Newer Agents, Combinations Being Studied for Targeted Therapies in CLL

Jennifer R. Brown, MD, PhD

Targeted agents, particularly ibrutinib (Imbruvica) and idelalisib (Zydelig), are becoming increasingly important in the treatment of chronic lymphocytic leukemia (CLL), and have replaced chemotherapy in many settings. Both are the go-to drugs for heavily pretreated patients, and ibrutinib, strictly, is the first choice as initial therapy for patients with a 17p deletion, and for older patients.

Those were the messages shared by Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, in a talk 2016 International Congress on Hematologic Malignancies.

“Not too many years ago, CLL therapy was based in chemotherapy with antibodies, and if patients had a long duration of remission, it was generally OK to retreat. If they had a short duration of remission or a 17p deletion, their options were limited, with a short PFS on the order of six months,” she said. “Then the world changed, starting with a couple of different targeted agents.”

Ibrutinib

An important goal now, Brown said, is to find drug combinations that can control disease without being administered indefinitely, and that are better tolerated. One contender is the combination of the novel agent venetoclax with rituximab (Rituxan).The oral, once-daily BTK inhibitor Ibrutinib works by forming a specific and irreversible bond with cysteine-481 in BTK. It has demonstrated excellent results in relapsed/refractory CLL, with a PFS of about 68% at 30 months, a number that rises to 87% in patients who are free of the 11q and the 17p deletions, Brown said.

The limitations of the drug, she pointed out, are that it’s not a cure—it mostly induces partial remissions and must be taken continuously—and about 10% of patients discontinue the drug due to adverse events.

Another downside is that patients who progress on ibrutinib are typically very difficult to salvage, Brown said.

The patterns of response often seen with ibrutinib are unique, and Brown stressed that doctors should not be alarmed by an initial rapid and dramatic increase in lymphocyte count that can last a month or more, since that will drop and then plateau over time.

Results from the 1102 study¹ of both pretreated and treatment-naïve patients, reported in 2014, showed that, as white counts came down, patients converted from “partial response with lymphocytosis” to partial remission and then in some cases to complete remission. Median time to best response was 7 months within 3 years of follow-up, and the response rate was 90%. Complete remissions were at about 23% in the upfront setting.

Three-year PFS was 96% in lower-risk patients, and 68% in the higher-risk group. Brown pointed out that patients without 11q or 17p deletions have a “quite remarkable 89% PFS at three years,” with patients affected by 11q mutations logging a 74% PFS rate and 17p deleted patients at 46%.²

Among treatment-naïve patients aged 65 and younger, 81% remained on ibrutinib at 2 years, with only one event of progressive disease that occurred in a patient with a 17p deletion, Brown noted. In the relapsed/refractory setting, 53% remained on ibrutinib after the same amount of time, with 21 patients experiencing progressive disease.

In pretreated patients, compared with the approved CLL drug ofatumumab (Arzerra), ibrutinib sparks better responses, according to the results of the RESONATE trial, Brown noted.³

“It’s still better than any other treatment we had to offer these patients, which is why ibrutinib got early approval for 17p deletion, but PFS still continues to decline in these patients, and there’s a reduction in overall survival,” she said. “We do have trouble salvaging these patients who were heavily pretreated when they relapsed, and there’s an incidence of Richter’s transformation in about a third of these patients.”

This transformation changes CLL into quickly growing diffuse, large B cell lymphoma, which is difficult to successfully treat. “Survival for patients with Richter’s is very poor, 3.5 months, whereas for patients with progressive CLL median overall survival (OS) is 17 months,” she said, citing a study from Ohio State University.⁴ “That may not be the same in patients who progress in frontline treatment, but we don’t know that yet.” The mutations that cause Richter’s are potentially targetable, Brown added.

Both 17p deletion and complex karyotype can account for the difficulty in treating some patients, and the University of Texas MD Anderson Cancer Center looked at these issues separately to learn more about predictive factors regarding patient outlook. They found that patients with complex karyotype were the ones most likely to do poorly. “The numbers are quite small, so there’s still a question, but both are factors to be aware of as potential risk factors for earlier relapse in your ibrutinib patients,” she said.

