Dasatinib (Sprycel®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Positive ALL: Results of the First 22 Patients Included in the EWALL-Ph-01 Trial (on Behalf of the European Working Group on Adult ALL (EWALL))
Authors: Rousselot Philippe , Cayuela Jean-Michel , Recher Christian , Leguay Thibaut , Salanoubat Célia , Witz Francis , Alexis Magda , Janvier Maud , Hunault Mathilde , Agape Philippe , Berthou Christian , Jourdan Eric , Fernandes José , Sutton Laurent , Banos Anne , Reman Oumedaly , Lioure Bruno , Gökbuget Nicola , Hoelzer Dieter , Delannoy André , Bassan Renato , Ribera Jose-Maria , Giebel Sebastian , Hayette Sandrine , Ottmann Oliver , Dombret Hervé 
Published: April 2020

Abstract
Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood. 2007;110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories.
A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1).
The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).