'Possibility of Cure' for Some Patients With CLL

Alexander M. Castellino, PhD

September 10, 2019

Treatment for chronic lymphocytic leukemia (CLL) is more patient-friendly now with the newer oral targeted therapies that have appeared within the last three years, Jennifer A. Woyach, MD, from the Ohio State University Comprehensive Cancer Center in Columbus, Ohio, told Medscape Medical News. She was referring to the oral agents, ibrutinib (Imbruvica, Pharmacyclics/Janssen) and venetoclax (Venclexta, AbbVie/Genentech) that have rapidly changed the treatment landscape for CLL.

"These agents are extremely exciting, and a high interest right now is in determining how best to use them, whether it is in combination versus sequential and intermittent versus continuous," Woyach told Medscape Medical News.

There is also excitement over the use of these two targeted agents together. The combination of ibrutinib plus venetoclax is not approved yet, but a recently reported clinical trial showed "impressive" results, with almost all patients showing a complete response, and most patients showing no minimal residual disease (MRD).

"This regimen has the potential to move the field forward if the high rates of MRD-negative disease translate into an extended drug-free interval or the possibility of a cure for some patients," Woyach wrote in a recent editorial, published online August 28 in the Journal of Clinical Oncology.

Woyach summarizes the strides that have been made in treating CLL since ibrutinib arrived on the scene (it was approved in the United States in 2014) and she also discusses the possibility of a paradigm shift when ibrutinib is used in chemotherapy-free combinations, especially with venetoclax (which was approved in the United States in 2016).

Targeted Therapies Now Preferred to Chemoimmunotherapy

The recent focus in CLL has been on the targeted therapies in various combinations. They have already been proven superior to chemoimmunotherapy (ie, chemotherapy combined with the anti-CD20 agents rituximab [Rituxan, Biogen, Roche/Genentech, and generics] or obinutuzumab [Gazyva, Roche/Genentech]).

The tide has shifted in recent years due to robust data from comparison trials, Nadia Khan, MD, of Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News.

"Targeted therapies [ibrutinib or venetoclax based] are now preferred over chemoimmunotherapies," she said.

"Chemoimmunotherapy is very rarely part of the treatment discussion [these days] and is now reserved for young fit patients with favorable CLL features for whom FCR [fludarabine, cytarabine, rituximab] has been shown to provide a long 10-year relapse-free period," she said.

However, chemoimmunotherapy carries a risk of second malignancies such as myelodysplastic syndrome and acute myeloid leukemia, she noted, so even these young fit patients, who account for less than 10% of all CLL patients, may opt for targeted therapies, Khan pointed out.

Time-Limited Treatment

While perhaps less toxic than chemotherapy-based regimens, ibrutinib and ibrutinib-based combinations do have adverse effects and also a high incidence of discontinuation.

"Although most patients do well with ibrutinib for many years, there are adverse effects that limit the treatment duration for almost half the patients in real-world analyses," Woyach notes.

Also, ibrutinib and venetoclax are both expensive therapies, so there has been great interest in determining if treatment could be used for a limited period of time, rather than remaining on therapy indefinitely.

There is already a precedent for this is the treatment of CLL. A time-limited combination has already been approved for front-line use — venetoclax with obinutuzumab, approved in May 2019, which needs to be taken only for one year.

Several studies are now evaluating the same approach for the combination of ibrutinib with venetoclax in CLL.

The phase 2 CLARITY study showed that the combination given to 53 patients provided a high overall response rate (ORR) of 89% (complete response [CR], 53%). After a median follow up of 21.1 months, only one patient progressed. MRD-negativity was seen in the peripheral blood of 53% patients, and 81% of patients had no morphological evidence of CLL in the bone marrow biopsy at 14 months. Depth of MRD reduction (defined as MRD4 [one CLL cell in 10,000 leukocytes] or below) was seen in 44% of patients at 26 months. After achieving MRD-negativity at 14 months, two patients stopped treatment and did not experience either relapse or loss of MRD-negativity.

In the phase 2 study reported recently by Medscape Medical News, MD Anderson Cancer Center investigators showed that in 80 treatment-naïve patients with CLL, the combination of ibrutinib and venetoclax given for 24 months provided impressive responses.

Woyach noted that in this MD Anderson study, 96% of patients who were receiving treatment were in CR or CR with incomplete count recovery, and 69% of patients had undetectable MRD in the bone marrow.

In a third phase 1b/2 study, investigators from the Ohio State University evaluated the combination of ibrutinib, venetoclax, and obinutuzumab given for 1 year. ORR was 96% for treatment-naïve patients and 92% for patients with relapsed/refractory CLL. One patient was reported to have disease progression, and was successfully retreated with ibrutinib.

However, Woyach cautions against using this combination of ibrutinib and venetoclax in clinical practice. "Right now, this combination should not be used outside of clinical trials," she said.

Right now, this combination should not be used outside of clinical trials. Dr Jennifer Woyach

Woyach told Medscape Medical News that randomized studies will determine whether this strategy [of limited-time treatment] is as effective as continuous single-agent therapy. She noted that two cooperative group phase 3 trials EA9161 and A041702 are addressing discontinuing therapy in a randomized fashion.

"Time-limited treatment is an attractive and viable option for patients with CLL," Khan told Medscape Medical News.

However, she added that "in my personal opinion, the likelihood of cure with ibrutinib and venetoclax in patients with CLL is low," Khan said. "It may happen in the most indolent of indolent cases, but this is rare," she added.

Both Woyach and Khan pointed out that the studies reporting impressive results with the combination of ibrutinib and venetoclax are too short to know how effective this strategy is in the long term.

"Together, these studies clearly indicate that the combination of ibrutinib and venetoclax produces remissions in almost all patients with CLL, and even produces high rates of MRD-negative CRs. These early data, although encouraging, are for the most part expected, because these agents have considerable activity on their own with limited overlapping toxicities," Woyach writes.

"Combination targeted therapies is the future of CLL treatment. This approach will target CLL clones from different angles and eradicate them more effectively," Khan said.

Ibrutinib is a BTK inhibitor and venetoclax inhibits BCL-2, an anti-apoptotic protein.

For now, while the combination of ibrutinib with venetoclax continues to be investigated in clinical trials, Woyach laid out her current treatment paradigm for patients with CLL.

Ibrutinib or the combination of venetoclax and obinutuzumab is appropriate front-line treatment, she said, with consideration of FCR for young fit patients with IGVH mutated disease.

Depending on front-line therapy, patients with relapsed/refractory CLL may be offered ibrutinib or the combination of venetoclax with rituximab, she added.

Woyach consults with or has an advisory role with Pharmacyclics and Janssen Oncology and receives research funding from Janssen Oncology, Karyopharm Therapeutics, MorphoSys, Verastem, Loxo Oncology, and AbbVie. Khan is on the advisory board of Seattle Genetics, has an advisory role with AbbVie, and receives research from Bristol-Myers Squibb.

J Clin Oncol. Published online August 28. Editorial

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