CLL in the Era of Targeted Therapies

Jacqueline Claudia Barrientos, MD

Over the past few years, remarkable advances have been achieved in the field of chronic lymphocytic leukemia (CLL) by rationally targeting pathways overexpressed and used by the malignant clone for proliferation and survival. These developments have been achieved by a better understanding of the underlying biology and the disease process. The current standard of care is to observe a patient with newly diagnosed CLL until disease-related symptoms warrant the need for therapy. Treatment is chosen based on the patients’ comorbidities and prognostic factors at the time therapy is initiated. Hence, physicians must carefully weigh the potential adverse effects and toxicities that can be expected from the chosen regimen. More important, prognostic markers should be obtained prior to initiating any line of therapy (frontline and at relapse) because certain drugs will not work for particular patients.

Patients with the dreaded deletion 17p (del17p) or TP53 mutation were previously inadequately treated by chemoimmunotherapy regimens. The regimens did not work, and if there was a response, the median progression-free survival was less than a year, leading to a median overall survival of about 2 to 3 years. Current management of patients with del17p or TP53 mutation warrants therapy with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), the only drug currently approved for this particular indication in the frontline setting. The BCL-2 inhibitor, venetoclax (Venclexta), is FDA approved for use in patients with relapsed del17p and is undergoing evaluation by the FDA for use in all patients with relapsed/refractory CLL in combination with the monoclonal antibody, rituximab (Rituxan).

If neither drug is an option for a patient with del17p, it is recommended that the patient be considered for hematopoietic stem cell transplant from an allogeneic donor, participate in a clinical trial with a promising agent, or be considered for the use of the PI3K-delta inhibitor idelalisib (Zydelig). Although idelalisib has not been specifically approved for this indication, there is clinical trial information to support this recommendation when neither ibrutinib nor venetoclax is a care option.

About 14,000 new cases of CLL are diagnosed in the United States annually, making this disease the most prevalent adult leukemia in the country and the Western hemisphere. CLL is traditionally known as a disease of elderly patients, with the majority of diagnoses in patients older than 65 years. Because CLL typically follows an indolent course, many patients do not need to initiate therapy until they are of advanced age, when frailty and reduced organ function can contribute to tolerability issues. Chemoimmunotherapy regimens have been able to get the disease into remission for a prolonged period following excellent responses in over 90% of patients. Some of these patients have even achieved over a decade of disease-free status without evidence of a relapse, hence the sense of having achieved a “cure” in a subset of patients treated with a chemoimmunotherapy regimen such as fludarabine, cyclophosphamide, and rituximab. Unfortunately, the majority of patients relapse after initial therapy. Moreover, because of comorbidity burden at the time of frontline therapy, the majority of patients with CLL are unable to take advantage of these remarkable regimens, thus experiencing inferior outcomes compared with their younger counterparts.

Although several chemoimmunotherapy regimens are available for use in elderly patients (eg, obinutuzumab [Gazyva] with chlorambucil, ofatumumab [Arzerra] and chlorambucil, rituximab and chlorambucil), the majority of US physicians are hesitant to use chlorambucil as the backbone of any frontline therapy. This is the reason why clinical practice is changing and ibrutinib is emerging as the new go-to drug for patients with comorbidities and frail and elderly patients. Ibrutinib as a monotherapy has shown little evidence for achievement of complete remissions and minimal residual disease—negative status, which traditionally correlate with longer remission durations. Hence, there are multiple ongoing trials worldwide combining novel targeted agents—such as ibrutinib and obinutuzumab, or venetoclax in combination with obinutuzumab or combinations with chemotherapy.

When asked about the role of the immunoglobulin-heavy chain genes in CLL, Nicholas Chiorazzi, MD, from the Feinstein Institute for Medical Research in Manhasset, New York, stated, “Our studies documented that CLL cases could be divided into 2 groups based on IGHV gene mutations: IGHV-unmutated (U-CLL) and IGHV-mutated. Subsequently, our group and one led by Freda Stevenson, BSc, MSc, DPhil, professor of immunology, University of Southampton, England, simultaneously published that this division had prognostic importance. These 2 sets of findings have stood the test of time.” Exciting data from The University of Texas MD Anderson Cancer Center, from Germany, and from Italy indicate that the distinction between U-CLL and IGHV-mutated cases probably has therapeutic importance as well. Thus, there appears to be a 2-fold value to determining IGHV mutation status for patients with CLL: prognostic and therapeutic.

This leads us to the next frontier. We have achieved enormous success over the past few years, so why should we continue to research this disease? The answer is that we still do not have a cure and even the best drugs come with safety profile issues. There are several drugs in the pipeline, including second- and third-generation BTK and PI3K inhibitors such as acalabrutinib (ACP-196), duvelisib (IPI-145), and umbralisib (TGR-1202). There are other novel monoclonal antibodies being tested, including ublituximab (TG-1101), which is currently under review by the FDA in combination with ibrutinib for high-risk CLL. Another drug with the potential to alter outcomes includes the recently approved chimeric antigen receptor T-cell technology of tisagenlecleucel (and several others in development), currently available only for patients with acute lymphocytic leukemia but with demonstrated clinical activity in patients with CLL.

Overall, the sky is the limit, and we expect that our future endeavors will lead to deeper remission and hopefully, finally, a cure.