A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis

Abstract

The fact that treatment with cytotoxic agents can induce myelodysplasia (MDS) and acute myeloid leukaemia (AML) in patients suffering from cancer and from other diseases has now been thoroughly documented (Kyle et al., 1970;Reimer et al., 1977;Casciato & Scott, 1979;Berk et al., 1981;Coltman, 1982;Green et al., 1982;Pedersen-Bjergaard & Larsen, 1982;Boice et al., 1983;Boivin & Hutchinson, 1984;Lakhani, 1984). However, quantitative relationships with the dose and duration of treatment for different agents, and the relative oncogenic potential of different drugs have yet to be clearly elucidated. It is also not known whether susceptibility to this outcome is influenced by the condition being treated. As a class, the alkylating agents have been shown to be particularly capable of inducing MDS and AML, and there are many reports of both cyclophosphamide and melphalan inducing MDS and AML in patients with mylelomatosis and other neoplasms (Kyle et al., 1970;Gonzalez et al., 1977;Bergsagel et al., 1979;Casciato & Scott, 1979;Buckman et al., 1982;Coltman, 1982). A quantitative comparison of the relative potency in doing so of these two drugs is more difficult to obtain. In the first two trials in myelomatosis of the Medical Research Council's Working Party on Leukaemia in Adults patients were allocated at random to be treated by either cyclophosphamide or melphalan, and the long-term follow-up of these patients offers a rare opportunity to assess the relative oncogenic potential of these two drugs. Patients and methodsThe population at risk comprised all patients randomised in the first two Medical Research Council trials (MRC, 1973; MRC, 1980a Evidence of MDS or AML was sought from routine follow-up reports to the trial headquarters. In addition the clinical notes of all five-year survivors and all patients developing MDS or AML were used to abstract details of all chemotherapy, including specific drugs and combinations and the exact sequences of times on and off therapy. The diagnosis of MDS or AML was reviewed by one of us (D.A.G.G.) and confirmed where possible by review of blood films and bone marrow aspirates. Bone marrow investigations were performed only on patients who developed unexplained cytopaenia.In examining the blood and bone-marrow films, the diagnosis of MDS or AML was made according to the proposals of the French-American-British (FAB) cooperative group (Bennett et al., 1982). In brief, the diagnosis of leukaemia was made only when blast cells accounted for >30% of the nucleated cells in the bone marrow; when the blast-cell count was 5-20% the condition was diagnosed as refractory anaemia with excess of blasts (RAEB) and when it was .20% but <30% as RAEB in transformation (RAEBt). Myeloma cells were omitted in performing the differential counts. The slides from one patient from the first MRC trial had been examined for our first follow-up study (Buckman et al., 1982) and the diagnosis was of MDS and AML, but the slides were not available for review on this occasion. Slides were available for review...

Long-term risk of second malignant neoplasm after a cancer in childhood

“…We nevertheless consider that there exists a lower carcinogenicity for cyclophosphamide than for the other alkylating agents (mainly procarbazine and melphalan). This result is in agreement with published observations on survivors from ovarian cancers (Greene et al, 1986), and on survivors from myelomatosis (Cuzick et al, 1987), that melphalan is more leukaemogenic than cyclophosphamide.…”

Polymorphism of the erythropoietin gene promotor and the development of myelodysplastic syndromes subsequent to multiple myeloma

“…1 So far, it has been shown that in vitro AML cells display an enhanced cholesterol metabolism. 2 Moreover, AML cells increase their cholesterol contents upon exposure to chemotherapeutic drugs, which may render them less …”

“…1 Alkylating agents have long been considered to be part of the cause. [2][3][4][5] Some, but not all, smaller investigations have reported that higher cumulative melphalan dose and longer duration of melphalan therapy are associated with an increased risk of AML. 6,7 The role of nontreatmentrelated factors is largely unknown.…”

Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

“…6,[12][13][14] Many of these studies showed that the risk of t-MDS and t-AML increases with the cumulative dose of drug 4,5,7,9,10,13,14 and with patient age. 3,6,13,14 After the first reports of t-AML it was realized that in most of these patients the disease presents in a preleukemic stage as t-MDS with abrupt thrombocytopenia 2-5 years after start of therapy with alkylating agents.…”

“…The first cytostatic drugs shown to be leukemogenic were alkylating agents, administered as single agents 1,2,4,5,[8][9][10] or included in combination chemotherapy regimens, 3,7,11 primarily for multiple myeloma 1,3,10 and Hodgkin's disease. 6,[12][13][14] Many of these studies showed that the risk of t-MDS and t-AML increases with the cumulative dose of drug 4,5,7,9,10,13,14 and with patient age.…”