Letter to Editor suggests FCR therapy may only benefit younger patients 

On 3rd November 2017, Stephen Opat and Eliza A. Hawkes of Monash University in Melbourne, Australia were the co-authors of a ‘Letter to the Editor’ published online in the Journal of Clinical Oncology (JCO). This correspondence was in response to a previously published commentary in JCO entitled, “Chemoimmunotherapy Is Not Dead Yet in Chronic Lymphocytic Leukemia.” This was a thoughtful and well-documented response that aims to curb the enthusiasm that fludarabine plus cyclophosphamide plus rituximab (FCR) can benefit a majority of the CLL patient population.

Opat and Hawkes articulately cite several key studies and underscore the fact that CLL is largely a disease of older patients with a median age at diagnosis of 70 years. And while the studies that have demonstrated FCR yields good long-term results in a proportion of patients, it’s hard to avoid the fact that the most compelling evidence was found in a study of young, fit, and relatively healthy (cumulative illness rating score of 6) patients with a median age of 61 years (CLL8 and CLL10 studies). Of additional note, studies of fludarabine-based regimens in older patients conducted in the United States, Germany, and the United Kingdom have failed to show a survival benefit over less intense regimens, essentially because of an excess of treatment-related complications. Other key points that the authors discuss:

Key Highlights
  • FCR is associated with unacceptable levels of both early and late toxicity, particularly in older patients, with morbidity evident in clinical practice that is poorly reflected in clinical trials
  • A study conducted in the general community showed that less than 20% of patients satisfy age, renal clearance, and fitness profile requirements to be considered suitable for aggressive chemoimmunotherapy in the frontline setting on the basis of inclusion criteria used for entry in either CLL10 or CLL8
  • FCR remains the current standard for younger and fitter CLL patients; however, the authors estimate this only equates to approximately 7% of all patients
  • Strong emphasis is needed for careful patient selection as well as strict criteria for determining patient eligibility that matches those of published studies, selecting only those who might truly benefit, as well as tolerate the costly toxicity
  • Treatment should be delivered in experienced centers with adequate supportive measures and careful, long-term monitoring
  • Balancing disease control with toxicity is paramount, and must be the primary goal of therapy, particularly in older patients
  1. Opat Set al. Chemoimmunotherapy May Not Be Dead Yet in Chronic Lymphocytic Leukemia, But Fludarabine Plus Cyclophosphamide Plus Rituximab Is Potentially Facing Life Support. Journal of Clinical Oncology. 2017 Nov 3. DOI: [Epub ahead of print]
  2. Brown K R. et al. Chemoimmunotherapy is not dead yet in chronic lymphocytic leukemia. Journal of Clinical Oncology 35:2989-2992, 2017
  3. Eichhorst B Fet al. Favorable toxicity profile and long term outcome of elderly, but physically fit CLL patients (pts) receiving first line bendamustine and rituximab (BR) frontline chemoimmunotherapy in comparison to fludarabine, cyclophosphamide, and rituximab (FCR) in advanced chronic lymphocytic leukemia (CLL): Update analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Blood 128:4382, 2016
  4. Hallek M. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet 376:1164-1174, 2010
  5. Sharman J al. Demographics by age group (AG) and line of therapy (LOT) in chronic lymphocytic leukemia (CLL) patients (Pts) treated in US practices from the Connect CLL registry. Blood 124:3338, 2014
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