Results of the AFR07 Prospective Study in De Novo Philadelphia Positive ALL Patients Aged over 55 Years: Efficacy and Safety of a Glivec® Based Induction Followed by Maintenance Therapy with Glivec® and Pegasys®.
Authors: Rousselot Philippe , Recher Christian , Buzyn Agnès , Witz Francis , Vey Norbert , Escoffre-Barbe Martine , Legrand Olivier , Turlure Pascal , Huguet Françoise , Leguay Thibaut , Delaunay Jacques , Audhuy Bruno , Fohrer Cécile , Maury Sébastien , Castaigne Sylvie , Vicaux Eric , Dombret Hervé , Cayuela Jean Michel 
Published: October 2019

Abstract
Our previous report concluded that an imatinib (Glivec®) based induction may be proposed as front line therapy in elderly patients (pts) with Philadelphia positive acute lymphocytic leukemia (Ph+ ALL) (Rea et al. Leukemia, 2006;20:400–3). We decided to test this hypothesis and to evaluate the value of maintenance therapy with Pegasys® and imatinib in a prospective study of pts aged over 55 years with de novo Ph+ ALL. The protocol consisted in IV injections of vincristine 2 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks as induction and then monthly for 4 months as consolidation. Imatinib was administered at 800 mg per day during the induction period and at 600 mg/d continuously with 6 mercaptopurine during consolidation. Pts in CR were allocated to maintenance with SC injections of Pegasys 45μg once a week and continuous administration of imatinib during 2 years. BCR-ABL analysis were performed in a centralized laboratory according to the ENL recommendations. 25 pts were included from May 2005 to July 2007. Median age was 68 years and sex ratio 0,92. After a median follow up of 13.2 months (1 to 27), median overall survival and DFS were not reached. The estimated proportion of pts alive and free of relapse at 18 months was 53.7%. The CR rate was 84%. Induction failures (n=4) were due to death in 3 cases and intolerance in 1 case. Extra haematological grade 2 to 4 adverse events during induction were mainly related to vincristine (ileus in 6 cases, neuropathy in 5 cases). Median duration of neutropenia (<1 G/l) was 18 days (0 to 32). Median duration of thrombocytopenia (<100 G/l) was 25 days (9 to 45). During consolidation 4 pts died (3 from infections and one from unrelated digestive haemorrhage) and 1 patient relapsed. Eleven pts were evaluable for maintenance. Three pts relapsed after 1, 4.5 and 8.4 months, one patient died from unrelated cause. Six pts are in continuing complete remission (63.6%). Two other pts undervent autologous HSCT. Cytogenetic analysis was performed at diagnosis in 18 patients. In 10 cases (55.5%) the Ph+ chromosome was associated with complex abnormalities or monosomy 7. All pts were in major cytogenetic remission after induction with a 69.2% CCR rate. 40% of pts in CR obtained a complete molecular remission (CMR) in blood and half of them were also in CMR in bone marrow (BM). None of the pts with BM CMR relapsed whereas 2 relapses occurred in pts with CMR in blood but not in BM suggesting that BM CMR is of prognostic value. BCR-ABL TK domain mutations were systematically detected at each time point by sequencing. No mutation was found at diagnosis. At relapse, only one patient out of 4 was mutated (G250E). The AFR07 protocol is highly effective in elderly patients with Ph+ ALL. Only 4 patients relapsed. Two third of the patients treated with imatinib and Pegasys® maintenance are in continuing CR. We observed 4 deaths in CR related to haemorrhage and sepsis. Second generation TKIs will be tested in futur joint European trials.