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Novel Agents Rapidly Emerging for CLL

Fuerst, Mark

doi: 10.1097/01.COT.0000441833.93762.03


NEW YORK—A handful of novel agents to treat chronic lymphocytic leukemia (CLL) continue to show promise in clinical trials, including perhaps most especially obinutuzumab, a third-generation type II anti-CD20 antibody that is the first drug with breakthrough therapy designation to receive FDA approval (OT 12/10/13).

Speaking here at the Chemotherapy Foundation Symposium, Kanti Rai, MD, Chief of the Division of Hematology/Oncology at Long Island Jewish Medical Center and Professor of Medicine at Albert Einstein College of Medicine, in a presentation that focused specifically on obinutuzumab and ofatumumab, called monoclonal antibodies the backbone of treatment of CLL and other malignancies: “In the current era of anti-CD20 agents, we are making important headway with new drugs. Both obinutuzumab and ofatumumab have demonstrated activity as single agents. Ongoing trials in which they are combined with other agents are extremely promising.”

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The newest anti-CD20 antibody is obinutuzumab, which was approved by the FDA on November 1 as a combination treatment with chlorambucil for patients with untreated CLL. The FDA had given the drug Breakthrough Therapy designation due to the significance of the positive progression-free survival (PFS) results from the Phase III CLL11 trial and the serious, life-threatening nature of CLL.

CLL11 is a randomized, open-label multicenter trial comparing obinutuzumab in combination with chlorambucil with chlorambucil alone in 356 patients with previously untreated CLL. Those who received the dual-drug therapy had significantly longer PFS (23 months) compared with those who received chlorambucil alone (11.1 months).

Similarly, about 75 percent of patients responded to obinutuzumab plus chlorambucil compared with only about 33 percent who responded to chlorambucil alone. More than one quarter of those who received the combination achieved a complete response.

The most common Grade 3/4 adverse events for those who received the obinutuzumab-chlorambucil combination were infusion-related reactions during the first infusion (21%), thrombocytopenia (11%), and neutropenia (34%). There were no increased rates of infections with the combination.

Asked for a comment after the presentation, the moderator of the session at which Rai spoke, Janice Gabrilove, MD, Professor of Medicine and Director of the Clinical Education Research Program at the Icahn School of Medicine at Mount Sinai, called obinutuzumab “a ground-breaking treatment that will move into the frontline setting as an upfront treatment, which will reduce patient exposure to cytotoxic agents.”

She added: “As an oral agent, it is easier to take by patients. It is designed to target the signaling cascade in molecular pathogenesis of the disease.”

Rai noted that the mechanisms of action of anti-CD20 monoclonal antibodies to kill B cells include complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and direct cell death—“All are effective mechanisms for killing B cells.”

Pointing to the results of a pivotal trial in Germany that compared obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and chlorambucil alone, he said that the combination with obinutuzumab showed superior results to combination with rituximab, and both were superior to chlorambucil alone: “There was a significantly better response rate with the obinutuzumab combination than with the rituximab combination. Also, the obinutuzumab combination achieved molecular response negativity that we cannot get with rituximab plus chlorambucil.”

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Another anti-CD20 monoclonal antibody, ofatumumab, received FDA approval four years ago. A pivotal Phase II trial in refractory CLL showed excellent responses in poor-prognosis patients. “The trial found a respectable overall response rate of 58 percent, with overall survival of 13.7 months,” Rai said. “This demonstrates that the drug has activity as single-agent therapy, and ofatumumab is also well-tolerated in elderly patients in the frontline setting.”

Researchers are now combining ofatumumab with other known therapeutic agents. “We can replace rituximab with ofatumumab in combination with fludarabine and cyclophosphamide [FC] for those with previously untreated and previously treated CD20-positive CLL,” he said. “This combination is very effective and equivalent to rituximab-FC.”

Ofatumumab is also being used in combination with other high-dose steroids. For example, he said, a combination of ofatumumab plus lenalidomide has been tested extensively at MD Anderson Cancer Center and shown to be extremely effective. Studies show an overall response rate of 68 percent and a complete response rate of 24 percent. The most common grade 3/4 treatment-related hematological adverse events have been neutropenia, thrombocytopenia, and anemia.



