Therapeutic Strategy for Elderly Patients with ACUTE Myeloid Leukemia (AML) Carrying the DNMT3A Mutation

BACKGROUND: AML in the elderly is associated with low complete remission (CR) rates after induction therapy, poor survival and high treatment-related mortality. 5-Azacytidine (5-AZA) has emerged as a valid substitute of the Conventional Care Regimens (CCR) in a small subset of patient with a bone marrow blast count ranging from 20% to 30%. However, in a off-label use, 5-AZA may also be used in patients with bone marrow blast infiltration >30%. Furthermore, 5-AZA can be also used for the maintenance therapy after the bone marrow blast count has been reduced under the 5% cut-off.

AIMS: to assess both safety and efficacy of in-label use of 5-AZA in elderly AML patients who have reached a bone marrow blast count between 5% and 30% after an induction conventional chemotherapy.

METHODS: from 2010 to 2013, 13 patients (8 males; 5 females) with a median age of 74 (range 64-86) years and a newly diagnosed AML have been enrolled. At the diagnosis, the median bone marrow blast count was 45% (range 24%-95%). Cytogenetics showed: normal karyotype in 7 patients, chromosome 8 trisomy in 2, complex karyotype in 4. A DNMT3A mutation was documented in 5 cases. Neither FLT3-ITD mutations nor NPM1 mutations were present. According to age, performance status and comorbidities, all patients received a CCR induction chemotherapy. Low Dose Cytarabine, 100mg/sqm, was given subcutaneously for 5 days in 4 patients, Fludarabine (25mg/sqm intravenously for 5 days) and Cytarabine (2gr/m2 intravenously for 5 days) in 4 and the ICE schedule- Idarubicine (10mg/sqm intravenously for 3 days), Cytarabine (100mg/sqm intravenously for 5 days) and Etoposide (50mg/sqm intravenously for 3 days) in 5. At the day +31 bone marrow evaluation, no one obtained a Complete Remission, in 5 patients blast count ranged between 20% and 30%; in 4 between 15% and 20%; and in 4 between 5% and 10%.

Then, all patients received 5-AZA at 75mg/sqm subcutaneously for 7 days every 28 days. The median number of cycles was 8 with a minimum of 1 cycle and a maximum of 15 cycles. Adverse hematological events were: grade III-IV neutropenia in 7 patients (54%) and thrombocytopenia in 9 patients (69%). Fever was the major non-hematological side effect during 5-AZA: fever was of unknown origin (FUO) in 4 patients, infection-related in 4 (2 pneumonias, 1 sepsis from Pseudomonas Aeruginosa and 1 from KPC). One patient died after the first cycle for septic shock due to KPC.

RESULTS: Among the 12 evaluable patients the median survival was 16 months (range 2 – 44). Our data showed a longer median survival (17 months) in the 5 patients with DNMT3A mutation in comparison with those with wild-type DNMT3A (11 months). In consideration of the limited number of patients, the p-value was 0.47. In addition, a reduction of transfusion requirements as well as an improvement of quality of life were obtained. Therapy with 5-AZA was overall well tolerated as only one patient needed a long-term hospitalization and died from septic shock. In conclusion, we showed that a bone marrow blast reduction after conventional induction chemotherapy and a subsequently treatment with 5-AZA can be a valid option in elderly patients with AML and DNMT3A mutation. More patients and longer follow-up are required for confirming these encouraging preliminary results.