Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia

Abstract

Hypomethylating agent (HMA) failure in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) carries a poor prognosis with limited treatment options. Although intensive, remission induction chemotherapy is often used subsequently, in particular to bridge to allogeneic transplantation, it is not clear whether an advantage exists for any particular regimen. Based on an international collaboration, we retrospectively analyzed induction response rate and survival in 366 patients after HMA failure. Patients received 7+3, intermediate- to high-dose cytarabine (IDAC), or purine nucleoside analog-based regimens. For the MDS cohort (n = 307), the overall response rate (ORR) was 41%; median overall survival (OS) was 10.8 months, and 40% of responding patients bridged to allogeneic stem cell transplant (allo-SCT). For the AML cohort (n = 59), the ORR was 32%, OS 6 months, and 42% of responding patients bridged to allo-SCT. Prognostic factors for response in MDS included adverse cytogenetics (odds ratio [OR], 0.46, = .01), age ≥65 years (OR, 0.47; < .01), and use of IDAC (OR, 2.91, = .01). Shorter survival was associated with adverse cytogenetics (hazard ratio [HR], 1.43; = .06). In the AML cohort, OS was decreased by disease progression at time of HMA failure (HR, 2.66; = .02) and prolonged with use of an anthracycline-containing regimen (HR, 0.37; = .01). In conclusion, intensive chemotherapy after HMA failure may be a reasonable treatment option for selected patients as a bridge to allogeneic transplantation and should be considered a potential platform for future investigations.

Management of myelodysplastic syndromes after failure of response to hypomethylating agents

“…Researchers in a study including 307 MDS patients after HMA failure, randomized patients to either classical induction chemotherapy with 7+3, intermediate- to high-dose cytarabine (IDAC), or purine-nucleoside-analog (PNA) based (fludarabine, cladribine, clofarabine). 78 The ORR was 41%, 64%, and 34% with IDAC and PNA induction chemotherapy, respectively, without differences in the median OS between the three groups. Age > 65, adverse cytogenetics, and the use of non-IDAC-containing regimens, were identified as factors that significantly decreased response to these cytotoxic therapies.…”

American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults

“…Similarly, patients with a recent exposure to hypomethylating agents as treatment of antecedent hematological conditions are not likely to respond to induction with another hypomethylating agent, and cytarabine can be considered in this situation, though rigorous data supporting this approach are lacking. 170 With regard to combination therapies, low-dose cytarabine-based combination therapies have largely not shown an important benefit compared with low-dose cytarabine monotherapy, and combinations should not be used unless there is evidence through randomized data from large phase 3 trials to support their use. Preliminary reports from the phase 3 VIALE-C trial, in which AML patients considered ineligible for intensive chemotherapy were randomized to low-dose cytarabine vs low-dose cytarabine and venetoclax, show no difference in survival for the combination vs monotherapy (a median of 7.2 months vs 4.1 months, P 5 .11).…”

How I treat MDS after hypomethylating agent failure

“…10 Recently, in a large number of MDS patients (n 5 307), of whom 31% were IPSS lower risk, treated after HMA failure with cytosine arabinoside plus anthracycline (713), intermediate-to high-dose cytosine arabinoside, or nucleoside analogs, median OS was 10.8 months and overall response rate (ORR) was 41%. 52 Negative prognostic factors were adverse cytogenetics, age $65 years, and use of intermediate-dose cytosine arabinoside. 52 Standard-dose clofarabine used after HMA failure in patients with advanced MDS showed excessive toxicity.…”

“…52 Negative prognostic factors were adverse cytogenetics, age $65 years, and use of intermediate-dose cytosine arabinoside. 52 Standard-dose clofarabine used after HMA failure in patients with advanced MDS showed excessive toxicity. 53 Low-dose chemotherapy The use of subcutaneous low-dose cytarabine after HMA failure does not have any advantage over supportive care, 10 with absence of response and OS of 7.4 months.…”