Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia

Abstract

Epigenetic therapies demonstrate significant clinical activity in acute myeloid leukemia (AML) and myelodysplasia (MDS) and constitute an important new class of therapeutic agents. However hematological responses are not durable and disease relapse appears inevitable. Experimentally, leukemic stem/progenitor cells (LSC) propagate disease in animal models of AML and it has been postulated that their relative chemo-resistance contributes to disease relapse. We serially measured LSC numbers in patients with high-risk AML and MDS treated with 5'-azacitidine and sodium valproate (VAL-AZA). Fifteen out of seventy-nine patients achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with VAL-AZA therapy. There was no significant reduction in the size of the LSC-containing population in non-responders. While the LSC-containing population was substantially reduced in all patients achieving a CR/CRi it was never eradicated and expansion of this population antedated morphological relapse. Similar studies were performed in seven patients with newly diagnosed AML treated with induction chemotherapy. Eradication of the LSC-containing population was observed in three patients all of whom achieved a durable CR in contrast to patients with resistant disease where LSC persistence was observed. LSC quantitation provides a novel biomarker of disease response and relapse in patients with AML treated with epigenetic therapies. New drugs that target this cellular population in vivo are required.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…Leukemia-initiating stem cells including preleukemic stem cells have been shown to persist even during morphologic remissions after these treatments and have to be targeted for future curative approaches. 1,2,8,9,20,41 It has been shown that leukemia-initiating cells can reside in different phenotypic stem and progenitor compartments at relatively low frequencies and are associated with transcription factor alterations that result in pathogenic transcriptional changes. [2][3][4][5][6][7][11][12][13]32,[42][43][44] Thus, to uncover newer stem cell-directed targets, we conducted a transcriptomic analysis on rigorously defined stem and progenitor populations in AML and MDS in comparison with their respective healthy counterparts.…”

Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

“…21 This is the first study to study the impact of concurrent DLI on AZA response, and we failed to demonstrate any benefit associated with the co-administration of DLI. Coadministration of a histone deacetylase inhibitor, such as sodium valproate or vorinostat, may increase both the overall response rate and its speed in patients with AML and MDS, [22][23][24] and it would be interesting to study such an approach in patients who relapse after an allograft. AZA has previously been shown to up-regulate the expression of epigenetically silenced tumor antigens, and one of its mechanisms of action in patients who have relapsed after an allogeneic transplant is the augmentation of a GvL effect.…”

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT

“…Retrospective analyses of AZA given at various doses and schedules for post-transplant relapse of AML and/or MDS have reported a response rate ranging from 55 to 72%, but with a poor survival ranging from 16 to 23% at 2 years. [22][23][24][25] Recently, Schroeder et al 26 conducted a prospective trial to evaluate the efficacy of AZA (100 mg/m 2 per day for 5 days) combined to DLI as first salvage therapy for relapse of AML or MDS after allo-HSCT. Seventy-three percent of the patients could receive DLI.…”