Though generally well-tolerated, ibrutinib can cause low-grade diarrhea, fatigue, and nausea, but it’s more often arthralgia, edema, and muscle spasms that result in patients discontinuing the drug, Brown said. Atrial fibrillation may occur in 5% to 10% of patients, but usually only requires a temporary break from the drug.

Bleeding-related adverse events, most commonly low-grade petechiae or ecchymoses, are associated with ibrutinib and can occur in up to half of patients, Brown said.

“I tend to take great care combining anticoagulation with ibrutinib,” she cautioned. “It’s a risk/benefit assessment in terms of how pretreated and how sick the patients are. But I try to avoid concomitant administration. It would be nice if we could develop a risk model for the bleeding.” To avoid undue bleeding, ibrutinib should not be given within 3 to 7 days of surgery, she added.

Drug discontinuation due to toxicity tends to occur fairly early, with Richter’s patients more often discontinuing a bit later at 6 to 18 months and those whose CLL progresses on the drug discontinuing at 12 to 18 months, Brown said.

Idelalisib

She noted that patients aged >80 have a much higher rate of discontinuation than younger patients, and that doctors should keep in mind that these patients may not tolerate ibrutinib well.Idelalisib is a specific inhibitor of the delta sub-unit of PI3 kinase that is highly active in both relapsed/refractory and untreated CLL, Brown explained.

Even in the most compromised patients—those who are high on the Cumulative Illness Rating Scale and short remission duration—idelalisib generates a median PFS of about 19 months, and that isn’t affected by a patient’s IGHV or 17p status.

Important questions remain about the drug, Brown said: How will patients fare on idelalisib if they’ve taken ibrutinib first, and what value will antibody combinations add to single-agent idelalisib?

Brown gave some examples of studies that have considered the usefulness of idelalisib in various populations of patients with CLL.

A phase I study of 54 patients with relapsed/refractory CLL with adverse treatment characteristics, which reported results in 2014,⁵ demonstrated on overall response of 72% and a lymph node response of 81%; median PFS and overall response hovered around 29 months with a dose of at least 150 mg BID.

These results led to the GILEAD 116 study in the relapsed setting,⁶ testing the monoclonal antibody rituximab with or without idelalisib. In GILEAD 116 and an extension study, patients taking the combination had a median PFS of 19.4 months versus 7.3 months for those in the control arm. There was no significant difference in outcome for patients by IGHV status or 17p deletion, Brown said.

Idelalisib has also improved the effectiveness of the bendamustine/rituximab regimen in patients with relapsed disease, more than doubling 1-year median PFS to 23.1 months in the GILEAD 115 study.⁷ OS was better in the experimental arm, but had not been reached in either arm when the results were reported at the ASH Annual Meeting in December 2015. There was a bit more neutropenia with the three-drug combination, but less colitis, Brown noted.

In a 2015 study,⁸ idelalisib and rituximab were explored in treatment-naïve patients who were over age 65. With a median follow-up of 22.4 months, there was an overall response rate (ORR) of 97% and a complete response rate of 19%, with a 3-year PFS of 83%. The drug worked at least as well in patients with the 17p deletion, who saw a 100% response rate and a 33% complete response rate.

Toxicity was higher among those patients than it typically has been in heavily pretreated patients, and that was the case, as well, in an ongoing study testing idelalisib in combination with ofatumumab in treatment-naïve patients, Brown noted. In that trial,⁹ Brown and fellow investigators have documented a 53% incidence of grade 3 /4 hepatotoxicity, which was autoimmune in nature and associated with decreased T regulatory cells in the blood.

Overall in CLL patients, toxicities include a 14% rate of transaminitis that can be resolved by temporarily holding the drug; a 14% rate of severe diarrhea/colitis that should be treated with steroids or oral budesonide, after which it’s more difficult to successfully reintroduce the drug; a 6% rate of rash; and a 3% rate of drug-related pneumonitis, Brown said. Severe adverse events are more common in less heavily pretreated patients, she pointed out.

