Treatment for CLL: Change Aplenty, More Coming

Nick Mulcahy

August 01, 2014

As hematologist-oncologists well know, changes in the treatment of chronic lymphocytic leukemia (CLL) keep on coming.

To help their colleagues remain current, a team of experts from Ohio State University in Columbus published a review intended to be an up-to-the-minute guideline for the treatment of CLL.

The review was published online July 21 in the Journal of Clinical Oncology.

Two days later, on July 23, the would-be guidance was already out of date, as the US Food and Drug Administration (FDA) granted full approval for the use of idelalisib (Zydelig, Gilead) in combination with rituximab (Rituxan, Roche) in patients with relapsed CLL and comorbidities.

Then, 5 days after that, on July 28, the review became further out of date. The FDA expanded the approved use of ibrutinib (Imbruvica, Pharmalytics) to patients with CLL who carry a deletion in chromosome 17 (17p deletion).

"How to best incorporate old and new therapies for CLL in this landscape is increasingly complex," the review authors write, presciently.

Indeed, the landscape keeps shifting and will shift some more, suggest the review authors, led by John Byrd, MD.

There are currently 11 ongoing phase 3 studies "with the potential to change the standard of care in CLL," the authors report. Most of the trials involve ibrutinib, idelalisib, and the investigational agent ABT-199 (AbbVie and Genentech), which was described recently as providing even more rapid cancer cell destruction than ibrutinib in relapsed CLL and lenalidomide (Revlimid, Celgene).

"It's incredibly exciting as better treatments come about," said expert Paul Barr, MD, from the Wilmot Cancer Center at the University of Rochester in New York, who was asked by Medscape Medical News for comment.

Despite the dizzying activity, an overarching "paradigm shift" is occurring that can help clinicians get their bearings, according to the Ohio State team, Dr. Barr, and other experts.

The shift is occurring as the 2 new oral agents, ibrutinib and idelalisib, both of which target the B-cell receptor signaling pathway, replace some of the current standard treatments, which predominantly involve chemoimmunotherapy.

Among other things, the shift means that clinicians are switching from episodic chemotherapy-based infusions to daily oral therapy to be taken indefinitely.

Ibrutinib and idelalisib are more effective than the old standards and represent a rational targeting of dysregulated pathways in CLL.

"No other drugs used alone have ever shown similar activity in relapsed or refractory CLL," writes Robin Foà, MD, from Sapienza University of Rome in Italy, in a recent editorial (N Engl J Med. 2014;371:273-274). He was referring to the clinical data that paved the way for the FDA approvals of both oral drugs.

In addition, both ibrutinib and idelalisib have adverse-effect profiles that are considered manageable by experts.

"With little doubt, these B-cell receptor antagonists are changing the landscape of CLL treatment," writes Dr. Foà.

As the landscape shifts from traditional chemotherapy-based treatment to new agents, what should clinicians do with existing and newly diagnosed CLL patients?

In their review, Dr. Byrd and colleagues examine treatments on the basis of traditional patient-group stratifications, such as age, functional status, and genetics.

Symptomatic Untreated Elderly Patients

Although neither ibrutinib nor idelalisib is approved for symptomatic untreated elderly patients, both drugs are being studied in this setting. Time will tell if they are suited for use in this population.

In the meantime, chlorambucil has been an "accepted therapy for elderly patients," according to the review authors. However, clinicians have transitioned to a "more superior" combination of chlorambucil plus rituximab or bendamustine plus rituximab.

But more change has been underway in the past 2 years, they say. The new anti-CD20 antibody obinutuzumab (Gazyva, Genentech) performed better in a large phase 3 trial than the older rituximab when both were added to chlorambucil in previously untreated patients with CLL and comorbidities.

In fact, median progression-free survival was better with obinutuzumab plus chlorambucil than with rituximab plus chlorambucil or with chlorambucil alone (26.7 vs 16.3 vs 11.1 months). These data led to the approval of obinutuzumab plus chlorambucil in the United States in November 2013 and in Europe just this week.

This study "represents a major advance in the treatment of elderly patients," say the review authors. It also establishes the combination of obinutuzumab plus chlorambucil as "one standard of care for both elderly patients and those with comorbid conditions that make aggressive chemotherapy unfeasible," they write.

The results "will certainly encourage future combination strategies of obinutuzumab with targeted agents such as ibrutinib, idelalisib, and ABT-199," according to an editorial by Kanti R. Rai, MB, from the North Shore–LIJ Cancer Institute in Lake Success, New York, and colleague (N Engl J Med. 2014;370:1160-1162).

Remarkably, none of these proposed combinations are among the 13 listed by Dr. Byrd and colleagues as potential practice changers. In other words, it is likely that even more landscape shifting data are in store.

Obinutuzumab is a "better rituximab," Dr. Rai told Medscape Medical News this week, and is his treatment of choice in this setting.

