FROM THE JOURNAL OF CLINICAL ONCOLOGY
Among children with de novo acute myeloid leukemia, shorter telomere length at the end of induction chemotherapy predicted delayed bone marrow recovery in later courses, according to a study of 115 patients published online in the Journal of Clinical Oncology.
“This association was not related to differences in host factors, telomere maintenance gene variants, AML disease characteristics, or therapeutic exposures,” wrote Robert Gerbing of Children’s Oncology Group (Monrovia, Calif.), and his associates. “If validated in a larger cohort, prospective ascertainment of telomere length at end of AML induction may permit individualized risk assessment for severe myelosuppression and toxicities with subsequent therapy, as well as clarify the influence of age and cytogenetic or molecular disease characteristics.”
Acute myeloid leukemia comprises about one in five childhood leukemias and requires intensive treatment that has led to mortality in up to 19% of patients, the researchers noted ( Blood 2008 Feb 1;111:1044-53 ).
“Prolonged, profound neutropenia is a well recognized risk factor for sepsis and invasive fungal infections, both major contributors to treatment-related mortality,” they added. In nonleukemic hematopoietic cells, telomere length is a “quantifiable host factor that may indicate potential risk for impaired bone marrow recovery after chemotherapy,” they wrote (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2016.67.3467 ).
To test this hypothesis, the researchers analyzed paired diagnostic and remission bone marrow samples for 115 children with de novo AML enrolled in a Children’s Oncology Group protocol (AAML0531) that involved five chemotherapy courses. After each course, 62 patients reached absolute neutrophil count (ANC) recovery (500 cells/mcL) within the expected time frame, meaning that the recovery time was always less than one standard deviation of the group average. The remaining 53 patients had significantly delayed ANC recovery, meaning that they exceeded the group average by at least one standard deviation after at least two courses of chemotherapy.
The study size was adequate to detect a 0.2-unit difference in average telomere length between the two groups, the investigators noted. To measure telomere length, they estimated telomere content based on quantitative polymerase chain reaction (PCR) of bone marrow samples taken after induction chemotherapy. Then they compared patients who fell within the lowest quartile of telomere content to those in quartiles 2 through 4.
Telomere content was not associated with days to ANC recovery after the first three chemotherapy courses. After the fourth and fifth courses (intensifications two and three), patients had longer ANC recovery times than during the first three courses (mean, 45.2 days for intensification two and 43.7 days for intensification three). But patients with the shortest telomeres (that is, the patients in telomere content quartile 1) had significantly longer average ANC recovery times compared with patients in telomere content quartiles 2 through 4, both for intensifications two (P less than .001) and three (P = .002).
“Analysis of individual quartiles confirmed the association between less telomere content in quartile 1 and delays in ANC recovery,” the investigators noted. After they accounted for age at diagnosis, short telomere length remained a significant predictor of delayed ANC recovery after the fourth (P = .002) and fifth (P = .009) courses. Finally, DNA sequencing revealed evidence of telomere biology disorders, the investigators said.
The work was supported by an Alex’s Lemonade Stand Young Investigators Award, by a St. Baldrick’s Foundation Scholar Award, and by the National Institutes of Health. Mr. Gerbing and senior author Maria Gramatges, MD, had no disclosures. Two coinvestigators disclosed ties to Pfizer, Novartis, Dexcom, and several other pharmaceutical companies.