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CLL: Debating the Choice of Chemo-Immunotherapy

Carlson, Robert H.

doi: 10.1097/01.COT.0000444385.11223.f3


NEW YORK—Arguments in favor of use of FCR/FR (fludarabine-cyclophosphamide-rituximab/fludarabine-rituximab) over BR (bendamustine-rituximab) for frontline treatment of chronic lymphocytic leukemia (CLL) appeared to win over a solid portion of undecided members of the audience here at a debate at the Lymphoma & Myeloma International Congress.

With the question noted on the meeting program—“CLL: Which is the optimal approach, BR or FCR/FR?”—rephrased as “Has BR replaced FCR as frontline therapy for CLL?,” a pre-debate vote by the audience of approximately 1,000 was found to be divided roughly in thirds: 29 percent voting “yes,” 35 percent “no,” and 35 percent “not sure.” The post-debate vote showed uncertain voters swinging to a “no” vote, that BR has not replaced FCR: 24 percent voted “yes,” 60 percent “no,” and only 16 percent said “not sure.”

Mitchell R. Smith, MD, PhD, Director of the Lymphoid Malignancy Program at Taussig Cancer Institute of the Cleveland Clinic, took the side of advocating BR. Bendamustine might be considered the newcomer, but the anticancer agent was synthesized in the former East Germany in the 1960s and was not available outside that country until 1990.

Taking the FCR/FR position was Richard R. Furman, MD, Director of the CLL Research Center at New York-Presbyterian/Weill Cornell Medical Center, scheduled as the moderator of the session but who stepped in for Michael Keating, MD, of MD Anderson Cancer Center, who could not attend.

Their respective arguments notwithstanding, both said the upcoming results from the randomized Phase III German CLL Study Group CLL10 Trial, of BR versus FCR, may settle the debate.

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Mitchell Smith: BR Is Best

Smith said yes, absolutely, that use of bendamustine-rituximab is best. He followed, though, with the question, “Can Smith win this debate?' and answered, less confidently, “Not so clear.”

Smith facetiously listed reasons Keating would have won the debate – he was “instrumental in developing FC/FCR, gets to use three drugs (vs. two), has a professorial demeanor, and has a cool accent”—attributes Smith said he could not claim. “So let's root for the underdog!” he said, launching into his own speech.

Both regimens have toxicity issues, including prolonged myelosuppression and therapy-related myeloid neoplasia, he said. “But most of us don't like to treat older folks with FCR because you get more immunosuppression,” he said. “Fludarabine also interferes with renal function and exacerbates autoimmune hemolytic anemia [AIHA].” The only toxicity he listed specific to bendamustine was rash/hypersensitivity, possibly related to interaction with allopurinol.



Smith cited two trials from Germany with similar patient populations that each tested one of the agents, FCR in CLL8 (Hallek et al: Lancet 2010;376:1164-1174) and BR in the Phase II CLL German Study Group (SG) trial (Fischer et al: JCO 2011;29:3559-3566).

In CLL8, with FCR for initial therapy, the rate of neutropenia was 34 percent, thrombocytopenia was seven percent, infection was 25 percent, and AIHA was one percent.

In CLL SG, with BR for initial therapy, the rate of neutropenia was far lower at 20 percent, thrombocytopenia was 22 percent, infection was eight percent, and AIHA was two percent.

Smith said the German CLL8 data also show that FCR does not overcome del 17p, with far superior survival fractions for patients in both the FCR and FC arms who did not have TP53 mutations compared with patients in either arm who had the mutation. “But FCR may overcome 11q, so I may grant my opponent that,” he said.



Not only is FCR acutely toxic in terms of neutropenia, but also in prolonged cytopenia, he said, citing data from an MD Anderson trial in which 207 CLL patients who had achieved a complete response (CR), CR with incomplete blood count recovery (Cri), or nodular partial response (nPR) had a rate of late infection of 38 percent by nine months after FCR, two-thirds of which was bacterial (Strati et al: Cancer 2013;119: 3805-3811).

Smith said the results are eagerly awaited from the randomized, Phase II CALGB 10404 study, now fully accrued, are eagerly awaited. The trial compares FC vs. FCR with patients stratified by genetic risk and treated with one of four fludarabine-antibody combinations.

