Frequency and impact of grade three or four toxicities of novel agents on outcomes of older patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma (alliance A151611)

Abstract

Objective

Older patients with cancer suffer from chemotherapy-related toxicities more frequently than younger patients. As novel agents are being used more commonly in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), toxicities of these agents in older patients have not been well studied. Further, impact of these toxicities on outcomes in the elderly is unknown. This study aimed to answer both questions.

Patients and Methods

We reviewed 14 Alliance for Clinical Trials in Oncology trials that enrolled CLL and/or NHL patients between 2004–2014. Toxicity was assessed per the NCI-CTCAE (version 3–5). Probabilities of experiencing grade three or four hematologic and non-hematologic toxicities were modeled as a function of clinical and disease-related factors using logistic regression.

Results

1199 patients (409 age ≥ 65; 790 age < 65) were analyzed; 438 received only biologic therapy (145 age ≥ 65; 293 age < 65), and 761 received biologic + chemotherapy (264 age ≥ 65; 497 age < 65). The odds of grade three or four hematologic [odds ratio (OR) 1.70; p = 0.009: 95% CI (1.57–1.84)] and non-hematologic toxicities [OR 1.47; p = 0.022; 95% CI (1.39–1.55)] were increased in older patients with CLL, as well as odds of grade three or four non-hematologic toxicities [OR 1.89; p = 0.017; 95% CI (1.64–2.17)] in older patients with NHL. Grade three or four hematologic toxicities were associated with inferior OS and PFS in older patients with NHL [HR 3.14; p = 0.006; 95% CI (2.25–4.39) for OS and 3.06; p = 0.011; 95% CI (2.10–4.45) for PFS], though not in CLL. A prognostic model predicting grade three or four toxicities was also developed.

Conclusions

CLL and NHL patients ≥ 65 year encounter more toxicities than younger patients even when treated with novel biologic agents. Development of grade three or four hematologic toxicities lead to inferior PFS and OS in NHL but not in CLL.

Introduction

Advanced age is associated with increased incidence of chronic lymphocytic leukemia (CLL) and Non-Hodgkin Lymphoma (NHL), with a median age of diagnosis >65 for both [1]. Chemoimmunotherapy has markedly improved outcomes in patients with CLL/NHL, but despite advances, older age has consistently been shown to be associated with poorer outcomes [2,3]. Older patients usually present with different characteristics, including increased cardiovascular and pulmonary comorbidities, and have worse outcomes than their younger counterparts, possibly due to an inability to tolerate cytotoxic therapy, potential under-treatment, and sequelae of aging itself [[4], [5], [6], [7], [8], [9]].

Models have been constructed to identify the risk of chemotherapy toxicity in older patients with cancer. A model employing geriatric assessment variables, laboratory test values, histologies, and treatment characteristics was developed to predict grade three through five toxicities in patients age 65 and older treated with chemotherapy [10]. However, <6% of patients in this model had hematologic malignancies, underscoring the need for predictive models designed specifically for hematologic cancers. The increasing use of novel agents in CLL and NHL provides different toxicities than what is encountered with traditional chemotherapy and need to be studied. The frequency of these toxicities and how they might influence outcomes have not been adequately studied.

We aimed to better understand the frequency of toxicities in older patients treated with novel agents for CLL and NHL. Moreover, we sought to assess the degree to which toxicity affected overall survival (OS) and progression free survival (PFS) among these patients.