Clinical and Molecular Response in Core Binding Factor Acute Myelogenous Leukemia with Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin.

Core binding factor associated acute myelogenous leukemias (CBF AML) are characterized by sensitivity to high dose cytarabine (ara-C). Attempts to modulate intra-cellular ara-C tri phosphate (ara-CTP) by induction/consolidation therapy with fludarabine, cytarabine and granulocyte colony stimulating factor (GCSF) (FLAG) has resulted in improved event free survival (EFS) (median EFS not reached after median follow-up of 118 weeks) in patients with CBF AML (Borthakur et al. 2008, Cancer 113:3181). Addition of gemtuzumab ozogamicin (GO) to induction and consolidation has resulted in improved disease free survival (DFS) in patients with AML and “favorable cytogenetics” (Burnett,A. et al. ASH 2006#13).

In an attempt to improve upon these results we have initiated a study incorporating GO with FLAG (GO-FLAG) in induction/consolidation for treating patients with newly diagnosed CBF AML. Patients with CBF AML, untreated or who received one cytarabine based induction regimen are eligible. Induction regimen comprises of fludarabine 30 mg/m² IV days 1- 5, cytarabine 2 g/m² IV days 1- 5 (3.5 h after completion of that day's fludarabine infusion, Gemtuzumab ozogamicin 3 mg/m² IV on Day 1, filgrastim (G-CSF) 5 mcg/kg body weight starting day-1 till recovery of absolute neutrophil count (ANC) to 1.0 × 10⁹/L or above (filgrastim is started on day 2 for patients with presenting WBC count > 10 × 10⁹/L). We report on clinical and molecular responses in patients enrolled in this study. Extracted RNA is reverse transcribed and analyzed by real-time quantitative PCR for the fusion transcript associated with CBF leukemias. Values are expressed as a percentage of fusion transcript to normalizing ABL transcripts. The sensitivity of detection is approximately 1 in 100,000 for AML1-ETO and 1 in 10,000 for CBFb-MYH11.

Thirty-four (Inv 16=10/t 8;21=24) patients (male=20)[median age 48 years (range, 29-73)]have been treated to date with a median follow-up of 11 months (range,1-24). Patient characteristics at presentation include median WBC 12.3 (range, 1.3-97.2) x 10⁹/L, hemoglobin 9.1 (range, 7.8-11.9) gm/dL, platelet count 22 (range, 6-365) x 10⁹/L. Additional cytogenetic abnormalities were present in 18 patients; +8 and –Y being most frequent. Three patients had kit mutations. Five patients were in complete remission at start (from other ara-C based induction) and except two deaths in induction all others achieved CR or CR with incomplete platelet recovery (CRp). Two patients died in CR from infectious complications. One patient has relapsed (initially resistant to “3=7” regimen). Median pre-treatment value for fusion transcript to Abl ratio by Q-PCR is 100 (range, 100-857). More than 3 log reduction in this median value has sustained post induction/consolidation in follow up evaluations extending up to 9 months at the time of this report. Grade≥3/4 induction toxicities included liver dysfunction (N=3, 9%), atrial fibrillation, pancreatitis, respiratory failure 1 patient each and 2 deaths in induction (one from pulmonary hemorrhage and other from intra-cranial bleed).

Induction/consolidation therapy with GO-FLAG regimen in CBF AML results in excellent clinical and molecular response. Accrual and multi-variate comparison with historical regimens used to treat patients with CBF AML at MDACC are ongoing.

Off Label Use: Use of Gemtuzumab Ozogamicin in frontline therapy of AML.