He said that as neither regimen is curative, either FCR or BR could be used as a platform to add additional agents in induction and/or consolidation/maintenance. But given that BR can be given to most CLL patients and is less myelosuppressive, he said it would be easier to add new agents to BR. “Meanwhile, BR has a response rate similar to FCR, and maybe a lower CR rate, but in a higher-risk population of patients. And BR is applicable to more CLL patients, with a wider age range and performance status, with less concern about renal function and AIHA.”

Smith summed up his pitch for BR:

  • It is less toxic, requiring fewer doctor visits and less supportive care;
  • It is less myelosuppressive, so there is less risk of therapy-related myeloid neoplasms (t-MN);
  • It is less immunosuppressive, so there are fewer late infections;
  • It is easier to administer later lines of therapy; and
  • It is easier to combine with novel agents.

“So for your CLL patient who is a 55-year-old marathon runner with 11q by FISH, I will concede that a patient might receive FCR,” Smith said. “For the rest of your patients, use BR.”

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Richard Furman: FCR/FR Is Best

Furman based his arguments for the debate on the fact that there are many more data supporting the use of FCR in the initial treatment of CLL, especially in progression-free survival, and that the toxicities of BR and FCR are not that different.

“And while the major concern people cite as to why they would choose BR over FCR is toxicity, with the exception of infections the toxicities are really not relevant and the patients do quite well with both regimens,” he said, elaborating in an interview after the debate. “That's really demonstrated by the fact that the patients enjoy progression-free survival and longer times between treatments.”

He said he believed that long-term data for bendamustine will show an increased risk of toxicities: “I'm sure it will, once we get further out and have more follow-up data.”

For his presentation, Furman delved into the chemistry of bendamustine, noting that it is touted as a bifunctional molecule with a purine-like benzimidazole ring and also an alkylating group. “But what we see clinically is its alkylating function—it's really just an alkylator, and we can expect bendamustine to have the toxicities of all alkylating agents,” he said.

“We don't know long term what happens when patients get bendamustine,” Furman said, adding parenthetically that this is a bit surprising since the agent has been in use in Germany since the 1970s.

“The other thing to keep in mind is that we do see very significant T-cell depletion with bendamustine, and the CD4 counts can drop as low as they do for fludarabine-based chemotherapy for as long as two years,” he said.

Returning to fludarabine, Furman recalled the CALGB 9712 trial, which added rituximab and saw a median overall survival of 85 months and median progression-free survival of 42 months. He compared that with the pivotal bendamustine vs. chlorambucil trial, in which median progression-free survival in the bendamustine arm was only 21.6 months.

And even the combination of bendamustine and rituximab in the GCLLSG CLL2M trial (Fischer et al: JCO 2012; 30: 3209-3216), showed a median event-free survival of only 33.9 months. The rate of grade 3 hematologic toxicities was 26.5 percent, and grade 4 was 25.6 percent. The overall response rate was 88.0 percent.

The rate of infection with BR in CLL2M was low—only 6.8 percent, Furman allowed.

“But the important question is: who does better overall? While there is an increased risk of infection with fludarabine, as long as these infections don't result in lasting morbidity or any mortality, we're still going to be doing okay for our patients.”

He cited a trial of FC with or without rituximab, the Phase III GCLLSG CLL8, which showed a progression-free survival time of 51.8 months for FCR vs. 32.8 months for FC, and overall response rates of approximately 95 vs. 88 percent, respectively.

In a 2012 update of CLL8 reported at the 2012 ASH Annual Meeting, with 5.9 years of follow-up, median progression-free survival had improved to 57 months for FCR but was virtually unchanged at 33 months for FC. (Fischer K. ASH 2012, Abstract 435).

The rate of infections in that trial were significantly higher than what would be seen with BR, he noted—25 percent for FCR and 21 percent for FC. But the important point in CLL8, he said, was the 95.1 percent overall response rate for FCR vs. 88.0 percent for BR in the CLL2M trial.

Overall, patients do better with FCR, Furman said, and rested his case.

© 2014 by Lippincott Williams & Wilkins, Inc.
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