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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2155-2158 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.054 Secondary Leukemias in Refractory Germ Cell Tumor Patients Undergoing Autologous Stem-Cell Transplantation Using High-Dose EtoposideFrom the Division of Hematology-Oncology and the Department of Medical and Molecular Genetics, Indiana University Medical Center and Walther Cancer Institute, Indianapolis, IN. Address reprint requests to Lawrence H. Einhorn, MD, Indiana Cancer Pavilion, 535 Barnhill Dr, RT #473, Indianapolis, IN 46202-5289; e-mail: Leinhorn{at}iupui.edu
PURPOSE: To quantify the risk of secondary leukemias in relapsed testicular cancer patients undergoing autologous stem-cell transplantation with high-dose etoposide. PATIENTS AND METHODS: Single institution, retrospective study of germ cell tumor patients who underwent autologous transplantation using high-dose etoposide from 1987 to 2001. RESULTS: One hundred thirteen patients received high-dose etoposide and carboplatin followed by autologous stem-cell transplantations for germ cell tumors. Follow-up ranged from 12 to 166 months (median, 51 months). Three patients (2.6%; 95% CI, 0.55% to 7.50%) subsequently developed leukemia at an average of 16 months post–autologous transplantation (range, 11 to 21 months). All three had received tandem transplantations and had been heavily pretreated, including at least one prior cycle of etoposide. Following autologous transplantation, all three patients exhibited refractory cytopenias before developing overt leukemia. All leukemias were of myeloid lineage. One patient developed an M2 with a t(8,21) chromosomal translocation; another, an M5 with a t(11,19); and one patient exhibited an unclassified leukemia with cytogenetic abnormalities resulting in monosomy for 7p and partial monosomy of 7q. Treatment of the leukemias involved allogeneic bone marrow transplantation. CONCLUSION: High-dose chemotherapy using high-dose etoposide as therapy for relapsed germ cell tumors was associated with a 2.6% risk of developing a secondary myeloid leukemia. This figure was not significantly different from the expected rate of secondary leukemias when patients receive additional cycles of standard-dose etoposide as salvage chemotherapy for germ cell tumors. Other factors, including the use of platinum agents, may also have a role in leukemogenesis in this patient population.
Germ cell tumors (GCTs) are uniquely responsive to chemotherapy. Cure rates with first-line chemotherapy using bleomycin, etoposide, and cisplatin (BEP) for three or four cycles approaches 80%.1 For those patients who relapse, second-line therapies include salvage surgery2; standard-dose chemotherapy including vinblastine, ifosfamide, and cisplatin (VeIP),3 or paclitaxel, ifosfamide, and cisplatin (TIP)4; or high-dose chemotherapy (HDCT) with autologous stem-cell rescue.5 Our preferred approach for nonseminomatous GCT patients in first relapse at Indiana University has been a single course of VeIP followed by two cycles of high-dose carboplatin and etoposide with rescue infusion of peripheral blood stem cells.5
The current cure rate for second-line therapy for GCT can be 50% to 70% in selected patients.4,5 This has raised concern about late sequelae of treatment, including secondary leukemias. Treatment with etoposide, a topoisomerase II inhibitor, entails a known risk of secondary leukemias that classically exhibit short (ie, < 2-year) latency periods, M4 or M5 origin, and a chromosomal translocation often involving an 11q23 chromosomal breakpoint.6 This leukemogenic risk may be dependent on the dose and duration of therapy.7-9 However, it is currently unclear whether the cumulative dose or peak dose of etoposide is more important for leukemogenesis. Treatment of testicular cancer with standard doses of etoposide that total To address the incidence of secondary leukemias, we performed a retrospective analysis of consecutive GCT patients treated with high-dose etoposide and carboplatin followed by autologous stem-cell transplantation at Indiana University from 1987 to 2001. Two hundred forty-six patients with relapsed GCTs underwent HDCT with stem-cell rescue during that period. One hundred thirteen patients who survived for longer than 12 months posttransplantation were identified. Median follow-up of these 113 patients was 51 months (range, 12 to 166 months), and 83% of patients were observed for more than 2 years. Three patients (2.6%; 95% CI, 0.55% to 7.50%) developed secondary leukemias after treatment with high-dose etoposide.
