The Evolving Role of PI3K Inhibitors in Double-Refractory CLL

A Conversation With Alexey V. Danilov, MD, PhD, and John C. Byrd, MD

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The treatment paradigm for chronic lymphocytic leukemia (CLL) continues to evolve in the first-line setting and beyond, with the availability of Bruton’s tyrosine kinase (BTK) inhibitors, the BCL2 inhibitor venetoclax, and novel combinations of these agents with anti-CD20 monoclonal antibodies.

Alexey V. Danilov, MD, PhD

Alexey V. Danilov, MD, PhD

John C. Byrd, MD

John C. Byrd, MD

The ASCO Post spoke with Alexey V. Danilov, MD, PhD, Co-Director, Toni Stephenson Lymphoma Center, and Professor in the Department of Hematology at City of Hope, Duarte, California, and John C. Byrd, MD, the Gordon and Helen Hughes Taylor Endowed Professor and Chair of the Department of Internal Medicine at the University of Cincinnati, Ohio, about choosing between a BTK and BCL2 inhibitor in the front-line setting and the management of patients with double-refractory CLL, including the potential role of phosphoinositide 3-kinase (PI3K) inhibitors.

First-Line Treatment of CLL

As Dr. Byrd explained, patients with symptomatic CLL have three great treatment options, depending upon the genomics of their disease. For younger patients with IGHV-mutated disease, the standard first-line treatment is the combination of fludarabine, cyclophosphamide, and rituximab, which is potentially curative in more than half of those treated. Unfortunately, only 10% to 20% of newly diagnosed patients are eligible for this regimen, said Dr. Byrd. Most patients end up receiving either a BTK inhibitor with or without the anti-CD20 monoclonal antibody obinutuzumab or venetoclax plus obinutuzumab.

“Several randomized studies have shown that BTK inhibitors without CD20 antibodies improve survival and induce durable remissions,” said Dr. Byrd. However, he noted, patients must remain on treatment indefinitely if treated exactly according to these study regimens.

Conversely, venetoclax and obinutuzumab offer the opportunity for time-limited therapy of 12 months. However, patients with 17p deletion likely have inferior results with venetoclax compared with BTK inhibition, said Dr. Byrd.

More recently, BTK inhibitors have been combined with venetoclax in first-line clinical trials of high-risk CLL. These combination therapies have demonstrated deep, durable response, with promising early progression-free survival with a time-limited approach,1 according to Dr. Byrd. This combination is approved in Europe but is not yet approved in the United States. “Longer follow-up is needed before using this regimen outside of a clinical trial,” said Dr. Byrd.

BTK Inhibitors vs Venetoclax

Dr. Danilov noted multiple factors that come into play when choosing between BTK and BCL2 inhibition. Although the latter is time limited, BTK inhibition is indefinite therapy, which is often an important consideration for patients. Comorbidities also matter, he said. Patients who are on an anticoagulant or have poorly controlled atrial fibrillation or hypotension, for example, may not be ideal candidates for BTK inhibitors. By contrast, patients who have trouble coming into the clinic for bloodwork might have more difficulty with venetoclax/obinutuzumab because of the intense monitoring for tumor-lysis syndrome required in the first month of therapy.

“CAR T cells can be effective in double-refractory CLL, but this is still a very small group of patients.”
— Alexey V. Danilov, MD, PhD

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“In the COVID-19 era, we have used the CD20 antibody less because it’s suppressive toward B cells more than our targeted therapies,” Dr. Danilov added. “With improved treatments for COVID-19, however, I’ve seen increased use of CD20 antibodies again.”

According to Dr. Byrd, the choice between BTK inhibition and venetoclax in the front-line setting is less complicated, given the limited amount of data supporting the latter.2 “It took 3 years for the hazard ratio of overall survival to flip in favor of venetoclax/obinutuzumab,” said Dr. Byrd, who also noted that secondary malignancies and long-term complications were not reported well. “Unless it’s very important for a patient to have time-limited therapy, I feel more comfortable using a BTK inhibitor.”

Double-Refractory CLL and PI3K Inhibitors

Although most patients respond well to BTK inhibitors and venetoclax, experiencing long progression-free survival, some with genetically high-risk CLL may fail to respond to either option. Unfortunately, said Dr. Danilov, the options remain limited in the double-refractory setting, but there are emerging agents in this space.

According to Dr. Danilov, the only drugs approved by the U.S. Food and Drug Administration (FDA) that could potentially be used for patients with double-refractory disease are PI3K inhibitors. However, these drugs, approved for relapsed or refractory CLL, have not been properly studied in patients who are refractory to both BTK inhibitors and venetoclax.

“This is a really, really tough group,” said Dr. Byrd, regarding patients with double-refractory disease. “Survival is 3 to 4 months, and patients typically progress quickly. There are no data on chemotherapy here, but in my limited anecdotal experience, it doesn’t work well.”

As Dr. Byrd explained, there are currently two FDA-approved PI3K inhibitors—duvelisib and idelalisib—that may produce durable remissions in approximately one-quarter to one-third of patients.

