Byrd Discusses Optimizing Ibrutinib and Idelalisib in CLL

John C. Byrd, MD

In a presentation at the inaugural ASH Meeting on Hematologic Malignancies, John C. Byrd, MD, discussed what his clinical experience has revealed about the optimal use of ibrutinib (Imbruvica) and idelalisib (Zydelig) in chronic lymphocytic leukemia (CLL), as well as unanswered questions and challenges concerning these novel agents.

“Therapies for this disease are rapidly changing. Until recently, CLL had no relevant common pathway for therapeutic targeting with a pharmacologic agent. The new agents are highly active in CLL both as monotherapy and in combination with other treatments. It’s currently unclear that their addition to other therapies improves efficacy,” said Byrd, director of the Division of Hematology and a CLL specialist at the Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “The responses to these drugs have been impressive in all genetic groups. The remissions, especially with ibrutinib have been highly durable, more than anything else we’ve used.”

Byrd described Bruton’s tyrosine kinase (BTK), which ibrutinib inhibits, as the best current target in treating CLL, noting that BTK mutations in humans give rise to X-linked agammaglobulinemia, an inherited disorder with decreased immunoglobulin G and a lack of B cells. According to Byrd, the pros of targeting BTK are that BCR signaling is vital to CLL cell survival and proliferation. Also, BTK activation leads to the activation of the PI3K, PLCγ 2, MAPK, and NF-kB pathways. Mouse models of BTK deficiency suggest that it is predominantly a B-cell defect that does not impair T cells or cause colitis, he said.

One concern about ibrutinib is that not enough is known about BTK in CLL and related non-Hodgkin lymphomas. Another is that targeting BTK may increase immune suppression due to its influence on B cells, NK cells, and neutrophils, Byrd said.

He emphasized that, as BTK is the current best target in CLL, then the BTK inhibitor ibrutinib is the best available agent. In addition to its potency, Byrd stressed its irreversible nature. “Before ibrutinib, virtually all drugs developed as kinase inhibitors were reversible due to concerns about toxicity in ubiquitous targets and adduct formation,” he said. “Until ibrutinib, irreversible kinase inhibitors were just not explored.”

Byrd noted 2 advantages to irreversible inhibitors for targets with great importance to tumors and redundancy in normal tissue. First, they inhibit the target more readily with less frequent dosing. Second, he called the ability to perform pharmacodynamics monitoring of target inhibition in vivo with labeled probe assays, “very beneficial.”

Summarizing what is currently known about ibrutinib, Byrd referred to the drug as the “most effective oral therapeutic available to treat del(17)(p13.1) CLL and relapsed CLL.” He noted that all data support continuous dosing and urged colleagues not to stop ibrutinib in the absence of progressive disease or intolerance.

“Early lymphocytosis is expected and, unless other signs of progression are present, therapy should be continued,” Byrd said. “Mild bruising and ecchymosis are common but major bleeding is infrequent in the absence of warfarin. Management of atrial fibrillation should substitute aspirin unless the patient is at high risk for embolic disease.”

Other common side effects that occur with ibrutinib but can generally be managed without discontinuing the drug include arthralgia, myalgia, panniculitis, and erythema nodosum. “The majority of patients tolerate long-term dosing without problems but, for the small subset who do become intolerant, other available options are idelalisib and second-generation BTK inhibitor clinical trials,” Byrd said, adding that, when infections occur early in therapy, patients’ immune function typically improves with resumed or continued ibrutinib treatment.

Ibrutinib resistance does occur in a small percentage of CLL patients. “Early identification of ibrutinib resistance can prevent a full relapse, so studies on how to identify these relapses early and manage them are a major area of research now,” Byrd said.

According to Byrd, when ibrutinib resistance emerges early in treatment, it is as Richter’s transformation. “This happens within 12 to 18 months of beginning treatment and is very difficult to treat, with no long term survivors,” he said. “Efforts for this group of patients should focus on early introduction of allogeneic transplantation if possible, although we still don’t have good data on how effective this approach is.”

Late relapse occurs as CLL, typically at the cysteine 481 site of BTK where the drug binds, Byrd said. “In 90% to 95% of these cases, the relapse shows up as small clones of the disease and they increase with time,” he said. “Experimental therapies directed at alternative targets can be effective.”

Byrd cautioned that, in both Richter’s transformation and CLL progression, substitute treatment must be identified before the ibrutinib is discontinued. “Otherwise, the patient can have a very rapid disease progression that can quickly become life threatening,” he said. “Continue ibrutinib until 1 to 2 days before the new therapy starts or even allow ibrutinib to overlap with the new therapy to avoid this.”

He highlighted unanswered questions about ibrutinib whose eventual answers will likely affect clinical practice:

• What pretreatment features beyond complex karyotype predict for early and late progression on ibrutinib?
• What is the origin of BTK and PLCG2 mutations? Are they pre-existing and selected out by ibrutinib, or are they acquired during therapy? And will they go away absent drug selection or with alternative therapy?
• What strategies can we employ to effectively prevent these? More pressure on targets via improved BTK inhibitor coverage or combination strategies?
• Can we stop treatment once the disease is in clinical remission or good partial remission and immune reconstitution occurs?

Discussing idelalisib, Byrd called the combination of the PI3K-delta inhibitor and rituximab (Rituxan) a reasonable therapy for previously treated CLL but noted that many questions remain. First of these is deciding how to prioritize it versus treatment with ibrutinib. He noted three main concerns:

• Lack of clarity whether idelalisib’s efficacy is similar to ibrutinib’s, particularly in del(17p) patients.
• Cost and convenience issues for dual therapy with rituximab compared with a monotherapy oral agent.
• Required toxicity monitoring for liver function, pneumonitis, and colitis.

One clinical benefit of idelalisib is that it can be used with patients who have an elevated risk of bleeding or who are already on anticoagulation. “My practice is to use idelalisib only when ibrutinib is contraindicated due to the patient’s need for warfarin or when ibrutinib is not tolerated,” Byrd said. “We know that ibrutinib works in idelalisib-refractory patients but the reverse is unknown.”

In his conclusion, Byrd listed emerging agents in the pipeline for relapsed CLL, including GS-9973 (entospletinib; PLCG2 mutations), IPI-145 (duvelisib) + GA101 (C481S; obinutuzumab), and ABT-199 (venetoclax; C481S).

For Byrd, this is good news for patients and clinicians alike. “We are seeing a host of second-generation BTK and PI3 kinase inhibitors coming. The clinical trials designed to obtain initial regulatory approval for the very active ABT-199 [a selective inhibitor of the Bcl-2 protein] have been completed,” he said. “I don’t think it’s unrealistic to hope we will one day be able to obtain molecular complete remissions and cure of the disease.”