Introduction

High dose ionizing radiation and chemotherapy, particularly alkylating agents and topoisomerase II inhibitors, are well known causes of secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Similarly, radiation exposure has been linked to chronic myelogenous leukemia (CML) in large epidemiologic studies of atomic bomb survivors and patients who received high-dose radiation for ankylosing spondylitis and cervical cancer. Patients with secondary AML have poorer survival outcomes compared to de novo AML patients. Little information exists on outcomes of patients with secondary CML. In our study, we investigated treatment responses in patients with secondary CML who have been treated with tyrosine kinase inhibitors (TKIs).

Study Design

Eight patients who developed CML after receiving chemotherapy, radiation therapy or both were identified between three academic institutions. Retrospective chart review was performed, and information was collected regarding the clinical characteristics and treatment of the patients’ first malignancies. Data about the patients’ CML was also gathered, including time between previous malignancy treatment and diagnosis of CML and type of CML treatment. Finally, hematologic, cytogenetic, and molecular responses to treatment were assessed.

Results

The mean age of our patients at diagnosis of CML was 58. Three patients were previously diagnosed with breast cancer, two with colorectal cancer, one with peripheral T-cell lymphoma, one with chronic lymphocytic leukemia, and one with Waldenstrom’s macroglobulinemia. One of the patients with colorectal cancer also had a history of cervical cancer, for which she received radiation therapy. Six of eight patients (75%) received radiation therapy prior to onset of CML, and six of eight patients (75%) had previously received chemotherapy, two of whom received alkylating agents. On average, patients developed CML eight years after receiving treatment for the previous malignancy (range 3 to 18 years). All of the patients were diagnosed in chronic-phase CML. Based on the Sokal score, three patients (37.5%) had low risk CML, two (25%) had intermediate risk CML, one (12.5%) had high risk CML, and the Sokal score was unable to be calculated in two (25%) patients due to limited information.

Six of the eight patients (75%) received imatinib as initial therapy. Only two of these six patients (33%) achieved a complete cytogenetic response (CCyR). The patient who received up-front nilotinib was the only patient who developed molecularly undetectable leukemia to initial therapy. Seven of the eight patients (87.5%) were alive at a mean four year follow-up. One patient had CML with additional cytogenetic abnormalities at diagnosis and progressed to blast-phase.

Discussion

This case series is the first study to specifically examine outcomes in secondary CML patients treated with TKIs. The data raise questions regarding the efficacy of imatinib in patients with secondary CML. Only two of the six patients who received imatinib achieved a CCyR. This is a significantly lower response rate than would be expected in de novo CML. This study suggests a role for the newer tyrosine kinase inhibitors as initial therapy in patients with secondary CML. Larger observational studies are needed to confirm these findings.

Table 1
Patient Initial Malignancy Radiation therapy Chemotherapy Age at diagnosis of CML Initial Treatment Response to Initial Treatment Best Overall Response Current Tyrosine Kinase Inhibitor
1  Breast  Y  N  75  Imatinib  mCyR  MUL  Bosutinib  
2  Breast  Y  N  68  Imatinib  MMR  MUL  Nilotinib  
3€  Colon  N  Y  55  Imatinib  Progression to blast phase  None  None  
4£  Breast  Y  Y  42  Imatinib  CCyR  CCyR  Dasatinib  
5¥  Peripheral T-cell lymphoma  Y  Y  57  Imatinib  mCyRα  mCyR  Imatinib  
6  Waldenstrom’s  Y  Y  66  Imatinib  No response  No response  Nilotinib  
7  Colon and breast  Y  Y  51  Nilotinib  CMR  MUL  Nilotinib  
8  CLL  N  Y  53  Dasatinib  PCyR  PCyR  Dasatinib  
Patient Initial Malignancy Radiation therapy Chemotherapy Age at diagnosis of CML Initial Treatment Response to Initial Treatment Best Overall Response Current Tyrosine Kinase Inhibitor
1  Breast  Y  N  75  Imatinib  mCyR  MUL  Bosutinib  
2  Breast  Y  N  68  Imatinib  MMR  MUL  Nilotinib  
3€  Colon  N  Y  55  Imatinib  Progression to blast phase  None  None  
4£  Breast  Y  Y  42  Imatinib  CCyR  CCyR  Dasatinib  
5¥  Peripheral T-cell lymphoma  Y  Y  57  Imatinib  mCyRα  mCyR  Imatinib  
6  Waldenstrom’s  Y  Y  66  Imatinib  No response  No response  Nilotinib  
7  Colon and breast  Y  Y  51  Nilotinib  CMR  MUL  Nilotinib  
8  CLL  N  Y  53  Dasatinib  PCyR  PCyR  Dasatinib  

€Patient with multiple cytogenetic abnormalities and T315I mutation prior to availability of ponatinib

£Patient relapsed from not taking imatinib as directed

¥Follow-up less than 6 months

αInternational Scale (IS) ratio > 10

CCyR – complete cytogenetic response; mCyR – minor cytogenetic response; PCyR – partial cytogenetic response; CHR – complete hematologic response; CLL – chronic lymphocytic leukemia; MUL – molecularly undetectable leukemia

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
imatinib mesylate, leukemia, myelocytic, chronic, nilotinib, protein-tyrosine kinase inhibitor, cancer, chemotherapy regimen, radiation therapy, dasatinib, alkylating agents, blast phase

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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