NEW YORK—More patients with chronic lymphocytic leukemia (CLL) are being diagnosed at earlier ages with early-stage disease before developing symptoms after being incidentally found to have lymphocytosis. At the Great Debates & Updates in Hematologic Malignancies meeting here, the question was debated about the best frontline regimen for a 60-year-old CLL patient who requires therapy: Should it be fludarabine-cyclophosphamide-rituximab (FCR) or the B-cell targeting agent ibrutinib without chemotherapy—two regimens that have not been compared head-to-head.
Matthew Davids: Use FCR
FCR is still the best regimen for younger CLL patients, said Matthew S. Davids, MD, MMSc. “We often face a conversation with a patient who asks, ‘How are you going to get me to age 85, doc?’”
Davids reviewed the timeline of frontline CLL therapy over the past 50 years: A big advance came in the 2000s, he noted, with chemoimmunotherapy, which led to high response rates, durable responses, and overall survival (OS) benefits. In the 2010s, “complete response [CR] has been variable, and CR is still important in terms of long-term disease-free survival.”
He described several other CLL therapies before focusing on FCR: “Ibrutinib is active and well-tolerated in the frontline setting in CLL, but there is little data on durability. Progression-free survival [PFS] and OS rates are impressive, but we don't know what happens three or four years out from therapy.” He noted that there are promising data in high-risk, untreated CLL patients taking ibrutinib, with initial durable responses.
The monoclonal antibody obinutuzumab is also active in frontline CLL, leading to an 80 percent response rate, with minimal residual disease (MRD)-negativity in the bone marrow and PFS benefits: “This active antibody in CLL needs to be studied in combination with other agents,” he said. “It is not durable for younger patients.”
A combination of bendamustine and rituximab (BR) is another effective option for frontline CLL treatment, leading to an overall response rate (ORR) of 88 percent, CR of 23 percent, and median event-free survival of 34 months.
But maybe more is better, Davids said: “The addition of rituximab to fludarabine and cyclophosphamide leads to about a 90 percent response rate and CR of about 50 percent, with a median PFS of four to five years, and the FCR regimen also overcomes 11q- deletion, with durable responses.”
The Phase III CLL10 trial was designed to determine whether FCR or BR is a better frontline therapy for CLL, he noted. The trial enrolled 564 patients with a confirmed diagnosis of B-cell CLL with no del(17p) from 158 sites in five countries. The primary endpoint was PFS after 24 months.
The results showed that FCR induces deeper, more durable responses than BR does. MRD-negativity in bone marrow was higher with FCR than BR does. Median PFS for those under age 65 was 54 months with FCR compared with 39 months for BR. Most severe infections occurred in patients over age 65. “Few would argue using FCR in older patients,” Davids said, noting that growth factor support is used routinely. “We see much lower rates of neutropenia with FCR.”
Attaining MRD-negativity is an important factor for survival in use of frontline CLL treatment. “The key is to get to MRD-negativity. Then you get good long-term survival after FCR,” he said.
He also cited the FCR 300 trial at MD Anderson Cancer Center of 300 untreated CLL patients: The results originally showed a 72 percent CR rate and an ORR of 95 percent. Follow-up data show that about 40 percent of patients are progression-free, and some are alive for more than 14 years, and the “data argue that some patients are cured.”
In terms of progression-free survival by IGHV (immunoglobulin heavy chain variable) mutation status, those with mutated IGHV have a durable response, with about 60 percent being progression-free. “For younger patients who want an aggressive approach, this is a building block for those who want a cure,” he said.
Davids admitted that FCR is not the optimal frontline therapy for patients with del(17p) CLL, where ibrutinib is a better choice.
He noted some selected ongoing studies, including ibrutinib plus rituximab versus FCR, and two studies involving older patients treated with bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib, and also ibrutinib versus chlorambucil: “These studies are exciting to develop a model agent for CLL,” Davids said.
