The terms secondary leukemia and therapy-related leukemia are used interchangeably to describe leukemia for which previous cytotoxic therapy is considered to have contributed to its etiology. This designation includes cases of myelodysplastic syndrome (MDS) and chronic myeloproliferative disorder.1 In the past, it was generally recognized that leukemia secondary to chemotherapy was due to the use of alkylating agents and/or topoisomerase II inhibitors in the treatment of ovarian cancer. Vay et al2 reported that the calculated incidence of secondary myeloid malignancies among their patients with primary ovarian cancer was 0.17%. Recently, many types of chemotherapeutic agents have been used in the treatment of gynecologic malignancies in addition to ovarian cancer.
The prognosis of patients with secondary leukemia is often poor because of the high risk of recurrence of leukemia even after the withdrawal of chemotherapy or because of difficulties in the treatment of patients with secondary leukemia due to severe bone marrow suppression after the treatment of the primary tumor.3–5
In the present study, we analyzed the clinical characteristics and outcome of patients with recent onset of secondary leukemia after the treatment of gynecologic malignancies and discussed the diagnosis and management of this complication.
MATERIALS AND METHODS
We reviewed the clinical charts and follow-up data of patients with gynecologic malignancies treated in the past 20 years (1993-2012). During this period, 2482 newly diagnosed invasive gynecologic cancers were treated in our institution. The breakdown according to different cancer types for invasive cervical cancer, endometrial cancer, and ovarian cancer was 1210, 812, and 365, respectively. A total of 1046 from 2482 patients (42.1%) were treated with chemotherapy for gynecologic cancer. The number of patients who were treated with radiation and chemotherapy versus that with chemotherapy only in the first treatment was 405 versus 641. Ninety-five percent of the patients were followed-up periodically at the outpatient clinic for more than 5 years.
All patients received regular screening for recurrence of gynecologic malignancies every 3 to 6 months. In each visit, serum tumor markers, routine cervical cytology, and pelvic examination were conducted. Furthermore, complete blood cell count and biochemical tests were conducted as required. Detection of a rise in the number of blast cells in peripheral blood was followed by bone marrow examination, May-Giemsa staining, peroxidase staining, and a cluster of differentiation by flow cytometry to determine the type of leukemia. The French-American-British classification (for the morphological classification of acute myelocytic leukemia [AML]) is based on May-Giemsa and peroxidase staining, but we also conducted karyotypic analysis for the diagnosis of leukemia and for the decision making on the treatment.
All patients with secondary leukemia were analyzed for clinical background, complications, latency period (interval periods between the diagnosis of primary carcinoma and the development of leukemia), the method used for the diagnosis of leukemia, treatment, and outcome. We also reviewed the literature for secondary leukemia under gynecology using the PubMed. All observational studies in our hospital are approved by the institutional review board at the National Kyushu Cancer Center.
Four patients were found to have developed secondary leukemia after the treatment of gynecologic malignancies during the 20-year period with a cumulative risk of secondary leukemia of approximately 0.38%. The Eastern Cooperative Oncology Group (ECOG) performance status at the diagnosis of secondary leukemia was 1 in 2 patients and 3 in the other 2 patients (Table 1). Their primary carcinomas were cervical cancers in 2 patients, endometrial cancer in 1 patient, and ovarian cancer in 1 patient. The patient with ovarian cancer had developed breast cancer 2 years after the diagnosis of ovarian cancer. So she was treated with internal daily use of cyclophosphamide (200 mg/d) for 6 months as postoperative adjuvant chemotherapy for breast cancer.
The cervical cancer patients received radiotherapy, and all patients received platinum-based chemotherapy. For platinum compounds, the relative risk rates of secondary leukemia after cumulative doses of less than 500 mg, 500 to less than 750 mg, 750 or more to less than 1000 mg, and 1000 mg or more were reported as 1.9, 2.1, 4.1, and 7.6, respectively.6 Three of 4 patients with secondary leukemia received chemotherapy with cisplatin of 500 mg over, and all patients with secondary leukemia received carboplatin of 3000 mg over (Table 1).
