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.

Table 1

SPMs in adult ALL

SPMNExpectedO/ECI lowerCI upperPERMean age at event, y
All sites 39 27.36 1.43* 1.01 1.95 .04 18.63 61.98 
All sites excluding nonmelanoma skin 39 27.25 1.43* 1.02 1.96 .04 18.81 61.98 
All solid tumors 30 24.31 1.23 0.83 1.76 .3 9.1 64.78 
 Oral cavity and pharynx 0.69 1.46 0.04 8.11 0.5 55.25 
 Digestive system 4.82 1.25 0.46 2.71 .7 1.89 77.38 
 Lung and bronchus 3.25 2.77* 1.27 5.26 .01 9.2 66.62 
 Breast 3.65 1.37 0.44 3.2 .6 2.16 66.52 
 Male genital system 5.3 0.38 0.05 1.36 .2 −5.29 63.13 
 Urinary system 2.51 0.81 5.85 .1 4.81 61.27 
 Brain and other nervous system 0.41 2.47 0.06 13.74 .6 0.95 33 
Hematologic malignancies 2.44 3.28* 1.42 6.47 <.01 8.9 48.94 
 AML 0.21 28.48* 10.45 61.98 <.001 9.26 49.63 
SPMNExpectedO/ECI lowerCI upperPERMean age at event, y
All sites 39 27.36 1.43* 1.01 1.95 .04 18.63 61.98 
All sites excluding nonmelanoma skin 39 27.25 1.43* 1.02 1.96 .04 18.81 61.98 
All solid tumors 30 24.31 1.23 0.83 1.76 .3 9.1 64.78 
 Oral cavity and pharynx 0.69 1.46 0.04 8.11 0.5 55.25 
 Digestive system 4.82 1.25 0.46 2.71 .7 1.89 77.38 
 Lung and bronchus 3.25 2.77* 1.27 5.26 .01 9.2 66.62 
 Breast 3.65 1.37 0.44 3.2 .6 2.16 66.52 
 Male genital system 5.3 0.38 0.05 1.36 .2 −5.29 63.13 
 Urinary system 2.51 0.81 5.85 .1 4.81 61.27 
 Brain and other nervous system 0.41 2.47 0.06 13.74 .6 0.95 33 
Hematologic malignancies 2.44 3.28* 1.42 6.47 <.01 8.9 48.94 
 AML 0.21 28.48* 10.45 61.98 <.001 9.26 49.63 

Totals: persons, 2168; PY, 6249.31; mean age at exposure, 41.66. CIs are 95%.

AML, acute myeloid leukemia; ER, excess risk per 10 000; N, observed number of SPMs.

*

P < .05.

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.

Authorship

Acknowledgment: The authors thank Dr Katrina Rolen for critical review and editing of the manuscript.

Contribution: K.B.G. designed the study, analyzed data, and wrote the manuscript; and B.K.S. was responsible for the research concept, design of the research, analysis of data, and writing the manuscript.

Conflict-of-interest disclosure: B.K.S. owns stock in Pharmacyclics and is a member of the Speaker Bureau of Teva Pharmaceuticals. K.B.G. declares no competing financial interests.

Correspondence: Dr Binay Kumar Shah, 1250 Idaho St, Lewiston, ID 83501; e-mail: binay.shah@gmail.com.

References

1
Jabbour
 
EJ
Faderl
 
S
Kantarjian
 
HM
Adult acute lymphoblastic leukemia.
Mayo Clin Proc
2005
, vol. 
80
 
11
(pg. 
1517
-
1527
)
2
Schmiegelow
 
K
Levinsen
 
MF
Attarbaschi
 
A
, et al. 
Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia.
J Clin Oncol
2013
, vol. 
31
 
19
(pg. 
2469
-
2476
)
3
Neglia
 
JP
Meadows
 
AT
Robison
 
LL
, et al. 
Second neoplasms after acute lymphoblastic leukemia in childhood.
N Engl J Med
1991
, vol. 
325
 
19
(pg. 
1330
-
1336
)
4
Warren
 
S
Gates
 
O
Multiple primary malignant tumors: a survey of the literature and a statistical study.
Cancer
1932
, vol. 
16
 (pg. 
1358
-
1414
)
5
Curtis
 
RE
Ries
 
LA
Curtis
 
RE
Freedman
 
DM
Ron
 
E
, et al. 
Methods.
New Malignancies among Cancer Survivors: SEER Cancer Registries, 1973–2000
2006
Bethesda, MD
National Cancer Institute
(pg. 
9
-
14
)
6
Siegel
 
R
DeSantis
 
C
Virgo
 
K
, et al. 
Cancer treatment and survivorship statistics, 2012.
CA Cancer J Clin
2012
, vol. 
62
 
4
(pg. 
220
-
241
)
7
Ghimire
 
KB
Shah
 
BK
Second primary malignancies in adult acute myeloid leukemia—a US population-based study.
Anticancer Res
2014
, vol. 
34
 
7
(pg. 
3855
-
3859
)
8
Shah
 
BK
Ghimire
 
KB
Second primary malignancies in chronic myeloid leukemia [published online January 23, 2014].
Indian J Hematol Blood Transfusion
 
doi:10.1007/s12288-013-0328-2
9
Hijiya
 
N
Hudson
 
MM
Lensing
 
S
, et al. 
Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia.
JAMA
2007
, vol. 
297
 
11
(pg. 
1207
-
1215
)
10
Bhatia
 
S
Sather
 
HN
Pabustan
 
OB
Trigg
 
ME
Gaynon
 
PS
Robison
 
LL
Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983.
Blood
2002
, vol. 
99
 
12
(pg. 
4257
-
4264
)