High Levels of Tumor Load Reduction after Intensive Chemotherapy Favorably Affect the Prognosis of BCR/ABL+ ALL Adult Patients Receiving Imatinib Mesylate Alone as a Post-Consolidation Treatment According to the Italian GIMEMA LAL 0201/A Protocol.
Authors: Cimino G. , Elia L. , Pane Fabrizio , Vignetti M. , Fazi P. , Iacobelli S. , Meloni G. , Vitale A. , Martini V. , Martinelli G. , Di Raimondo F. , Bonifacio M. , Fabbiano F. , Saglio G. , Baccarani M. , Foà R. , Mandelli F. 
Published: April 2020

Thirty-six adult patients aged between 20 and 60 years (median age: 44) with BCR-ABL+ ALL were prospectively monitored by Q-RT-PCR between December 2001 to November 2005. All patients were treated according to the GIMEMA LAL 0201/A protocol, in which Imatinib alone, was administered as post-consolidation therapy, in responding patients after high-dose induction and consolidation treatment, at the dosage of 400 mg x 2 daily for at least six months and continued on the basis of the opinion of physicians. Twenty-three (64%) were p190+ and 13 (36%) p210+. At presentation, the median BCR-ABL/ABL ratio was 1.33 (range 0.23 to 7.8). Before Imatinib, all patients were in 1st CR (34 after the first induction and consolidation course; 2 after a salvage treatment). At this time point, the median reduction from baseline in BCR-ABL transcripts, calculated for each individual patients, was 2.1 log (range: 0 to 6.1). In particular, 18 of the 36 cases showing a log reduction of the BCR-ABL/ABL ratio &gt; 2.1 (p190=14 cases; p210 = 4 cases) were considered as good responders to the antecedent chemotherapies, whereas 18 cases (p190=9; p210=9 cases) showing a log reduction ≤2.1 were considered as bad responders. The median reduction from baseline in BCR-ABL levels was 2.49 log (range: 0.00–6.1) and 1.45 log ( range: 0.19–5.34) in p190 and p210 positive cases, respectively (p=.16). During Imatinib treatment, 10 (56%) of the 18 poor responders patients presented a relapse of disease versus 5 (28%) ( 3 =BM; 2=CNS) of the 18 good responders.At last follow-up 16 patients were in first CR; of these patients, only 4 were allo-transplanted (2 good, 2 bad responders), therefore 12 (9 good, 3 bad responders) persisted in first CR maintained by Imatinib alone after a median follow-up of 24 months (range: 7–48). At 24 months, the cumulative incidence of relapse was 29% vs 44% for good and bad responders (p=.034), respectively, whereas, the DFS and OS rates were 65% vs 33% ( p=.0032) and 76% vs 32% (p=.0056) for good and poor responder patients, respectively. Monitoring of MRD was prospectively evaluated at the starting of Imatinib therapy and afterwards at the 3rd, 5th and 6th month. At these time points, the median BCR-BCR/ABL ratio were 0.015, −0.006, −0.008 and −0.009, respectively. In addition to the classification as good/ bad responders, the current variation of BCR-ABL ratio (used as time-dependent covariate in a Cox model), was associated with an increase of the hazard of failure (hazard ratio of an increase by 2 log of the BCR-ABL levels compared to a constant ratio equal to 2.1). In conclusion, Imatinib mesylate is a highly effective post-consolidation treatment for adult Ph+ ALL patients. However, the clinical outcome after Imatinib was significantly affected by the level of molecular response evaluated before the starting of Imatinib, resulting excellent for the good responders but remaining dismal for patients who responded poorly to the initial chemotherapy.