Although secondary leukemia is a collective term used to describe therapy-related acute myelocytic leukemia AML (tAML) or therapy-related MDS (tMDS), 1 patient developed acute biphenotypic leukemia (BAL), a rare secondary leukemia (patient 2, Table 1). The bone marrow puncture of this patient showed abundant blasts with negative peroxidase staining result; thus, the patient’s condition was diagnosed with BAL with the scoring of the lineage marker of bone marrow cells.
In addition, a discrepancy between morphological findings of the bone marrow examination and the karyotype analysis was noted in 1 patient with AML (patient 1, Table 1). Peripheral blood tests and bone marrow biopsy examination showed increased numbers of blast cells that were filled with azurophil granules and Auer body, which are characteristic of acute promyelocytic leukemia (M3). However, karyotype analysis of the bone marrow of the same patient showed t(11; 12)(p15; q13) but no translocation of chromosome 15 and 17, which are typically seen in M3. Furthermore, fluorescence in situ hybridization analysis confirmed the absence of typical PML/RARα fusion (data are not shown). Consequently, the patient was diagnosed as tAML with t(11; 12)(p15; q13) that seemed like M3 morphologically on bone marrow biopsy examination.
Combination chemotherapy and/or bone marrow transplantation were not used in 2 patients due to advanced age and severe bone marrow suppression after the treatment of the primary cancer (patients 1 and 3, Table 1). Both of these 2 patients died within 5 months after the diagnosis of secondary leukemia. The other 2 patients received combination chemotherapy and/or bone marrow transplantation and lived for more than 1 year from the diagnosis of secondary leukemia. One of these 2 patients lived more than 6 years but died of recurrent ovarian cancer.
During the use of alkylating agents as the main adjuvant chemotherapy for ovarian cancer, secondary leukemia was considered the most serious complication of chemotherapy. Vay et al2 reported that the development of secondary leukemia was a terminal event in patients with epithelial ovarian cancer, with a significantly shorter median survival time than in patients who did not develop secondary leukemia.
Four patients were found in the present study to have developed secondary leukemia after treatments of gynecologic cancer. Two of the 4 patients who could not receive treatment of secondary leukemia died within 5 months after the diagnosis of secondary leukemia. However, 1 patient with tAML after treatment of ovarian cancer survived for more than 6 years. In this regard, 2 previous studies reported that the management of secondary leukemia patients with t(8; 21), t(15; 17), or inversion 16 by combination chemotherapy or bone marrow transplantation resulted in improvement of prognosis to a level similar to that observed in de novo AML.7,8 These findings suggest that the prognosis is not necessarily poor in all patients with secondary leukemia. Thus, long survival is expected in patients who show complete response to bone marrow transplantation and/or combination chemotherapy for secondary leukemia.
Several cases of secondary leukemia in ovarian cancer have been reported during the past 26 years. Tables 2 and 3 provide summaries of the reported case series and case reports of secondary leukemia in patients with ovarian cancer. Most of these studies reported the risk of secondary leukemia after chemotherapy using alkylating agents, topoisomerase II inhibitors, and platinum. The cumulative dose of anticancer drugs has been reported for topoisomerase II inhibitors and platinum. The reported relative risk rates of secondary leukemia after cumulative doses of less than 1.2 mg/m2 and 1.2 to 6 g/m2 of topoisomerase II inhibitors are 0 and 3.9, respectively. For platinum compounds, the relative risk rates of secondary leukemia after cumulative doses of less than 500 mg, 500 to less than 750 mg, 750 or more to less than 1000 mg, and 1000 mg or more are 1.9, 2.1, 4.1, and 7.6, respectively.8 However, there is no information about the correlation between the cumulative doses of paclitaxel-containing chemotherapies and secondary leukemia. However, few case reports have described secondary leukemia after paclitaxel-containing chemotherapy (Table 3).9–12 We could not find any statistically significant difference in cumulative paclitaxel doses between patients who developed leukemia and those who did not. However, the cumulative doses of cisplatin and carboplatin in cervical cancer patients who developed leukemia had a tendency to be higher than that in patients who did not develop leukemia. The mean cumulative doses of cisplatin and carboplatin in cervical cancer patients who did not develop leukemia were 93 ± 131 mg/body and 2629 ± 1436 mg/body, respectively. The mean cumulative dose of paclitaxel in cervical cancer patients who did not develop leukemia was 1543 ± 664 mg/body. The mean cumulative doses of cisplatin, carboplatin, and paclitaxel in ovarian cancer patients who did not develop leukemia were 526 ± 274 mg/body, 1173 ± 536 mg/body, and 1249 ± 415 mg/body.
