Chronic Myeloid Leukemia After Adjuvant Treatment For Breast Cancer: Is It Therapy Related?
Authors: Kishtagari Ashwin , Bowman Isaac Alexander , Tallman Martin S. , Douer Dan , Berman Ellin , Maslak Peter G. , Brentjens Renier J , Stein Eytan M 
Published: October 2019

Abstract
Chronic Myeloid Leukemia (CML) is a rare myeloid neoplasm with an age-adjusted incidence of 1.6 per 100,000 people in the United States (http://seer.cancer.gov/statfacts/html/cmyl.html). Despite the understanding of the pathogenesis of CML – the fusion of BCR-ABL leading to a constitutively activated tyrosine kinase – underlying events that lead to a 9;22 translocation are incompletely elucidated. Although CML was the most common leukemia seen among survivors of Hiroshima and Nagasaki, other causative factors are not well defined.
There is a known association between exposure to radiation and/or cytotoxic chemotherapy and therapy-related acute myeloid leukemia (t-AML). This relationship is best described after adjuvant treatment for breast cancer (BC), but has also been reported in patients treated for lymphoma, testicular cancer and colorectal cancer. Based on a number of patients we have seen at Memorial Sloan-Kettering Cancer Center with CML who had prior adjuvant treatment for BC, we hypothesized that a subset of patients with CML have therapy-related disease and the acquisition of a 9;22 translocation may be related to prior exposure to cytotoxic chemotherapy and/or radiation.
Using ICD-9 codes for BC, we queried the Memorial Sloan-Kettering institutional database from 1983-2012 to search for patients who had a co-occurring diagnosis of CML, as defined by a bone marrow aspirate or biopsy that was morphologically consistent with CML and either a cytogenetic report that confirmed a 9;22 translocation and/or a BCR-ABL p210 fusion transcript. Charts of patients identified in the institutional database were individually reviewed to confirm their eligibility for this retrospective study.
In total, 15 patients who developed a diagnosis of CML after adjuvant treatment of BC were identified (table 1). Of those identified, all had received prior adjuvant chemotherapy (n=11), prior adjuvant radiation (n=12) or both (n=15). The cumulative doses of anthracycline and alkylating agents are detailed in table 1. The interval between the adjuvant treatment of breast cancer and CML was 4.7 years. Patients diagnosed with CML after treatment of BC tended to be younger than those with CML diagnosed in the general population (50.47 years vs. 64 years) and were overwhelmingly Caucasian. All patients were diagnosed in chronic phase and none of the patients had an additional cytogenetic abnormality. The cumulative incidence of CML was markedly higher than in the general population; while 78,000 unique patients with BC were seen at MSKCC between 1985 and 2012, 15 patients subsequently received a diagnosis of CML. This incidence is considerably greater than the age-adjusted incidence of 1.6 per 100,000 in the United States population.Table 1Patient CharacteristicsTotal15At time of Breast Cancer DiagnosisMedian Age (years)*46.59 (38-73)Race Caucasian13Asian2 African-American0Adjuvant Chemotherapy11 Anthracycline (n)5  Cumulative dose*240 mg/m2 Alkylator (n)10  Cumulative Dose*4800mg/m2Adjuvant Radiation12At time of CML DiagnosisMedian Age (years)*50.42Interval - Breast Ca and CML (years)*4.7 (1.2-18.8)White count at presentation*31 (24-188)Hgb at presentation*12.5 (7.9 – 14.1)Platelets at presentation*397 (185-1082)Initial Treatment Imatinib13 Dasatinib or Nilotinib0 Other2#*Median (range)#One patient received hydrea and one received an allogeneic stem cell transplant
To our knowledge, our data represent the first comprehensive description of CML after adjuvant treatment of BC. The markedly elevated incidence of CML after receipt of adjuvant chemotherapy and/or radiation for BC as compared to the general US population suggests that this entity might be classified as a therapy-related leukemia. The exact pathogenesis of CML after adjuvant treatment for BC and reason patients more commonly develop t-AML requires further investigation. Given the remarkable efficacy of tyrosine kinase inhibitors in preventing progression to accelerated or blastic phase disease, the practicing oncologist focused in breast cancer should consider a diagnosis of t-CML in any BC patient, previously treated with adjuvant chemotherapy or radiation, who presents with an elevated white blood count.