Furman Advises In CLL: Choose Appropriate Agents and Focus on PFS Endpoint

Richard R. Furman, MD

Richard R. Furman, MD

When Richard R. Furman, MD, presented a “How I Treat” session on chronic lymphocytic leukemia (CLL), he emphasized clinicians’ expertise and autonomy, noting that FDA approval of any drug is based on a review of the trials submitted to earn that regulatory decision.

“Once a drug is approved, we can use it, as needed, to help our patients,” he said. “An FDA approval is not a treatment recommendation.”

Furman, director of the CLL Research Center at Weill Cornell Medicine and New York-Presbyterian, made these remarks during the 2016 Annual ASH Meeting on Hematologic Malignancies. In an interview withTargeted Oncology, he emphasized that physicians should follow their best independent judgment regarding therapy selection in CLL. This led with venetoclax (Venclexta), which received FDA approval in 2016 for relapsed patients with del 17p CLL. “If you have a patient with CLL of any type and you believe venetoclax is best for [that patient], you absolutely should use it,” he said. “There’s nothing about the specificity of the FDA approval that should prevent you. Insurance coverage may be another matter, but clinically speaking, you’re on solid ground.”

Physicians should also consistently view treatment recommendations through the lens of progression-free survival (PFS), he added. “Hands down, PFS is the single most important thing to patients,” Furman said. “As oncologists who must balance many clinical concerns, it can be easy for us to forget that fact.”

There are a plethora of agents available as treatments for patients with CLL, Furman explains, with ofatumumab (Arzerra), venetoclax, and frontline ibrutinib (Imbruvica) also being approved in 2016. Others in the armamentarium included idelalisib (Zydelig); obinutuzumab (Gazyva); fludarabine, cyclophosphamide, and rituximab; bendamustine; alemtuzumab (Lemtrada); and chlorambucil.

Furman said that physicians often prefer to use ibrutinib with an adjuvant agent. “Some people always want to include chemotherapy, no matter what,” he added. However, to support evidence of efficacy of ibrutinib as a single agent, he referenced Hillmen et al’s 2015 paper inBlood, which compared single-agent ibrutinib, bendamustine plus rituximab (BR), and ibrutinib plus BR in previously treated patients with CLL and small lymphocytic leukemia.¹“Ibrutinib did just as well as a single agent, but there is a lot of bias in favor of using chemotherapy,” he said.

Furman also discussed ibrutinib’s 3-year PFS data,²noting that 5-year data will be presented at the 2016 ASH Annual Meeting in December. “The data look the same: the PFS line is flat, but at nearly 100%—except for the 17p del patients whose PFS is trending downward,” he said.

Ibrutinib, of course, does come with associated toxicities—particularly diarrhea, bleeding, thrombocytopenia, atrial fibrillation, and hypertension. “I emphasize these adverse events with my patients,” said Furman. “They are consistent and reproducible.”

Furman then summarized the relevant findings from key trials by adverse event (AE). Diarrhea may be caused by EGFR inhibition in the gastrointestinal tract, he said. In the RESONATE trial, 48% of patients on ibrutinib experienced diarrhea compared with 18% of those on ofatumumab.³

In HELIOS, about one-third of the ibrutinib patients had diarrhea compared with 21% of those who took a placebo.⁴In the RESONATE-2 trial, ibrutinib caused diarrhea at almost double the rate of chlorambucil (42% vs 22%).⁵Furman suggested instructing patients to take ibrutinib at night to help manage any diarrheal events. “Helping them work through any AEs is critical to keeping our patients on therapy,” he said.

Bleeding is also a possible (AE) with ibrutinib, said Furman, which is possibly due to its inhibition of BTK and Tec in platelets. In RESONATE, the rate of bleeding was nearly 4 times as high: 44% of ibrutinib patients experienced bleeding, while only 12% of ofatumumab patients did. In HELIOS, the rate of bleeding for ibrutinib compared with placebo was just more than double (31% vs 15%).

According to Furman, thrombocytopenia that occurs with ibrutinib may be due to shortened platelet lifespans. He noted that in RESONATE, 17% of patients taking ibrutinib experienced thrombocytopenia, while 12% of the ofatumumab group experienced it.

Atrial fibrillation and hypertension are less common with ibrutinib. An atrial fibrillation frequency of 5% of patients on ibrutinib compared with only 1% of patients in the ofatumumab arm was confirmed in the HELIOS and RESONATE-2 studies, “Possibly due to ibrutinib metabolic product or the presence of BTK and TEC in heart atria,” Furman said.

Regarding hypertension, data from the HELIOS study showed that it occurred in 10% of patients in the ibrutinib arm versus only 5% for placebo. As for RESONATE-2, results from that trial showed that 14% of the ibrutinib patients developed hypertension while on trial compared with no patients in the chlorambucil arm.

According to Furman, AEs typically occur during the first 2 years of treatment. “People always worry about their patients being on ibrutinib long-term, but my biggest concern is when a patient starts the drug—because that’s when AEs are most likely to occur,” he said.

A common question regarding treatment with ibrutinib is, does successful ibrutinib therapy need to be lifelong? “The short answer is yes, at least for now, although we’ll have better answers in about 5 years,” Furman said. “Patients are having deeper responses as time passes. My belief is that if the drug controls an otherwise deadly illness, it behooves us to continue treatment even before we have the data.”

Additionally, researchers often question whether there is an advantage to adjuvant chemotherapy or immunotherapy with ibrutinib. “There will always be oncologists who feel more comfortable using chemotherapy,” he concluded. “However, adjuvant therapies have not been shown to improve PFS, and that is, by far, the most important thing to patients.”

References:

1. Hillmen P, Fraser G, Jones J. Comparing single-agent ibrutinib, bendamustine plus rituximab (BR) and ibrutinib plus BR in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an indirect comparison of the RESONATE and HELIOS trials.Blood. 2015;126:2944.
2. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib.Blood. 2015;125(16):2497-2506. doi: 10.1182/blood-2014-10-606038.
3. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.N Eng J Med. 2014;371(3):213-223. doi: 10.1056/NEJMoa1400376.
4. Chanan-Khan AA, Cramer P, Demirkan F, et al; HELIOS Investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study.Lancet Oncol. 2016;17(2):200-2011. doi: 10.1016/S1470-2045(15)00465-9.
5. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia.N Eng J Med.2015;373(25):2425-2437. doi: 10.1056/NEJMoa1509388.