Second primary malignancies in adult acute lymphoblastic leukemia: a US population–based study

To the editor:

Acute lymphoblastic leukemia (ALL) accounts for one-fifth of leukemia in adults.¹  The rates of second primary malignancies (SPMs) in childhood ALL are significantly higher than in the general population.^2,3  However, there is a lack of information on SPMs in adult patients. Therefore, we conducted this study to analyze the risk of SPMs in adult ALL patients from the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) database.

We selected adult ALL patients (aged ≥18 years) coded as “Acute lymphocytic leukemia” diagnosed during January 1992 to December 2006 from the SEER 13 database. We excluded cases diagnosed at autopsy and only with death certificate, and those that did not have follow-up after diagnosis. Using the Warren and Gates criteria⁴  as modified by NCI,⁵  SPM was defined as a metachronous malignancy developing ≥6 months after an index ALL.

We used SEER*Stat software (version 8.0.4, April 15, 2013) to calculate standardized incidence ratio (SIR), excess risk, and confidence interval (CI) of SPM in patients with ALL. Expected SPM was calculated for a reference SEER cohort of identical age, gender, and time period.

SIR, also known as relative risk, is a relative measure of the strength of association between 2 cancers. Absolute excess risk (AER) is an absolute measure of the clinical burden of additional cancer occurrences in a given population. It measures the actual number of excess events normalized to the number of person-years (PY) observed: AER = (observed − expected)/PY.

A total of 2168 adult patients (median age 38 years, range: 18-93 years) with ALL diagnosed with primary ALL met the inclusion criteria. Among them, 643 (29.66%) patients had received cranial irradiation. Median follow-up time was 6.41 years (range, 6 months to 14.21 years). Median age at the time of diagnosis of all SPMs was 66.66 years (range, 21.5-91.25 years). A total of 35 (1.6%) patients developed 39 SPMs, an observed/expected (O/E) ratio of 1.43 (CI, 1.01-1.95; P = .04), and an AER of 18.63 per 10 000 population (see Table 1). Median age of the patients who developed SPM was 57 years (range, 18-87 years). There was a significantly higher risk of lung and bronchial tumors and hematologic malignancies (6 acute myeloid leukemia [AML] and 2 non-Hodgkin lymphoma cases). AML was increased (O/E = 36.25; CI, 11.77-84.6; P < .001) within the first 5 years after ALL diagnosis. Lung and bronchial malignancies were significantly increased (O/E = 5.52; CI 2.03-12.02; P = .002) after 5 years of latency.

Younger patients (age 18-59 years) had increased risk of AML (cases, 5; O/E = 43.82; 95% CI, 14.23-102.27; P < .001; AER, 8.7 per 10 000 population) and cancer of lung and bronchus (cases, 5; O/E = 4.04; 95% CI, 1.31-9.42; P = .02; AER, 6.68 per 10 000 population). Older patients (≥60 years) were at higher risk of female breast cancer after 5 years of diagnosis of ALL (cases, 3; O/E = 9.31; 95% CI, 1.92-27.20; P < .01; AER, 179.16 per 10 000 population).

Because of earlier detection of malignancies and improvement in the treatment, the number of cancer survivors is increasing and is expected to reach 18 million by 2022.⁶  The cancer survivors are at risk of several long-term complications including secondary malignancies.^7,8 

A retrospective study showed increase in cumulative incidence of SPMs over 30 years after treatment of childhood ALL.⁹  The majority of late-occurring SPMs were low-grade tumors. In a cohort of 8831 pediatric ALL patients enrolled in Children’s Cancer Group therapeutic protocols from 1983 to 1995, the cumulative incidence of SPMs was 1.18% at 10 years, more than a sevenfold increased risk compared with that of the general population.¹⁰ 

Our study is the first to report SPMs in adult ALL patients. We found a 43% relative increase in SPMs in ALL patients (O/E = 1.43; 95% CI, 1.01-1.95) compared with the general population. The risk of specific SPM depends on the patient’s age and the latency period. Cancer-specific screening during follow-up of ALL survivors may help diagnose the SPM at an earlier stage.

The strengths of our study include the large number of patients with long-term follow-up from a large geographic area. There are several limitations. The SEER database does not have information on the chemotherapy used, comorbid conditions, social habits, exposure to carcinogens, or family history.