Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment In Elderly Patients with De Novo Philadelphia Positive ALL (EWALL-PH-01): Kinetic of Response, Resistance and Prognostic Significance
Authors: Rousselot Philippe , Cayuela Jean Michel , Hayette Sandrine , Récher Christian , Leguay Thibaut , Salanoubat Celia , Witz Francis , Alexis Magda , Hunault Mathilde , Janvier Maud , Agape Philippe , Berthou Christian , Jourdan Eric , Fernandes José , Sutton Laurent , Banos Anne , Reman Oumedaly , Lioure Bruno , Thomas Xavier , Ifrah Norbert , Gokbuget Nicola , Hoelzer Dieter , Delannoy Andre , Bassan Renato , Ribera Jose M. , Giebel Sebastian , Dombret Herve , Ottmann Oliver G. 
Published: October 2019

Abstract 172

Background.

Dasatinib (Sprycel®) is a potent inhibitor of BCR-ABL and SRC family kinases. Based on the rapid and clinically meaningful activity observed when dasatinib was used as a single agent a consensus has been reached by the EWALL (European Working Group for Adult ALL) to conduct an international study evaluating the combination of dasatinib and low-intensity chemotherapy in patients with Ph+ ALL aged 55 years or more.

Patients and Methods.

After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, dasatinib was administered at 140 mg QD (100 mg in patients over 70y) during the induction period in combination with IV injections of vincristine 1 mg and dexamethasone 40 mg 2 days (20 mg over 70y) repeated weekly for 4 weeks. Consolidation cycles consisted of dasatinib 100 mg/d administered sequentially with methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and L-asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of dasatinib alternating with 6-MP and methotrexate orally every other month and dexamethasone/vincristine once every 2 months for up to 24 months. Patients were molecularly monitored by a central laboratory for BCR-ABL RTQ-PCR and T315I resistance mutation ASO RTQ-PCR.

Results.

Seventy one patients were included from August 2007 to study termination in May 2010. Median age was 69.1 years (range: 58–83). Median follow-up was 16.3 months. At diagnosis, the Ph chromosome was associated with other abnormalities (complex, -7, Ph duplication or others) in 64.5% of cases. The CR rate after induction was 90% and 55.7% of the patients achieved a BCR-ABL/ABL ratio ≤0.1% at the time of CR. Failure to achieve CR was mainly related to death (n=5.7%). Serious adverse events (SAEs) during induction were infections (11%), elevated transaminases (7%), hemorrhage (5.6%), renal failure due to tumor lysis syndrome (4.2%) and cardiovascular events (5.6%). Only 2 pleural effusions were observed. During consolidation and maintenance, most frequent SAEs were infections (33.3%). One pleural effusion was observed. Nineteen patients relapsed after a median response duration of 19.2 weeks and 12 of them died. Thirteen patients presented mutations in the BCR-ABL TK domain at relapse (12 T315I, 1 F317L), no mutation was detected in 3 patients and results are pending in 3 patients. T315I ASO RTQ-PCR analysis during follow-up was predictive for relapse. The rise of the T315I signal over 0.1% was always associated with relapse and occurred 1 to 3 months before relapse in 6 of the 12 T315I cases and concomitantly in the 6 remaining patients. Four patients received RIC allogenic stem cell transplantation and were censored at the time of SCT. Median RFS and OS were 22.1 and 27.1 months, respectively. Cytogenetics findings at diagnosis were good predictors for RFS: the median RFS for patients with isolated Ph was not reached while it was 19.2 months in patients with additional cytogenetic abnormalities (p=0.03)). Molecular BCR-ABL transcript level after induction had no effect on RFS. However, a BCR-ABL ratio ≤0.1% after induction and then confirmed during consolidation was significantly associated with a better RFS (5.1 months versus not reached, p=0.006).

Conclusions.

Dasatinib combined with low-intensity chemotherapy is highly effective in elderly patients with Ph-positive ALL with a 90% CR rate and a 22.1 months RFS. Cytogenetics at diagnosis is a strong predictive factor for RFS. Most relapses were associated with the T315I mutation. Serial monitoring for T315I allowed us to predict for hematological relapse and may offer an opportunity to adapt therapy before relapse.

Disclosures:

Rousselot: Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy in Ph ALL.