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CLL: Predicting the End of Using Chemotherapy

Carlson, Robert H.

doi: 10.1097/01.COT.0000444055.46009.77

NEW ORLEANS—Investments in basic biology to understand B-cell pathogenesis in CLL are translating into effective targeted therapies, some producing deep complete remissions, minimal residual disease, and even improved overall survival. The novel drugs are generally well tolerated with little off-target toxicity.

But the positive reports on ibrutinib, idelalisib, obinutuzumab, IPI-145, ABT199, and others discussed here at the American Society of Hematology Annual, brought up the next question of how best to use them.

“They all work, but how to choose, and how to sequence? That's the $64,000 question,” said Jennifer Brown, MD, PhD, Director of the CLL Center at, Dana-Farber Cancer Institute and the moderator of a news conference on “The Changing Landscape of CLL.”

Sequencing and selection will depend on emerging patterns of resistance and combination trials, she said. “But overall, it's an exciting time with new agents.”

Richard R. Furman, MD, Director of the CLL Research Center at New York-Presbyterian/Weill Cornell Medical Center, also at the news conference, talked about the promise in that changing landscape including the end of traditional chemotherapy: “This is a great opportunity to do what I consider the most important thing for our patients, which is to eliminate chemotherapy from our treatment paradigm. We've always focused on the idea that for medically unfit patients we need to find alternatives to chemotherapy, but what gets missed is that our medically fit patients treated with chemotherapy do well for a period of time but then relapse or develop complications of chemotherapy like secondary neoplasia or infections.

“My hope is that even in medically fit patients, these novel agents may make long-term survival, without long-term side effects, a reality.”

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Elderly, Unfit Populations Benefit

The elderly and medically frail who are generally deemed unfit for standard regimens were the focus of several important clinical trials here.

In the German CLL11 study, discussed in a plenary session, the combination of the anti-CD20 antibody obinutuzumab and chlorambucil showed increased survival over chlorambucil alone in elderly and unfit patients, which experts say is the first time an agent has been able to do so (See page 15).

Furman also spoke about an elderly and unfit population in a late-breaker presentation, on a Phase III randomized, double-blind, placebo-controlled trial of idelalisib (GS1101), an oral PI3K-delta inhibitor. Study 116 measured the efficacy and safety of rituximab-idelalisib versus rituximab-placebo for previously treated CLL (Abstract LB6).



The 110 patients in each study arm with CLL refractory/relapsed to prior therapy were considered unfit for receiving additional chemotherapy. Idelalisib inhibits proliferation and induces apoptosis in many B-cell malignancies, and inhibits homing and retention of malignant B cells in lymphoid tissues, thus reducing B-cell survival, he explained.

In the trial, median progression-free survival was 5.5 months for patients receiving rituximab-placebo but had not been reached for those receiving rituximab-idelalisib, Furman said, noting that while median overall survival has not been reached in either group, there was a trend favoring rituximab-idelalisib.

There was no statistically significant difference in safety between the two study arms, with an adverse-event rate of 90.9 percent for rituximab-idelalisib vs. 94.4 percent for rituximab-placebo. The rates of grade 3/4 adverse events were 56.4 vs. 47.7 percent, respectively.

He said that unlike other new therapies discussed at the meeting, “idelalisib heralds the dawn of a new age for CLL patients, affording the opportunity not just to treat patients who have refractory disease but also to treat them more safely than ever before.”

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ABT-199 Triggers Apoptosis

Relapsed/refractory CLL was also the target of the Bcl-2 inhibitor ABT-199, used as monotherapy in a first-in-human Phase I open-label, dose-escalation, multicenter, international trial ( Abstract 872).

John F. Seymour, PhD, Director of the Department of Hematology and Chair of the Hematology Service at Peter MacCullum Cancer Centre in Australia, explained that ABT-199 is a selective, orally bioavailable, small molecule BCL-2 inhibitor that can trigger apoptosis in vitro, even in del(17p) CLL cells, making it a promising agent for treating patients with high-risk relapsed/refractory CLL and small lymphocytic lymphoma (SLL).

The study he reported was on the safety and efficacy of ABT-199 in 67 patients with CLL or SLL. The most common adverse events were three cases (5%) cases of Grade 3 febrile neutropenia, and three (5%) of Grade 3 tumor lysis syndrome. Among 56 patients evaluable for response, the overall response rate was 84 percent, including 23 percent with complete responses.



Patients experiencing responses included 14 of 17 (82%) with 17p(del), and 24 of 27 (89%) who were refractory to fludarabine. The median time to a 50 percent reduction was week 6.

Seymour said that a safety expansion trial is now under way, as are Phase II trials of ABT-199 monotherapy in patients with relapsed del(17p) CLL, as well as combination studies with rituximab or obinutuzumab in relapsed/refractory CLL.

Brown said that the mechanism of ABT199 could suggest significant synergy between BCL-2 inhibition and kinase inhibition with a potential for combinations that could be very promising.

