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. 2021 Jul 1;106(7):1828-1838.
doi: 10.3324/haematol.2020.260935.

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  1 , Michela Ansuinelli  2 , Antonella Vitale  2 , Loredana Elia  2 , Mabel Matarazzo  2 , Alfonso Piciocchi  3 , Paola Fazi  3 , Francesco Di Raimondo  4 , Lidia Santoro  5 , Francesco Fabbiano  6 , Catello Califano  7 , Giovanni Martinelli  8 , Francesca Ronco  9 , Felicetto Ferrara  10 , Nicola Cascavilla  11 , Catia Bigazzi  12 , Alessandra Tedeschi  13 , Simona Sica  14 , Nicola Di Renzo  15 , Angela Melpignano  16 , Germana Beltrami  17 , Marco Vignetti  3 , Robin Foa  18
Affiliations

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 et al. Haematologica. .

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.

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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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