A single-institution medical record review was performed including all patients who underwent autologous stem-cell transplant using high-dose etoposide and carboplatin from 1987 until 2001. All patients had to survive for a minimum of 1 year posttransplantation to be eligible for inclusion in the study. The institutional review board at Indiana University approved the study. Stem cells were collected before HDCT, initially by bone marrow harvest, and in subsequent years, with peripheral blood collection. After 5 days of mobilization with granulocyte colony-stimulating factor at a dose of 10 µg/kg subcutaneously, daily apheresis was initiated and continued until 5 x 108 mononuclear cells/kg per cycle, or 2 x 106 CD 34+ cells, had been collected. Phase I and II trials that used varying doses (carboplatin 350 to 700 mg/m2 and etoposide 400 to 750 mg/m2) and schedules of etoposide and carboplatin were conducted prior to 1993 in 25 patients. The regimens used were reported in a previous article.11 Of the 88 patents treated after 1993, 91% received tandem HDCT for 3 consecutive days with carboplatin 700 mg/m2 intravenously over 15 to 30 minutes, plus etoposide 750 mg/m2 intravenously over 2 hours.5 This dose and schedule was given to 83% of the total 101 patients in the study who received tandem transplants. Reinfusion of the stem cells followed the HDCT. Twelve of the 113 patients on this study were treated with only a single course of HDCT. Reasons included either a specific protocol or toxicities from the first of a planned tandem transplantation. Of the 12 patients who received single transplantation, daily etoposide doses were 400 mg/m2 (n = 4), 500 mg/m2 (n = 3), and 750 mg/m2 (n = 5) for 3 consecutive days. Frozen stem cells from the autologous transplant were available from the patient with a secondary leukemia and a karyotype of 46,XY, t(11,19)(q23;13.3) (showing in 9 cells)/or 46,XY (showing in 11 cells). The stem cells were tested for any evidence of the aberrant chromosomal translocation at the time of the autologous transplant. Cells were thawed and prepared using Carnoy's fixative, and dropped onto slides. Fluorescent in situ hybridization (FISH) probes, the LSI MLL (11q23) Breakaway probe (1123; Vysis, Downer's Grove, IL), and the centromere probe for chromosome 8, CEP 8 (locus D8Z2; Vysis) were used. Two observers analyzed each probe in 100 cells. For event rates, 95% CIs were calculated based on the exact binomial distribution.
A total of 113 patients meeting the inclusion criteria were identified from a total of 246 GCT patients undergoing HDCT with stem-cell rescue. Median age of the 113 patients at time of autologous transplant was 32 years (range, 16 to 56 years). All patients had previously received etoposide at doses ranging from 500 mg/m2 to 6.15 g/m2. Before high-dose salvage therapy, 100 patients had received  2 g/m2 of etoposide, while 13 had received more than 2 g/m2 of etoposide. The median total dose of carboplatin at transplant was 4.2 g/m2 (range, 1.1 to 4.2 g/m2), and the median total dose of etoposide was 4.5 g/m2 (range, 1.2 to 4.5 g/m2). Median follow-up was 51 months (range, 12 to 166 months) posttransplantation. Of the 113 patients, 83% have been observed for more than 2 years. Three patients (2.6%) were identified as having acute secondary leukemias (Table 1) .
Ten patients in the study died. Eight deaths were due to recurrent GCT. One patient died secondary to recurrent secondary leukemia, and the final death resulted from a fungal infection complicating standard-dose chemotherapy for relapsed secondary leukemia. FISH analyses with the 11q23 locus–specific probe and the centromere probe for chromosome 8 demonstrated normal results. Ninety-seven percent of cells analyzed with the MLL Breakaway probe and 94% of cells analyzed with the centromere probe for chromosome 8 demonstrated a normal signal pattern. There were a total of three patients with secondary leukemias. The first patient was a 56-year-old man diagnosed with nonseminomatous GCT (NSGCT) in March of 1998. Initial treatment included four cycles of standard-dose BEP (total dose of etoposide, 2 g/m2). He recurred and received VeIP. Subsequent relapse 20 months after initial diagnosis led to HDCT with autologous stem-cell rescue using etoposide 4.5 g/m2, at a total dose of 8.8 g. The patient became platelet transfusion–independent at 28 days posttreatment. Nine months post–autologous transplants, pancytopenia developed. He was platelet transfusion–dependent, and a symptomatic normocytic anemia developed. Bone marrow biopsies were inadequate for diagnosis. A repeat bone marrow biopsy 11 months posttransplant showed an M2 acute myelogenous leukemia, and cytogenetics demonstrated an 8;21 translocation. He underwent a match-related transplantation and has no evidence of recurrence of his leukemia or GCT 27 months posttransplantation. The second patient was a 26-year-old man diagnosed with NSGCT in May 1999. Initial treatment