Novel Treatments of Special Cases in Chronic Lymphocytic Leukemia

John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research and director, Division of Hematology at The Ohio State University, recently spoke at the American Society of Hematology’s inaugural meeting on Hematologic Malignancies in Chicago about novel agents in treating chronic lymphocytic leukemia (CLL).

The focus of his lecture, titled “How I Treat Special Cases in CLL: Novel Agents,” was about the emergence of new targeted therapies, including ibrutinib (Imbruvica) and idelalisib (Zydelig), and what clinicians should know about them.

“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,” Byrd noted in an interview withTargeted Oncologyafter the meeting. “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 discussed the rationale for targeting B-cell receptor (BCR) signaling in CLL, summarized clinical data on approved agents for CLL, addressed clinical management of complications arising from these agents, and explored strategies for managing patients who develop resistance to BCR signaling agents.

While discussing important points for pursuing BCR targets, Byrd emphasized that current preclinical models used for new therapeutics in CLL have been unable to identify the promise of BCR signaling agents.

“All BCR antagonists are inactive in most B-cell lines and xenograft models. BCR antagonists mediate only modest apoptosis against primary CLL cells,” he said. “This emphasizes the need for migration, stromal and proliferation models to assess the potential of new therapeutics.”

Byrd also examined the pros and cons of targeting PI3K p110-δ, saying that the PI3K p110-δ pathway is constitutively active in CLL cells; siRNA can antagonize this and also other survival signaling. “The predominantly B-cell phenotype of the p110-δ inactive mouse suggests that targeting is possible,” he said. “α and β isoform knockouts are embryonic lethal and γ isoform knockout has predominant T-cell and granulocyte defects.”

Touching on the negatives of targeting Pl3K p110-δ, Byrd said that a P110-δ—inactive mouse has on-target inflammatory bowel disease in its cecum and rectum that could complicate long-term recovery. He also noted that other isoforms of p110 could promote rapid resistance to selective isoform inhibitors.

Byrd said the oral agent, idelalisib, targets PI3K- δ, providing selectivity and allowing good target coverage. Byrd referred colleagues to what he called the “pivotal” study published by Furman, et al in theNew England Journal of Medicine.¹

Byrd called the combination of idelalisib and rituximab a reasonable therapy for previously treated CLL, but he stated some concerns:

• Deciding how to prioritize the combination versus treating with ibrutinib monotherapy
• Lack of clarity whether or not idelalisib’s efficacy is similar to ibrutinib’s in patients with del(17p)

• 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 in 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 discourse, Byrd acknowledged Bruton’s tyrosine kinase (BTK) as the best current target in treating CLL. He saidBTKmutations 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, PLCγ2, 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.

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

Byrd emphasized that if 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 cited two 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.”

Byrd summarized what is currently known about ibrutinib, referring to it 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,” he 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-yet-manageable side effects that occur with ibrutinib 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. He added 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 in the form of 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 ofBTKandPLCG2mutations? 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?

Byrd listed a variety of ongoing new trials as well. For mutation-only,MOR208is being investigated, while Selinexor is being studied as an agent to combat Richter’s transformation. For relapsed CLL, he indicated these possible agents:

• GS-9973 (PLCG2mutations)
• IPI-145 + GA101 (C481S)
• ABT-199 (C481S)

According to 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.”

Reference

1. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007