Survival and risk of second primary malignancies in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors: A retrospective US population-level analysis Free

The introduction of tyrosine kinase inhibitors (TKIs) has significantly increased the survival of patients (pts) with chronic myeloid leukemia (CML). With a growing population of long-term CML survivors, there are now questions about the durability of improved survival rates and potential carcinogenicity with prolonged TKI therapy. In this study, we examined the impact of TKIs on survival rates and the risk of developing second primary malignancies (SPMs) in CML pts by comparing cohorts from the pre-TKI era (1975-2000) and the post-TKI era (2001-2021).

We queried two Surveillance, Epidemiology and End Results (SEER) registries – SEER 8 (1975-2021) and SEER 17 (2001-2021) and identified three CML cohorts – pre-TKI cohort [SEER8, 1975-2000] and two post-TKI cohorts [post-TKI cohort 1 – SEER8, 2001-2020, and post-TKI cohort 2 – SEER 17, 2001-2020]. We selected post-TKI cohort 2, particularly for SPM and CI analyses, considering it has a greater number of CML pts (3-fold more than cohort 1), which would allow for more precise risk estimates. Inclusion criteria included pts ≥15 years (yrs) with CML as the index cancer who subsequently developed a SPM ≥1 yr after CML diagnosis. All third and higher-order cancers were excluded. SPMs excluded all leukemias except chronic lymphocytic leukemia (CLL). All cancers were identified using ICD-O-3/WHO-2008 diagnostic codes. Kaplan-Meier survival estimates stratified by 3 age cohorts [age 15-39 yrs; 40-59 yrs and ≥60 yrs] were generated with survival time calculated from CML diagnosis to date of death, follow-up cutoff date of Dec 31, 2020, or the date of last known follow-up, whichever occurred first. Differences in survival between groups were assessed using the log-rank test. The risk for development of SPM was estimated by standardized incidence ratios (SIRs), defined as the ratio of observed number of SPM in the CML population to the expected number of cases in the general US population adjusted for age, sex, race, and calendar year, using SEER*Stat software (version 8.4.5). As small case numbers can lead to unstable SPM estimates, only those SPM sites with ≥20 cases were included for SIR analysis. Cumulative incidence (CI) for development of SPM was calculated using Fine-Gray competing risk regression analyses with death as a competing risk. All analyses were conducted in R version 4.2.2 and SAS 9.4.

We observed continued significant improvement in 10-yr survival rates in CML pts across successive calendar periods of CML diagnosis – 8.76% (95% CI: 7.42%-10.34%) in 1975-84, 17.05% (95% CI: 15.35%-18.94%) in 1985-94, 54.1% (95% CI: 52.48%-55.77%) in 1995-04, and 68.59% (95% CI: 67.54%-69.66%) in 2005-14. After 2014, the survival rates stabilized. The largest improvement in 10-year survival was observed in the 15-39 yr age group (from 17.04% in 1975-84 to 87.26% in 2005-14), and the least in the ≥60 yrs (from 3.92% in 1975-84 to 46.17% in 2005-14). The incidence rates of SPMs were comparable across pre-TKI and post-TKI cohorts –1070.9 (95% CI: 947.9,1209.4) cases per 100,000 person-yrs in the pre-TKI cohort; 927.1 cases (95% CI: 826.4,1039.8) per 100,000 person-yrs in the post-TKI cohort 1 and 978.9 cases (95% CI: 920.5,1041.0) per 100,000 person-yrs for the post-TKI cohort 2. Among the CML pts who developed SPM in each cohort, the median time to development of SPM in the pre-TKI cohort was 5.88 yrs (Interquartile range (IQR): 2.48-13.37), 5.17 yrs (IQR: 2.5-8.42) in post-TKI cohort 1, and 4.92 yrs (IQR: 2.5-8.92) in post-TKI cohort 2. CI rates revealed a significant increase in SPM incidence in the post-TKI era compared to the pre-TKI era (p<0.0001). For the pre-TKI cohort, the 10-yr CI of SPMs was 4.3% (95% CI: 3.7%-4.9%) and stabilized thereafter. In post-TKI cohort 2, the 10-yr CI was 7% (95% CI: 6.5%-7.5%), reaching 12.1% (95% CI: 11.1%-13.1%) at 20 yrs. SIR rates were significantly increased for ear, nose and throat cancers in the pre-TKI cohort [2.32, 95% CI: 1.47-3.48] and for CLL in the post-TKI cohort 2 [1.98, 95% CI: 1.29-2.9].

Survival of CML pts showed a significant increase over successive 10-year calendar periods from 1975 to 2014, but thereafter stabilized. We noted a small but significant increase in the CI of SPM in CML pts in the post-TKI era. However, no excess risk of SPM was observed in the post-TKI era when compared to the matched general population, except for CLL – an observation which requires further investigation.