consisted of four cycles of etoposide, ifosfamide, and cisplatin. Ten months later, the patient had a CNS relapse treated with surgery and radiation therapy. He subsequently received a single cycle of BEP followed by VeIP. Approximately 19 months after diagnosis, disease recurrence necessitated tandem HDCT with autologous stem-cell rescue. He received 4.5 g/m2 of etoposide at transplant with a total dose of 9.9 g. He was transfusion-independent after the second course of HDCT by day 14. Subsequently, the patient began to develop rapidly progressive pancytopenias marked by a macrocytic anemia 12 months after HDCT. At 15 months following HDCT, he was diagnosed with an M5 myeloid leukemia. Cytogenetics demonstrated an 11;19 chromosomal translocation with an 11q23 breakpoint. He delayed allogeneic transplant and received cytoreductive chemotherapy twice for relapses of his leukemia. He subsequently died of a pulmonary fungal infection without evidence of a GCT relapse. The third patient was a 32-year-old man with NSGCT initially diagnosed in November 1985. Initial treatment consisted of BEP for three cycles (etoposide 1.5 g/m2). Relapsed disease was treated with four courses of VeIP. Four months following the resection of a residual pulmonary mass, his GCT recurred. Third-line therapy consisted of six cycles of epirubicin. Thirteen months later, another relapse necessitated HDCT and tandem autologous transplantation. He received 2.4 g/m2 of etoposide with a cumulative dose of 3.98 g. He became platelet transfusion–independent within 3 weeks posttransplantation; however, without the use of stimulatory cytokines, he remained neutropenic for 34 days posttherapy. Twenty-one months after high-dose etoposide, new macrocytic anemia and thrombocytopenia prompted a bone marrow biopsy. The specimen revealed an unclassifiable myeloid leukemia with a karyotype of 46,XY, der(7)iso(7q10)del(7)(q22.1q34), resulting in a loss of 7p and partial loss of 7q. He died of recurrent leukemia 8 months after match-related donor allogeneic transplantation. There was no evidence of recurrent testicular cancer.
Testis cancer is a model for a curable neoplasm. Etoposide plays a role in many treatment strategies for testicular cancer. In patients with refractory GCTs, treatment options include standard-dose chemotherapy regimens,3,4 as well as HDCT with stem-cell rescue. While phase III studies proving superiority of HDCT to standard-dose cisplatin and ifosfamide–based regimens are not currently available, our single-institution experience with tandem autologous stem-cell rescue following high-dose carboplatin and etoposide found that 57% of relapsed GCT patients were disease-free at a median of 39 months posttreatment.5 Current evidence also supports using HDCT in patients who are platinum-refractory.12 In addition, HDCT with carboplatin plus etoposide followed by autologous stem-cell transplant has a cure rate of approximately 20% even when used as third-line treatment.13 A recently concluded Intergroup study (Eastern Cooperative Oncology Group trial E3894 and Southwest Oncology Group study 9442) addressed the role of HDCT in advanced GCT patients as initial treatment. In that study, advanced-disease patients were randomly assigned to four courses of BEP chemotherapy versus two courses of BEP followed by two courses of HDCT with stem-cell transplantation. Numerous articles have described the leukemogenic risk of treatment with etoposide and other topoisomerase II inhibitors in many different diseases, particularly in pediatric and young adult populations.14,15 The National Cancer Institute Cancer Therapy Evaluation Program, using data from 12 studies, calculated a 6-year rate of secondary leukemias of 0.7% to 3.2% after epipodophyllotoxin therapy.16 The available data on testicular cancer suggest that the risk of secondary leukemias is dose-related, and that the risk of treatment with etoposide totaling more than 2 g is approximately 2% to 3%.10 This corresponds to our results with high-dose etoposide in which three cases (2.6%) of secondary leukemia developed. Secondary leukemias related to treatment with etoposide have typical appearances. They usually involve rearrangement of the mixed lineage leukemia (MLL) gene and exhibit a chromosomal translocation with an 11q23 breakpoint.6,17 Although this translocation characteristically results in an M4 or M5 acute leukemia,6 all myeloid subtypes have been reported.6,14 Etoposide-related secondary lymphoid leukemias have also been reported.6,17,18 While all three patients in our cohort exhibited myeloid leukemias, only one had the translocation with the characteristic 11q23 breakpoint. These findings are not in discordance with the previously published literature. However, other factors, including the use of platinum compounds,19 may be playing a role in leukemogenesis. Therapy-related secondary leukemias often have short latency periods. Most reported cases occur within 2 to 3 years of