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

Sabina Chiaretti, Michela Ansuinelli, Antonella Vitale, Loredana Elia, Mabel Matarazzo, Alfonso Piciocchi, Paola Fazi, Francesco Di Raimondo, Lidia Santoro, Francesco Fabbiano, Catello Califano, Giovanni Martinelli, Francesca Ronco, Felicetto Ferrara, Nicola Cascavilla, Catia Bigazzi, Alessandra Tedeschi, Simona Sica, Nicola Di Renzo, Angela Melpignano, Germana Beltrami, Marco Vignetti, Robin Foa, Sabina Chiaretti, Michela Ansuinelli, Antonella Vitale, Loredana Elia, Mabel Matarazzo, Alfonso Piciocchi, Paola Fazi, Francesco Di Raimondo, Lidia Santoro, Francesco Fabbiano, Catello Califano, Giovanni Martinelli, Francesca Ronco, Felicetto Ferrara, Nicola Cascavilla, Catia Bigazzi, Alessandra Tedeschi, Simona Sica, Nicola Di Renzo, Angela Melpignano, Germana Beltrami, Marco Vignetti, Robin Foa

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.

Figures

Figure 1.
Figure 1.
Protocol scheme and patients’ disposition. Dashed lines represent protocol deviation. n= number; CHR: complete hematologic remission; CMR: complete molecular response; allo-SCT: allogeneic stem cell transplant; MRD: minimal residual disease; CTX: cyclophosphamide.
Figure 2.
Figure 2.
Minimal residual disease clearance. Patients were stratified according to fusion protein (A) and molecular status at the end of induction (B). CMR: complete molecular response; d= day.
Figure 3.
Figure 3.
Cumulative incidence of relapse. CI: Confidence Interval; CHR: complete hematologic remission; yrs: years.
Figure 4.
Figure 4.
Survival estimates. (A) Disease-free survival (DFS) and (B) overall survival (OS). CI: Confidence Interval; CHR: complete hematologic remission; yrs: years.
Figure 5.
Figure 5.
Survival stratified according to molecular response at the end of induction. (A) Disease-free survival (DFS) and (B) overall survival (OS). CI: Confidence Interval; CHR: complete hematologic remission; yrs: years.
Figure 6.
Figure 6.
Impact of genetic lesions on survival. (A) Disease-free survival (DFS) and (B) overall survival (OS) of IKZF1 deletion with or without other abnormalities. CI: Confidence Interval; CHR: complete hematologic remission; yrs: years.

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