Maintenance Lenalidomide Prolongs PFS in High-Risk CLL

Alexander M. Castellino, PhD

December 04, 2016

SAN DIEGO — Patients with chronic lymphocytic leukemia (CLL) at risk for early relapse benefit from maintenance therapy with lenalidomide (Revlimid, Celgene), according to results of an interim analysis from the CLL M1 study by the German CLL study group.

Results show that patients who received lenalidomide as maintenance therapy had a greater than 80% reduced risk of progression compared with patients who did not, as reported here at the American Society of Hematology 58th Annual Meeting (abstract 229).

"There was also a conversion of a number of patients to minimal residual disease negativity with lenalidomide maintenance," presenter Anna Maria Fink, MD, of the University Hospital Cologne, Germany, told Medscape Medical News.

"This is the first study to show the benefits of lenalidomide maintenance in this patient population," she said. "However, it is unclear if this will have an impact on treatment in the future," she added. Recent years have seen a number of new targeted therapies that have altered the treatment landscape. Still, lenalidomide maintenance may be a treatment option for selected patients on an individual basis, Dr Fink contended.

Nadia Khan, MD, from the department of hematology/oncology at the Fox Chase Cancer Center, Philadelphia, Pennsylvania, agreed.

"The greatest challenge of utilizing results from this study is the availability of other oral tolerable therapies," Dr Khan told Medscape Medical News.

Dr Khan added that this trial confirms data from other studies that minimal residual disease (MRD) negativity is the greatest predictor of outcomes after chemoimmunotherapy. Apart from clinical practice, clinical trial design may also change, Drs Fink and Khan suggested. "The MRD risk assessment model successfully used in this study may be used in future trials," Dr Fink said.

Study Details

In the CLL M1 study, 468 patients were screened who had received at least four cycles of first-line treatment with standard chemoimmunotherapy for CLL. For first-line therapy, most patients (approximately 60%) received the combination of rituximab (Rituxan, Genentech) and bendamustine (Treanda, Teva Pharmaceutics) or rituximab and chemotherapy with fludarabine and cyclophosphamide.

Most patients (373 of 468, 79.7%) were excluded from maintenance treatment, mainly because they were MRD negative or at low risk for relapse or disease progression.

To be considered for maintenance therapy, patients were required to have had a response to first-line therapy but be at high-risk for progression, defined as high MRD ≥ 10-2. Patients with intermediate MRD (≥10-4 to <10-2) were also required to have unmutated IGHV gene status or del(17p) or TP53 mutation at baseline.

Of 89 patients who met the criteria, 60 patients were randomized to lenalidomide maintenance and 29 patients to placebo. Maintenance lenalidomide was started at a dose of 5 mg daily of a 28-day cycle. Lenalidomide doses were increased over subsequent cycles — 10 mg, 15 mg, 20 mg, and 25 mg — to achieve MRD negativity. After 18 cycles, all patients who were MRD positive continued to receive lenalidomide 25 mg until disease progression. Patients in the placebo arm received matching placebo.

"Based on the interim results, the data monitoring safety board considered these results significant, robust, and reliable in favor of lenalidomide and recommended unblinding of the study," Dr Fink said.

"The study was stopped, no crossover was allowed, and patients were observed following study unblinding" Dr Fink told Medscape Medical News.

Study Results

The 89 randomized patients had a median age of 64 years and were relatively fit, with a median cumulative illness rating score of 2. Of randomized patients, 87% achieved a partial response and 9% achieved a complete response.

Patients on lenalidomide maintenance received a median of 11.1 cycles (range, 0.4–40.5), and those on placebo received a median of 8.3 cycles.

Dr Fink reported that maintenance therapy was discontinued in fewer patients on lenalidomide than for placebo (42.9% vs 72.4%). More patients on lenalidomide discontinued because of adverse events (32.1% vs 20.7%). However, discontinuation rates because of progression were significantly higher for patients on placebo than lenalidomide (44.8% vs 7.1%).

There were three deaths — one in the lenalidomide arm (acute lymphoblastic leukemia) and two in the placebo arm (progressive multifocal leukoencephalopathy, Richter's syndrome). Dr Fink also noted the low rates of venous thromboembolic events because of the use of low-dose aspirin or anticoagulant therapy.

After a median follow up of 17.7 months, median survival was significantly longer for patients on lenalidomide maintenance, which was not reached, compared with 13.3 months for placebo. With a hazard ratio of 0.148, patients on lenalidomide maintenance were at a greater than 80% reduced risk of progression, Dr Fink noted.

Lenalidomide maintenance provided significantly longer PFS in patients with high or intermediate MRD at randomization. Dr Fink reported that for lenalidomide maintenance median PFS was 32.3 months in high-risk patients (vs 3.7 months for placebo) and was not reached in patients with intermediate MRD (vs 19.4 months for placebo). However, overall survival was not different in the two arms of the trial.

Clinical Significance

Dr Fink explained to Medscape Medical News that for patients with a poor prognosis, results from this study indicate that changing therapeutic approach instead of intensifying treatment may lead to better outcomes. However, she expressed uncertainty as to whether lenalidomide maintenance will be the new standard of care.

Currently, patients are given chemoimmunotherapy and no maintenance therapy, she explained. She also said that, since the trial was initiated, several targeted therapies have been approved for patients with CLL. Drs Fink and Khan pointed out that between 2014 and 2016, ibrutinib (Imbruvica, Pharmacyclics), idelalisib (Zydelig, Gilead Sciences), venetoclax (Venclexta, AbbVie/Genentech), and obinutuzumab (Gazyva, Genentech) have been approved for patients with CLL.

"With the approval of novel agents, chemoimmunotherapy is being used less frequently as first-line therapy," Dr Khan told Medscape Medical News. She explained that, in current practice, patients who progress on one therapy are offered another. "However, FCR [fludarabine/cytarabine/rituximab] remains an important standard for young, fit patients with good disease prognosis," she said.

"It is now difficult to know how the standard of care might change with these new chemoimmunotherapy-free agents," Dr Fink admitted.

She pointed out that a large trial (CLL 13) in underway to address this question. Three arms of this four-arm study will evaluate chemoimmunotherapy-free therapies and compare each of them with chemoimmunotherapy (rituximab in combination with bendamustine or fludarabine/cytarabine).

Dr Khan added that the ALLIANCE is also conducting a similar study — a three-arm study — which is comparing ibrutinib, ibrutinib/rituximab, and bendamustine/rituximab to determine the best first-line strategy.

"Results from these studies study will determine if the current treatment paradigm is poised to change," Dr Fink told Medscape Medical News.

Dr Khan also explained that although some of the novel therapies are given indefinitely, few patients achieve a complete response. "But those who do may be evaluable for future trials to determine when one can stop therapy, much like in chronic myeloid leukemia," she said.

Dr Fink reported receiving travel or research grants or honoraria from Mundipharma, Roche, Celgene, and AbbVie. Disclosures for the coauthors are listed in the abstract.

American Society of Hematology 58th Annual Meeting. Abstract 229. Presented December 3, 2016.

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