Randomized Comparison of Imatinib Versus Imatinib Combination Therapies in Newly Diagnosed Chronic Myeloid Leukaemia (CML) Patients in Chronic Phase (CP): First Results of the Phase III (SPIRIT) Trial from the French CML Group (FI LMC)
Authors: Guilhot Francois , Mahon François-Xavier , Guilhot Joelle , Rigual-Huguet Francoise , Maloisel Frederic , Rousselot Philippe , Gardembas Martine , Corm Selim , Guerci Agnes , Vekhoff Anne , Etienne Gabriel , Legros Laurence , Kiladjian Jean- Jacques , Jourdan Eric , Schoenwald Michele , Berger Marc , Eclache Virginie , Roche-Lestienne Catherine , Nicolini Franck E , Preudhomme Claude 
Published: April 2020

Imatinib (IM) at 400 mg daily is the first line therapy for newly diagnosed CML patients (pts); however, less than 50% of major molecular responses (MMR) are obtained at 12 months. To improve these results, we designed a phase III, multicenter, open-label, prospective randomized trial. The reference arm was IM 400 mg daily (n=159). The 3 experimental arms were IM 600 mg daily (n=160), IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles)(n=158) and IM 400mg in combination with Peg-IFN alfa-2a (Peg-IFN2a, 90 μg weekly) (n=159). Treatment was delivered at least 12 months or until treatment failure (disease progression) or major toxicity. The primary endpoint is the overall survival. Other endpoints are: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response (major molecular response ie MMR) and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization was stratified according to Sokal risk groups. The current interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization was planned in order to select the best experimental arm for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months was centralized, blinded and calculated according to International score (IS). Pts were recruited between 9/2003 and 10/2007.[median age 51 yrs (18–82), 62% of pts were male; Sokal distribution was low risk 33%, intermediate risk 41% and 27% high risk]. Median follow-up is 36 months (range 8–57) at the time of analysis. Overall, at 3 months 86 % of pts achieved complete hematologic response. The MCyR, CCyR and MMR rates at 6 and 12 months are:

IM-400 IM-600 IM-Ara-c IM-PegIFN *p&lt; 10−2 (overall); ** p&lt;10−2 (overall) At 6 months (636 pts, ITT) MCyR 74% 79% 68% 74% CCyR * 48% 67% 55% 56% At 12months (562 evaluable pts) MCyR 64% 76% 77% 74% CCyR 57% 65% 66% 71% MMR at 6 months** 21% 33% 27% 39% MMR at 12 months 40% 52% 51% 61%

Interestingly the rate of MMR at 6 months was significantly higher for IM-PegIFN as compared with IM-400 (p&lt;10−3). The 4-log reduction rate in the BCR-ABL/ABL transcript were 18%, 21%, 22%, 34%, for the IM-400, IM-600, IM-Ara-c and IM-PegIFN arms respectively. The corresponding numbers of undetectable (complete molecular response) pts were 2%, 2%, 3% and 9% at 12 months respectively. Grade 3/4 neutropenia and/or thrombocytopenia occurred in 8% of IM-400 pts, in 14% of IM-600 pts, in 41% of IMAra- c pts and in 40% of IM-PegIFN pts respectively. Grade 3/4 non hematological events were reported in 19% of IM-400 pts, in 30% of IM-600 pts, in 27% of IM Ara-c pts and in 31% of IM-PegIFN pts. Among them a relationship between treatment and event was suspected for 21 pts (13%) with IM-400 (7 liver toxicity; 7 oedema+muscle cramps), for 31 pts (19%) with IM-600 (7 liver toxicity, 11 oedema+ muscle cramps) for 36 pts (23%) with IM-Ara-c (2 liver toxicity; 10 gut side effect) and for 47 pts (29%) with IM-PegIFN (6 liver toxicity, 13 skin rash). Discontinuation of experimental treatment occurred within the first 6 and 12 months in 26% and 18% of IM-Ara-c pts and in 35% and 11% pts of IM-PegIFN pts respectively. Within the first 12 months 36% of 600-IM pts reduced their dosage. Although a substantial number of pts stopped PegIFN, this first analysis indicates the usefulness of a combination of IM-PegIFN for the initial treatment of pts with CML CP with a significant molecular response rate improvement. Complete analysis of the 636 pts with a follow-up of 12 months will be presented.