Page 59 - 2021_07-Haematologica-web

Final results of the GIMEMA LAL1509 for Ph+ ALL
Introduction
Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) was historically recognized as the ALL subset with the most unfavorable outcome. The Ph chromosome desig- nates the shortened chromosome 22 which encodes the BCR-ABL fusion gene/protein kinase. It arises from a translocation termed t(9;22)(q34;q11) and leads to BCR- ABL1 rearrangement.1 The incidence of the Ph+ ALL increases with age, is detected in more than 50% of elderly B-lineage ALL patients, and represents the most common genetic abnormality in adult ALL.2-4
The advent of tyrosine kinase inhibitors (TKI) has dra- matically changed the management and the prognosis of this high-risk group of patients.5-9 In fact, in the pre-TKI era, treatment with standard chemotherapy rarely produced sustained complete remissions and less than 20% of Ph+ ALL patients were long-term survivors. Allogeneic stem cell transplant (allo-SCT), when feasible according to age and comorbidities, represented the only possibility of cure, if complete hematologic remission (CHR) was achieved.10-12 Nowadays, TKI with5,9,13-15 or without7,8,16,17 systemic chemotherapy in induction represent the gold standard approach. TKI-based schemes have led to a significant improvement in terms of CHR, reached in virtually all patients, disease-free survival (DFS) and overall survival (OS) rates. Nevertheless, the combination of TKI with con- ventional chemotherapy is aggravated by toxicities and treatment-related mortalities and a 2-7% death rate during induction has been reported in different studies.9,13,18 De- intensified chemotherapy regimens have been utilized to limit toxicity associated with the combined use of a TKI and standard chemotherapy.19,20
In order to overcome the treatment-related toxicity of the combined TKI-chemotherapy approach, the GIMEMA (Gruppo Italiano Malattie EMatolologiche dell’Adulto) group has applied - over the past 15 years - a chemotehrapy-free induction strategy using first, second or third generation TKI in combination with steroids and cen- tral nervous system (CNS) prophylaxis. The first trial with imatinib (clinicaltrials gov. Identifier: LAL0201) was designed for elderly patients (>60 years) and represented the proof of principle that CHR could be achieved without the use of systemic chemotherapy in Ph+ ALL.7 In the fol- lowing study (clinicaltrials gov. Identifier: LAL0904) the same induction backbone was applied to adults up to the age of 60 years of age and patients received chemotherapy as consolidation treatment; if feasible by donor availability and clinical fitness, patients then underwent allo-SCT. The results of this study showed an OS and DFS at 60 months of 48.8% and 45.8%, respectively.17 The subsequent GIMEMA trial (clinicaltrials gov. Identifier: LAL1205) used the second generation TKI dasatinib for 12 weeks as first- line induction treatment for all Ph+ ALL over 18 years of age and with no upper age limit. All 53 patients obtained CHR at the end of the induction with eight patients (15.1%) being in complete molecular response (CMR) and no deaths or progressions were recorded during induction; consolidation was left to each treating center. At 20 months, the OS was 69.2% and the DFS was 51.1%.16 In the subsequent GIMEMA LAL1509 protocol the same induction strategy was utilized - dasatinib in combination with steroids together with CNS prophylaxis - followed by a consolidation strategy modulated according to the molec- ular response upon induction: patients in CMR continued
dasatinib until relapse/progression, while patients who did not reach CMR status continued with systemic chemother- apy and/or allo-SCT. We herein report the final results of the study.
Methods
Study design, therapy and endpoint
The GIMEMA LAL1509 trial (clinicaltrials gov. Identifier: EudraCT 2010-019119-39) was designed for adult Ph+ ALL patients (18-60 years). The identification of the BCR-ABL1 tran- script was performed centrally within the steroid pre-phase (see below). Induction consisted of 12 weeks of dasatinib administra- tion (140 mg/day), preceded by a 7-day steroid pre-phase (escalat- ing doses from 20 up to 60 mg/m2): steroids were administered for 24 days, then tapered until day 31. Patients continued treatment with dasatinib until day 84 after induction, cases in CMR contin- ued dasatinib until progression or minimal residual disease (MRD) increase or occurrence of toxicity (grade ≥3). MRD-positive patients were stratified according to transplant eligibility: i) those with a promptly available human leukocyte antigen-compatible donor proceeded to an allo-SCT (by protocol guidelines, a hap- loidentical donor was not permitted); ii) those with a compatible, but not readily available donor, received one chemotherapy con- solidation cycle prior to allo-SCT; iii) those non-eligible for allo- SCT received two chemotherapy consolidation cycles. The first consolidation cycle consisted of clofarabine (40 mg/m2, days 1-5) and cyclophosphamide (400 mg/m2, days 1-5); the second consol- idation cycle consisted of 3 days of the same combination; dasa- tinib was interrupted during the 5 and 3 days of chemotherapy consolidation to avoid excessive toxicity and was restarted as soon as possible, at hematologic recovery. Upon consolidation, patients received dasatinib, until intolerance or relapse. Figure 1 summa- rizes the treatment scheme and patients’ disposition.
CNS prophylaxis is detailed in the Online Supplementary MaterialsandMethods.
The primary endpoint of the study was to evaluate the rate of patients alive in CHR.
The study was approved by the Ethics Committees of all partic- ipating centers; patients gave their written informed consent in accordance with the Declaration of Helsinki.
Hematologic response assessment
CHR was defined as bone marrow (BM) containing less than 5% blasts, absence of blasts in the peripheral blood (PB) and no extramedullary involvement. Hematologic relapse was defined as the re-appearance of blasts in the BM and/or in extramedullary sites.
Molecular diagnosis, definition of molecular response and MRD monitoring
Molecular analyses were centrally performed at the Hematology Center of the Sapienza University of Rome. Molecular testing was carried out to identify the presence of BCR-ABL1 gene in BM sam- ples at baseline and for MRD monitoring. MRD monitoring was performed by quantitative real-time polymerase chain reacxtion21,22 during induction at days +22, +45, +57 and +85 (end of induction) and at fixed time points according to the post-induction therapy (Online Supplementary Materials and Methods). CMR was defined as a BCR-ABL1/ABL1=0, with a confirmatory molecular BM aspirate after 15 days. Molecular relapse was defined as an at least 2-log increase of the BCR-ABL1/ABL1 gene expression confirmed in an additional control, which was solicited as soon as a molecular increase was documented.
haematologica | 2021; 106(7)
1829