Making clinical trials work for older patients with chronic lymphocytic leukemia

Abstract

Despite the growing numbers of older patients with cancer, there is a historic and continued under-representation of older patients on therapeutic clinical trials [1,2]. A quick pubmed search or a browse through this Journal's table of contents reveal that while there are many investigators interested in the treatment of cancer in older patients, there remains significant variability by which disease-focused investigators have incorporated older patients into clinical trials.Chronic lymphocytic leukemia (CLL) is one of the cancers that is disproportionately represented in older patients. The median age at diagnosis is 72, and 75% of people are diagnosed after the age of 65 [3]. Despite this, it was not until recently that clinical trials began to focus on the older and less fit patient population. In the large studies that demonstrated the superiority of chemotherapy plus anti-CD20 monoclonal antibody treatment (chemoimmunotherapy) in this disease between 2000 and 2010, median ages were between 58 and 64 years [4][5][6]. One of the first hints that therapy in CLL was not one size fits all came from the German CLL5 study, which showed that fludarabine was not superior to chlorambucil in older patients, despite this being true in the definitive phase 3 study that included all ages [7,8]. This finding was confirmed in a retrospective study of the US cooperative group trials [9], and led to new efforts to design trials in CLL that would be relevant to the patient population seen in the community.Since the CLL5 study, five phase 3 clinical trials in frontline CLL have been performed specifically for older or frail patients. CLL11 and CLL14 were designed to include patients with significant comorbidities, RESONATE 2 (NCT01722487) and A041202 (NCT01886872) were designed to include patients age 65 or greater, and iLLUMINATE (NCT02264574) enrolled either. CLL11 (NCT01010061) compared chlorambucil alone to chlorambucil + rituximab and chlorambucil + obinutuzumab, while CLL14 (NCT02242942) compared chlorambucil + obinutuzumab to venetoclax + obinutuzumab. For both of these studies, eligible patients were required to have a cumulative illness rating scale (CIRS) of at least 6 or Creatinine Clearance (CrCl) of 30-69 mL/min [10,11]. These criteria naturally skewed to an older patient population, with a median age of 73 years in the CLL11 study, and 72 years in the CLL14 study. Median CIRS score was 8 in CLL11, and over half of patients reported hypertension, cardiac, and endocrine/metabolic comorbidities.On CLL14, median CIRS score was also 8, and over half of patients reported hypertension and ear, nose, and throat disorders. Patients still tended to have preserved renal function, with CrCL of 62 mL/min in CLL11 and 66 mL/min in CLL14. In CLL11, median Eastern Cooperative Oncology Group (ECOG) performance status was 1, and for CLL14, over half of patients had performance status of 1-2. iLLUMINATE randomized patients to chlorambucil + obinutuzumab versus ibrutinib + obinutuzumab. On this study, patients were required to be eit...

Ibrutinib as first line therapy in chronic lymphocytic leukemia patients over 80 years old: A retrospective real‐life multicenter Italian cohort

“…Additionally, CLL trials are not sufficiently patient‐friendly, worsening the issue. Indeed, although CLL is a typical disease of the elderly, large clinical studies dealing with the efficacy of chemo‐immunotherapy included patients with a median age between 58 and 64 years 14 …”

“…Indeed, although CLL is a typical disease of the elderly, large clinical studies dealing with the efficacy of chemo-immunotherapy included patients with a median age between 58 and 64 years. 14 More importantly, even though the pivotal RESONATE-2 study encompassed patients up to 80 years of age, it did not provide specific details about this particular elderly subgroup. 3,4 Likewise, realworld evidence investigating the effectiveness and safety of ibrutinib in the elderly, involved patients with a median age ranging from 69 to 75 years.…”

First-Line Treatment of Older Patients with CLL: A New Approach in the Chemo-Free Era

“…Despite CLL being a disease of the elderly with a median age at onset of around 70 years, the majority of published clinical trials until 2010 enrolled patients with a median age between 58 and 64 years [42]. The need for clinical trials specifically designed for older patients was recognized, and the CLL5 trial showed that the purine analog fludarabine was not superior to chlorambucil in older patients [43].…”