Capecitabine Induced Therapy Related Acute Myeloblastic Leukemia with t(10;11) (q22;q23) in a Patient with Breast Cancer

Capecitabine is an oral agent that is used either as single agent or in combination therapy. Therapy related acute myeloblastic leukemia after capecitabine use is rarely reported. We presented a 39-year-old woman with metastatic breast cancer. She admitted with acute myelomonocytic leukemia after treating with oral Capecitabine. t(10;11)(q22;q23) was determined in conventional cytogenetic analysis. She achieved complete remission with intensive chemotherapy but relapse developed. She died although the salvage chemotherapy. To our knowledge our patients is the first report with t-AML with t(10;11)(q22;q23) secondary to Capecitabine use for breast cancer treatment. Capecitabine should be carefully used especially in patients with high risk for t-AML.


INTRODUCTION
Breast cancer is among the most frequent malignancy in females. The treatment of breast cancer rapidly developed, but the frequent cause of therapy related acute leukemia (t-AML) is still breast cancers (1). Cytotoxic chemotherapy is the main treatment of metastatic breast cancer. Capecitabine is a prodrug of Flourouracil (FU), which is an antimetabolite with activity against certain cancers including colorectal, metastatic breast, prostate, renal cell, ovarian, and pancreatic cancers (2). Capecitabine is converted to FU via thymidine phosphorylase that is found higher levels in tumor than healthy tissue. Cytotoxicity of FU results from both the incorporation into RNA or DNA and blockade of thymidine synthesis. The drug has FDA approvement more than 10 years. The toxicities of capecitabine are well known. Generally, the most frequent adverse effects of capecitabine are hyperbilirubinemia, diarrhea, nausea, hand-foot syndrome, and dermatitis. Hematological side effects of capecitabine including anemia, lymphopenia, neutropenia, and thrombocytopenia is well-known (2), however the leukemogenic effect of capecitabine was rarely reported (3)(4)(5)(6)(7). Here we present a patient with metastatic breast cancer and therapy related acute myeloblastic leukemia after capecitabine treatment.

CASE REPORT
A 39-year-old woman was diagnosed as breast cancer with bone metastasis (stage IV) at February 2010. Estrogen receptor and HER2/neu were positive, and progesterone receptor was negative. She was treated with transtuzumab, tamoxifen, leuprolid acetate and ibandronic acid. 21 months later, treatment was changed to lapatinib (1250 mg/day) and capecitabine (2000 mg/m 2 orally on day 1 through 14 of a 21-day cycle) and ibandronic acid due to progression of bone lesion. Capecitabine was stopped at June 2013 due to thrombocytopenia. She was admitted to hospital due to fatigue at September 2013. Complete blood count revealed that hemoglobin was 7.4g/dl, white blood cell was 105000/mm 3 , and platelet was 15000/mm 3 . Blast cells were seen in peripheral smear. Bone marrow aspiration and flow cytometry revealed acute myelomonocytic leukemia. CD13, CD33, CD34, CD117, MPO, CD64, and CD11b were positive. In bone marrow biopsy, reticulin fibrosis (grade 2/3) and tree-linage dysplasia were identified. Clonal 46XX, (10;11)(q22;q23) rearrangement was found in conventional cytogenetic analysis. JAK2 mutation and the rearrangements of BCR-ABL, PML-RARA, AML1, CBFß-MYH11 were negative. She achieved complete remission with intensive chemotherapy (idarubicine and cytarabine), four courses of consolidation chemotherapy with high dose cytarabine was given. 57 Case Report / Olgu Sunumu Letrozole was started due to metastatic bone lesion related to breast cancer. After 10 months of leukemia free survival, relapse was identified. FLAG-Ida salvage chemotherapy was administered, and partial remission was obtained. After, re-induction with FLAG-Ida regime percentage of blasts in the bone marrow increased markedly. She received best supportive care, but she died 18 months after the leukemia diagnosis.

DISCUSSION
t-AML is a well-known late complication of cancer therapy including chemotherapy, radiotherapy and immunosuppressive treatment (1,8). In the classic forms of t-AML, leukemia develops within 5-7 years following chemotherapy with alkylating agents such as melphalan and cyclophosphamide or radiotherapy. The other agents causing t-AML is topoisomerase-II inhibitors. Topisomerase-II inhibitors related t-AML occurs within 2-3 years and it is rapidly progressive with higher blast count, and it has poor prognosis inspite of the high response rate of induction therapy (1). Topoisomerase inhibitors related t-AML with is characterized by translocations involving MLL, PML-RARA or core binding factor (CBF) genes.
We documented the relationship between t(10; 11)(q22;23) and capecitabine induced t-AML. Clinical course and laboratory findings of our case were similar to t-AML related topoisomerase inhibitors. Leukemic manifestation occurred within 3 years after use of capecitabine, and blastic infiltration, tree-linage dysplasia with MLL gene abnormality was found.
After the first remission induction therapy complete remission was achieved, but leukemia free survival was quite short. The MLL gene was identified in 11q23 translocation, and various 11q23 translocations have been observed until now (1,8). There are limited information about AML with t(10; 11)(q22;q23) (9, 10), but the reports published recently showed that the t(10; 11)(q22;q23) is a poor prognostic feature despite intensive induction and allogeneic stem cell transplantation (11,12).
Several studies reported that breast cancer therapy is a risk factor of t-AML (1,13,14). Addition of G-CSF to routine therapy regimens, use of antracyclines, cyclophosphamide, radiotherapy, and high dose therapy followed by autologous stem cell transplantation were described as significant risk factors for t-AML (1). Capecitabine induced t-AML in patients with breast cancer was not reported yet and classically capecitabine is not accepted as a leukemogenic agent. To our knowledge the presented patient is the first report with t-AML secondary to capecitabine use for breast cancer treatment. Literature review revealed only five patients were reported developed t-AML after therapy with capecitabine until now (3-7). These patients' characteristics were shown in table 1. All of these patients had gastrointestinal cancer and they were older than our patient. Poor prognostic course of our patient was similar to other t-AML secondary capecitabine except who had acute promyelocytic phenotype. The leukemia free survival was very short despite the intensive chemotherapy regimens. In addition she was not accepted as a candidate for allogeneic stem cell transplantation since her breast cancer was not in remission.
In conclusion, capecitabin might have a leukemogenic effect via MLL gene in our patient. This group of AML has very poor prognosis, and capecitabine should be used carefully especially in patients with high risk for t-AML.