Is Vacuolization Clinically Relevant When Examining Acute Myeloid Leukemia Blasts?

Researchers recently examined whether vacuolization correlates with clinically relevant features in acute myeloid leukemia (AML) blasts.

In this retrospective single-center study, the authors said they observed blast vacuolization in a subset of AML patients. Given that a literature review revealed scant information about the frequency of blast vacuolization in patients with AML, and no information about their biological function or their clinical significance, researchers sought to evaluate the association of positivity for vacuolization in AML blasts with molecular and cytogenetic AML features, as well as with early treatment response and survival rates.

Researchers analyzed bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013. Additionally, patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival.

Two bone marrow slides of each patient were retrospectively screened for blast vacuolization, and the quantity of vacuoles for each of 100 AML blasts was separately documented for all patients. AML blasts were deemed positive for vacuolization if more than 10% of AML blasts had at least 1 vacuole.

A marker expression in immunophenotyping was considered positive if more than 20% of the cells in the blast gate were positive for the tested marker. Blast clearance was achieved if more than 10% of myeloid blasts persisted in cytological examination of day 15 bone marrow evaluation after intensive induction chemotherapy known as the 7+3-regime, where cytarabine 100mg/m2 is given as a continuous intravenous (IV) infusion for 7 days, and combined with daunorubicin 60mg/m2 as a 30-minute IV infusion on days 3, 4, and 5.

Patients under the age of 60 received a second induction therapy with 7+3 if early blast clearance was achieved upon day 15 bone marrow evaluation or with high-dose cytarabine using the HAM protocol (cytarabine 3000mg/m2 administered by 3-hour IV infusion every 12 hours on day 1 through 3 and mitoxantrone 10mg/m2 by 30-minute IV infusion given on day 3,4, and 5) if blast clearance was not achieved on day 15 bone marrow evaluation.

Patients older than age 60 received a second induction chemotherapy with HAM (with reduced cytarabine dose of 1000mg/m2), only if the first induction chemotherapy cycle was not sufficient to achieve bone marrow blast clearance on day 15.

The percentage of blasts persisting on day 15 bone marrow evaluation determined whether there was a poor response, stratified by age: more than 10% blasts persisted for patients under 60, and for patients above the age of 60, more than 5% blasts persisted.

Vacuolization of AML blasts was found in 16 of 134 patients (11.9%); 118 patients had AML without blast vacuolization. Thirty-four patients went on to receive nonintensive chemotherapy due to advanced age or bad performance status. After exclusion of those patients, 14 patients (14%) with vacuolized AML blasts and 86 patients (86%) with nonvacuolized AML blasts were further investigated.

Positivity for vacuolization correlated with a CD15-positive immunophenotype and with a higher incidence of high-risk AML. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival.

The Kaplan-Meier estimates for overall survival (OS) showed poor survival for AML patients with blast vacuolization, and the multivariate analysis showed blast vacuolization to be independently associated with OS. A limitation of the study is the limited number of AML patients and the low percentage of patients being positive for blast vacuolization. Studies with larger sample studies are needed; however, the authors said the study is the first to detail findings and characteristics about vacuolization in myeloid leukemia blasts. The results show that vacuolization can easily be determined and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival, they said.

Reference

Ballo O, Stratmann J, Serve H, Steffen B, Finkelmeier F, Brandts C. Blast vacuolization in AML patients indicates adverse-risk AML and is associated with impaired survival after intensive induction chemotherapy [published online September 30, 2019]. PloS One. doi: 10.1371/journal.pone.0223013.