New Options for First-Line Treatment of Chronic Lymphocytic Leukemia

Most patients with chronic lymphocytic leukemia (CLL) now have several options for first-line therapy, thanks to new clinical trial results and novel targeted agents.

Many patients with CLL, a slowly progressive blood cancer in which the bone marrow makes too many white blood cells, don’t need immediate treatment but can be observed — sometimes for many years — until they become symptomatic or the disease begins to progress rapidly.

A number of different drugs are used to treat CLL at that point. Until recently, the standard regimen for initial treatment has been a combination of:

  • chemotherapy (fludarabine and cyclophosphamide (FC))
  • an antibody immunotherapy (rituximab), known as FCR, for patients younger than 65
  • and bendamustine and rituximab if older than 65.

These regimens were developed because the combination of fludarabine and cyclophosphamide kills CLL cells synergistically in the laboratory, and the addition of rituximab to FC in a randomized clinical trial improved overall survival for the first time in CLL.

In the last five years, a deeper understanding of the biology of CLL has led to a number of exciting targeted therapies. Ibrutinib targets the Bruton tyrosine kinase, or BTK, which is crucial to signaling downstream of the B cell receptor and is now known to be a lynchpin in CLL cell survival.

After multiple studies in relapsed CLL, in 2016, ibrutinib was approved as a single agent given continuously for first-line treatment of CLL, and recently was also approved in combination with obinutuzumab, a monoclonal antibody drug.

Even newer, in 2019, was the frontline approval of a one year time-limited combination of venetoclax, another targeted drug that inhibits a lynchpin of CLL cell survival, namely BCL-2, plus obinutuzumab for untreated patients with CLL.  Both ibrutinib with obinutuzumab and venetoclax with obinutuzumab were compared to a standard therapy for older patients, chlorambucil with obinutuzumab, and were found to have superior PFS.

Now, oncologists have to determine which drugs will work best for which patients.

Ibrutinib vs. other agents

Young, fit patients without significant medical problems, who have the lower risk subtype of CLL — in other words, whose CLL is considered IGHV mutated based on the presence of mutations in the immunoglobulin variable region gene — should generally still receive the standard treatment: chemoimmunotherapy with FCR.

“Studies suggest that FCR is potentially curative,” says Jennifer Brown, MD, PhD, director of the CLL Center at Dana-Farber. “55% of patients with  mutated IgVH are still in remission 12 years later — after only six months of therapy.”

Jennifer Brown, MD, PhD.

For CLL patients with unmutated IGHV, however, the picture is more complicated. For them, “ibrutinib improved disease control in recent studies, but did not increase overall survival,” Brown notes.

However, ibrutinib alone in patients who are young and fit and are eligible for FCR chemoimmunotherapy has downsides, she adds: The ibrutinib must be given indefinitely, which can be difficult for patients, and comes with significant cumulative side effects and cost.

Furthermore, some patients with unmutated IGHV — for example, those with trisomy 12 or other lower risk cytogenetic markers — can do quite well with 6 months of FCR. The benefits of ibrutinib frontline increase the greater the disease risk, such that patients with 17p deletion or TP53 mutation should not receive chemoimmunotherapy but rather ibrutinib or another targeted agent, while mutated IGHV patients have similar outcomes with chemoimmunotherapy or ibrutinib.

The newest targeted agent to be approved frontline was in late May 2019, when a one year combination of venetoclax and obinutuzumab got the nod from the FDA.  The two-year progression-free survival on this regimen, which is planned as one year of therapy, was 88 percent, identical to that seen with continuous ongoing ibrutinib therapy.  This regimen also works well in high-risk disease including del17p disease, and in general venetoclax has fewer chronic side effects than ibrutinib.  Also in contrast to ibrutinib, venetoclax obinutuzumab also achieves deep remissions with undetectable MRD, facilitating discontinuation of therapy.  Many academic CLL specialists favor this regimen and it should start to be used more in the community.

The bottom line

Treatment with new drugs and combinations is enabling patients to live longer. So far, this survival improvement is most noticeable in patients whose disease has high-risk characteristics, because those with low-risk features have always done very well, Brown says.

Even more drugs are on the horizon, such as the second generation ibrutinib-like drug acalabrutinib, which has been granted breakthrough therapy designation by the U.S. Food and Drug Administration as a single agent therapy for adults with CLL, and is expected to be approved in the first half of 2020.

Acalabrutinib and other second generation BTK inhibitors are generally better tolerated than ibrutinib, which may make it easier for patients to stay on them indefinitely.

“Still, our vision in the CLL Center is to move toward combination, time-limited therapy and we currently have many clinical trials based on this vision,” Brown says. “For example, we are studying the three drug regimen acalabrutinib venetoclax obinutuzumab, with a cohort currently open for patients whose CLL has 17p deletion. We will soon be opening acalabrutinib with the novel PI3kinase inhibitor umbralisib and the novel anti-CD20 antibody umbralisib. For relapsed patients we are investigating duvelisib venetoclax.”

“There are truly many possibilities, attesting to the bright future of CLL therapy and outcomes,” Brown notes.

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