Secondary acute lymphoblastic leukaemia following oxaliplatin for adjuvant chemotherapy in colon cancer

To the Editor A highly increased risk of myelodysplasia and acute leukaemia is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors [1]. Recently, new chemotherapeutic agents have been introduced in the clinical practice and their late complications have not yet been described.

Oxaliplatin has resulted in a significant progress in the treatment of colorectal cancer both in the advanced disease and in the adjuvant setting [2–4]. Late toxicity and particularly secondary cancer are a very important topic in adjuvant setting where potentially cured patients may receive a toxic regimen. We report a case of a patient with possible treatment-related acute leukaemia after adjuvant chemotherapy with oxaliplatin.

In October 2005, a 65-year-old woman underwent resection of sigma for an adenocarcinoma (pT4 N0/3 M0, G2). From November 2005 to May 2006, the patient received 12 cycles of infused 5-fluorouracil, leucovorin, and oxaliplatin (the FOLFOX-4 regimen). She tolerated it well except for minimal peripheral neuropathy and mild leucopoenia. During follow-up she remains in remission and a computer tomography scan didn't show any lesion consistent with recurrence. In November 2006, she developed fatigue, nightly sweatiness and quotidian mild fever. The platelet count was 283 · 10⁹/l and the white cell count 17.9 · 10⁹/l with 7.6% blasts; she has a mild anaemia (haemoglobin level was 10.5 g/dl). Peripheral blood examination established the diagnosis of acute lymphoblastic leukaemia-associated antigen (CALLA) positive (80% blasts). After 2 days, she rapidly developed a heavy headache. A computed tomography scan of brain showed a wide haemorrhage in the temporal hemisphere. The platelet count changed to 145 · 10⁹/l and the white cell count 21.4 · 10⁹/l with 72% blasts and the haemoglobin level was 7.5 g/dl. The clinical conditions of patient rapidly aggravated. The bleeding in brain increased and she went into an irreversible coma. Death occurred rapidly before any specific treatment was started. It was not possible to have a cytogenetic and karyotype analyses.

The most frequently occurring type of chemotherapy related leukaemia is acute myeloid leukaemia while acute lymphoblastic leukaemia (ALL) is rare occurring in about 0.5–1‰ of treated patients [3], [4]. Although some cases of secondary ALL with t(4;11) (q21;q23) have been reported in literature [5], the clinical-biological features of these leukaemias are poorly defined [6], [7]. Single-agent fluorouracil has demonstrated no carcinogenic potential, either in animals or in humans. Cisplatin and carboplatin have been widely associated with leukaemia, whereas oxaliplatin is associated with acute haematological disease in only two reports. Acute promyelocytic leukaemia in a patient, with metastatic colon adenocarcinoma, treated with 46 cycles of leucovorin plus 5-FU followed by three cycles of irinotecan and three cycles of oxaliplatin was recently published [8]. The second case involved a 56-year-old woman with cecal adenocarcinoma presenting a remission of metastases to ovaries, omentum, after 12 cycles of FOLFOX-4 regimen. Bone marrow biopsy was consistent with therapy-related acute myelogenous leukaemia [9]. Nevertheless, no cases of secondary oxaliplatin-related ALL have been documented.

The occurrence of acute leukaemia in a patient treated with chemotherapy raises the question of whether the disease is aetiologically related to one or more cytotoxic agents [10], [11]. Currently, 10 to 20% of all new cases of acute leukaemias and myelodysplastic syndromes diagnosed annually are secondary to therapeutic regimens. They tend to appear with a latency period between 12 to 60 months. In our case, the lack of a chromosome analysis is the weak element but the latency of development and the aggressive clinical course make us suspect a correlation assume with previous chemotherapy. And, as the number of new chemotherapeutic drugs is increasing, clinicians’ attention might particularly be drawn to atypical secondary disorders. Delayed toxicity is a complication which must be considered for patients receiving adjuvant therapy, also to identify the true cost-effectiveness of the treatment. We believe that epidemiological surveys with long-term haematological follow-up are needed to monitor carefully their potential for the development of secondary leukaemia.