NEW YORK—In this era of novel agents, is a complete response (CR) and minimal residual disease (MRD) negativity still required for chronic lymphocytic leukemia (CLL) patients? That was the question debated by two experts at the Great Debates and Updates in Hematologic Malignancies meeting.
Matthew S. Davids, MD: Yes, But CLL Therapy Differs By Age
The precedent for cure is first attaining MRD negativity, said Matthew S. Davids, MD, Assistant Professor of Medicine at Harvard Medical School, Boston. “The question is nuanced, and the answer is ‘It depends,’” Davids said. “An 80-year-old with CLL has a life expectancy of 5-10 years. The younger set at age 40 or 50 may be on therapy for 40 years. The answer is different for these two populations.”
For older patients, novel therapies may be preferred. Ibrutinib is very active and well-tolerated in the frontline setting with not a lot of disease progression. “This is a great option for older patients,” he said. “The tolerability and progression-free survival (PFS) for relapsed/refractory CLL patients on acalabrutinib is impressive. The numbers look good early with 14 months median follow-up, but we don't know what is going to happen after that.”
Should Bruton's tyrosine kinase (BTK) inhibitor monotherapy be given forever? he asked. “Achievement of CR is rare. Resistant mutations to BTK have already been described. The duration of response in del (17p) and complex cytogenetics CLL is far shorter than for other patients,” Davids said. Long-term adherence is an issue, as is cost, which can be significant in a younger patient.
To illustrate a point, Davids showed a photo of Don Johnson circa his Miami Vice days with a quote, “You want me to take a pill for how long?” Then Davids asked, “What is the optimal curative strategy for younger, fit patients with CLL—chemotherapy, novel agents, or an immune-based approach?”
A combination of fludarabine, cyclophosphamide, and rituximab (FCR) may cure a substantial fraction of low-risk CLL patients. “Patients who do well attain MRD negativity, and IgHV mutations show improved survival with frontline chemo-immunotherapy,” he said.
Side effects and long-term risks include secondary malignancies. “As we obtain more data from randomized trials, we will see the true increased risk of secondary malignancies with those drugs,” he said, suggesting that, rather than giving up on chemotherapy, dial it back and use MRD negativity to stop therapy.
FCR-based therapy has an impact of bone marrow MRD months post-therapy. “MRD negativity levels have an impact on long-term outcomes in CLL. It improves survival, and the depth of response improves survival,” said Davids, noting long-term survival or cure with allogeneic hematopoietic cell transplantation or CAR T-cells is possible in select patients.
Novel agents, such as venetoclax plus rituximab and B-cell lymphoma 2 inhibitors, induce rapid, deep responses in CLL patients. “Novel agents can be used to build a curative strategy. Venetoclax plus rituximab achieves CR in nearly half of patients with significant MRD negativity. Those who achieve MRD negativity show greater PFS. Patients who stop venetoclax in MRD-negative CR may stay in remission,” he said.
Future approaches to curative therapy in CLL include “chemo-plus,” such as ibrutinib plus FCR, and “minus-chemo,” including venetoclax with obinutuzumab and ibrutinib. Both of these strategies need to be explored in clinical trials. “The next few will be even more exciting in CLL than the last few years have been,” said Davids. “We have an alphabet soup of therapies and all the key tools we need to achieve a cure.”
Going back to the original question, Davids said “now is not the time to back down and say we are fine with a partial response in a 50-year-old patient. Novel agents only, such as ibrutinib, are great for older patients.” Younger patients roll the dice by going on ibrutinib at age 50, he said. “FCR, immune-based therapy, or novel agent combinations is the right way to go for the younger population. If we are bold about this and go about it the right way, we will reach a cure for CLL,” Davids said.
Richard R. Furman, MD: No, A Partial Response Is Preferable
A partial response with ongoing response suggests novel agent therapy is preferable, said Richard R. Furman, MD, Director of the CLL Research Center at Weill Cornell Medicine, New York.
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.
Mark L. Fuerst is a contributing writer.