Hypomethylating agents after allogeneic blood stem cell transplantation

Abstract

Allogeneic blood stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but relapse remains the major cause of treatment failure. So far, therapeutic options for patients with AML or MDS who relapse after allo-SCT generally consisted of palliative care, low-dose or intensive chemotherapy as well as cellular therapies such as donor lymphocyte infusions (DLI) and second transplantation in selected cases. Nevertheless, the prognosis of patients with myeloid malignancies relapsing after allo-SCT remains dismal therefore asking for novel treatment strategies. Considering their wellbalanced profile of good efficacy and moderate toxicity in the non-transplant setting, the hypomethylating agents (HMA) azacitidine (Aza) and decitabine (DAC) have also been tested either alone or in combination with DLI in the post-transplant period. This review summarizes the current knowledge about the use of these two HMA as pre-emptive, salvage or consolidation therapy mostly retrieved from retrospective studies but also from a few prospective trials. Within this review, we also comment on some practical issues such as optimal dose and schedule, the choice of HMA candidates and the role of additional cellular interventions.Finally, we also give an overview on the assumed mode of actions, ongoing research, clinical studies and potential combination partners aiming to improve this treatment approach.

A Modified Post-Transplant Cyclophosphamide Regimen, for Unmanipulated Haploidentical Marrow Transplantation, in Acute Myeloid Leukemia: A Multicenter Study

“…A pre-emptive approach with cellular therapy [16], or with azacytidine [17], is one option, but requires close monitoring of a marker for minimal residual disease (MRD). Post-transplant prophylaxis of relapse is another possibility, as shown in a German cooperative study with panobinostat [18], or again with azacytidine [19][20][21][22]. Salvage strategies may need to be personalized in haploidentical graft recipients, as relapse can occur with loss of the HLA mismatched haplotype [23].…”

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT

“…77 A combination of a hypomethylating agent and DLI is safe with no apparent increase in GvHD or infection risk compared to DLIalone. 78,79 In a prospective study using azacitidine with DLI for relapsed disease after HLA-matched allo-HCT, the CR rate was 23% and the 2-year OS was 17%. 80 Another retrospective study utilizing decitabine followed by DLI for relapsed myeloid malignancies showed an overall response rate of 25% with 2-year OS of 11%.…”

Leki wpływające na mechanizmy epigenetyczne w ostrej białaczce szpikowej

“…Skuteczność HMAs w leczeniu nawrotu AML po allo-HSCT wykazano w wielu badaniach (tab. 1) [66][67][68][69][70][71][72][73]. Większość opublikowanych wyników dotyczy azacytydyny.…”

“…W innym badaniu Schroeder i wsp. [67] przeprowadzili analizę retrospektywną 154 chorych z nawrotem choroby po allo-HSCT, Kamil Wiśniewski, Joanna Góra-Tybor, Leki wpływające na mechanizmy epigenetyczne w AML w tym 128 pacjentów z AML. U większości pacjentów (93%) podanie azacytydyny stanowiło pierwszą interwencję po nawrocie choroby.…”

“…[66] zaobserwowali lepszą odpowiedź na leczenie azacytydyną u pacjentów, u których nastąpił późniejszy nawrót choroby. Nie ustalono liczby cykli niezbędnych do uzyskania odpowiedzi klinicznej, jednak wydaje się, że konieczne jest podanie co najmniej 4 kursów leczenia [67]. Optymalizacja dawkowania oraz lepsza identyfikacja pacjentów mogących odnieść korzyść z terapii azacytydyną może prowadzić do poprawienia wyników leczenia w przyszłości.…”