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Richard Furman, M.D. A partial response with ongoing response suggests novel agent therapy is preferable, said Richard R. Furman, M.D., Director of the CLL Research Center at Weill Cornell Medicine.

With tongue in cheek, Furman began by noting that Don Johnson is now 66 years old and would no longer be considered a younger patient.

“The most important part of the debate surrounds survival. PFS and overall survival are the single most important issues to remember,” Furman said. “Sometimes improving depth of response is at significant cost. A combination of fludarabine-rituximab-alemtuzumab gets patients into deep remission. But 8 percent of patients die of secondary myeloid neoplasias. We may have 60 percent long-term survival, but we still lose 8 percent of patients who would still be alive.”

Improved survival of CLL patients over the past few decades shows an apparent change in the natural history of the disease. But Furman claims the real advance in overall survival is related to lead-time bias. “We are diagnosing patients earlier in Binet stage A. There has been an increase in overall survival for patients as a group. By stage, there is no benefit for Binet stage A and B. A benefit is seen for Binet stage C. This may be due to better supportive therapies and novel agents, or to a shift to earlier stage disease at diagnosis,” he said, noting there is a great need for prognostic markers.

Novel agents in CLL have proven effective therapeutic targets, including BTK inhibitors such as ibrutinib, acalabrutinib, and others. There are issues with B-cell receptor (BCR) antagonists. “Response criteria redefine clinical endpoints and evolution of response over time. We no longer use maximal tolerable dose to dose patients,” he said. Threshold dosing and fixed dosing with a wide therapeutic window are used. “Prognostic markers and MRD have to be reevaluated,” he added.

Response criteria redefine clinical endpoints and identify patients who should stay on treatment or come off due to a lack of efficacy. “We need to provide a means for determining the need for treatment discontinuation. For novel agents, response criteria don't measure the effect of thalidomide/lenalidomide tumor flares and BCR antagonist lymphocytosis (not a tumor flare),” he said.

Up to three-quarters of patients with ibrutinib experience lymphocytosis that peaks at about 4 weeks and may take a median of 19 weeks to resolve. For the duration and persistence of lymphocytosis, a return to baseline does not necessarily indicate a poor outcome.

Responses evolve over time. “Achievement of best response is time-dependent. Studies show a proportion of CR and partial response (PR) increases during follow-up and that the proportion of patients with PR and lymphocytosis diminishes as the lymphocyte count declines over time. PRs become CRs,” Furman said.

Achieving MRD correlates with PFS. “Lower MRD is associated with improved PFS. Lower MRD levels can be achieved with FCR at 2 months post-treatment. FCR correlates with MRD negativity and PFS. No one should be getting just chemotherapy,” he said.

MRD does need to be re-evaluated as an endpoint. “MRD is validated at 2 months post-FCR or FC as a predictive prognostic endpoint for PFS. It has been validated as a continuous variable, although it is used as positive or negative. There are no data for BCR antagonists. They may be predictive, but we are unable to define a time to measure and know the time to clearance of lymphocytosis based upon biology and not on prognosis. We could likely give an MRD-negative post-FCR patients ibrutinib and make them MRD-positive,” Furman said.

Also, response rate does not always predict outcome or indicate benefit with chemotherapy. “For treatment-naive patients over age 65, those continuing in PR on chemotherapy, add in something else if there is no clear clinical benefit. For treatment-naïve patients with good prognosis, none progress on ibrutinib after a median of 30 months,” he said.

The PFS of patients with persistent lymphocytosis is not different from other patients. “BTK enzymatic activity inhibits at all time points. PFS is a more important indicator. Do not use response to continue therapy. The most important indicator of the duration of lymphocytosis is IgVH mutation status,” Furman said.

“In the era of novel agents, response really does not make a difference,” he continued. There are exceptions, including BCR antagonist resistance and Richter's transformation. “As long as we avoid that, we have many options to control disease,” he said.

He noted acquired resistance has been seen following ibrutinib treatment in CLL patients. “The patients who develop resistance have high-risk genetics or 17p karyotype, with genomic instability to develop mutations and become resistant.” For this definable patient population, oncologists may need to do something different therapeutically, he said.