FROM LANCET ONCOLOGY
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote ( Lancet Oncol 2017; 18: 100–11 ).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues ( Lancet Oncol 2017; 18:112-21 ).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.