Trends in Grade 5 Toxicity and Response Rates in Phase I Trials for Hematologic Malignancies

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In a study reported in the Journal of Clinical Oncology, Chihara et al found that rates of grade 5 toxicity have remained low and that rates of overall and complete response have increased over time in phase I trials for patients with hematologic malignancies sponsored by the National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP).

The study involved analysis of integrated patient-level data for patients with hematologic malignancies who participated in phase I trials between January 2000 and May 2019.

Key Findings

A total of 161 trials with 3,308 patients were analyzed. All patients were assessed for toxicity, and 2,404 were evaluable for response to therapy.

The overall rate of grade 5 toxicities was 1.81% (95% confidence interval [CI] = 1.36–2.27%; 60 patients), with no significant change in the rate over time (2.2% in 2000–2005, 1.2% in 2006–2012, 2.1% in 2013–2019; overall P = .289). Baseline characteristics associated with increased risk of grade 5 toxicity were age (odds ratio [OR] =1.02 for each 1-year increase in age, 95% CI = 1.01–1.04, P = .007) and Eastern Cooperative Oncology Group performance status ≥ 2 vs 0 or 1 (OR = 2.76, 95% CI = 1.42–5.37, P = .006).

Among the response-evaluable patients, overall and complete response rates during the entire study period were 25.1% (95% CI = 23.3%–26.8%) and 14.7% (95% CI = 13.3%–16.2%), respectively. Significant increases in both overall response rate and complete response rate were observed over time. Overall response rates were 18.5% in 2000 to 2005, 25.9% in 2006 to 2012, and 50.6% in 2013 to 2019 (P < .001). Complete response rates were 10.5%, 17.3%, and 26.0% during the respective time periods (P = .001).

Over the entire study period, overall response rates were 20.2% in patients with acute myeloid leukemia, 9.1% in those with myelodysplastic syndrome, 43.2% in those with lymphoma, 42.9% in those with chronic lymphocytic leukemia, 15.1% in those with acute lymphoblastic leukemia, and 16.5% in those with myeloma.

The investigators concluded, “Over time, the overall response rates and complete response rates in phase I trials for hematologic malignancy have improved meaningfully, whereas the rate of toxicity-related death remains stable. This study provides broad experience that physicians can use when discussing the potential outcomes for patients with hematologic malignancy considering participation in phase I trials.”

Dai Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Intramural Research Program of the National Cancer Institute, National Institutes of Health. For full disclosures of the study authors, visit

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