EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE

ORLANDO (FRONTLINE MEDICAL NEWS) – The choice of first-line therapy in symptomatic chronic lymphocytic leukemia patients depends largely on comorbidity burden, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.

“This is a disease of elderly patients. Frequently they have comorbidities,” he said. Categorizing these patients as having a low or high comorbidity burden can be done with the Cumulative Index Rating Scale score, which involves scoring of all organ systems on a 0-5 scale representing “not affected” to “extremely disabled.”

“We use this to determine first-line therapy,” said Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York. Dr. Zelenetz is chair of the NCCN Non-Hodgkin Lymphoma Guidelines panel.

Patients with a score of greater than 12 on the 0- to 56-point scale, are “no-go” patients with respect to therapy, and are typically treated only with palliative approaches. Those with a score of 7-12 (“slow-go” patients) have a significant comorbidity burden, but can undergo treatment, thought typically to be at reduced intensity. Those with a score of 0-6 are “go-go” patients with respect to treatment, as they are physically fit, have excellent renal function, and have no significant comorbidities, he said.

Treatment options for ‘go-go’ CLL patients

Among the treatment options for the latter is FCR–the combination of fludarabine, cyclophosphamide, and rituximab, which was shown in the phase III CLL10 trial of patients with advanced CLL to be associated with improved complete response rates compared with the popular regimen of bendamustine and rituximab (BR), both overall and in patients under age 65. In older patients, the advantage disappeared, Dr. Zelenetz said.

FCR was also associated with improved outcomes vs. BR in patients with del(11q).

The primary endpoint of the study was progression-free survival, which favored FCR (median of 55.2 vs. 41.7 months; hazard ratio, 1.643), he said, noting that no difference was seen between the two regimens in terms of overall survival.

In a recent publication, MD Anderson Cancer Center reported its experience with its first 300 CLL patients treated with FCR. With long-term follow-up of at least 9-10 years (median of 12.8 years), patients in this trial have done extremely well.

“But interestingly, when you stratify these patients by whether they have IGHV [immunoglobulin heavy chain variable] mutated or unmutated [disease], the IGHV mutated patients have something that looks a whole lot like a survival plateau, and that survival plateau is not trivial – it’s about 60%,” he said. “So there is a group of patients with CLL who are, in fact, curable with conventional chemoimmunotherapy.

“This is an appropriate treatment for a young, fit, ‘go-go’ patient, and it has a big implication,” he said. That is, patients who are young and fit require IGHV mutation testing, as “you will absolutely choose FCR chemotherapy for the fit, young patients who has IGHV mutated disease.

“In that setting IGHV testing is now mandatory,” he stressed, noting that the benefits in this population extend to overall survival as well as progression-free survival.

Dr. Zelenetz also emphasized the need for increasing the single dose of rituximab from 375 mg/m2 during cycle 1 to 500 mg/m2 during cycles 2-6 in those receiving FCR, as this is often forgotten.

The data demonstrating the efficacy of FCR were based on this approach, he said.

Fludarabine is to be given at a dose of 25 mg/m2, and cyclophosphamide at a dose of 250 mg/m2 – both for 2-4 days during cycle 1 and for 1-3 days during cycles 2-6.

Treatment options for ‘slow-go’ CLL patients

In “slow-go” patients, an interesting approach is to use new anti-CD20 antibodies such as ofatumumab and obinutuzumab, which have features that are distinct from rituximab.

Both have been studied in CLL. The CLL11 trial compared chlorambucil, rituximab+chlorambucil, and obinutuzumab+chlorambucil, and the latest analysis showed substantial improvement in progression-free survival with obinutuzumab+chlorambucil vs. the other two regimens (26.7 months vs. 11.1 and 16.3 months, respectively), Dr. Zelenetz said, noting that rituximab+chlorambucil was also superior to chlorambucil alone, but that only the obinutuzumab regimen had an overall survival advantage vs. chlorambucil alone.

An updated analysis to be reported soon will show emerging evidence of a survival advantage of obinutuzumab+chlorambucil vs. rituximab+chlorambucil, he said.

“This suggests that obinutuzumab is a far better antibody,” he added, noting that the reasons for that are under debate, “but the way it’s given, it works better in CLL, and that, I think is unequivocal.”

A similar study looking at chlorambucil with and without ofatumumab in “slow-go” patients also demonstrated an improvement in PFS with ofatumumab, but showed “no difference whatsoever in overall survival.”

“This is actually very similar to the rituximab result, and I actually call this the ‘death of ofatumumab’ study, because clearly obinutuzumab in CLL is, I think, a superior anti-CD20 antibody,” Dr. Zelenetz said.

Studies in which obinutuzumab is substituted for rituximab in the FCR combination are currently underway as are a number of other studies of obinutuzumab, he noted.

Another treatment option in the up-front setting is ibrutinib, which was shown to be effective in the RESONATE 2 trial .

“But notice, a very, very small [complete response rate]. CRs are very difficult to achieve with ibrutinib alone, so this drug is given continuously, lifelong,” Dr. Zelenetz said, noting that it was, however, associated with an overall survival advantage vs. chlorambucil.

“Should this be the standard of care? I think it is in patients who have del(17p) or mutation of TP53. Outside of that setting, I’m still concerned about the cost of long-term tolerability of the agent,” he said.

Future of first-line CLL treatment

Avoidance of long-term therapy and conventional chemotherapy in patients with CLL is a goal, he added, noting that new understanding from studies in patients in the relapsed/refractory CLL setting – such as recent findings from a phase Ib study of venetoclax plus rituximab, which demonstrated potentially durable responses after treatment discontinuation in minimal residual disease (MRD)–negative patients – are providing insights into achieving MRD negativity that could be applied in the front line treatment setting.

“We’re still trying to figure out how to best use this. We want to try to use some of this knowledge about achievement of MRD negativity in the up-front setting so we don’t have to give patients long-term therapy, and we would like to avoid conventional chemotherapy,” he said. “So I’m hoping we’re going to be able to replace chronic long-term therapy of CLL with a defined course of treatment with high levels of MRD negativity.”

Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Acerta Pharma, Amgen Inc., BeiGene, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, Janssen Pharmaceutica Products, MEI Pharma, NanoString Technologies, Pharmacyclics, Portola Pharmaceuticals, Roche Laboratories, and Takeda Pharmaceuticals North America.

sworcester@frontlinemedcom.com

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