Decitabine as good as, but safer than, chemo in AML

Extended treatment with decitabine is as good as, but safer than, standard induction chemotherapy (IC) in older patients with acute myeloid leukaemia (AML), according to a phase III study presented at EHA 2022.

The 4-year overall survival (OS) rates were not significantly different between the two treatment arms (26 percent with decitabine vs 30 percent with IC (hazard ratio [HR], 1.04; p=0.68), but decitabine had an added advantage of a better safety profile.

“We saw fewer toxicities, shorter hospitalizations, and better quality of life with decitabine,” said lead study author Dr Michael Lübbert, haematologist at the University of Freiburg Medical Center in Freiburg, Germany, during his presentation. “Decitabine provides a better-tolerated alternative to aggressive chemotherapy in older, fit patients with similar transplant rates on protocol and subsequent transplants.”

The findings suggest that some patients may safely forgo standard IC prior to transplantation, without affecting survival.

A closer look at decitabine

Decitabine is a hypomethylation agent that helps the bone marrow to produce normal blood cells and kill abnormal cells. The team investigated if decitabine is a viable alternative to IC before hematopoietic stem cell transplantation (HSCT) in 606 patients with newly diagnosed AML (de novo or secondary) from 54 centres in Germany. [EHA 2022, abstract S125]

Patients (mean age, 68 years) were randomly assigned 1:1 to a 10-day regimen of decitabine 20 mg/m² in cycle 1 (n=303) and either 10 or 5 days in subsequent cycles or IC (n=303), consisting of daunorubicin 60 mg/m² for 3 days, cytarabine 200 mg/m² for 7 days, followed by 1–3 additional chemotherapy cycles prior to HSCT.

Those with stable disease and human leukocyte antigen–matched donors were encouraged to undergo HSCT after 1 treatment cycle. Patients in the decitabine arm who did not undergo HSCT could continue with decitabine maintenance. The primary endpoint was OS, with several secondary endpoints, including complete response (CR)/CR with incomplete count recovery (CRi), transplantation rate, and outcome, among others.

Roughly half of the patients in both arms had a normal karyotype. Many had an ECOG performance status of 0, with an intermediate-risk disease based on the European LeukemiaNet 2017 stratification.

Eighteen percent in each arm had TP53 mutations; 23 percent of patients in the decitabine arm vs 14 percent in the chemotherapy arm had NPM1 mutations.

A higher percentage of patients in the IC arm achieved CR or CRi (61 percent) than those in the decitabine arm (48 percent). Forty percent of patients in the decitabine arm and 39 percent in the IC arm underwent HSCT on protocol.

Notably, the rates of progression at 4 years were comparable between the two treatment arms (57 percent with decitabine vs 51 percent with IC), and so was transplant-related mortality (TRM) at 21 percent and 25 percent, respectively.

Patients aged 60–64 years and those with NPM1 mutations benefited more from IC whereas patients aged 70 years and older and those with monosomal karyotype-positive disease had improved OS with decitabine. 

Looking at HSCT recipients alone, the 4-year OS was 47 percent in the IC arm vs 45 percent in the decitabine arm. The rates of disease progression were 22 percent and 24 percent, respectively. TRM rates were 33 percent and 31 percent, respectively.

Less toxicity with decitabine than chemo

During induction, there were generally more grade 3–5 adverse events with the IC arm than with the decitabine arm. Specifically, rates of blood and lymphatic disorders, infections, and gastrointestinal disorders were all higher with IC. 

However, the incidence of fatal treatment-related adverse events (TRAEs) after HSCT was comparable between treatment arms (25 percent with decitabine vs 22 percent with IC. 

Toxicities prior to HSCT, including diarrhoea and febrile neutropenia, among others, were lower with decitabine (1 percent vs 8 percent and 37 percent vs 57 percent, respectively). Importantly, decitabine resulted in fewer hospitalization days (p=0.007), fewer patients requiring intravenous antibiotics (p<0.001), and fewer red blood cell (p=0.024) and platelet (p<0.001) transfusions.

“Practice-changing” was how EHA president-elect Dr António Almeida, from Hospital da Luz, Lisbon, Portugal, described the findings. “For the first time, we have a head-to-head trial of a hypomethylating agent [decitabine] vs intensive chemotherapy before considering allogeneic transplantation. With these results, we know that we can take patients on hypomethylating agents to stem cell transplantation with less toxicity, so more patients can get to the transplant option,” he said quite positively.

Older patients with AML often have poor survival, without allogeneic HSCT, said Lübbert. However, many have a low tolerance to induction chemotherapy, which is a standard, prior to HSCT to achieve remission.

Milder DNA-hypomethylating agents such as decitabine may spare patients the toxicity while attempting to achieve CR.

“Although CR rate prior to HSCT was lower with decitabine than with induction chemotherapy in our study, OS outcomes after HSCT were similar. This means that CR is not an absolute condition for a successful transplantation,” emphasized Lübbert. “Importantly, bridging to transplant with decitabine is feasible in older patients with AML managed at experienced centres.”