expert roundtables

Initial Treatment for Older (Age >70), Nonfrail Patients With Chronic Lymphocytic Leukemia

by Jennifer R. Brown, MD, PhD; Anthony Mato, MD, MSCE; and Susan O’Brien, MD

Overview

The over-70 age group is highly represented among those starting treatment for chronic lymphocytic leukemia (CLL). Frontline treatment in this population is increasingly chemotherapy free, regardless of the patient’s level of frailty or fitness, owing to the success and tolerability of small molecules.

Q: How do you approach the frontline treatment of very fit, but older, patients with CLL? Is there an upward age cutoff for the use of chemotherapy-containing regimens such as FCR?

Susan O’Brien, MD

Associate Director for Clinical Science
Chao Family Comprehensive Cancer Center
Medical Director
Sue and Ralph Stern Center for Cancer Clinical Trials and Research
University of California, Irvine Health
Irvine, CA

“In a general sense, the small molecules are so well tolerated and are producing such good results that I just would not even bother giving chemotherapy to a patient over 70 years of age, although there may be a few exceptions.” 

Susan O’Brien, MD

It is important to take note of both performance status and the presence of comorbidities in older patients. I am generally a strong advocate of fludarabine, cyclophosphamide, and rituximab (FCR) because it produces a plateau of response on the progression-free survival (PFS) curve, but, obviously, I am not going to offer it to a 70-year-old patient who walks into the office with a cane and/or is in poor health otherwise. If you consider a 70-year-old woman who seems fit and is quite active, playing tennis twice a week, for example, that might be different. But, say she has comorbidities such as diabetes, mild hypertension, and hyperlipidemia. Are you going to give her FCR? I am not saying that there is a clear right or wrong answer to that question; however, I would generally not offer FCR to patients over 70 years of age. For these individuals, I would likely treat their CLL with small molecules, especially if they have other comorbidities, and my goal would be to protect their natural life expectancies (ie, had they not developed CLL). Achieving the plateau of response on the PFS curve is not as great of a concern in an older patient in that the duration of response becomes less relevant as fewer years remain in the natural life span. Moreover, the use of bendamustine/rituximab (BR) is less common in this age group. Historically, BR had been used extensively in patients older than age 70 years who were in good shape, with a goal of buying them time and not risking the toxicity of FCR. However, with small molecules, that has changed because you can now keep many patients going for 10 years or more with these agents. An exception might be the patient who cannot tolerate ibrutinib, because you may not be able to get 10 years’ worth of treatment with small molecules in that case. But, in my mind, the small molecules are so well tolerated and are producing such good results that I just would not even bother giving chemotherapy to a patient over 70 years of age.

Anthony R. Mato, MD, MSCE

Director, Chronic Lymphocytic Leukemia Program
Associate Attending, Memorial Sloan Kettering Cancer Center
New York, NY

“With respect to the use of BR as frontline therapy in older patients, it is not my practice to initiate this treatment in this age group and it has not been a common treatment pattern in referrals to my practice over the last several years.”

Anthony Mato, MD, MSCE

As a rule of thumb, I generally think that patients who are 65 years of age or older are not the best candidates for standard doses of FCR. In the older literature, there was a suggestion that the benefits of adding rituximab to fludarabine and cyclophosphamide really started to diminish for patients over 70 years of age, although this age group had been underrepresented. Now, the ECOG-E1912 trial reported recently by Shanafelt and colleagues did allow patients who were up to 70 years of age to be included in the trial, in which patients with untreated CLL were randomized to receive either ibrutinib plus rituximab or FCR. However, my own experience is that, once you have patients who are beyond 65 years of age, it is difficult for them to tolerate FCR. And this has been reported, to some extent, in the long-term follow-up data from the FCR studies. In the CLL10 trial, there was no significant difference in PFS in the over-65 age group in the FCR-treated group compared with the BR-treated group. So, age over 65 years is my own personal cutoff point.

With respect to the use of BR as frontline therapy in older patients, it is not my practice to initiate this treatment in this age group and it has not been a common treatment pattern in referrals to my practice over the last several years. Most older patients are initiated on ibrutinib or obinutuzumab-based therapy today. I think that the use of BR as frontline therapy for elderly patients with CLL is more historical than anything else at this point.

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Boston, MA

“In general, ibrutinib is taking over as the top anti-CLL drug among older patients, but I still see some use of BR in the community.” 

Jennifer R. Brown, MD, PhD

I agree that patients over age 65 years usually do not tolerate FCR. I have occasionally violated that age cutoff by offering FCR to people who are 67 or 68 years of age, under unique circumstances, but I think that the age cutoff of the ECOG-E1912 study (ie, up to 70 years) was too high. We have data, particularly from the CLL10 trial, showing that patients over age 65 have more toxicity on FCR compared to BR, which was primarily seen as febrile neutropenia or as infectious toxicity. The best predictor of this toxicity was age greater than 65 years, with this age group having an approximately 2-fold increased rate of infection. In fact, as reported by Eichhorst and colleagues, the numerical age cutoff at 65 years differentiated efficacy and toxic effects in CLL10 better than various cutoffs using the Cumulative Illness Rating Scale, including severity and number of involved organ systems. 

In general, ibrutinib is taking over as the top anti-CLL drug among older patients (in both the frontline and relapsed, post-chemoimmunotherapy settings), but I still see some use of BR in the community. The main issues are time-limited therapy vs continuous therapy and costs, in terms of co-pays. We now have the option of venetoclax plus obinutuzumab as a time-limited, chemotherapy-free option for patients who might have otherwise received BR. But, in the context of all of the considerations such as costs, the need for continuous therapy, and the presence of comorbidities, there might be a small subset of patients (eg, those with mutated IGHV) for whom it might not be unreasonable to give BR. In the Alliance trial (NCT01886872), which compared ibrutinib regimens with BR, no significant interaction between IGHV mutation status and the effect of treatment on PFS was found, with mutated patients having longer PFS across treatment arms at the time of data cutoff (median follow-up, 38 months).

References

Eichhorst B, Fink AM, Bahlo J, et al; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942.

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236.

Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56.

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.

Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975-980.

Tedeschi A, Greil R, Demirkan F, et al. A cross-trial comparison of single-agent ibrutinib versus chlorambucil-obinutuzumab in previously untreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Haematologica. 2019 Aug 14. pii: haematol.2019.223743. doi: 10.3324/haematol.2019.223743. [Epub ahead of print]

Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.

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