A Paradigm Shift in CLL Treatment

Optimal sequencing of targeted therapies

The emergence of B-cell receptor (BCR) and B-cell lymphoma 2 (BCL-2) inhibitors has transformed the treatment of chronic lymphocytic leukemia (CLL). With each development and study, we move closer to chemotherapy-free treatments for this most common leukemia. Brian T. Hill, MD, PhD, an oncologist at Cleveland Clinic Cancer Center, is on the forefront of these developments as the field begins to determine how best to utilize these newer but ever more widely used treatments.

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B-cell receptor inhibitors

Researchers continue to gain a more in-depth understanding of the role of the BCR signaling pathway in the development and maintenance of B-cell malignancies. The downstream effects of BCR activation include the activation of intracellular transduction molecules with kinase function. These kinases ultimately influence cell survival, proliferation, function and differentiation.

Ibrutinib, the first Bruton tyrosine kinase (BTK) inhibitor developed, was initially approved for patients with relapsed CLL and/or del(17p). Its use has now been expanded to all CLL patients, including those previously untreated.

Idelalisib was developed to inhibit PI3K, another BCR pathway critical to CLL survival. It is approved in combination with rituximab for patients with relapsed CLL.

While ibrutinib and idelalisib are kinase inhibitors, venetoclax functions by inhibiting the anti-apoptotic effects of BCL-2. It has been approved for patients with CLL with del(17p).

Indications for all of these therapies are expected to expand with the anticipated results of front-line Alliance (NCT01886872) and ECOG (NCT02048813) studies comparing chemoimmunotherapy to ibrutinib-based therapy as well as other studies with venetoclax in combination with monoclonal antibodies.

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“These therapies are relatively new,” says Dr. Hill, “and while we knew anecdotally that many patients discontinued the therapies for many reasons, we didn’t have data on why or to what effect, or if a certain sequence of these drugs affected efficacy or discontinuation rates.”

Real-world outcomes of CLL patients treated with KI therapy

In a study published in Blood in late 2016, Dr. Hill and colleagues from 10 U.S. academic medical cancer centers, including first author Anthony R. Mato, MD, at the Hospital of the University of Pennsylvania, sought to answer these questions in relation to ibrutinib and idelalisib. “We found that toxicity was the most common reason for discontinuation for both ibrutinib and idelalisib,” says Dr. Hill.

For patients discontinuing because of toxicity, an alternate KI was the most common follow up therapy and was associated with an estimated progression-free survival (PFS) of 11.9 months. Among those patients who discontinued because of CLL progression, PFS was considerably shorter (seven months), suggesting that novel therapies should be considered before switching KIs.

“Interestingly, we found that over 50 percent of patients who discontinued their first KI during the study period did so due to toxicity,” says Dr. Hill. “In the studies that led to the FDA approval of these drugs, progression of disease, not toxicity, was the major reason for discontinuation. For patients who discontinue KI due to disease progression, our data suggest subsequent treatment with cellular therapies, stem cell transplantation, venetoclax or clinical trials with novel agents is likely to be of more benefit  than a second KI.”

Do outcomes depend on sequence?

“In our initial study, KI choice did not appear to impact progression-free or overall survival,” says Dr. Hill (PFS [HR 0.3, 95% CI 0.08-1.2]; OS [HR 0.4, 95% CI 0.08-2.1]). “We and others have found a high overall response rate (ORR) for patients treated with venetoclax after KI discontinuation, and we decided to investigate this finding further.”

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In a multicenter study of 683 CLL patients published in Annals of Oncology in January 2017, the consortium, including Drs. Mato and Hill, as well as Allison Winter, MD, a Cleveland Clinic Cancer Center fellow, reported a strong preference for once sequence—ibrutinib followed by idelalisib—for patients in all settings: front-line (HR 2.8, CI 1.3-6.3, P  = 0.01), relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), or complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02).

Caption: PFS (A) by first kinase inhibitor (ibrutinib versus idelalisib) in the front-line setting. PFS (B) by frist kinase inhibitor (ibrutinib versus idelalisib) in the relapsed refractory setting. Republished with permission from Mato et al. Ann Oncol. Published online January 25, 2017.

PFS (A) by first kinase inhibitor (ibrutinib versus idelalisib) in the front-line setting. PFS (B) by frist kinase inhibitor (ibrutinib versus idelalisib) in the relapsed refractory setting. Republished with permission from Mato et al. Ann Oncol. Published online January 25, 2017.

“We also found that if initial kinase inhibitor therapy failed, treatment with an alternate KI or venetoclax was superior to existing chemoimmunotherapy combinations,” says Dr. Hill. “It also appears that using venetoclax after ibrutinib failure is slightly superior to using it after idelalisib failure.”

The study is the largest on KI discontinuation and clinical outcomes after discontinuation, and it describes for the first time beyond anecdotal reports what happens when a patient switches from one KI to another.

Implications for patient care

The introduction of targeted therapies for CLL marks a move away from a chemotherapy paradigm, and this work offers insight into how best to use and sequence these agents both for individual oncologists and for leaders setting guidelines in the field. “Sequence is important because we want to maximize patient outcomes and minimize toxicity,” says Dr. Hill, “but it’s also important to establish the algorithms and care paths that are becoming central in the transition to value-based care. As we develop these best practices, the results of these studies are influencing our approach at Cleveland Clinic.”