A Prospective Monocentric Study of Fractionated Gemtuzumab Ozogamicin (GO) Combined to Standard-Dose Cytarabine in Older Patients with Acute Myeloid Leukemia (AML) in First Relapse,
Authors: Pilorge Sylvain , Rigaudeau Sophie , Sarkozy Clémentine , Taksin Anne L , Farhat Hassan , Merabet Fatiha , Anitei Marcela , Ghez Stéphanie , Raggueneau Victoria , Garcia Isabel , Renneville Aline , Preudhomme Claude , Castaigne Sylvie , Rousselot Philippe 
Published: October 2019

Abstract
Abstract 3603

Aim.
Gemtuzumab Ozogamicin (GO) is a potent antibody-directed chemotherapy against CD33 antigen. We have previously conducted a phase 2 study evaluating fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 combined to standard 3+7 DNR/cytarabine in patients aged 50 to 70 years with relapsed acute myeloid leukemia (AML) (Farhat et al., AJH, accepted). We decided to determine whether the omission of daunorubicin may retain the efficacy of fractionated GO combined to standard-dose cytarabine.

Methods.
GO was proposed to patients (pts) with CD33 positive AML in relapse according to the French Temporary Authorization (ATU) program. All consecutive pts from our center were eligible if they were in first relapse and aged of 50 years or more. Refractory patients and patients with a first CR of less than 6 months were excluded. Induction consisted of cytarabine 200 mg/m2/d CI on day 1–7 with GO at 3 mg/m2/d on day 1, 4 and 7. Pts achieving CR/CRp received two consolidation courses with cytarabine 1 g/m2/12h on day 1–2 with GO at 3 mg/m2/d on day 1. A maintenance phase with low-dose cytarabine was allowed. Minimal residual disease (MRD) monitoring based on NPM1 mutation or WT1 expression was assessed in informative and evaluable patients.

Results.
From October 2007 to June 2011, 22 pts (median age, 67 years) were recruited. All pts received an intensive regimen as part of their first line therapy (3+7 schedule or more intensive). Median duration of first CR was 16 months (6 to 33). Cytogenetic analysis at relapse was successfully assessed in all pts and karyotype was classified as favorable in 3 pts (t(8;21); t(16;16); t(15;17)), intermediate in 18 pts and adverse in 1 pt. Molecular profile analysis of intermediate-risk patients revealed the presence of a FLT3 internal tandem duplication (FLT3 -ITD) in 3 pts, a NPM1 mutation in 8 pts (including 2 cases with a concomitant FLT3 -ITD), a single CEBPA mutation in 1 pt, a EVI1 hyperexpression in 2 pts, and a MLL rearrangement in 1 pt. CR+CRp was achieved in 17/22 pts (77.3%) including 2 CRp. The 5 primary resistant pts corresponded to 1 pt with complex karyotype, 1 pt with a MLL rearrangement, 1 pt with EVI1 hyper expression, 1 pt with FLT3 -ITD, and 1 pt without any identified genetic alteration. There were 2 (9%) induction deaths including one patient that experienced veino-occlusive disease (VOD) and one patient with severe sepsis. A second case of reversible grade 2 VOD was documented during induction. Four patients (18.1%) experienced G3-4 infections and only one severe mucositis was observed. Median duration of G3-4 neutropenia and thrombocytopenia was 24 days (16–30) and 30 days (20–60), respectively. Prolonged grade ≥ 3 thrombocytopenia was observed in 2 patients. With a median follow-up of 22 months, median DFS was 17.2 months and estimated at 66.3% at 18 months. To date, the duration of CR2 was superior to that of CR1 in 5 non transplanted patients. Median overall survival was 22.6 months. Four pts who received a reduced intensity allogeneic stem cell transplantation in CR2, and one of them subsequently died. We were able to compare the molecular response obtained after CR2 and after CR1 using the same MRD marker in 6 patients that achieved CR2. In 5 out of 6 paired samples, MRD levels after CR2 were found equal or inferior to MRD levels after CR1 (see fig 1).

Conclusion.
Fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) combined to standard-dose cytarabine in older pts with AML in first relapse is associated with a high CR rate, a prolonged survival and a low rate of toxic deaths. A gain in MRD levels was noted in paired CR1 and CR2 samples.

Disclosures:
Castaigne: Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.