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IPI-145 Targets ‘Nexus of Survival Signals’

Preliminary safety and efficacy data on IPI-145, an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma ( Abstract 677), were presented by Ian Flinn, MD, Director of the Blood Cancer Research Program at Sarah Cannon Research Institute.

In an interview before the meeting, he explained that phosphoinositide sits downstream of a variety of cell-signaling events that occur to cause CLL cells to proliferate and then survive—a “nexus of survival signals.”

He emphasized that IPI 145 is both a PI3K-delta and -gamma inhibitor. “In solid tumors there has been a lot of development and work done on the pain inhibitors, the alpha and beta isoforms, which don't seem that important in CLL and low-grade lymphoma. On the other hand, the delta and gamma isoforms are restricted to cells of hematopoietic origin, so by inhibiting them you can hopefully have all the efficacy without the off-target toxicity that you might expect with a pain inhibitor.”



The broad activity of IPI-145 might also be important in countering cell-cell interactions in the microenvironment that make CLL and lymphoma cells resistant to treatment, Flinn added. “The gamma isoform may help decrease those interactions and blocking signals in the tumor cells and also in the microenvironment—that's one of the reasons this drug is being developed.”

One of the challenges and frustrations in developing new therapies for CLL is that, unlike the Philadelphia chromosome in CML, no one event causes it, so there is no specific drug or problem to target. But by targeting and blocking a variety of signaling events, IPI-145 can block multiple cell surface signals for CLL proliferation, he said.

The study, which was funded by Infinity Pharmaceuticals, included 52 patients with relapsed-refractory CLL who had a mean of 4.5 prior therapies—some as many as 12.

“We've had a 47 percent overall response rate—true responses using the IWCLL [International Workshop on Chronic Lymphocytic Leukemia] response criteria,” Flinn said. “That includes one patient who had a complete remission, which is unusual in this highly pretreated cohort.”

Looking at only the nodal response rate, almost 98 percent of patients had a reduction in adenopathy, and 89 percent of patients treated at a 25 milligram dose or less had greater than a reduction in their lymph nodes of at least 50 percent. And eight of 19 patients with 17p(del) or p53 mutation responded to the drug.

He said that whereas new drugs are typically destined for combination therapy, he hoped IPI-145 would be developed as a single agent. Such trials are now under way in refractory low-grade lymphomas not responding to rituximab, and there are also trials combining IPI-145 with rituximab and with bendamustine-rituximab.



“Those combination trials will be done, but I'm wondering if this class of drugs isn't so effective that we don't need to be doing that in the future,” he said.

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Ibrutinib: Response Rates Above 80 Percent

Bruton's tyrosine kinase (BTK) plays a critical role in CLL cell survival by modulating B-cell receptor signaling. Ibrutinib, a first-in-class oral inhibitor of BTK, inhibits proliferation migration, and adhesion in CLL cells, according to researchers.



“The message about ibrutinib is that it is an incredibly active drug, with remissions in relapsed and refractory patients as well as previously untreated patients, given either as monotherapy or in combination,” said John C. Byrd, MD, Chair of Leukemia Research, Director of the Division of Hematology, and Professor of Medicine and Medical Chemistry at Ohio State University Comprehensive Cancer Center, where approximately 400 patients have been treated with the drug.

He is senior author on a long-term follow-up study of ibrutinib, presented at the meeting by Susan O'Brien, MD, which showed patients maintaining their remission for two and three years.

“The disease is being controlled, patients are maintaining their quality of life, and we're not seeing late-term side effects or an increased risk of infections,” Byrd said. “We're seeing that patients are going to be able to stay on ibrutinib continuously for a long period of time.”

The overall response rate in the study of 148 patients with CLL or SLL was 80.6 percent for previously untreated patients, and 83.2 percent for patients with relapsed/refractory disease. At 30 months, 95.8 percent of treatment-naïve and 69.7 percent of relapse/refractory patients were alive without disease progression, and the median duration of response had not been reached.

“This validates how these kinase inhibitors are really impacting care,” he said in an interview, predicting that over the next decade, completely chemotherapy-based approaches would give way to targeted treatment approaches, either with immune therapies or drugs that target different B cell receptor kinases.

“We're on the cusp, in certain patient populations, of doing away with chemotherapy completely—for the elderly, who are not appropriate for intensive chemo-immunotherapy, or those who don't benefit from it who are young, as with deletion 17p.”

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iPad Extra!

Watch on the iPad edition of this issue as Richard Furman, MD, discusses, in an interview with OT reporter Dan Keller, the Phase III trial of idelalisib, a first-in-class oral kinase inhibitor and highly selective inhibitor of the delta isoform of PI3 kinase, used in combination with rituximab. The latest data show better progression-free survival and objective response rates compared with rituximab plus placebo in CLL patients who had already received standard treatments and were not considered candidates for additional chemotherapy.



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