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Abstract

The prognosis for patients with secondary AML, primary resistant AML or ALL and early (Ͻ12 months) relapse of acute leukaemia remains extremely poor with conventional chemotherapy. As part of a strategy to improve the outcome for these patients we have treated 22 consecutive patients (18 AML, four ALL, median age 35 years) with either primary resistant disease (n = 3), early relapsed leukaemia (n = 12) or secondary AML (n = 7, four RAEBt, two antecedant ALL and one antecedant Hodgkin's disease) with 'FLAG' induction chemotherapy with the aim of proceeding to early allogeneic transplantation either from sibling or unrelated donors. Eighteen patients achieved CR after one course of FLAG, including five patients who had documented p-glycoprotein-induced multidrug resistance and 10 patients with adverse cytogenetic abnormalities. Eight patients were consolidated with a second course of FLAG prior to transplantation and so far 16 patients have undergone allogeneic transplantation, 10 from unrelated donors and six from sibling donors (one mismatched). By the time of transplant three patients had progressed and were in early relapse and all have relapsed post BMT. Of the remaining 13 patients transplanted in remission, nine remain in CCR at a range of 4-26 months, three have died of transplant-related complications (18%) and one patient has relapsed. We conclude that the use of FLAG induction therapy followed by early allogeneic transplantation from either a sibling or unrelated donor can be an effective strategy for the treatment of this difficult group of young patients with poor risk acute leukaemia and appears to be associated with a low procedure-related risk.

Synthesis of a Dual Functional Anti-MDR Tumor Agent PH II-7 with Elucidations of Anti-Tumor Effects and Mechanisms

“…The importance of P-gp proposed a strong rationale for the inhibition strategy, hence three generations of P-gp inhibitors have been developed, but most of which were discontinued for pharmacological or pharmacokinetic side effects [10]–[15]. Other P-gp-targeting anti-MDR strategies include but not limited to: P-gp specific peptides [16] or antibodies [17], downregulation of MDR1 gene with transcriptional repressors [18], [19] or siRNAs [20], [21], novel agents that are not substrates of P-gp [22], [23], or encapsulation of chemo-agents to evade P-gp efflux [24].…”

Analysis of the interaction of induction regimens with p-glycoprotein expression in patients with acute myeloid leukaemia: results from the MRC AML15 trial

“…The FLAG (Fludarabine, Ara-C plus G-CSF) regimen with or without the addition of idarubicin (FLAG-Ida) has featured in several studies as induction therapy for relapsed AML and for patients who failed to achieve remission with standard daunorubicin and Ara-C (DA) regimens, 13, 14 and has been a successful strategy in refractory AML with documented Pgp-induced multidrug resistance. 14 The cytotoxicity of FLAG is from the individual toxicities of fludarabine and Ara-C and from the potentiation of Ara-C toxicity by fludarabine and G-CSF.…”

“…14 The cytotoxicity of FLAG is from the individual toxicities of fludarabine and Ara-C and from the potentiation of Ara-C toxicity by fludarabine and G-CSF. As fludarabine and Ara-C are not Pgp-substrate drugs, this combination may be effective at bypassing Pgp-related resistance mechanisms in primary AML cells.…”