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“We also have a new era of tyrosine kinase inhibitors,” Rai said. “Idelalisib combined with ofatumumab shows a substantially increased overall response rate over idelalisib monotherapy. This combination, which has a significant signal in PI3K abnormalities, is attractive.”

In another presentation at the symposium, Morton Coleman, MD, Director of the Center for Lymphoma & Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center and Clinical Professor of Medicine at Weill Cornell Medical College, discussed ibrutinib and idelalisib in CLL.

The B-cell antigen receptor (BCR)-associated kinases PI3K, Bruton's tyrosine kinase (Btk), and Syk have been shown to be effective therapeutic targets when the B-cell receptor is turned on, he explained.

“B-cell antigen signaling is required for B-cell survival. The pathways are more complicated than we thought—They look somewhat like the New York City subway system,” he joked.

To interrupt PI3 kinase signaling in B cells, researchers developed idelalisib. A Phase I study in hematologic malignancies found 150 mg twice daily to be the best therapeutic dose in CLL. “Idelalisib induces a response in a new way. Nodal inhibition is rapid in CLL. The white blood cell count goes way up, and ultimately comes down.”

The drug induces an 80 percent nodal response and 72 percent overall response. “Almost all refractory/relapsed CLL patients respond,” Coleman said. “The drug is potent. It hits the lymph nodes rapidly, but does not have as much impact on blood counts.”

Initial studies found a PFS of 17 months, with overall survival not yet reached. Side effects, he noted, include explosive diarrhea, pneumonia, and transaminase increases.

Researchers are now testing combinations of idelalisib with rituximab, bendamustine, or both rituximab and bendamustine. “These combinations get an 80 to 90 percent response in nodes, and an 80 percent response in lymph counts, and the addition of other drugs to idelalisib hits cells as they get into the peripheral blood,” he said.

Pivotal studies in idelalisib in CLL are ongoing. Coleman predicted that the drug would be approved in the next year or two.

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Btk is another essential element of the BCR signaling pathway, and potent inhibitors of Btk, such as ibrutinib, block BCR signaling and induce apoptosis, he explained. In a Phase Ib/II study in CLL, about 85 percent of patients responded to ibrutinib.

“Relapsed/refractory patients showed virtually the same response rate. More than three-quarters seemed to respond, which is remarkable. We now have two drugs—idelalisib and ibrutinib—with amazing response rates,” said Coleman.

Ibrutinib leads to an estimated PFS rate of 96 percent at 26 months, with an estimated 92 percent PFS for those with no deletion 17 p or 11q, he continued. “Again, these are remarkable results, almost identical to idelalisib.”

Coleman noted that ibrutinib studies at Ohio State led by John Byrd, MD, have found a 100 percent response rate among CLL patients, with sustained improvement seen among patients with pretreated cytopenia.

The frequency of Grade 3 adverse events with ibrutinib is “rather small,” Coleman said. These include pneumonia and diarrhea, but less intense than the diarrhea seen with idelalisib.

Ongoing CLL trials are comparing oral ibrutinib with intravenous ofatumumab, and also combining ibrutinib with ofatumumab. He said he also sees approval of ibrutinib within the next year or two.

In conclusion, Coleman said, “Idelalisib and ibrutinib, two potent BCR pathway inhibitors, are highly effective in both untreated and treated CLL. Both drugs work well in combination with other CLL-directed therapies, and represent a new non-chemotherapeutic approach. Both drugs have very acceptable toxicity profiles. They will profoundly change the way we approach CLL in the future.”

Gabrilove added: “PI3K inhibitors and tyrosine kinase inhibitors have an impact on CLL and other low-grade leukemias. There optimal use is unknown as of yet. In the current post-genomic era, we have a rapidly emerging armamentarium to treat proliferating diseases. Ultimately, we run out of all treatment options. These new drugs will have a significant impact.”

Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.
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