Several Phase I/II, single-arm studies of novel agents, including IPI-145, are underway, he noted. Another Phase Ib/II study of ibrutinib plus FCR in previously untreated younger CLL patients has led to MRD-negativity at three months. “This shows that a novel agent can be used to maximize rates of MRD-negativity, and allows for rapid readout of the efficacy of novel agents,” Davids said.
Researchers are also thinking of strategies to enhance FCR: “If we expose CLL patients to a novel agent along with FCR, this may be curative.”
So, back to the question he hears from patients: How to get them to age 85? “I still vote for FCR for younger patients,” Davids concluded.
Richard Furman: Use Ibrutinib-based Treatment without Chemotherapy
The other debater, Richard Furman, MD, presented data to support the use of ibrutinib therapy without chemotherapy for younger CLL patients.
“Everything that applies to patients over age 65 who are unfit should also apply to patients who are fit and under age 65. Young patients just have more to lose if we make a mistake,” Furman said.
As did Davids, Furman also noted that the evolution of CLL therapies has changed over time: The introduction of chemoimmunotherapy improved response rates. In 2000 to 2010, CR rates were 41 to 70 percent and ORR rates were 90 to 95 percent. I'm not interested in getting patients to CR unless this translates into OS,” he said. “The role of MRD, an extreme example of CR, is meaningless. We have to revise what we are looking at. With revised response criteria, we have to have a close eye on CRs.”
A change in the natural history of CLL may have led to an increase in overall survival as a group, Furman said. By stage, there is no benefit for Binet stage A and Binet stage B patients, but a benefit is seen for Binet stage C patients. Perhaps that is due to better supportive therapies and novel agents, and a shift to earlier stage disease at diagnosis.
From 2000 to 2010, MD Anderson researchers reported an increase in OS in CLL, but this may have been due to a lead time bias, Furman theorized. “They may have just been diagnosing patients earlier.”
In discussing the FCR 300 trial at MD Anderson, he noted that the 30 percent PFS rate is over-represented by a group of patients who were mutated. Nearly three-quarters of long-term survival is from mutated patients. Unmutated patients have a PFS rate of 10 percent.
Do we need such aggressive therapy? he asked. “About 70 percent of patients treated with FCR relapse. They are not responsive to other therapies, and median survival is 51 months after disease progression. If we are talking about young patients, we hope that they live a long time.”
There is also an issue of secondary malignancy induced by FCR, he noted. A study of second cancers comparing FCR versus non-genotoxic therapies at MD Anderson in CLL patients over age 65 found an eight percent risk of AML/MDS with FCR and a one percent risk with non-genotoxic therapies—“a significant difference,” he said, adding that there is also an increase in Richter's transformation with FCR.
“This is more reason to avoid chemotherapy in CLL. Some 40 percent of deaths among CLL patients are associated with second solid tumors, acute leukemia or MDS, or Richter's transformation,” Furman said. This includes 71 percent of deaths in first remission.
On the other hand, BCR-associated kinases have proven to be effective therapeutic targets in CLL. In an early Phase II trial of ibrutinib in CLL, among patients who initially achieved a partial response (PR), the majority of patients achieved a classic response by IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria. The combined response rate was 84 percent in previously untreated patients and 88 percent in relapsed/refractory patients.
In addition, a significant number of patients moved from a PR with lymphocytosis to PR or from PR to CR: The 30-month PFS rate is high—96 percent in treatment-naïve and 69 percent in relapsed/refractory patients.
Furman summed up: “A large number of patients are still on ibrutinib for more than 30 months. It works effectively to control CLL. When a patient does progress, specific genetic mutations may be responsible, and the most common cause of genomic instability is chemotherapy.”
Before the debate, more than two-thirds of the audience voted that they believed FCR was the most appropriate therapy for a younger CLL patient. But afterwards, the vote indicated that many thought Furman made a strong case: More than half of the audience said that ibrutinib was the ideal treatment.