Urgent Cytoreductive Chemotherapy for Newly Diagnosed Patients with AML Is Safe and Feasible and Facilitates Enrollment on Investigational Clinical Trials

Background : AML is a life-threatening, rapidly progressive malignancy that frequently presents with uncontrolled leukocytosis, organ infiltration, and the need for urgent chemotherapy. Recent advances in genomic profiling have identified significant heterogeneity in AML, that is best addressed with individualized, targeted approaches, often on clinical trials. The requisite cytogenetic and molecular data to inform definite treatment, however, is not rapidly available. Studies have suggested that delaying initial therapy in newly diagnosed AML may worsen OS. Implementing formal cytoreduction strategies may allow time for treatment selection and clinical trial enrollment without adversely affecting outcomes.

Methods: We piloted an approach with our frontline clinical trials in AML to allow cytoreductive therapy with hydroxyurea (HA) and/or higher doses of Cytarabine (Ara-C) for disease control prior to definitive therapy. 3 frontline chemotherapy protocols were designed to allow HA and up to 2 grams/m² of Ara-C for urgent disease control prior to starting therapy. We reviewed the feasibility and outcomes of this approach in older and younger pts with newly diagnosed AML treated between April 2014 and May 2020.

Results: We reviewed 276 patients, 97 (35%) which received cytoreductive therapy prior to starting definitive therapy. Baseline characteristics of patients who did or did not receive cytoreductive therapy are summarized in Table 1. The median time from presentation to definitive treatment was 6 days (range 1-21 days) and 6 days (1-46 days) in patients with or without cytoreduction, respectively. Patients with cytoreduction had higher median peripheral blasts 44% (Interquartile Range, IQR : 46-79) vs. 6% (IQR: 4-7) than patients without cytoreduction. More patients with cytoreduction were female (64%; p=0.007), ECOG performance status (PS) >1 (27%; p<0.001), and adverse ELN 2017 risk (36%, p=0.008) compared to patients without cytoreduction. Patients receiving cytoreduction more frequently had mutations in NPM1 (p<0.001), FLT3 (p<0.001) and RAS (p=0.006). In multivariate logistic regression, patients with high peripheral blasts (over 20%) were 5.0 times more likely to receive cytoreductive therapies (OR 5.0, CI 2.6-9.5 p<0.001). ECOG > 1(OR 3.5, 95% CI 1.6-8.0), FLT3 mutation (OR 2.7, p=0.006), female gender (OR 2.4, CI 1.3-4.3) were also associated with a higher likelihood to get cytoreductive therapeutics.

Response rates and outcome are summarized in Table 2. There was no difference in rate of CR/CRi (89% vs. 87%; P=0.72) among patients with or without cytoreduction, respectively. Similarly, there was no difference in 30- and 60-day mortality between the groups. When stratified with cytoreduction treatment regimen, there was no significant difference in CR and/or CRi. Of the 16 patients who died within 60 days of diagnosis, only 5 (31%) had documented CR or CRi at the time of death.

Median overall survival among patients with or without cytoreduction was 11.3 vs. 11.5 months, respectively (P=0.57) (Figure 1). There remained no difference in OS after adjustment of age, secondary AML, ECOG, ELN, TP53, and type of frontline treatment: Hazard Ratio of 1.1 (95% CI 0.7-1.7). Similarly, there was also no difference in progression free survival between the 2 groups (p=0.59).

Conclusions: Pretreatment cytoreductive therapy was safe and feasible in pts with newly diagnosed AML who are in need of urgent therapy, allowing collection of genomic data and enrollment on clinical trials. Despite having higher baseline WBC, blast %, incidence of FLT3 mutations, advanced PS, and higher ELN risk among pts who received cytoreduction, there was no difference in OS, PFS, or early mortality between the 2 groups. These data suggest that urgent cytoreduction may be reasonable alternate option to immediate induction.