“We’ve seen remissions lasting between 6 and 12 months, which can help bridge patients to another treatment,” said Dr. Byrd. In addition, he noted, both duvelisib and idelalisib are structurally similar and are “fairly clean” PI3K-delta inhibitors. “If you’re in a practice that doesn’t have access to a robust portfolio of clinical trials, I would recommend one of these agents with appropriate follow-up, as this class of drug has unique toxicities.” In this setting, clinical trials are always favored.

Problematic Pivotal Trials for PI3K Inhibitors

Despite the efficacy observed in a real-world setting, Dr. Byrd noted several problems with the design of the pivotal trials that led to the approvals of idelalisib and duvelisib. The confirmatory study of idelalisib randomly assigned patients with relapsed CLL to receive idelalisib plus rituximab vs placebo plus rituximab.3 The problem, said Dr. Byrd, is the control rituximab had never been given as monotherapy with the schedule used in this trial before, so idelalisib was essentially compared against a placebo control.

“I’m always a believer in clinical trials for this patient population [with double-refractory CLL].”
— John C. Byrd, MD

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“Of course, when you’re randomly assigning patients between a placebo and a new therapy combination that has some efficacy, you’re going to see increased progression-free survival and hopefully a favorable trend for overall survival, and the investigators did,” explained Dr. Byrd.

Although the phase III DUO study,4 which led to the approval of duvelisib, had the same eligibility criteria as the idelalisib study, patients were randomly assigned to receive either duvelisib or ofatumumab, which is an active drug, he said. According to Dr. Byrd, however, the methods used in the study were also problematic. “In the DUO trial, patients could cross over and were on other therapies, so examination of overall survival is not a valid endpoint,” he added. “If the same logic were applied to the CLL14 study [that led to approval of venetoclax plus obinutuzumab], venetoclax would never have been approved.”

Because idelalisib is approved only in combination with rituximab, which is “not even an active drug in this setting,” Dr. Byrd noted he’s more likely to administer duvelisib than idelalisib for patients with resistant CLL.

Clinical Trial Remains Best Option

Despite the availability of two FDA-approved agents, Dr. Danilov emphasized that a clinical trial remains “by far the best option” for patients with double-refractory CLL. There are approximately 10 to 15 drugs being investigated in this space, including immunotherapy, bispecific antibodies, small molecules, noncovalent BTK inhibitors (eg, pirtobrutinib), and chimeric antigen receptor (CAR) T-cell therapy.

In the phase I TRANSCEND CLL 004 study, the CAR T-cell therapy lisocabtagene maraleucel demonstrated an overall response rate of 82% in relapsed or refractory CLL or small lymphocytic lymphoma.5 Although just 11 patients enrolled had “double--refractory” CLL, the median progression-free survival in this cohort was approximately 18 months.

“CAR T cells can be effective in double-refractory CLL, but this is still a very small group of patients,” said Dr. Danilov. “Of course, CAR T cells are also associated with their own toxicities, including cytokine-release syndrome and neurotoxicity, and the treatment often requires a hospital stay of a couple of weeks.”

Dr. Danilov also noted the potential role of allogeneic stem cell transplantation in certain subgroups of CLL. “Most of our patients with CLL are older, so they are not great candidates for allogeneic stem cell transplantation, but younger patients with double-refractory CLL would be one indication,” said Dr. Danilov, who noted the treatment is highly toxic. “Younger patients with TP53-aberrant CLL, who experienced disease progression on a BTK or BCL2 inhibitor, may also be candidates for -transplantation.”

For those patients with access, however, a clinical trial should be the first choice for patients with double-refractory CLL. “I’m always a believer in clinical trials for this patient population,” Dr. Byrd concluded. “Clinical trials should be our first choice at all stages in the disease because that’s how we move the field forward.” 

DISCLOSURE: Dr. Danilov has served as a consultant to AstraZeneca, AbbVie, BeiGene, Genentech, Nurix, MorphoSys, Incyte, TG Therapeutics, Bayer Oncology, and Pharmacyclics and has received research funding from AstraZeneca, Takeda Oncology, Bayer Oncology, SecuraBio, MEI, Nurix, Cyclacel, TG Therapeutics, and Bristol Myers Squibb. Dr. Byrd has served as a consultant to Syndax, Trillium, AstraZeneca, Novartis, Newave Pharmaceuticals, and Kronos Bio and is Chair of the scientific advisory board and a major stockholder in Vincerx Pharma.


1. Tam CS, Allan JN, Siddiqi T, et al: Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: Primary analysis of the CAPTIVATE FD cohort. Blood 139:3278-3289, 2022.

2. Al-Sawaf O, Zhang C, Tandon M, et al: Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): Follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 21:1188-1200, 2020.

3. Sharman JP, Coutre SE, Furman RR, et al: Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 37:1391-1402, 2019.

4. Flinn IW, Hillmen P, Montillo M, et al: The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 132:2446-2455, 2018.

5. Siddiqi T, Soumerai JD, Dorritie KA, et al: Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood 139:1794-1806, 2022.