Emerging Agents Lead to Extended Survival, Reduced Toxicity in CLL


Jacqueline C. Barrientos, MD, MS, discusses emerging agents and combinations in CLL based on recent trial data.

Jacqueline C. Barrientos, MD, MS

Jacqueline C. Barrientos, MD, MS

The armamentarium for chronic lymphocytic leukemia (CLL) has been significantly strengthening with the addition of new agents, particularly next-generation BTK and PI3K inhibitors, said Jacqueline C. Barrientos, MD, MS, at the 23rd Annual International Congress on Hematological Malignancies.®Although toxicities remain an issue, Barrientos explained tolerability may be improving.

During the meeting, Barrientos, an associate professor in the Department of Medicine at the Zucker School of Medicine at Hofstra/Northwell and attending physician at the CLL Research & Treatment Program of the Division of Hematology and Medical Oncology, Department of Medicine, in the North Shore—LIJ Cancer Institute in Lake Success, New York, discussed emerging agents and combinations in CLL based on recent trial data.

Among the FDA-approved monoclonal antibodies for CLL, ofatumumab (Arzerra) appears to be making an exit, as it consistently failed as a comparator in clinical trials. Now obinutuzumab (Gazyva) may even be elbowing rituximab (Rituxan) aside, Barrientos said.

The combination of obinutuzumab and chlorambucil reduced the risk of death by 24% versus rituximab plus chlorambucil in treatment-naïve patients with CLL with comorbidities, according to long-term follow-up data from the phase III CLL11 study presented at the 2018 European Hematology Association (EHA) Congress.1

More evidence of this trend is likely to emerge from new clinical trials, Barrientos said.

The BTK inhibitor ibrutinib (Imbruvica) delivered impressive 5-year outcomes in the phase Ib/II PCYC-1102 trial evaluating single-agent ibrutinib in treatment-naïve patients with CLL/small lymphocytic lymphoma. In the treatment-naïve cohort (n = 31), median progression-free survival (PFS) and overall survival (OS) were not reached and 5-year PFS and OS were each 92%. These data, reported in 2016, “were incredible” and unprecedented, Barrientos said, but she added that there’s room for improvement, given toxicities associated with ibrutinib.

“I’m sure that many of you have patients who have been using this drug and they find out after a few years they have hypertension that’s very difficult to control, and you have patients who develop arthralgias that are very debilitating,” she said.

An analysis of 582 patients treated with ibrutinib at the James Comprehensive Cancer Hospital of Ohio State University found that 76 developed atrial fibrillation, with a 6 month, 1-year, and 2-year cumulative incidence of 5.9%, 7.5%, and 10.3%, respectively.2The rate of atrial fibrillation was almost 4 times as high with ibrutinib versus non-ibrutinib therapy. This deserves monitoring, Barrientos said. “If your patients are having some issues with toxicities, please refer them to a cardiologist.”

The second-generation BTK inhibitor acalabrutinib (Calquence) has a more moderate toxicity profile and in the ACE-CL-001 study achieved an objective response rate (ORR) of 85% for relapsed/refractory CLL. It should be “the first drug you try” in the event of intolerance to ibrutinib, Barrientos said. “It’s already approved for mantle cell lymphoma and it’s in the guidelines, which means your insurance can cover this drug.”

Acalabrutinib causes headaches in about half of patients, and these are managed with coffee or off-the-shelf pain killers and generally resolve after 3 months, Barrientos said. What’s also important to remember about this drug is that it’s not effective in ibrutinib-resistant patients.

In data from the treatment-naïve cohort of the ACE-CL-001 study, the best ORR was 97% (5% complete response [CR]) and median time to response was 3.7 months.3Barrientos noted, “We have a drug that is more selective for BTK inhibition, but we still have the issue of patients having to continuously take it because they do not achieve complete remission.”

In the ELEVATE trial (N = 533), acalabrutinib is being compared head-to-head with ibrutinib in relapsed/refractory CLL. The trial includes del17p and del11q patients with 1 or more prior therapies, with a primary outcome measure of PFS noninferiority and secondary outcomes including grade ≥3 infections.

Early data indicate activity with next-generation BTK inhibitors known as irreversible inhibitors. These include tirabrutinib (GS-4059/ONO-4059) and zanubrutinib (BGB311). Reversible inhibitors are further behind in development.

Rituximab in combination with idelalisib (Zydelig) produced an ORR of 83.6%—all partial responses—in a comparative trial with placebo plus rituximab. The PFS for the active combination was 19 months.

Barrientos also mentioned the second-generation PI3K inhibitor duvelisib (Copiktra), which in September 2018 gained FDA approval in relapsed/refractory CLL based on phase III trial results in comparison with ofatumumab. The ORR was 73.8%, including 70% in del17p patients, and the PFS was 13 months overall and 12.7 months in del17p patients.

“The issue that I see with this drug is that it again has the same toxicities that we saw with idelalisib, such as diarrhea,” Barrientos said. The diarrhea can be grade 3/4, so it’s important, again, to monitor patients. “If they’re going to be using this drug, they should tell you the moment that they develop diarrhea so that you can stop this drug.”

Another emerging PI3K inhibitor is umbralisib (TGR-1202), which is being investigated in patients intolerant to prior BTK or PI3K inhibitor therapy. It has a smaller adverse event profile and may be well tolerated, although adverse events may not be revealed in the short term, Barrientos said.

Another exciting drug to watch is venetoclax (Venclexta), which has demonstrated impressive results as monotherapy and has also been tested in combination with rituximab in relapsed/refractory CLL. In the latter, phase Ib trial, the regimen delivered an ORR of 86% (51% CR/CR with incomplete blood count recovery [CRi]) and 59% of patients achieved marrow minimal residual disease negativity.

The phase III MURANO trial compared venetoclax plus rituximab with bendamustine plus rituximab. Median PFS was not reached versus 17 months, respectively (HR, 0.17; 95% CI, 0.11-0.25;P<.001). Meanwhile, the phase II CLARITY trial of ibrutinib plus venetoclax in relapsed/refractory CLL resulted in a response rate of 94% (n = 47) and a CR/CRi rate of 54% (n = 27) in evaluable patients after 12 months of venetoclax treatment. &ldquo;The rate of MRD negativity was high with 39% (n = 19) of patients achieving undetectable disease in the bone marrow after 12 months,&rdquo; Barrientos said.

Finally, the phase III CLL14 study is investigating venetoclax plus obinutuzumab in patients with treatment-na&iuml;ve CLL and coexisting medical conditions. At month 30, the PFS rate was 80.2% and the OS rate 92.3%. &ldquo;This is the one we&rsquo;ve all been waiting for, so we&rsquo;re all excited,&rdquo; Barrientos said.


  1. Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
  2. Wiczer TE, Levine LB, Brumbaugh J, et al. Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib.Blood Adv. 2017;1:1739-1748. doi 10.1182/bloodadvances.2017009720.
  3. Byrd JC. Woyach JA, Furman RR, et al. Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study. Presented at: 2018 American Society of Hematology Annual Meeting; San Diego, CA. Abstract 692.
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