As shown in Table 2, it is possible to reduce the cumulative risk of secondary leukemia after ovarian cancer by changing the chemotherapeutic regimen. In ovarian cancer chemotherapy, alkylating agent–containing chemotherapy was changed to paclitaxel-containing chemotherapy after the report in American Society of Clinical Oncology (ASCO) 1999.13 Furthermore, pegylated liposomal doxorubicin hydrochloride or gemcitabine hydrochloride has been used recently for advanced ovarian cancer that has relapsed at least 6 months after the completion of platinum-based therapy. Considered together, the previously mentioned studies suggest that changes to the first-line and second-line chemotherapies could be associated with changes in the cumulative risk of secondary leukemia.
Most previous studies did not report the cytogenetic abnormalities in patients with secondary leukemia.5,14–17 Cytogenetic abnormalities were reported in 4 case reports of secondary leukemia after paclitaxel-containing chemotherapy (Table 3).9–12 One study reported patients with secondary leukemia associated with chromosomal aberration inversion 16 (acute myelomonocytic leukemia). Two other reports described patients with tAML (erythroleukemia [M6]) and tAML (acute megakaryocytic leukemia [M7]) and abnormal karyotype with multiple complex abnormalities. M6 and M7 are not common in AML and are associated with poor prognosis. In patients with M7, the reported median survival time was only 5 to 7 months.18 Thus, the type of leukemia and associated cytogenetic abnormalities are important factors with regard to prognosis and clinical decision making on the treatment in patients with secondary leukemia. For example, all-trans retinoic acid was effective in 1 patient with M3. Although there is risk of retinoic acid syndrome in patients treated with all-trans retinoic acid, the remission rate is often high, and long survival time can be expected.19 Our study also included patients with BAL and tAML who showed discrepancy between the results of morphological analysis of bone marrow biopsy findings and karyotypic analysis. The results confirmed that cytogenetic and molecular features at diagnosis of secondary leukemia are important for the prognosis of patients with leukemia and clinical decision on treatment of these patients.
Our results confirmed the low incidence of secondary leukemia in patients with ovarian cancer after switching from alkylating agents to paclitaxel-based chemotherapy as the main adjuvant chemotherapy. In this study, 1046 of 2482 patients received chemotherapy and/or radiotherapy for invasive cervical cancer, endometrial cancer, or ovarian cancer. The cumulative risk of secondary leukemia was approximately 0.38%. Two of 4 patients with secondary leukemia had been treated with radiation therapy and chemotherapy for the primary cancer. It seems that prior administration of radiation might have affected the final outcome. This is not surprising because patients treated with combined treatments will likely experience more damage to their bone marrow. This may also explain why they were not able to tolerate aggressive treatment and why they died of leukemia rather than of initial solid tumor.
In recent years, we have aggressively used various types of anticancer drugs for the treatment of not only ovarian cancer but also uterine cervical cancer and endometrial cancer. We also see many long-term survivors with advanced gynecologic carcinoma after the use of these anticancer drugs. Such patients tend to receive larger cumulative doses of anticancer drugs to prevent recurrence than ever used in the past. Physicians need to keep in mind the risk of secondary leukemia in the follow-up of long-term survivors after several courses of chemotherapy and radiotherapy.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Secondary leukemia; Gynecologic cancer; Chemotherapy