NEW YORK—The best frontline regimen for chronic lymphocytic leukemia (CLL) patients under age 65 who meet treatment criteria is fludarabine, cyclophosphamide, and rituximab (FCR), but bendamustine plus rituximab (BR) may be better for older patients since it leads to fewer infections, less myelosuppression, and is easier to administer. That was the recommendation of speakers here at the Great Debates and Updates in Hematologic Malignancies meeting, debating the question of the best frontline regimen for CLL patients younger than 60 who meet treatment criteria.
Fludarabine, Cyclophosphamide, and Rituximab
Michael Keating, MD, Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, started his talk by presenting an update of a recent International Workshop on CLL study of 300 patients who received FCR: “All of these patients had prior therapies. Initially, median progression-free survival was three years, and median overall survival was five to six years,” he said. “Now overall survival has not been reached after 14 years. There is strong evidence of a plateau on the survival curve emerging after seven to eight years of follow-up.”
He noted that one-third of patients have not had disease progression, and the vast majority of them are negative for minimal residual disease (MRD).
Combination approaches such as FCR for younger patients under 65 show that two-thirds are alive at 10 or more years. Some patients in their 70s on FCR are healthy with no co-morbidities, Keating pointed out.
“In clinical practice, mutational status is far and away the best predictor of success in overall survival and disease-free groups,” he said, recommending the collection of mutational status and FISH data. “Patients with 17p mutations have a bad prognosis, and those with 11q mutations have a worse outcome.”
Although researchers have attempted to improve on the FCR combination by adding in more courses of rituximab, or mitoxantrone, alemtuzumab, or granulocyte macrophage colony-stimulating factor, he said that his group has found no differences—except some reduction in the rates of secondary acute myeloid leukemia (AML) and myelodysplasic syndromes (MDS), up to 10 percent. “Modifications have not led to benefits in survival,” he said.
Keating then highlighted the results of the CLL 10 trial, a non-inferiority trial that compared FCR with BR in frontline therapy of patients with untreated, active CLL without 17p mutations who had good renal function and low comorbidity.
He noted there were imbalances in the patient population in favor of FCR, with fewer patients over age 70. All prognostic factors also favored the FCR arm. There was also a significant difference in the number of cycles, with more patients discontinuing in the FCR group than in the BR group.
The results show an improvement in complete response (CR) to 40 percent in the FCR arm versus 36 percent in the BR arm, he reported. Median PFS was significantly better with FCR and has not been reached with BR at 45 months. There was no difference in OS. There was a statistically significant improvement in the number of patients who achieved MRD negative status in the FCR arm.
In respect for the opposing side of the debate, Keating asked: “Are the results due to imbalances or not? There was less neutropenia and a reduced infection rate in the group receiving BR. Do we have the right dose and schedule? We don't know.”
Multivariate analysis shows that imbalances are important, but even after accounting for that, the progression-free survival rate is still significantly in favor of use of FCR, he said. “The CLL 10 researchers will continue to report results. The question remains: Is MRD negativity important to achieve? Sixty percent of patients at the end of treatment became MRD negative on FCR, but how long will it last?”
He noted that the improvement was greater in patients with 17p mutation, who are least likely to achieve MRD-negative status.
In summation, Keating said: “It's clear that age, mutational status, and FISH characterization are important. Why get rid of FCR? Should we replace it with cytotoxic chemotherapy as frontline therapy? Some 40 percent of deaths of CLL patients are associated with secondary solid tumors, AML/MDS, or Richter's transformation. This includes 71 percent of deaths in the first remission. We need something better and safer than FCR.”
Researchers are looking at non-genotoxic therapy with monoclonal antibodies, lenalidomide, or B-cell receptor antagonists. “Since the OS is similar with both therapies, there is no harm starting off with a more conservative agent for CLL therapy,” he said. “FCR is still the standard. We just need to make it better.”
Bendamustine Plus Rituximab
The other speaker, an MD Anderson colleague, was Allessandra Ferrajoli, MD, Associate Professor in the Department of Leukemia, who presented the case for bendamustine plus rituximab as frontline therapy for CLL.
