Atallah and colleagues point out a significant problem for investigators taking part in clinical trials on acute leukemias: they state that “the standards of reporting adverse events required by the regulatory authorities are, in general, not appropriate in this context.”
The authors analyze the incidence of baseline events considered to be grade 3 or 4 by the National Cancer Institute's Cancer Therapy Evaluation Program (NCI-CTEP) criteria version (Common Terminology Criteria for Adverse Events [CTCAE] v3.0), and also analyze what can be expected from standard chemotherapy by reviewing 1543 acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) patients observed at M. D. Anderson Cancer Center who received various “standard” treatments during a 16-year period. They demonstrate that at baseline, about 50% of these patients already had hemoglobin, platelet, and white blood cell levels that would be considered grade 3 or 4 toxicity by NCI-CTEP criteria. Moreover, during induction chemotherapy, the percentage of patients with grade 3 or 4 toxicity for these factors increased to 65%, 72%, and 91%, respectively. Furthermore, febrile episodes noted in 36% of patients at baseline occurred in 94% of patients following initiation of chemotherapy, and in 64%, they were due to documented infections. Finally, admission to the intensive care unit was needed for 9% of patients at diagnosis, but was required for 28% during induction chemotherapy. As expected, the rates of nonhematologic grade 3 or 4 toxicities were significantly higher in older patients. Following the current NCI-CTEP guidelines, “serious adverse events” in this cohort of patients would have to be reported before starting any therapy in over 50% of patients, and upon therapy in over 90% of patients. These rates of serious adverse events in patients with acute leukemias upon chemotherapy far exceed those observed in solid tumors; as a consequence, the authors propose a new adverse-event–reporting policy for clinical leukemia studies.
It is hard to argue with the data reported by the authors. At diagnosis, a high proportion of patients with acute leukemia invariably present with severe myelosuppression and cytopenias, and may have infections that require hospitalization and affect organ function. During induction chemotherapy, these pre-existing complications are expected to worsen if effective treatment is given. Despite that, the regulatory authorities have required similar reporting criteria as in solid tumors for studies evaluating the toxicities of new agents or regimens in acute leukemias. As a consequence, the pre-existing complications or expected events frequently observed in acute leukemias are often required by these authorities to be reported as adverse or serious adverse events, overburdening investigators and institutions with unnecessary documentation.
This report is very important because it deals with one of the essential problems in clinical studies evaluating the toxicities of new agents or regimens in the setting of acute leukemias, and it comes at a time when clinical trials are becoming more difficult to set up. For the first time, a qualified group of investigators propose that the standard approach to reporting adverse events in this setting should be modified. The proposal suggested by these investigators should be considered as a starting point for initiating discussions that will be beneficial to all parties involved in clinical studies.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
