The Combination of Xanafide and Cytarabine Has Unique Activity in Acute Myeloid Leukaemia

European Oncological Disease, 2007;1(2):30-1

Secondary acute myeloid leukaemia (sAML) evolves from a prior myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) or occurs due to prior exposure to leukaemogenic therapy – also called treatment-related AML (tAML).1 Patients with sAML have an extremely poor prognosis, with only approximately 25% achieving remission following therapy with the standard regimen of bolus daunorubicin for three days and continuous-infusion cytarabine for seven days, the so-called ‘3+7’ regimen.2 The probability of achieving complete remission (CR) is affected by both patient- and diseaserelated factors.3 Important patient-related factors include age, associated co-morbid diseases and major organ dysfunction. Diseaserelated factors present in the leukaemia cells include specific numerical and structural chromosomal (cytogenetic) abnormalities. Patients with sAML are more likely to be older and have other serious medical problems; the blast karyotype is more likely to have complex cytogenetic changes and/or abnormalities of chromosomes 5 and 7, which have been associated with a poor outcome.

Leukaemic blasts from sAML patients are more often resistant to therapy than those from de novo AML patients. One of the many proposed mechanisms of drug resistance involves the expression of the membrane-associated efflux pumps (transporters) that actively export drugs out of the cell before they can enter the nucleus.4 Since all effective cytotoxic regimens interfere with DNA synthesis, this is an important and common cause of drug resistance. One of the most important proteins in this class of transporters is P-glycoprotein (P-gp/MDR-1).4 Expression of P-gp in the blast cells from elderly patients with AML ranges from 50 to 71%.2,5–7 The anthracyclines, mitoxantrone, etoposide and calicheamicin (the toxin linked to the anti-CD33 monoclonal antibody of gemtuzumab ozogamicin), cytotoxic drugs commonly used for remission induction therapy, are all substrates for this efflux pump. Thus, resistance to one drug usually translates to cross-resistance to all of the others, and has given rise to the concept of multidrug resistance (MDR).

The role of MDR in treatment outcome has been evaluated in several recent clinical studies. In one such study, Southwest Oncology Group (SWOG) 9031, the CR rate following standard 3+7 therapy among patients whose leukaemic blasts expressed the P-gp/MDR-1 efflux protein was only 32%, and among the subset with sAML was only 12%.5 In this study the independent variables predictive of response were age, sAML, MDR-1 expression and unfavourable-risk blast karyotype. The decrement in CR rate increased with the coupling of these risk factors in the same patient – no risk factor, 81% CR; 1 factor, 44% CR; 2 factors, 24% CR; and 3 factors, 12% CR2 – underscoring the importance of considering clinical risk factors in evaluating therapeutic results in AML. However, attempts to improve the rate of CR through pharmacological inhibition of the P-gp/MDR transporter with cyclosporine, PSC-833 (valspodar) and zosuquidar have been unable to show clinical benefit.7–12

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