topoisomerase II inhibitor therapy.6,20 In one study, 22 of 24 cases of leukemias developed within 24 months of treatment.17 However, cases have been reported as late as 65 months posttherapy.20 At the time of autologous transplant, the single patient whose stem cells were available to be tested by FISH did not have evidence of an 11q23 abnormality, indicating that the malignant transformation occurred after HDCT. All three secondary leukemias seen in this study occurred within the first 2 years after high-dose etoposide therapy. Since 83% of our cohort was observed for at least 2 years, we feel that few, if any, further cases of leukemia will be observed. The development of therapy-related leukemias was heralded by sudden and progressive cytopenias. Two of the three patients developed pancytopenia, and the third had bicytopenias. Two patients developed progressive macrocytic anemia, one had a normocytic anemia, and all had thrombocytopenia. One patient required platelet transfusions, and two required packed RBC transfusions peridiagnosis. Interestingly, the time to independence from platelet transfusions after HDCT was similar in the three patients to those who did not develop leukemia, when compared with a past series.5 In summary, these data are reassuring. Using high-dose etoposide in patients with refractory GCTs does not seem to entail a higher incidence of secondary leukemias than would be expected with four courses of standard-dose etoposide contained in a salvage chemotherapy regimen. However, data concerning initial treatment of higher-risk GCTs with HDCT followed by autologous stem-cell transplant, as is currently being investigated, are lacking and may need to be addressed in that cohort of patients. We feel that HDCT with etoposide and carboplatin with stem-cell salvage remains an appropriate strategy for initial salvage therapy in NSGCTs.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Lawrence H. Einhorn, Bristol-Myers Squibb.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Einhorn L: Testicular cancer: An oncological success story. Clin Cancer Res 3:2630–2632, 1997
2. Murphy B, Breeden E, Donohue J, et al: Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 11:1294–1299, 1993 3. Loehrer P, Gonin R, Nichols C, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16:2500–2504, 1998[Abstract]
4. Motzer R, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18:1173–1180, 2000
5. Bhatia S, Abonour R, Porcu P, et al: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18:3346–3351, 2000 6. Felix C: Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 36:525–535, 2001[CrossRef][Medline] 7. Pedersen-Bjergaard J, Daugaard G, Hansen S, et al: Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet 338:359–363, 1991[CrossRef][Medline]
8. Nichols C, Breeden E, Loehrer P, et al: Secondary leukemia associated with a conventional dose of etoposide: Review of serial germ cell tumor protocols. J Natl Cancer Inst 85:36–40, 1993
9. Bajorin D, Motzer R, Rodriguez E, et al: Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst 85:60–62, 1993 10. Kollmannsberger C, Hartmann J, Kanz L, et al: Risk of secondary leukemia and myelodysplastic syndrome following standard dose chemotherapy or high dose chemotherapy with stem cell support in patients with potentially curable malignancies. J Cancer Res Clin Oncol 124:207–214, 1998[CrossRef][Medline] 11. Broun E, Nichols C, Turns M, et al: Early salvage therapy for germ cell cancer using high dose chemotherapy with autologous bone marrow support. Cancer 73:1716–1720, 1994[CrossRef][Medline] 12. Vaena D, Abonour R, Einhorn L: Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. Proc Am Soc Clin Oncol 22:383, 2003 (abstr 1538)
13. Broun E, Nichols C, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117:124–128, 1992
14. Le Deley, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 21:1074–1081, 2003 15. Pui C, Ribeiro R, Hancock M, et al: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325:1682–1687, 1991[Abstract]
16. Smith M, Rubinstein L, Anderson J, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17:569–577, 1999 17. Andersen M, Ribeiro R, Hancock M, et al: Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: Report on two new cases and review of the literature since 1992. Br J Haematol 114:539–543, 2001[CrossRef][Medline] 18. Pedersen-Bjergaard J: Acute lymphoid leukemia with t(4;11) (q21;q23) following chemotherapy with cytostatic agents targeting at DNA-topoisomerase II. Leuk Res 16:733–735, 1992[CrossRef][Medline]
19. Travis L, Andersson M, Gospodarowicz M, et al: Treatment associated leukemia following testicular cancer. J Natl Cancer Inst 92:1165–1171, 2000
20. Bokemeyer C, Schmoll H, Kuczyk M, et al: Risk of secondary leukemia following high cumulative doses of etoposide during chemotherapy for testicular cancer. J Natl Cancer Inst 87:58–60, 1995 Submitted November 10, 2003; accepted March 3, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
