A paper in Biomedicine and Pharmacotherapy reports on the risk of therapy-related MDS and acute myeloid leukemia (tMDS/AML) in patients with CLL treated with fludarabine and cyclophosphamide.
This was a retropective look-back from Serbia. They found 4 cases among 210 patients treated with FC at a single center. Two of the patients had only been treated with FC (2/130, 1.7%), but two had been previously treated with CHOP or CHOP + Fludarabine, mitoxantrone and dexamethasone (FND) (2/80, 2.3%). The median time to develop the secondary disease was 41 months (range 7-56) and the median survival after diagnosis was 4 months (2-8).
Reviewing the literature they note that in the CALGB 9011 study the frontline combination of fludarabine plus chlorambucil was responsible for the development of 3.5% tMDS/AML wheras fludarabine or chlorambucil were responsible for only 0.5% and 0% respectively, suggesting that it is the combination of purine analog and alkylating agent that is dangerous.
A rate of 4% was found in NHL treated with FND followed by alpha interferon maintenance. A much higher incidence of 20% was found in a mixed bag of indolent lymphomas, including about 40% CLLs who received FC as second line after prior alkylating agent treatment. In another study 137 patients with lymphoma (38% CLLs) developed 2.5% tMDS/AML in previously untreated patients and 9.3% in previously treated patients.
A particularly high rate of tMDS/AML (12.4%) was found in patients treated with fludarabine who proceeded to autologous transplant.
This paper largely confirms what was already known. In CLL the fludarabine/cyclophosphamide combination carries a small risk of tMDS/AML and this is greater in patients who have been treated previously with alkylating agents. My own theory for why this combination is particularly dangerous is that the alkylating agent causes genetic damage, allowing a malignant clone to emerge. The clone is normally controlled by regulatory T cells but these are abolished by fludarabine treatment allowing the tMDS/AML to emerge. tMDS/AML is a very unpleasant condition that is often rapidly fatal.
I have often stressed that we should be looking for less aggressive regimens in patients who need treatment but whose disease is not particularly aggressive such as those with mutated IGHV genes. It looks as if John Byrd's study with FR might be supporting this idea.