1. Fuerst, Mark L.

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NEW YORK-Clinicians have a toolkit of novel agents to put together in a rational way to optimize response for chronic lymphocytic leukemia (CLL) patients, according to two experts who presented at the 2018 Great Debates & Updates meeting. They debated whether novel agent-based combination therapy should become the standard of care in CLL.


Combination Therapy Is the Goal

Time-limited novel agent-based combination therapies should be the goal in CLL, said Matthew Davids, MD, Assistant Professor of Medicine at Harvard Medical School. "Novel agents in CLL are mechanistically diverse and have transformed the CLL landscape," Davids noted. "We have keen insights into the CLL stroma microenvironment and have targeted CD20 more effectively."


One novel agent, ibrutinib, is highly effective for relapsed/refractory CLL. It was developed as a single agent and "has led to remarkable results. Five-year data of ibrutinib show it is highly effective in relapsed/refractory CLL as monotherapy. Progression-free survival (PFS) looks excellent, with 80 percent of patients still in remission," he said.


Ibrutinib is generally well-tolerated, although adverse events and progression do lead to discontinuation for many patients. Most serious toxicity occurs early on. Ongoing issues include diarrhea, myalgia, arthralgia, and bleeding, so ibrutinib should be held before surgery, he said. Some patients early on develop Richter's transformation and others develop infections.


Ibrutinib dosing outside clinical trials reveals a high number of patients who hold ibrutinib. Studies show 15-20 percent of patients have dose reduction due to toxicity at 17 months follow-up, and about half of CLL patients come off ibrutinib due to toxicity. As many as one-quarter of patients develop atrial fibrillation in clinical trials. "This is concerning in a real-world setting. We see more toxicity even with well-tolerated agents like ibrutinib," Davids noted.


Why not use ibrutinib monotherapy indefinitely? he asked. "Achievement of complete response (CR) is rare. For high-risk patients with del(17p) or del(11q), the duration of response is clearly shorter. There are ongoing side effects and long-term adherence issues. And the cost of 10 years of ibrutinib would be more than $1 million per patient."


The challenge is to develop a curative regimen using the tools now available by combining novel agents with chemoimmunotherapy, CD20 monoclonal antibodies, or with other novel agents. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab is a promising, new frontline approach for young, fit CLL patients. "Bone marrow minimal residual disease (MRD)-negativity is 83 percent, higher than any prior chemoimmuno therapy or novel agent regimen. Response deepens over time in both IGHV-mutated and unmutated patients with ibrutinib maintenance," he said.


Venetoclax plus rituximab is a highly active combination in relapsed/refractory CLL, with an impressive CR rate of 51 percent. With longer follow-up, patients may respond to venetoclax rechallenge at progression, he said.


A doublet combination of PI3K/BTK inhibitors also has shown promising efficacy and safety in relapsed/refractory CLL, and ibrutinib plus venetoclax is being explored in relapsed/refractory CLL. Venetoclax plus obinutuzumab is safe and active in frontline CLL, and ibrutinib plus venetoclax is under investigation in treatment-naive CLL.


A phase Ib/II study of obinutuzumab plus ibrutinib plus venetoclax is underway for a short duration to get patients into deep remission. "Ongoing randomized trials may define a new standard of care for frontline CLL treatment," Davids noted. He predicts the next-generation drug will be a more selective BTK inhibitor. "We have reached the end of the beginning of the novel agent era. We now have a powerful toolkit of novel agents, with more coming," he stated. "Novel agent monotherapy may be appropriate for frail, older patients and for some patients with low-risk disease. Fit, younger patients, especially those with high-risk markers, should be considered for combination therapy clinical trials."


Sequential Therapy: The Correct Choice?

The best way to use novel agents in CLL to maximize duration of response is by giving them sequentially as monotherapies, said Richard Furman, MD, Director of the CLL Research Center at Weill Cornell Medicine in New York. "If a patient has trouble with ibrutinib as a single agent, he will have trouble with ibrutinib in combination. As we combine agents, there is still a huge amount of cumulative toxicity. Combinations do not only have synergy in efficacy, but synergy in toxicity as well," he said. "It's not how quick the patient gets into deep remission, but how long it lasts. PFS is important."


He outlined three treatment strategies: simultaneous combination therapy, sequential monotherapies to progression, and tailored treatment to tumor load.


For simultaneous combination therapy, "we need to select for agents that are synergistic and without overlapping toxicities. The goal is to achieve rapid MRD-negative CRs," he said. The advantages are avoiding development of resistance by using drugs with non-overlapping modes of action. The disadvantages are increased risk of toxicities given the use of multiple agents at the same time, the potential for additive or synergistic adverse events, and cost.


For sequential monotherapies, each agent is used until maximal response, then the next agent is started. This maximizes each agent's effectiveness; allows an agent to be held until needed; allows for maximizing dose given single-agent use; avoids an increase in adverse events due to combination toxicities; and lowers cost, he said. The disadvantage is single-agent use allows for resistance.


For tailored treatment to tumor load, each agent is used to achieve a specific goal, for example, debulking, induction, or maintenance. This allows for selection of agents that are best suited to each phase of treatment, prophylactically intervenes prior to emergence of resistant clones, and avoids an increase in adverse events due to combination toxicities. Again, the disadvantage is single-agent use allows for resistance.


Many novel agents are now in use. "With different mechanisms of action, there is always something else to offer a patient who progresses," said Furman.


He noted that avoiding chemotherapy is important for ibrutinib to be effective. "For 92 percent of the population, single-agent ibrutinib is all they need," said Furman. "The longer they are on ibrutinib, the fewer adverse events, except for hypertension."


Those patients who progress on ibrutinib have other therapies, such as venetoclax. Venetoclax post-BCR appears to be safe and effective, he said. "Sequential therapy is the correct choice," Furman stated. "It enhances overall survival, which is more important than depth of response; avoids increase toxicity; and allows clarification of the offending agent. We have the opportunity to choose an agent and move on to another and preserve the quality of life of patients."


Mark L. Fuerst is a contributing writer.