High Rates of Molecular Response and Low Incidence of Mutations in Patients Treated with Newly Diagnosed Chronic Myeloid Leukemia (CML) Treated with a Dose-Escalated Combination of Imatinib and Cytarabin.
Authors: Cornelissen Jan J. , Valk Peter , Verhoef Gregor E.G. , Smit Wim M. , van Marwijk-Kooij Marinus , Wittebol Shulamit , van Oers Marinus H.J. , Kluin-Nelemans Hanneke C. , Lowenberg Bob , Willemze Roelof , Schattenberg Antonius V.M.B. , Ossenkoppele Gert 
Published: October 2019

Abstract
Imatinib mesylate (IM) induces a high rate of cytogenetic remissions in first chronic phase CML, but molecular remissions are rare. A recent phase II study suggested a higher rate of molecular remissions upon treatment with 800 mg IM (Cortes et al. Blood 2004). Cytarabin (Ara-C) is an active drug in myeloid leukemias, especially when intensified dosages are applied. In-vitro studies of IM and Ara-C have been shown synergistic anti-proliferative effects. With the aim to prevent resistance and to induce an early, high rate of molecular remissions, we set out to evaluate the combination of IM and Ara-C in a dose-escalation study of consecutive cohorts treated with daily IM at dosages of 200 mg, 400 mg, 600 mg or 800 mg combined with intravenous Ara-C, added as 2 consecutive cycles of i.v. therapy at days 1–7 at a dose of 200 mg/m2/24 hrs or 1,000 mg/m2/24 hrs. Primary endpoints are dose-limiting-toxicity (DLT) and quantitative molecular response as assessed by standardized real-time Taqman PCR of bcr/abl transcripts. Patients without a major molecular response after 12 months are evaluated for mutations by direct sequencing. From the start in August 2001, thusfar 127 pts are included in cohorts I through V. The median age is 48 (20–66) years. Sofar, 2 DLTs were observed following evaluation of 112 pts, including reversible grade IV CZS toxicity (cohort IIIb, Ara-C 1,000/IM 400) and one pneumonia, complicated by lethal respiratory failure in cohort IIIa (Ara-C 200/IM 600). The median number of neutropenic (<500/m l) days following 200 and 1,000 mg/m2 Ara-C was 14 and 16, respectively. Hematological recovery appeared not significantly affected by an increased dose of IM. Opportunistic infections were predominantly central venous catheter related and 7 pneumonias, CTC grade II-III, were observed. Cohorts I-IV were demonstrated feasible, accrual is continued (cohorts IV and V) for evaluation of efficacy. Overall probabilities of developing a major (≥ 3 log reduction of bcr/abl copies) or complete (>4.5 log) molecular response were, respectively, 51% (±7) and 28% (±7) at 18 months from the start of treatment. Probabilities for major and complete cytogenetic response rates were 83% and 67%, respectively, at 18 months. Overall survival was 99 (±1) at 18 months and progression-free survival was 94% (±3). Two patients developed accelerated disease, 1 patients lost a complete hematological response. Among 30 pts without a major molecular response at 12 months, 2 pts acquired a point mutation of the Abl kinase domain resulting in amino-acid substitutions Phe359→ Val and Glu459→ Lys, respectively. These results suggest that the combination of escalated Imatinib combined with standard or intensified Ara-C may prevent resistance and mirrors the synergy of both drugs that was found in-vitro.