Secondary Logo

Share this article on:

CLL: New Drugs Bring Paradigm Shift for High-Risk Disease

Fuerst, Mark

doi: 10.1097/01.COT.0000453424.55228.f9


CHICAGO—Several novel agents may represent a paradigm shift as they appear to fill the unmet need for effective treatments of patients with chronic lymphocytic leukemia (CLL) positive for del(17p) and other adverse prognostic factors, according to research reported here at the American Society of Clinical Oncology Annual Meeting.

The natural history of CLL is highly variable, with a median survival from diagnosis of more than 10 years in low-risk patients to two years in high-risk patients, noted Jeff Sharman, MD, Medical Director of the Hematology Research Program at US Oncology Research.

“New therapies are needed for high-risk, relapsed CLL patients, especially those who are unfit for chemo-immunotherapy,” he said in an interview.

“CLL therapy is essentially changing completely because of the development of tyrosine kinase inhibitors [TKIs]. Cytotoxic therapy is going to be challenged for efficacy.”

Currently, about 30 percent of CLL patients in the United States receive single-agent rituximab, he noted. Frontline fludarabine, cyclophosphamide, and rituximab therapy in the del(17p) population shows a complete response of five percent and a median progression-free survival (PFS) of less than two years.

Back to Top | Article Outline


Idelalisib is a potent and selective inhibitor of PI3Kδ, which is critical for activation, proliferation, and survival of B cells and their homing and retention in lymphoid tissues. At the ASCO meeting, Sharman reported on the results from a Phase III, randomized, double-blind, placebo-controlled trial of idelalisib in combination with rituximab in 220 high-risk, relapsed CLL patients (Abstract 7011).



Samples for del(17p), del(11q), TP53 mutation, IGHV mutation, ZAP70 and CD38 expression, and β2-microglobulin were collected prospectively and tested using standard methods. Patients were stratified based on the presence of del(17p) and/or TP53 mutation, and on IGHV mutational status.

About one-quarter of the patients had del(17p), and slightly more than one-third had TP53 mutations. More than 80 percent were IGHV unmutated. The endpoints evaluated in the high-risk subpopulations in the preplanned first interim analysis include PFS and overall response rate (ORR).

The ORR was significantly higher in the idelalisib-plus-rituximab group (80.7%) compared with the placebo-plus-rituximab group (12.5%). Idelalisib plus rituximab retained robust efficacy across all high-risk subpopulations, he reported.

“Importantly, idelalisib plus rituximab achieved 76.5 percent ORR and PFS HR 0.13 in the highest-risk patients who were positive for both del(17p) and TP53 mutation, compared with 80.4 percent ORR and PFS HR 0.17 in those who had neither present.”

The main adverse events were diarrhea, pneumonitis, and abnormal liver function tests. “Across the database, half the patients who discontinued were, after dose reductions, able to restart treatment,” Sharman said. “The longest follow-up is four and a half years. We don't know how patients will do if they stay on the drug for 15 years, or how long they will stay on it. Novel long-term toxicities certainly will evolve as we monitor patients longer.

“These results confirm the retained robust efficacy of idelalisib in high-risk CLL subpopulations and identify idelalisib as a potentially important novel treatment for all CLL patients, regardless of risk factors.”

The trial was terminated early because of an overall survival (OS) benefit in the idelalisib group. “The study was not powered for survival, but the results showed a benefit,” he said. “The effect of therapy, including survival benefit, accrues to patients with high-risk markers, including del(11q), del(17p), and IGVH, who appear to fare in a way similar to that of patients without high-risk markers.

“With the dramatic benefit in quality of life, PFS, and OS, doctors will have to prescribe idelalisib,” Sharman said. “The patient community is aware of the drug and will demand that it be prescribed.”

Similar data sets with similar TKIs will appear shortly, he predicted. “There will be cross-trial comparisons. Genomic markers will find the right subpopulations to treat. In certain populations, it may prove to be better than chemotherapy alone.”

Future studies will compare idelalisib against chemotherapy. “The next step is to test bendamustine plus rituximab with or without idelalisib, which is proceeding in clinical trials,” he said. “Looking into the future, two years from now when ibrutinib and idelalisib are approved for CLL, the majority of CLL patients requiring therapy will get some TKI either alone or in combination with other agents, such as rituximab or bendamustine.”

The Discussant for the study, Javier Pinilla-Ibarz, MD, of H. Lee Moffitt Cancer Center and Research Institute, said, “In the more heavily pretreated population, we see a dramatic benefit with the addition of idelalisib with rituximab. The IGHV-mutated patients show a dramatic effect.”

He added: “In the CLL world, we are happy to see so many drugs coming to the clinic. Second-generation monoclonal antibodies will also be of more importance. Immune therapy may have a role in combination with these drugs. We need to understand toxicity and how to sequence or combine these inhibitors.”

This includes adding in Bcl-2 inhibitors, such as ABT-199/GDC-0199. “Because of profound immune system suppression, lenalidomide and PD1 or PDL1 monoclonal antibodies may be important tools to incorporate into the treatment of these patients,” he said.

