Real-World Data Support Use of Hypomethylating Drugs in Elderly Patients With Acute Myeloid Leukemia

The use of hypomethylating drugs such as azacitidine and decitabine improved outcomes for patients of advanced age with acute myeloid leukemia, according to findings from a recent retrospective study of real-world data.

Hypomethylating drugs were effective and tolerable in real-world treatment settings for patients aged 75 years and older with acute myeloid leukemia (AML), according to data from a retrospective study published recently in Cancers.

Additionally, multivariate analyses showed age, Charlson comorbidity index (CCI), and creatinine clearance to be among the strongest independent predictors of survival in this patient population.

After a median follow-up of 7.8 months (interquartile range [IQR], 3.2-16.2),the median overall survival (OS) was 8 months (95% CI, 5.9-10.2) across a group of 220 patients with AML aged 75 years and older. The rates of OS at 1 and 2 years were 39.4% (95% CI, 32.7%-46%) and 17.4% (95% CI, 11.7%-23.1%), respectively.

The best response obtained was a complete response in 51 patients (23.2%), a partial response in 23 (10.5%), and stable disease in 45 (20.5%). Moreover, in a subset of 57 patients who were treated with at least 12 cycles of hypomethylating drugs (defined as 'long survivors’), median OS was 24.3 months. Forty-seven patients (34%) achieved overall transfusion independence after a median time on treatment of 3.5 months (95% CI, 2.7-4.2).

In a multivariate analysis, patients younger than 80 years had a median OS of 10.5 months (95% CI, 7.4-13.5) vs 6.2 months (95% CI, 3.0-9.5) in those 80 years of age or older (P = .001). Having a CCI of less than 3 also predicted improved survival, correlating with a median OS of 14.3 months vs 6.7 months in those with a CCI of 3 or greater (P = .029). Patients who achieved transfusion independence during hypomethylating drug treatment had a median OS of 19.3 months (95% CI, 15.4-27.3) vs 3.3 months (95% CI, 0.8-5.8) in those who didn’t (P < .001).

“Many elderly patients with AML are not even referred to the attention of hematologists, given the perceived dismal prognosis. Indeed, a large proportion of hematologists consider such elderly patients with AML as candidates for best supportive care only, as reported in a large cohort, where only 38.6% received leukemia therapy within three months of diagnosis,” the investigators wrote. “[T]he main purpose of our study was to identify specific [prognostic] characteristics of elderly patients, and, to our knowledge, this is the first report to focus on baseline organ functions in [patients with AML] aged older than 75 years.”

The multicenter retrospective study analyzed 220 patients who received hypomethylating drugs as a frontline treatment in any of 8 hematological centers across Lazio, Italy, from September 2010 to December 2021.

Most of the examined patients (74.5%) received subcutaneous azacitidine (Vidaza) at 75 mg/m2 for 7 days according to the 5+2 schedule every 4 weeks. The rest received intravenous decitabine (Dacogen) at 20 mg/m2 for 5 consecutive days every 4 weeks until unacceptable toxicity or progression.

The median age was 78.2 years (IQR, 75-86.2). Most patients had de novo AML (61.4%) rather than secondary AML (38.6%). A plurality of patients (49.1%) had a CCI of 3 or greater and 39.5% presented with an ECOG performance status of 2 or greater. Across the entire cohort, patients underwent a median of 5 treatment cycles (IQR, 1-46). Ninety-three patients (42.2%) received fewer than 4 cycles.

Multivariate logistic regression analysis associated both ECOG status of less than 2 (OR 2.96; 95% CI, 1.13-7.74; P = .027) and CCI of less than 3 (OR 4.47; 95% CI, 1.70-11.71; P < .001) with higher odds of achieving a complete response. Significantly higher OS was observed in patients with bone marrow blasts between 20% and 29% vs those with 50% or greater (13.7 vs 4.1 months; P < .001).

However, no such difference was found between patients with 20-29% and 30%-50% bone marrow blasts (P = .127). Furthermore, there was no difference in OS between the 2 treatment arms (8.3 months with azacitidine vs 7.8 months with decitabine; P = .810).

The median event-free survival (EFS) across the entire cohort was 7.3 months (95% CI, 5.0-9.6). The EFS rate was 33.6% (95%, 27.1-40.1) at 1 year and 16.3% (95% CI, 11-21.6) at 2 years. Nearly all the same predictive factors identified in analyses of OS were also relevant to EFS.

Roughly half of patients (49.5%) died from disease progression and 22.2% died from infectious complications, the most frequent of which were radiologically documented pneumonia (occurring in 11% of patients) and septic shock (lethal in 5.4%).

Most of the 126 evaluable patients experienced one or more adverse effect (AE; n = 122), and most of these were infections, affecting 103 patients. Grade 3/4 infectious AEs occurred in 62 patients (28.1%), including 42 cases (19%) of radiologically documented pneumonia, 15 (6.8%) cases of septic shock, and 4 (2.2%) cases of other infections. A total of 9 patients had significant bleeding during treatment, 2 of whom died with intracranial bleeding and 1 of whom died with massive gastrointestinal bleeding. There were no significant differences between the toxicity profiles of the two hypomethylating drugs.

“AML in the setting of very advanced age continues to pose a significant challenge in the treatment [of this cancer],” the investigators concluded. “Future molecules such as the hedgehog signaling pathway inhibitor, glasdegib [Daurismo], two IDH inhibitors, ivosidenib (IDH1 inhibitor) [Tibsovo] and enasidenib (IDH2 inhibitor) [Idhifa], the fully absorbable oral formulation of the hypomethylating agent decitabine and partially orally absorbable azacitidine will be, together with venetoclax [Venclexta], the expanding armamentarium against AML in the elderly.”

Reference

Molica M, Mazzone C, Niscola P, et al. Identification of predictive factors for overall survival and response during hypomethylating treatment in very elderly (≥75 years) acute myeloid leukemia patients: a multicenter real-life experience. Cancers (Basel). 2022;14(19):4897. doi:10.3390/cancers14194897