Dasatinib as Front-Line Monotherapy for the Induction Treatment of Adult and Elderly Ph+ Acute Lymphoblastic Leukemia (ALL) Patients: Interim Analysis of the GIMEMA Prospective Study LAL1205.
Authors: Foa Robert , Vignetti Marco , Vitale Antonella , Meloni Giovanna , Guarini Anna , De Propris Stefania , Elia Loredana , Cimino Giuseppe , Luppi Mario , Castagnola Carlo , Sica Simona , Nieddu Rosa , Martinelli Giovanni , Baccarani Michele 
Published: October 2019

Abstract
Dasatinib (SPRYCEL, formerly BMS-354825) is a potent, orally active inhibitor of the BCR-ABL, c-KIT and SRC family of kinases, which play a critical role in oncogenesis and persistence of malignant phenotypes. In preclinical studies, dasatinib has proven to be a more potent inhibitor of BCR-ABL and c-KIT than imatinib mesylate, and has been shown to be effective in the clinical setting in patients with all phases of chronic myeloid leukemia (CML) or Ph+ ALL resistant to or intolerant of imatinib. We present the first interim results of the GIMEMA protocol LAL 1205 designed to assess the efficacy, safety and tolerability of dasatinib in Ph+ ALL patients at the onset of the disease. The protocol enrolls patients ≥18 years who receive dasatinib p.o. at a dose of 70 mg BID. A steroid regimen (prednisone up to 60mg/m2 day po) is started 7 days prior to the first dasatinib administration and is continued until day 31. The 7-day prednisone pre-phase allows identification of the BCR/ABL transcript. Dasatinib is administered for a total of 84 days. Two intrathecal methotrexate infusions at days +22 and +43 are included. All cases are processed and analyzed through central handling of samples at presentation and are investigated for morphology, immunophenotype, cytogenetics and molecular biology. Minimal residual disease (MRD) is also centrally evaluated by flow-cytometry and Q-RT-PCR at days +22, +43, +57 and +84. A total of 23 patients with BCR/ABL+ ALL have been enrolled to date; median age 57 yrs (30–74), 15 females. All 23 patients have shown a complete hematological response by day +22. One patient relapsed after completing dasatinib administration and died of disease progression, while all other patients are at present alive and well after a median time of observation from diagnosis of 4.5 months (1.7 – 8.0). Monitoring of MRD documented that dasatinib plus prednisone was capable of inducing a very marked clearance of leukemic cells already at day +22, confirmed and strengthened in the subsequent steps of observation. The results of the immunophenotypic and BCR/ABL Q-RT-PCR monitoring are reported in the accompanying table:
This interim analysis indicates that in adult and elderly Ph+ ALL induction monotherapy with dasatinib plus prednisone is capable of inducing a rapid hematological remission in all patients so far treated without important toxicity and no fatality. This is associated with a very marked and rapid debulking of the disease as documented by the close phenotypic and molecular monitoring of MRD.
DAYS IMMUNOPHENOTYPE Q-RT-PCR (% of leukemic cells) (copy number) <3% - >1% <1% - >0.01% <0.01% 0% >1 x 10² <1 x 10² +22 3/18 pts 8/18 pts 7/18 pts 0/18 pts 11/20 pts 9/20 pts +43 0/17 pts 4/17 pts 12/17 pts 1/17 pts 5/20 pts 15/20 pts +57 0/16 pts 4/16 pts 12/16 pts 0/16 pts 2/19 pts 17/19 pts +84 0/16 pts 4/16 pts 11/16 pts 1/16 pts 4/16 pts 12/16 pts