulates apoptosis. Bcl-2, in particular, is overexpressed in CLL and makes cells resistant to apoptosis. By inhibiting Bcl-2 with venetoclax, antiapoptotic activity is downregulated and apoptosis is promoted.
Venetoclax has high specificity for Bcl-2 and, unlike a previous, more toxic compound, has much lower specificity for Bcl-XL, meaning less risk for thrombocytopenia, the limiting factor with its predecessor. A dose-escalation scheme also helps to avoid tumor lysis syndrome, which was also previously observed.
“The strategy is to initiate venetoclax at a low dose—20 mg/d—and dose-escalate weekly up to the target dose of 400 mg/d by week 5,” he said. With 400 mg/d or higher, median progression-free survival for fludarabine-refractory and/or del(17p) patients was not reached in the Seymour study.
In a 49-patient study that evaluated venetoclax plus rituximab, the response rate was 88%, with 31% complete responses and activity in the high-risk population with minimal residual disease in the bone marrow.5 Registration studies, as well as venetoclax combination studies, are now in progress.
CLL Treatment Directions
According to Dr. Wierda, future treatment directions for clnical trials will focus on the following areas:
- Early intervention in untreated, high-risk patients, including first-line therapy according to mutation status: (1) For fit, IGHV-mutated, chemoimmunotherapy-eligible patients, FCR with maintenance or transplant for minimal residual disease; (2) for fit, IGHV-unmutated and elderly patients, a B-cell receptor inhibitor with or without a Bcl-2 inhibitor (delaying exposure to chemotherapy and utilizing nonchemotherapy options to achieve deep, durable remissions)
- Second-line therapy for active disease: Expanding options for consolidation strategies, including consolidation for persistent disease on a Bruton’s tyrosine kinase inhibitor (first-line and later), “pushing patients into remission with additional agents”
- Use of effective new agents in Richter’s transformation
- Evaluation of novel treatment approaches, including immunomodulating agents (checkpoint inhibitors and others), chimeric antigen receptor (CAR)-modified T cells, and other cellular therapies ■
Disclosure: For Dr. Wierda’s disclosure, see online version of this article on ASCOPost.com.
References
1. O’Brien SM, Furman RR, Coutre SE, et al: Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17b disease. 2014 ASCO Annual Meeting. Abstract 7014. Presented June 3, 2014.
2. Thompson PA, Wierda W, Ferrajoli, A et al: Complex karyotype, rather than del(17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens. 2014 ASH Annual Meeting. Abstract 22. Presented December 6, 2014.
3. Sharman JP, Coutre S, Furman R, et al: Second interim analysis of a phase 3 study of idelalisib plus rituximab for relapsed chronic lymphocytic leukemia. 2014 ASH Annual Meeting. Abstract 330. Presented December 8, 2014.
4. Seymour JF, Davids MS, Pagel JM, et al: ABT-199 (GDC-0199) in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. 2014 European Hematology Association Annual Meeting. Abstract S702. Haematologica 99(suppl 1), 2014.
5. Roberts AW, Ma S, Brander D, et al: Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia. 2014 ASH Annual Meeting. Abstract 325. Presented December 8, 2014.