“It’s important to be vigilant regarding onset of the classic pattern of toxicity,” Brown said. “Hold the drug early in the event of significant transaminitis, diarrhea or interstitial pneumonitis. Evaluate completely for infection, and start steroids if the infection is likely drug-related and not resolving.” In fact, Brown said that she usually treats patients prophylactically against infection, both when administering idelalisib and when giving ibrutinib.

Refining Treatment with Newer Agents

In response to these findings, the FDA announced that it had placed six clinical trials exploring idelalisib in combination with other therapies on hold, due to reports of an increased rate of adverse events, including death, for patients with hematologic malignancies. The halted studies were exploring idelalisib in CLL, small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas. The FDA has not issued a statement concerning currently approved combinations.Going forward, Brown said, scientists will seek to find effective, well-tolerated—and, especially, finite—treatments with biologic agents, since many patients with CLL do not want to stay on therapy indefinitely, due to side effects and cost. These kinds of regimens may also make it more possible to salvage patients who fail treatment, she added.

What’s being investigated in this regard? Combining ibrutinib with rituximab, so far, has not proven to be better than ibrutinib alone. Combining the targeted drug with both bendamustine and rituximab in the HELIOS trial¹⁰ did improve the complete response rate in patients from 6% to 21%, but Brown is not sure those results are powerful enough to promise a treatment that can be administered and then successfully stopped.

Obinutuzumab looks promising and will be studied, although there will be a risk of tumor lysis.

A very good candidate, Brown said, is the novel agent venetoclax. The drug is a BCL2 inhibitor, a class that, in vitro, has been very effective at clearing CLL cells from the blood in patients already on ibrutinib.

In a phase I study, venetoclax induced severe tumor lysis, causing several deaths, however, and the study had to be redesigned to include smaller doses that tapered up over time, Brown said.

Published recently, the study’s results demonstrated an ORR of 79% (71% in patients with the 17p deletion) and a median PFS of 25 months in patients without 17p deletions and 16 months in patients with deletions.¹¹

Particularly exciting, Brown said, have been the results from a combination of venetoclax with rituximab in a study of patients who were previously treated with up to two therapies: at 24 months, they had an OS of 94% and a PFS of 83%.¹² The patients had an ORR of 86%, half of them complete responses, and half of all the complete and partial responses in the trial were negative for minimal residual disease (MRD).

Eleven MRD-negative patients stopped treatment with the regimen, and nine remain in remission, while the two others have experienced asymptomatic progression, Brown said. “This suggests the possibility that this drug will result in deep remissions that will allow us to do time-limited therapy and give patients treatment breaks,” she said.

Venetoclax is also being looked at as a means of salvaging patients who fail ibrutinib, and one study has demonstrated a 53% rate of response.

References

1. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16).
2. O’Brien SM, Furman RR, Coutre SE, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol. 2014;32:5s, 2014 (suppl; abstr 7014).
3. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
4. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncology. 2015;1(1):80-87.
5. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
6. Sharman JP, Coutre SE, Furman RR, et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG) Plus Rituximab for Relapsed Chronic Lymphocytic Leukemia: Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Presented at the Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 330.
7. Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. Presented at the Annual Meeting of the American Society of Hematology; December 5-8, 2015; Orlando, Florida. Abstract LBA-5.
8. O’Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015. DOI:http://dx.doi.org/10.1182/blood-2015-03-630947.
9. Lampson BL, Matos T, Kim HT, et al. Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities. Presented at the Annual Meeting of the American Society of Hematology; December 5-8, 2015; Orlando, Florida. Abstract 497.
10. Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. J Clin Oncol. 2015;33 (suppl; abstr LBA7005).
11. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016; 374(4):311-322.
12. Ma S, Brander DM, Seymour JF, et al. Deep and Durable Responses Following Venetoclax (ABT-199 / GDC-0199) Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from a Phase 1b Study. Presented at the Annual Meeting of the American Society of Hematology; December 5-8, 2015; Orlando, Florida. Abstract 830.

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