Is There an Increased Risk of ALL in Patients with First Cancers Treated with Radiotherapy and/or Chemotherapy?
Authors: Molenaar Remco J , Radivoyevitch Tomas , Gerds Aaron T. , Nazha Aziz , Carraway Hetty E. , Advani Anjali S. , Kalaycio Matt , Majhail Navneet S. , Maciejewski Jaroslaw P. , Sekeres Mikkael A. , Mukherjee Sudipto 
Published: October 2019

Abstract
Background
External-beam radiotherapy (RT) and chemotherapy (CT) are commonly used modalities in cancer therapy and have been associated with increased risk of second hematological malignancies, especially myeloid neoplasms. Acute lymphoblastic leukemia (ALL) is typically not considered a treatment-related complication and the risk of ALL in patients treated with chemotherapy and radiation for other cancers is poorly defined. In this study, we interrogated the US Surveillance Epidemiology and End Results (SEER) registry to analyze the risks of ALL in cancer patients treated with RT, CT or combined modality regimens at the population level.
Methods
We used our previously validated R program, SEERaBomb (Leukemia 2016; 30: 285-94) to query all 18 SEER registries, 1973-2014. We identified all first cancer cases treated with RT and/or CT that subsequently developed ALL ≥1 year after diagnosis of the first cancer. First cancer cases of lymphoid lineage were excluded. Diagnosis was derived from the International Classification of Diseases. Relative risk (RR) time courses for developing ALL after treatment of first cancers was calculated based on the ratio of the observed and expected cases of ALL. The expected number of ALL patients was calculated using the background incidence rates of ALL in the US population and the person-years at risk for ALL after treatment of first cancer. RRs were adjusted for age at diagnosis, sex, and year of diagnosis. Multivariate Cox regression analyses were used to calculate hazards of ALL development to adjust for more covariates.
Results
In total, 4,851,222 eligible first cancer patients were identified, of whom 821,004 (17%) received RT only, 571,035 (12%) received CT only, 488,930 (10%) received RT + CT and 2,970,253 (61%) received neither. A total of 849 patients developed ALL; 176 (21%) in the RT only group, 137 (16%) in the CT only group, 106 (12%) in the RT + CT group and 430 (51%) in the no RT/CT group. Compared to the risk in general population, patients treated with CT or RT had an elevated risk of developing ALL in the first 10 years after first cancer diagnosis (RR for RT only, 1.59 [95% CI 1.33-1.88] P < 0.0001; RR for CT only, 3.47 [2.87-4.16] P < 0.0001; RR for CT + RT, 3.22 [2.69-3.97] P < 0.0001). Patients with prior cancers but not treated with these modalities had no increased risks for ALL (RR for no RT/CT, 1.05 [0.93-1.17] P = 0.44; see Figure). In a more homogeneous cohort of breast cancer patients, elevated risks of developing ALL in the first 10 years after breast cancer diagnosis were seen in patients treated with CT + RT (RR, 3.46 [2.46-4.73] P < 0.0001) or RT only (RR, 1.82 [1.33-2.43] P = 0.0001) but not in those treated with CT only (RR, 1.76 [0.98-2.89] P = 0.06) or no CT/RT (RR, 0.77 [0.53-1.07] P = 0.15).
In multivariate regression analyses in the entire cohort of cancer patients, significant predictors for subsequent ALL were younger age at diagnosis, male sex, receipt of CT or RT and if a non-lymphoid hematological malignancy preceded development of ALL (Table 1). Among patients with solid tumors as first cancers, CT + RT was associated with the highest hazards for developing ALL followed by RT only and then CT. Among patients with hematological first cancers, CT only, but not CT + RT or RT only, was associated with increased hazards for ALL.
Conclusion
Among patients treated for a first cancer, receipt of RT and/or CT was associated with higher relative risks and hazards for developing ALL than those not receiving cytotoxic modalities. Patients with hematologic first cancers (myeloid lineage or plasma cell dyscrasias) had the highest hazards of developing ALL as second cancer. When considering the risk kinetics and subgroup analyses in patients with solid first cancers, RT only or RT + CT, but not CT only, associate with increased risks for ALL. To our knowledge this is the largest evaluation of the risk of ALL in cancer patients treated with various modalities. Differentially elevated risks of ALL observed in cancer cohorts based on the treatment modality that was received for a prior cancer suggests a possible biological mechanism that needs to be explored further.

Disclosures
Gerds: Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy. Nazha:MEI: Consultancy. Carraway:Jazz: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; FibroGen: Consultancy; Novartis: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.