Neil Osterweil

March 16, 2015

HOLLYWOOD, Florida — New and highly effective targeted therapies promise to change the landscape in the management of chronic lymphocytic leukemia (CLL), and those changes will soon be reflected in guidelines from the National Comprehensive Cancer Network (NCCN).

Although watch and wait is still the standard of care for patients with asymptomatic, early-stage CLL, even for patients with high-risk disease, strategies for first-line therapies are evolving, said William G. Wierda, MD, PhD, from the University of Texas MD Anderson Cancer Center, in Houston, here at the National Comprehensive Cancer Network 20th Annual Conference.

"Right now, the standard of care is chemotherapy in the frontline setting, and then the small molecule inhibitors as salvage therapies, but I think that's going to change relatively soon," Dr Wierda said in an interview with Medscape Medical News.

Results of a current clinical trial comparing chemotherapy with ibrutinib (Imbruvica, Pharmacyclics Inc, Janssen Pharmaceuticals Inc) plus rituximab (Rituxan, Genentech Inc) with conventional FCR chemotherapy (fludarabine, cyclophosphamide, rituximab) in the frontline setting will be likely to tip the balance in favor of the targeted agents up front, he said.

Although ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), has shown good activity against mantle cell lymphoma, "it's even more remarkable in CLL, because the durability of responses is better," he added.

The current iteration of the NCCN guidelines for non-Hodgkin's lymphoma, which include CLL as a subcategory, highlight the evidence confirming the superiority of FCR over bendamustine plus rituximab (BR) in patients aged 65 years and younger, although the latter regimen is a reasonable alternative for older patients who may not be able to tolerate aggressive chemoimmunotherapy.

Also new to the current version is a note that after treatment for CLL, minimal-residual disease (MRD)–negative status in peripheral blood correlates with better progression-free survival if the peripheral blood is negative for MRD and residual splenomegaly is not clinically significant.

Chemo Still the Go-To

Dr Wierda reviewed the current standards of practice for both first-line therapy and treatment of relapsed/refractory disease.

Under the current chemoimmunotherapy-first doctrine, there are important considerations about selecting first-line treatment relating to age, comorbidities, and cytogenetics assayed with FISH (fluorescent in situ hybridization), Dr Wierda said.

Younger, more fit patients should optimally be treated with FCR, but BR and fludarabine plus rituximab (FR) are acceptable, he said. For elderly and/or frail patients with significant comorbidities, the guidelines prefer a combination of chlorambucil plus the CD-20 monoclonal antibodies obinutuzumab or ofatumumab.

For patients with the 17p chromosomal deletions, which are associated with low response rates to chemotherapy, ibrutinib monotherapy is recommended.

In addition to ibrutinib, which is currently approved for relapsed/refractory CLL, there are other BTK inhibitors in early clinical trials. Other agents in development or being explored as first-line agents include the following:

  • Idelalisib (Zydelig, Gilead Sciences, Inc), an inhibitor of the PI3 kinase, approved for relapsed CLL with comorbidities appropriate for rituximab monotherapy

  • Inhibitors of the spleen tyrosine kinase (Syk), which are in early trials or the preclinical stage

  • Venetolcax (ABT/GDC-199), in registration phase III trials, a novel inhibitor of BCL-2 and a suppressor of cellular apoptosis, or programmed cell death

The path ahead with the B-cell receptor inhibitors, Dr Wierda said, is to clearly define clinical objectives, which include better understanding of transformation events and how to prevent them, as well as prevention of secondary cancers and infections.

For elderly and frail patients, oncologists need to find more effective drug combinations, and for younger, more fit patients, the focus should be on curative strategies, he said.

For example, for younger patients with mutations/rearrangements of genes encoding for the immunoglobulin heavy chain variables (IGHV) who have favorable responses to FCR, the goal should be to aim for MRD-negative complete remissions with minimal chemotherapy. For patients without IGHV mutations, clinicians should develop immune-based strategies for maintaining remissions, minimizing toxicities, and preserving immune function.

An oncologist who was not involved in guidelines development said in an interview with Medscape Medical News that, as Dr Wierda described, there seems to be a shift favoring up-front use of a TKI rather than chemotherapy.

"It's reassuring that we're on the same wavelength in terms of where we're headed," said Rasmia Khalid, MD, from Charles River Medical Associates, in Framingham, Massachusetts.

"I think there are many caveats when it comes to looking at patient populations ― their age and their comorbidities ― but, yes, we are moving toward more targeted therapies in the first line," she said.

Dr Wierda has received grants, research support, honoraria, and fees from multiple companies. Dr Khalid has reported no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 12, 2015.

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