Therapy Related Myelodysplastic Syndrome and Acute Myeloid Leukaemia (tMDS/tAML) in Patients Treated with Purine Analogues (PA) for Lymphoproliferative Disorders (LPD); An Association with Alkylator Combination, Dose and Previous Alkylator Therapy.

tMDS/tAML are recognised late complications of chemotherapy and increased risk associated with advancing age. The rate of development of tMDS/tAML following fludarabine therapy has been reported to range between 4% - 20% with combination treatments particularly anthracyclines and cyclophosphamide, usually after second and subsequent lines of therapy. To date, none of the large first line trials using PA with cyclophosphamide have reported increased incidence of tMDS. We analysed the incidence of tMDS/tAML in patients treated with PA, predominantly fludarabine for LPD in two centres.

All patients treated with PA for LPD between 1993 and 2004 (Sidcup) and 2006 to 2008 (Maidstone) were analysed. If significant cytopenias (Hb<8g/dL, neutrophils<1×10⁹/L, platelets<50×10⁹/L) occurring >10weeks after chemotherapy were not due to recent chemotherapy or disease infiltration, bone marrows were independently reviewed by 2 haematologists. Cytogenetics were performed for most.

93 patient records were studied; median age 74 years (53-89). 43 patients received fludarabine for treatment of Chronic lymphocytic leukaemia, 33 patients for follicular lymphoma, 12 patients for lymphoplasmacytic lymphoma (one received additional Cladribine), 3 for mantle cell lymphoma and 2 for marginal zone lymphoma. After exclusion of patients who had immediate allogeneic bone marrow transplantation (AlloBMT) and those who survived less than 12 months post completion of therapy, 68 patients were included in the study. 13/68 (19%) patients developed tMDS/tAML at median times of 19 months. Around 50% had poor/complex cytogenetic abnormalities. Of these 13 patients, 9 (69%, 13.2% of total) have died, 2 are on a waiting list for alloBMT, 1 is on 5-Azacytidine therapy for monosomy 7 and 1 on regular transfusion programme. Of the 9 patients who have died, 7 died from tMDS/tAML, 1 post alloBMT complications, and 1 from pancreatic carcinoma. Median age of patients who developed tMDS/tAML was 72 years (57-82). All patients who developed tMDS/tAML and 46/55 of the others had received previous chemotherapy with alkylating agents. All 13 patients had received fludarabine in combination with cyclophosphamide and there appears to be a dose threshold. None of those who received PA monotherapy developed tMDS.

In our unselected series 19 % of patients who received PA combined with cyclophosphamide developed tMDS/tAML. All have previously received alkylator therapy and there appears to be a dose threshold. Complex/poor cytogenetics were seen in those with positive results and the prognosis is exceptionally poor with a mortality rate of 70% of those affected in our series. Our higher incidence than other reports may be due to the older age of our patients, previous alkylator therapy and use of PA in combination with cyclophosphamide. None of those who received Fludarabine monotherapy developed tMDS. We urge close follow up and dose monitoring of patients receiving PA and alkylators following previous therapy with alkylating agents. We suggest that where PA are effective, they are used first line.

Rassam:Johnson and Johnson: Research Funding.