Bendamustine has a unique antitumor profile and is a powerful alkylator, and was first combined with rituximab as frontline therapy in CLL in 2011, she noted. The standard BR regimen is rituximab at 375 mg/m2 on day 0, cycle 1 500 mg/m2 cycles 2–5, every 4 weeks plus bendamustine at 90 mg/m2 on days 1–2, cycles 1–6, every 4 weeks.
“The efficacy of BR ranges from 40 to 80 percent,” she said, adding that there is an increased risk of skin rash and marked photosensitivity with this combination.
She also used the CLL 10 study to support her position: “As Dr. Keating described, the randomization was not perfect. This makes the evaluation of the results more challenging,” she said, noting that there were more patients over age 70 years in the BR group.
The CR rates favored FCR (47.4%) over BR (38.1%), but the overall response rate (ORR) was 97.8 percent in both groups. “CR was higher with FCR, and the ability to eradicate MRD was superior in the FCR arm. The primary endpoint, PFS, was significantly longer in the FCR arm,” she said. FCR also led to superior partial response, particularly in patients with absence of 11 q mutation.
Feigning defeat, she said, “So, is this the end of the debate? Not quite. Let's look at the details.”
Multivariate analysis shows that overall survival at 24 months slightly favors use of BR (95.8%) over FCR (94.2%). Progression-free survival in an unmutated immunoglobulin heavy chain variable (IGHV) group also slightly favors BR. “Significant factors for OS include age, comorbidity score, beta 2 microglobulin, and patient status,” she said. “There is no difference at this point in terms of OS at 24 months. We will see if this changes in reports later this year.”
In support of BR, Ferrajoli said that the rates of infection, severe infection, and neutropenia were lower in the BR group, and noted that in most of the population, patients in both regimens are doing well.
She said that 40 percent of the patients in the CLL 10 study were over 65. “In those who were younger than 65, the PFS is statistically significant in favor of FCR. However, there is no PFS difference in those over 65.
“In addition, BR is less myelosuppressive, and is associated with a reduced rate of infection, particularly in patients over age 65. When infection occurs between assessment and the end of therapy, there is an advantage of lowering infection and severe infections with BR,” she said, adding that it is also easier to administer six cycles of BR than FCR for any age, and in particular for older patients.
BR is the treatment choice over FCR, because “it's better for older patients, there is no difference in PFS or OS, it has an advantage in terms of infections, it is less myelosuppressive, it is easier to administer, and offers an easier backbone to combinations with other agents,” Ferrajoli said.
She added that other agents are being tested in combination with these drugs in CLL patients. One agent being tested in previously untreated CLL patients is GA101 along with fludarabine and cyclophosphamide or bendamustine. “We will see if this drug plays a role in these combinations.”
In addition, ibrutinib has been combined with BR or FCR in patients with relapsed/refractory CLL or small lymphocytic leukemia. In a Phase I study, the combination with BR led to a high ORR rate (93.4%) at 16 months. “The response duration is quite good—superior to anything before in the laboratory setting. This combination leads to mild neutropenia and no increased rate of infection, which is an advantage,” she said.
In the post-debate voting, just less than two-thirds of the audience continued to vote for FCR as the best therapy. But a large percentage of the “Undecided” group switched their votes, so BR now received more than one-third of the votes, up from one-quarter pre-debate, giving the debate to Ferrajoli.
In the question-and-answer session, an audience member asked whether patients taking ibrutinib who develop leukocytosis need to have their therapy adjusted.
Ferrajoli answered: “I would continue the therapy. Eventually, leukocytosis resolves and is seldom a problem in CLL. This is more of an emotional issue. It's hard for the physician and patient to wait. Allow the treatment to show its potential. B-cell receptor therapy is not fast acting.”
She added: “I would exclude opportunistic infections if the patient has an increase in eosinophils. Expansion of T cells is well-documented in CLL.”
Keating added that if a patient has atypical lymphocytes, then the development of Richter's transformation may obviate discontinuation of therapy.