Clonal Hematopoiesis Increases Risk of Therapy-related Myeloid Malignancies

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Clonal hematopoiesis at the time of primary cancer diagnosis was associated with a significantly increased risk of therapy-related myeloid neoplasm development.
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.

RELATED: FDA Grants Priority Review for Pembrolizumab in Treatment of Hodgkin Lymphoma

"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."

Reference

  1. 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.

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