Transitioning to Targeted Treatment for Patients with CLL Using BTK Inhibitors

Patients with Chronic Lymphocytic Leukemia (CLL) may no longer have to head to the hospital for a chemotherapy infusion. Oral targeted therapies such as Imbruvica (ibrutinib), Calquence (acalabrutinib) and Venclexta (venetoclax) have radically changed the field, extending life and reducing side effects.

In an interview with CURE®, Dr. Lindsey Roeker, a third-year clinical fellow at Memorial Sloan Kettering Cancer Center in New York City, discussed these medications and their side effects and explained how oncologists match each with patients.

CURE®: Please explain how a Bruton tyrosine kinase (BTK) inhibitor works and why these agents are used to treat CLL.

Roeker: To understand why BTK inhibitors are effective in CLL, it’s important to first understand how a normal B cell works and how it uses a B cell receptor. A normal B cell is a type of white blood cell that is born in the bone marrow, travels through the peripheral blood, and then takes up residence in a lymph node or the spleen.

B cells throughout our body use the B cell receptor to help the body identify infections. When a B cell receptor encounters an infection, it activates or “turns on” the B cell through a series of signaling proteins. BTK is one of those signaling proteins that amplifies the “on” signal. This “on” signal prompts the B cell to survive and proliferate, or make copies of itself, in order to fight off infection.

In a CLL cell, the B cell receptor is excessively “on” and tells the CLL cell to survive and proliferate. By blocking the B cell receptor “on” signal with BTK inhibitors, the cell no longer receives the message to live or make copies of itself. The CLL cell with blocked BTK either dies or can’t move around normally, thus stopping CLL growth.

Since Imbruvica’s approval by the Food and Drug Administration (FDA) in 2016, what has been shown regarding the agent’s overall survival and toxicity?

Imbruvica has been studied in patients who have never been treated and patients who have had prior treatments for CLL, also called relapsed/refractory (disease). Many studies examining Imbruvica have been performed. Some of the first studies are those with the longest follow up periods, so they give a window into how well these drugs work over longer time periods.

In the study that examined Imbruvica in patients with relapsed/refractory CLL, we have five and a half years of follow-up, and we know that patients do well with this treatment. Ninety-one percent of patients in this study benefited from the drug with some reduction in their disease, and we see that Imbruvica works for a long time for many patients, even when prior medications used to treat CLL had stopped working. For patients who had never been treated for CLL and were given Imbruvica, a similarly high proportion of patients benefited from the drug and patients who received Imbruvica lived longer on average than patients who received oral chemotherapy.

A few more recent studies have compared Imbruvica to stronger IV chemotherapy regimens and have shown that patients go longer without having CLL progression when they are treated with Imbruvica. The trials really reinforce that Imbruvica works very well.

The most common side effects of Imbruvica are diarrhea, nausea and fatigue. Some other side effects, which are less common but can be more dangerous, are high blood pressure, atrial fibrillation (an abnormal heart rhythm) and bleeding.

When looking at patients who are prescribed Imbruvica by their doctors, as opposed to receiving the medication on a clinical trial, we know that a fair number of patients experience these side effects and stop Imbruvica because of side effects.

Some of these side effects seen with Imbruvica are due to Imbruvica’s ability to block proteins that look like BTK but are different, which we call off-target effects.

In November 2019, Calquence was FDA approved. How is this BTK inhibitor different from Imbruvica?

Calquence is a second-generation BTK inhibitor, and it was designed to be more selective in blocking BTK. By blocking fewer proteins that look like BTK but have other functions, there should be fewer off target effects.

Calquence has been studied in patients who had never been treated for CLL and patients with relapsed/refractory CLL. Like Imbruvica, the proportion of patients who benefit from this drug is really high, and patients are able to take the drug for a long time before the drug stops working.

For instance, in a recent study, 90% of patients who got Calquence in combination with Gazyva (obinutuzumab), an antibody against CD20 that is expressed in B cells, had not had any progression in their CLL after two and a half years.

The most common side effects of Calquence are anemia (low hemoglobin), neutropenia (low neutrophil count, or decreased number of infection-fighting cells), low platelets, headache, upper respiratory tract infections and diarrhea.

One of the goals in designing second-generation BTK inhibitors like Calquence was to minimize side effects by reducing off target effects. It is difficult to compare side effect profiles of drugs studied in the results of different clinical trials since the patients included in one trial might be very different than the patients included in another clinical trial. We are awaiting the results of a trial that compares Imbruvica and Calquence head-to-head. When that trial is done, we will have answers about how well these drugs work compared to one another and whether the side effects are really different.

What factors help a health care professional decide on the best course of treatment for a patient?

When deciding on treatment for a patient, we look at the whole picture. This includes the genetic characteristics of the disease and a patient’s other medical problems. Both Imbruvica and Calquence, as well as Venclexta in combination with Gazyva (obinutuzumab), and chemoimmunotherapy treatments are approved as first therapy for CLL. Imbruvica and Calquence are pills that are taken daily for as long as they’re working. Venclexta and Gazyva is a combination of treatments that are given for one year and then stopped, based on how these drugs were used in the clinical trial that led to their approval by the FDA.

The decision about which to pursue depends on a patient’s preference. Some patients really want to avoid IV medications, in which case Imbruvica or Calquence may be good choices.

Some want to be on therapy for a limited period, in which case Venclexta and Gazyva may be a better fit.

We also look at a patient’s other medical problems to make sure that their treatment won’t make an existing medical problem worse. In general, being open with your doctor about your preferences and, once you start a drug, any side effects that you experience is important. Some patients do really well with one drug while others experience side effects, and patients who have side effects some- times do better with another medicine.

Communicating your experience is an important step in helping your doctor find the right therapy for you.

How have BTK inhibitors changed the treatment landscape in CLL?

BTK inhibitors have really revolutionized the treatment of CLL. CLL used to be a disease that was treated primarily with chemotherapy, and now it is much more commonly treated with targeted medicines. These targeted medicines, including BTK inhibitors, have helped patients experience fewer side effects and control their CLL better.