There might be a causal relation between etoposide and/or platinum-containing chemotherapy and the development of chronic myelogenous leukemia (CML), researchers report.
A case series of three patients with germ cell tumor (GCT) who achieved remission with cisplatin–etoposide-based combination chemotherapy and subsequently developed BCR–ABL-positive CML is described in a research letter published onlineDecember 3 in JAMA Oncology.
This is not the first time this treatment has been associated with a leukemia.
"Etoposide-based chemotherapy in patients with GCT is leukemogenic, with a well-established association with acute myelogenous leukemia," first author Nabil Adra, MD, from the Melvin & Bren Simon Cancer Center and Indiana University School of Medicine in Indianapolis.
However, there are "limited cases of secondary CML in the literature," he told Medscape Medical News.
The first case in the series is that of a man in his mid-30s with nonseminomatous GCT who underwent orchiectomy in 1999 followed by four courses of bleomycin, etoposide, and cisplatin (BEP). In 2011, he was found to have a white blood cell count of 111,700/μL. Examination of bone marrow revealed morphologic findings of chronic-phase CML, and a t(9;22)(q34;q11) translocation was identified. Treatment with imatinib was initiated, and the patient achieved complete molecular remission. However, in 2014, he developed teratoma with malignant transformation to an undifferentiated neuroendocrine carcinoma with unresectable hepatic metastases, and died of his disease.
The second case is that of a man in his early 30s who underwent orchiectomy in 2006 for nonseminomatous GCT and opted for a single cycle of BEP. He suffered a relapse that same year, and was treated with three cycles of etoposide, ifosfamide, and cisplatin (VIP). In 2007, he relapsed again and received two cycles of high-dose carboplatin and etoposide followed by peripheral blood stem cell rescue. Roughly 4 years later, he was found to have leukocytosis (white blood cell count, 91,700/μL), and bone marrow assessment confirmed chronic-phase CML with a t(9;22)(q34;q11) translocation. The patient was treated with dasatinib (Sprycel, Bristol-Myers Squibb) and achieved molecular remission. "To date, he continues to be in remission for his CML and recurrent GCT," the authors report.
The third case is that of a young man with Klinefelter syndrome who presented in 2012 with intermittent chest pain and was found to have a 15 cm primary mediastinal nonseminomatous GCT. He was treated with four cycles of VIP followed by resection of residual mediastinal mass, which showed teratoma. Roughly 2 years later, his white blood cell count was 44,000/μL, bone marrow examination confirmed chronic-phase CML with morphologic characteristics, and a t(9;22)(q34;q11) translocation was identified. Dasatinib was initiated and the patient achieved a hematologic response. "To date, his BCR–ABL transcript declined appropriately from 55% to 9%. He continues to be in remission for his GCT," Dr Adra and his colleagues report.
"This case series poses questions regarding the connection of etoposide and cisplatin-containing combination chemotherapy and secondary CML," Dr Adra told Medscape Medical News.
Previous reports have linked GCT regimens containing cisplatin and etoposide or high-dose cytotoxic therapy plus carboplatin and etoposide to an increased risk for secondary acute leukemia and solid tumors, the authors note. And a literature review turned up seven cases of GCT with subsequent development of CML (J Clin Oncol. 2013;31:3807-3814).
The authors note that the "relatively low risk of secondary leukemia in patients treated with potentially curative combination chemotherapy for GCT continues to be reassuring. However, physicians should be aware of possible late toxic effects of these treatment regimens and the need for diligent follow-up in these patients."
CML is an increasingly manageable leukemia, said an expert not involved with the study.
"Etoposide is well described as causing the acute form of myelogenous leukemia. Cases of CML are less common with this drug," said Mark Litzow, MD, a hematologist/oncologist at the Mayo Clinic in Rochester, Minnesota. "It's a known but rare entity."
However, "we do have excellent treatment now for CML, so it doesn't have the life-threatening implications that it use to have, and it's relatively less serious than acute leukemia," he told Medscape Medical News.
Nevertheless, CML is a challenge for patients and clinicians, said Dr Litzow, who was reached for comment enroute to the American Society of Hematology annual meeting in Orlando. "It's very serious and I wouldn't wish it on anyone, but it's more manageable. We've really turned it into more of a chronic illness, with people living many, many years with good control on oral treatment."
The authors and Dr Litzow have disclosed no relevant financial relationships.
JAMA Oncol. Published online December 3, 2015. Letter