Clonal Hematopoiesis Increases Risk of Therapy-related Myeloid Malignancies
Clonal hematopoiesis at the time of primary cancer diagnosis was associated with a significantly increased risk of therapy-related myeloid neoplasm development.
SAN DIEGO – Among patients with lymphoma who received frontline chemotherapy, clonal hematopoiesis at the time of primary cancer diagnosis was associated with a significantly increased risk of therapy-related myeloid neoplasm development, according to a study presented at the American Society of Hematology (ASH) 58th Annual Meeting and Exposition.1
"Five percent of patients develop therapy-related myeloid neoplasm after chemotherapy/radiotherapy," said Koichi Takahashi, MD, of the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas. "These malignancies have a median overall survival of 8 months and 5-year overall survival rate of less than 10%."
To determine whether patients with clonal hematopoiesis have a higher risk for developing therapy-related myeloid neoplasms, researchers performed targeted capture sequencing on 14 patients with therapy-related myeloid neoplasm bone marrow samples.
Results revealed 29 driver mutations in 17 genes in 13 patients, with the most common being TP53 mutations in 36%. Among those, 21 mutations were detectable as pre-leukemic clonal hematopoiesis in the peripheral blood samples of 10 patients.
Researchers also found that the variant allele frequency was significantly higher in the mutations that became drivers (8.5%) than in those that did not become driver mutations (1.2%; P < .001).
"The risk of therapy-related myeloid neoplasms may be affected by variant allele frequency and the mutation of clonal hematopoiesis," noted Dr Takahashi.
Compared with a control cohort of 54 patients with lymphoma who did not develop therapy-related myeloid neoplasms after treatment, researchers found that at 5 years, 30% (95% CI, 16-51) of patients with clonal hematopoiesis at the time of diagnosis had developed therapy-related myeloid neoplasms compared with 7% (95% CI, 2-21) of those without (P = .016).
The investigators then validated the association between clonal hematopoiesis and therapy-related myeloid neoplasms in a separate cohort of 74 patients with lymphoma who received frontline CHOP-based therapy. Similar to the case-control study, 29% (95% CI, 8-53) of patients with clonal hematopoiesis developed therapy-related myeloid neoplasms at 10 years vs 0% (95% CI, 0-0) of those without (P = .0009).
The positive predictive value and negative predictive value of clonal hematopoiesis was 26.7% (95% CI, 7.8-55.1) and 98.3% (95% CI, 90.9-99.9), respectively. Multivariate analyses revealed that clonal hematopoiesis (P = .013) and autologous hematopoietic cell transplantation (P = .043) increased the risk of therapy-related myeloid neoplasms.
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"Our data provide proof of concept to use clonal hematopoiesis as a marker for prediction, early detection, and surveillance for therapy-related myeloid neoplasms," Dr Takahashi concluded. "Risk stratification of clonal hematopoiesis is needed to define clinically relevant clonal hematopoiesis."
- Takahashi K, Wang F, Kantarjian HM, et al. Clonal hematopoiesis increases risk of therapy-related myeloid neoplasms. Paper presented at: American Society of Hematology (ASH) 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.