The review authors agree. For older patients lacking the 17p deletion, "strong consideration should be given to initial treatment with obinutuzumab plus chlorambucil or bendamustine plus rituximab," they write.

Symptomatic Untreated Younger Patients

For younger, more fit CLL patients who lack the 17p deletion, the review authors favor fludarabine, cyclophosphamide, and rituximab (FCR) therapy. The combination was superior to fludarabine plus cyclophosphamide in a large phase 3 trial, and "seems most justified at the present time," they write.

Patients with "significant disease burden" after completion of FCR treatment should be considered for clinical trials targeting the elimination of minimal residual disease, they add.

Symptomatic Patients With 17p Deletion

"There is no clear consensus among experts as to the best therapy" for symptomatic patients with the 17p deletion, write the review authors.

But they favor ibrutinib, citing results in the relapse setting that "have been the most promising."

"Given the improved toxicity profile of ibrutinib over high-dose steroids and alemtuzumab, this might represent the best available option for these patients," they write.

Dr. Rai is less reserved about the use of ibrutinib in these patients.

He believes that the recent FDA approval expanding the use of ibrutinib to patients with the 17p deletion is the most dramatic of all the recent developments in the treatment of CLL.

Effective treatment of these patients is a "seriously unmet need." Patients with the 17p deletion "die relatively rapidly," he told Medscape Medical News.

In these patients, "ibrutinib has demonstrated remarkable responses and durability of response and had a remarkable lack of serious toxicities," he explained.

In fact, in the first randomized clinical trial comparing ibrutinib alone with the anti-CD20 antibody ofatumumab (Arzerra, GlaxoSmithKline) alone, ibrutinib significantly improved both progression-free and overall survival. In the study, 33% of the patients carried the 17p deletion. At a median follow-up of 9.4 months, the patients with the deletion responded as well as those without.

Idelalisib is also approved for use in CLL patients with the 17p deletion. However, there are some questions about the use of both ibrutinib and idelalisib in this patient population.

The "long-term effect" of these drugs in this 17p deletion subgroup "still needs to be clarified," according to Dr. Foà.

The problem with using an oral therapy in these patients is that the drugs will not eradicate the disease, he explains in his editorial. "Controlling the disease over time may not be the most effective strategy," he writes. Thus, allogeneic stem-cell transplantation and other disease eradication approaches should be offered.

The review authors still advocate the use of ibrutinib when transplantation is pursued. "We generally treat with ibrutinib for 1 year to increase the depth of remission before transplantation to avoid rapid tumor flare," they write.

Treatment of Relapsed CLL

Ibrutinib is also approved for use in CLL patients who have received at least 1 previous therapy. The review authors think it is the best bet in this setting.

"Although a host of therapies exists for relapsed CLL," they write, "recent trials with ibrutinib suggest it to be the best initial choice for this patient population."

In the phase 3 RESONATE trial, the overall response rate at a median follow-up of 9.4 months was significantly higher with ibrutinib than with ofatumumab (42.6% vs 4.1%; P < .001) (N Engl J Med. 2014;371:213-223). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = .005).

At 12 months, the overall survival rate was 90% with ibrutinib and 81% with ofatumumab.

Idelalisib will have a lesser role in this setting, according to Dr. Byrd, who is a RESONATE investigator, and colleagues.

"It is likely that its use will be more limited based on reported shorter duration of remission with the single agent compared with ibrutinib in patients with relapsed CLL with or without del(17)(p13.1)," they write.

Idelalisib was approved in relapsed CLL on the basis of a placebo-controlled trial of 220 patients that was stopped early for benefit.

In the first prespecified interim analysis, progression-free survival was significantly longer in patients treated with idelalisib plus rituximab than in those treated with placebo plus rituximab (10.7 vs 5.5 months). A significant improvement was also seen in the second interim analysis.

"Idelalisib is not a me-too drug," Dr. Barr told Medscape Medical News.

He explained that ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase, and idelalisib is a first-in-class selective and reversible inhibitor of PI3K.

In addition, he noted that there is room for improvement in the treatment of all CLL patients.

Even with the more effective new drugs, "we aren't curing anybody of CLL," he said. The prospect of having 2 approved targeted therapies for CLL, and possibly more on the way, inspires the investigator in Dr. Barr. "How can we combine these agents and cure CLL?" he wondered aloud.

Dr. Barr, also a RESONATE investigator, likes what he sees in experimental agents. "ABT-199 looks incredibly promising," he said.

In a phase 1 study recently presented at the Congress of the European Hematology Association, the overall response rate with ABT-199 was 77%, and 23% of patients showed a complete response, as reported by Medscape Medical News. Similar efficacy was seen in high-risk patients with the 17p deletion and those with fludarabine-refractory disease. Importantly, patients in that study had been treated with a median of 4 previous therapies.

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