Addition of Lomustine (CCNU) to Induction and Post-Remission Chemotherapy for Fit Elderly AML Patients without Unfavorable Cytogenetics: Results of the Lamsa-2007 Goelams Trial
Authors: Pigneux Arnaud , Recher Christian , Bene Marie C , Asselineau Julien , Mineur Ariane C. , Leguay Thibaut , Delaunay Jacques , Bonmati Caroline , Guieze Romain , Luquet Isabelle , Cornillet-Lefebvre Pascale , Lacombe Catherine , Ianotto jean-Christophe , Ojeda Mario , Hunault Mathilde , Banos Anne , Lioure Bruno , Bernard Marc , Jourdan Eric , Vey Norbert , Zerazhi Hacene , Yosr Hichri , Delepine Roselyne , Salmi Rachid , Dreyfus Francois , Cahn Jean-Yves , Ifrah Norbert 
Published: October 2019

Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010).

Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR <3), with non-unfavorable cytogenetics. Secondary AML to MDS and MPS were excluded, but not AML secondary to chemotherapy or radiotherapy. As induction therapy, the patients received idarubicin 8 mg/m2/d iv on days 1-5, cytarabine 100 mg/m2/d iv on days 1-7 ± lomustine, 200 mg\m2 orally at day 1. Patients achieving complete response (CR) or CRi received then a first consolidation with idarubicin 8 mg/m2/d iv on days 1-3 and cytarabine 100 mg/m2/d s/cut on days 1-5 ± lomustine, 80 mg orally at day 1, then 6 courses of reduced doses consolidation with idarubicin 8 mg/m2/d iv on day 1 and cytarabine100 mg/m2/d s/cut on days 1-5 ± lomustine, 40 mg orally at day 1. This was followed by 6 months maintenance therapy with alternating courses of purinethol and methotrexate. The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free (EFS) survival, as well as safety.

Results: From February 2008 to December 2011, 459 patients were enrolled and 424 were evaluable. The median age of analyzed patients was 68 yo (60-81), 58% were male. Cytogenetics was favorable (5.2%), intermediate (90.3%) or failure (4.5%). Overall, 26% of the patients had a favorable genotype based on NPM, CEBPa and FLT3 ITD mutational status. The two arms were comparable for pre-treatment characteristics. There were 3.7% induction deaths in the IC arm and 7.7% in the ICL arm (p=0.11). The rate of primary resistant AML was 21.4% after IC versus 7.7% after ICL (p<10-4). CR or CRi was achieved in 74.9% of IC patients versus 84.7% in ICL patients (p= 0.01). At two years, OS was much better than expected for such a population, and improved in the ICL arm at 56% versus 48% in the IC arm. As expected at this age, a significant number of events occurred after two years, resulting in the absence of statistical significant difference for OS over the whole period of follow-up. At two years, EFS was improved in the ICL arm at 41% versus 26% in the IC arm (p=0.01). The CIR at two years was 41.2% in the ICL arm versus 60.9% in the IC arm (p=0.003). Grade 3 and 4 toxicities were significantly different between treatment arms after induction and after the first consolidation. Neutropenia <0.5 G/L was prolonged of 2 days in the ICL arm (23 versus 21 for the IC arm, p=0.0001) after induction and of 4 days (11 versus 7 for the IC arm, p<0.0001) after first consolidation. Thrombopenia < 20G/L was prolonged of 5 days in the ICL arm (19 versus 14 for the IC arm, p<0.001) after induction and of 7 days (11 versus 4 for the IC arm, p<0.001) after first consolidation.

Conclusion: Thisschedule using the same drugs at decreasing doses during induction, consolidation and reinductions provided unusually good results in the IC arm, further improved in the ICL arm by the addition of lomustine, in fit elderly AML patients without unfavorable cytogenetics, with acceptable toxicity. The higher rate of CR, reduced relapse incidence and improved EFS in the ICL arm support the anti-leukemic effect of lomustine in elderly AML patients, even if it does not translate in a significantly prolonged long term overall survival. New strategies for maintenance therapy remain to be improved in this setting to sustain this positive effect.

Disclosures

Vey: Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.