Clonal Hematopoiesis Predicts Patients Likely to Develop Therapy-Related Myeloid Neoplasms

Screening for clonal hematopoiesis at the time of cancer diagnosis could help identify patients with an increased risk of developing secondary, therapy-related myeloid neoplasms (t-MNs), according to research presented by Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.

The researchers also found that t-MNs can occur years after patients complete cancer treatment. “t-MNs are a problem that needs urgent attention,” Dr. Takahashi said during his presentation of the study results. “Since many cancer patients are now living longer, t-MNs are an increasing concern for many cancer survivors.” Results were also published in the Lancet Oncology.

This study included 14 patients with t-MNs who provided paired samples of bone marrow (BM) and peripheral blood (PB) at the time of t-MN diagnosis and the time of primary cancer diagnoses, respectively. After performing targeted capture sequencing on t-MN BM samples and molecular barcode deep sequencing on t-MN PB samples, the researchers detected pre-leukemic driver mutations or clonal hematopoiesis in 10 patients.

To determine whether the mutations could reliably predict the development of t-MNs, the researchers then compared the prevalence of clonal hematopoiesis in a control cohort of pre-treatment PB samples from 54 patients with lymphoma who did not develop t-MNs.
Targeted capture sequencing of the 14 t-MN BM samples revealed 29 driver mutations in 16 genes, including TP53 mutations in five patients (36%). Twenty-one of those mutations were detectable as pre-leukemic clonal hematopoiesis in the prior PB samples (e.g., at the time of diagnosis of the primary cancer diagnosis) of 10 patients (71%). There were also 12 mutations detected in prior PB samples that did not become drivers in t-MN BM. The median variant allele frequency (VAF) was significantly higher in the mutations that became drivers than in those mutations that did not (8.5% [range = 0.7-36.9%] vs. 1.2% [range = 0.1-7.6%]; p<0.001).

The researchers detected 22 mutations in the PB samples of 17 patients (31%) who did not develop t-MNs, but detected clonal hematopoiesis in 10 patients (71%) who developed t-MNs (p=0.0009). The rate of t-MN development at five years also was higher in patients with clonal hematopoiesis than in patients without (30% [95% CI 16-51] vs. 7% [95% CI 2-21]; p=0.015). Again, the median VAF of the mutations detected as clonal hematopoiesis was significantly higher in the t-MN cases than in the control cohort (2.4% [range = 0.1-37%] vs. 0.8% [range = 0.3-1.8%]; p=0.001).

The results were validated in a cohort of 74 patients with lymphoma who received frontline chemotherapy with a CHOP-based regimen (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone). Sequencing of pre-treatment PB samples detected 17 total mutations as clonal hematopoiesis in 15 patients (23%); during a median follow-up of 14.8 years, five patients (7%) developed t-MNs after a median of 5.4 years post-treatment.

Clonal hematopoiesis was detected in four of five patients (80%) who developed t-MNs and in 11 of 69 patients (16%) who did not (p=0.005). The rate of t-MN development at 10 years also was significantly higher in patients with clonal hematopoiesis, compared with patients without (29% [95% CI 12-59] vs. 0%; p=0.001).

Overall, the positive and negative predictive values of clonal hematopoiesis in the validation cohort were 26.7 percent (95% CI 7.8-55.1) and 98.3 percent (95% CI 90.9-99.9), respectively.

“Genetic mutations that are present in t-MN leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr. Takahashi added. “The data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs.”


References

  1. Takahashi K, Wang F, Kantarjian HM, et al. Clonal hematopoiesis increases risk of therapy-related myeloid neoplasms. Abstract #38. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.
  2. Takahashi K, Wang F, Kantarjian HM, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100-11.

SHARE