Back to Top | Article Outline

Single-Agent Ibrutinib

In another study reported at the meeting, single-agent ibrutinib continued to be effective three years after initiation of therapy in patients with CLL/small lymphocytic leukemia (SLL), including those with deletion 17p disease (Abstract 7014).

CLL/SLL is generally very responsive to chemo-immunotherapy, said Susan O'Brien, MD, Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, who reported the data. “However, relapses occur, and resistance develops. In particular, del(17p) is associated with poor outcomes using all currently available treatments. Effective targeted therapies are needed.”

The independent analyses she presented were based on all patients treated from first dose on the first study until data cut-off on the long-term follow-up study.

Patients in the study received 420 or 840 mg of ibrutinib daily. Included were 132 patients, median age of 68; 31 patients had not received previous treatment and 101 had relapsed/refractory disease. Slightly more than one-quarter of the patients had del(17p) and a similar number had del(11q). The relapsed/refractory patients with del(17p) had a median of four prior therapies.

The updated best overall response rate by independent review was 78 percent for all-treated patients, including about 84 percent for previously untreated patients, 76 percent for the relapsed/refractory patients, and 56 percent for relapsed/refractory patients with del(17p), she reported.

Additionally, five relapsed/refractory patients, two with del(17p), had a best response of partial response (PR) with lymphocytosis.

“Five of six patients who received prior idelalisib responded to ibrutinib,” O'Brien said. Two of the five responders continue treatment, with one additional patient moving on to stem cell transplant.

The median duration of response was not reached for all treated patients, and was 25 months in patients with del(17p). The median time on study was 29.4 months for all treated patients, and 27.3 months for relapsed/refractory patients with del(17p).

The median time to best response was 7.3 months, she said. More than 90 percent of patients who achieved a partial response with lymphocytosis converted to a better response. “The best response to ibrutinib improves over time.”

The 30-month PFS rate was 96.3 percent in the previously untreated group and 68.4 percent in the relapsed/refractory group. The 30-month overall survival rates were 96.6 and 79.9 percent, respectively. The median PFS and OS have not been reached, she said.

More patients receiving prior therapy experienced serious or grade 3 or higher adverse events, which decreased after one year on treatment, O'Brien noted. The most common adverse events were hypertension, pneumonia, and neutropenia. No new safety signals were observed in long-term follow-up. About two-thirds of patients remain on treatment with ibrutinib.

In conclusion, O'Brien said, “Single-agent ibrutinib leads to rapid and durable responses, and the median duration of response has not been reached. Ibrutinib therapy was well-tolerated, allowing for extended dosing. Continued treatment in the extension study shows that 64 percent of patients remain on single-agent ibrutinib.”

The Discussant for the study, Nicole Lamanna, MD, Associate Clinical Professor of Medicine in the Hematologic Malignancies Section of New York-Presbyterian Hospital, said, “The data is holding up well. Adverse events decline with time. Most adverse events leading to study discontinuation are early—10 percent. Responses are rapid with a high ORR, which continues to improve the longer patients are on therapy. This data will change clinical practice.”

She noted that 42 percent of relapsed/refractory patients came off therapy. “There is a need for additional studies in this patient population and continued evaluation of mechanisms of resistance,” she said. “Can these patients be salvaged with other novel agents? We are eager to see long-term updates and determine whether any new or late-term toxicity issues may arise the longer patients are on oral therapy.”

Back to Top | Article Outline

Ibrutinib versus Ofatumumab

In another study, ibrutinib was compared with ofatumumab in CLL/SLL relapsed/refractory patients in a randomized, Phase III trial (Abstract LBA7008). Patients who had not responded to one or more prior therapies received 420 mg of oral ibrutinib daily (195 patients) until disease progression or intravenous ofatumumab at 300 or 2,000 mg for 12 doses (196 patients).

After a median follow-up of 9.4 months, “ibrutinib significantly lengthened PFS—median not reached—compared with use of ofatumumab (8.1 months), and significantly improved OS—median also not reached—compared with ofatumumab,” said John Byrd, MD, Professor of Medicine and Medicinal Chemistry at Ohio State University.

The ORR was significantly higher with ibrutinib (42.6%) than with ofatumumab (4.1%). Similar effects were seen in del(17p) and purine analog refractory subsets.

In conclusion, Byrd said: “Ibrutinib significantly improved survival and response as compared with ofatumumab. The impact of ibrutinib on PFS was observed irrespective of baseline clinical characteristics or molecular features.”

He noted that the overall survival benefit was observed despite crossover of 57 patients after confirmed progression.

He said toxicities were considered manageable and did not frequently result in dose reduction (needed by 4% of patients) or treatment discontinuation (also 4%), with 86 percent of patients continuing on ibrutinib.

“This study validates ibrutinib as an effective new single-agent therapy for CLL/SLL patients,” Byrd said.

In her Discussant remarks for this study, Lamanna said that the results overwhelmingly favor ibrutinib over ofatumumab. “Adverse events are similar between the two. It is important to keep in mind with ibrutinib and probably other oral agents that despite well-tolerability, patients report adverse events for a prolonged period of time given the continuous treatment versus the intravenous counterpart. This study represents a treatment paradigm shift for patients with relapsed CLL.”

© 2014 by Lippincott Williams & Wilkins, Inc.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!