Risk of therapy-related acute lymphoblastic leukemia (t-ALL) in cancer patients secondary to either chemotherapy, radiation, or both: A retrospective cohort study from 1975-2021 using SEER registry Free

Background:

The incidence of therapy-related leukemias is exponentially increasing with the widespread use of chemotherapy (CTX) and radiation (RT). Therapy-related Acute Lymphoblastic Leukemia (t-ALL) is a separate entity from de novo ALL. t-ALL is secondary to cytotoxic therapies used to treat a different primary malignancy. Despite its equal incidence to other therapy-related myeloid malignancies [therapy-related Acute Myeloid Leukemia (t-AML) and therapy-related MDS (t-MDS)], t-ALL is not yet recognized as a distinct entity in the WHO classification. In this retrospective cohort study from 1975-2021, we emphasize various factors associated with the occurrence of t-ALL.

Methods:

We included patients aged 18 to 84 years whose first primary malignancy was other than leukemia diagnosed between 1975-2021 from 8 SEER registries. We then identified ALL occurring as secondary cancer after treatment with either CTX, RT, or both.

Standardized incidence ratios (SIRs) were calculated as the ratio of the observed-to-expected (O/E) number of ALL. The expected number of ALL was computed from age, race, sex, and calendar year–specific incidence rates of ALL from the general SEER population, multiplied by the appropriate person-years at risk. We calculated

Poisson-based 95% confidence intervals (CIs) about the SIRs. We also computed the excess absolute risk (EAR) [(O-E)*10,000/person-years at risk] to estimate the number of excess cancers beyond that expected per 10,000 persons per year.

For the first primary sites with at least 20 secondary ALL cases, we conducted multivariate Poisson regression analyses comparing SIR. P-trend and p-homogeneity were adjusted by the age group, race, sex, receipt of the initial CTX +/- RT, and latency to t-ALL to compare the SIR between different calendar year groups.

Cox regression was performed to assess the hazard of developing secondary acute lymphoblastic leukemia (ALL), both in univariate and multivariate analyses, by cancer site. Final multivariable models were constructed using a backward selection procedure basedon a p-value threshold. Overall survival (OS) was estimated using the Kaplan–Meier method, with interval estimates reported. Differences in survival were evaluated using the log-rank test and corresponding p-values were reported.

Results:

A total of 435 cases were identified with t-ALL as secondary to CTX +/- RT. There was a 1.5-fold increased risk of t-ALL as compared to the general population (95% CI 1.29-1.56). Only primary cancers with at least 20 cases of secondary ALL were considered for further analysis. Of all primary sites, ALL was most commonly seen in genitourinary, breast, lymphoma, colon & rectum, myeloma, female genital tract, and thyroid cancer. The highest risk for t-ALL was seen with Myeloma, which was 12-fold higher than the general population. (p<0.0001, 95% CI 8.67-18.34). The incidence of t-ALL secondary to Myeloma has been the highest since 1995 and is uptrending based on the year of diagnosis (1995-2004, 2014-2021). Most recent cohort 2014-2021 shows a statistically robust increase of 20 times higher incidence as compared to the general population (Ptrend<0.0001, Phom<0.0001). We further analyzed these t-ALL patients based on the treatment modalities received for their myeloma. The results were consistent with a low risk of t-ALL with RT alone up to ~40 years after treatment, whereas an equal increased incidence of t-ALL with CTX and CTX+RT from 5 to 15 years after initial therapy. The risk after 15 years increases with CTX alone and stays plateaued up to ~40 years after initial myeloma treatment (p = 0.019).

Conclusions:

In our retrospective cohort study from 1975-2021, we observed the most notable findings for the occurrence of ALL secondary to myeloma treatment with CTX +/- RT, with almost an 8 to 18-fold increase as compared to the general population. The incidence rate for t-ALL is also increasing with advances in myeloma treatment. The highest and the most longitudinal risk is seen with CTX alone, followed by CTX + RT, and lowest with radiation alone. The cumulative risk continues to remain high for t-ALL as long as 40 years after initial exposure to CTX. As the overall incidence of secondary ALL continues to peak, it is imperative to consider t-ALL as a distinct entity amongst the treated associated myeloid malignancies along with t-AML and t-MDS.