A multicenter total therapy strategy for <i>de novo</i> adult Philadelphia chromosome positive acute lymphoblastic leukemia patients: final results of the GIMEMA LAL1509 protocol

Abstract

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era

“…Due to the relatively small number of patients with p210 studied, we could not perform survival analysis between the two transcripts in the setting of TKIs-2nd. Of note, the results from other studies performed on dasatinib, blinatumomab, and allo-HSCT showed no difference in prognosis between p190 and p210 [ 22 , 27 , 28 , 31 ]. These results suggest that the adverse prognosis of p210 can be offset by a highly potent therapy.…”

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

“…Moreover, to reduce the initial treatment toxicity, several phase 2 trials evaluated chemotherapy-free induction regimens based on steroids and TKIs administration as an alternative to systemic chemotherapy for patients younger than 60 years and fit for intensive treatment [ 26 , 53 , 54 , 55 , 56 , 57 ]. Patients in CR1 received subsequently chemotherapy with TKIs and allo-HSCT if eligible.…”

“…CR rates were >95% for most of these trials, with no or few deaths in induction, and irrespective of the administered TKI (imatinib or dasatinib). Long-term survival seems to be improved with dasatinib compared to imatinib administration, probably due to deeper molecular response [ 54 , 56 ]. However, relapses remain a matter of concern, especially for patients who did not undergo allo-HSCT.…”

Applicability of droplet digital polymerase chain reaction for minimal residual disease monitoring in Philadelphia‐positive acute lymphoblastic leukaemia

“…time polymerase chain reaction (Q-RT-PCR); (ii) an induction therapy based on tyrosine kinase inhibitors (TKI) with [3][4][5][6][7] or without chemotherapy [8][9][10][11][12][13] ; (iii) an accurate minimal residual disease (MRD) monitoring to evaluate the response to therapy, to personalize treatment and predict relapse. [14][15][16][17][18] Since the outcome of adult patients with Ph + ALL has greatly improved following the introduction of TKIs and may be further improved by combining this class of compounds with immunotherapeutic strategies, 12 MRD negativity must be considered the primary goal of treatment.…”