Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa D Marin 1 , S Marktel 1 , M Bua 1 , RM Szydlo 1 , A Franceschino 1 , I Nathan 1 , N Foot 1 , C Crawley 1 , T Na Nakorn 1 , E Olavarria 1 , A Lennard 2 , A Neylon 2 , SG O’Brien 2 , JM Goldman 1 and JF Apperley 1 1 Department of Haematology, Imperial College London at Hammersmith Hospital, London, UK; and 2 Department of Haematology, Royal Victoria Infirmary, Newcastle, UK We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-a failure and were thus eligible for treatment with imatinib at the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (o35% Ph- negative marrow metaphases) at 3 months as principal independent predictive factors and incorporated them into a three-tier prognostic scoring system for individual patients. For patients in the low-, intermediate- and high-risk groups, the probabilities of survival at 24 months were 100, 82 and 40% (Po0.0001) and progression-free survival 100, 66 and 15% (Po0.0001), respectively. This Hammersmith prognostic scor- ing system was validated with an independent cohort of patients treated at another UK centre. Leukemia (2003) 17, 1448–1453. doi:10.1038/sj.leu.2402996 Keywords: chronic myeloid leukaemia; imatinib mesylate; cytogenetic response; neutropenia; prognostic factors Introduction Chronic myeloid leukaemia (CML) is a clonal haematological malignancy that results from transformation of a multipotent haematopoietic stem cell. 1 This transformation is believed to be due to the constitutive activation of the kinase component of the BCR-ABL oncoprotein present in the leukaemia cells from 495% of patients with CML. Typically, CML is diagnosed while still in a readily defined chronic phase (CP) that can usually be controlled with ease for some years. Invariably, the disease progresses eventually to a more advanced phase which is usually subclassified as either accelerated phase or blastic transformation; the latter phase is especially resistant to therapy and leads to death within 6–8 months. 2 Allogeneic stem cell transplant is the only therapy that can cure CML, but age and lack of a suitable donor limit this procedure to a minority of patients. 3 Interferon-a (IFNa) has until recently been the gold standard for treating patients who are not candidates for transplant. With IFNa therapy the best survival is seen in patients who achieve complete cytogenetic response (CCR) 4 and thus achievement of CCR has been one of the main targets of treatment in CML and can be considered as a surrogate marker for survival. 4 Imatinib mesylate, a synthetic ATP analogue, occupies the ATP-binding site of the ABL tyrosine kinase component of the BCR-ABL oncoprotein and maintains it in an inactive conforma- tion. 5,6 It is given orally, is well tolerated, and has a manageable side-effect profile. Preliminary results from phase II and III trials suggest that CCR can be obtained in a proportion of patients in all phases of the disease. 7,8 In the ongoing phase III study involving previously untreated patients in chronic phase, progression-free survival (PFS) is significantly better for patients treated initially with imatinib compared with the combination of IFNa and cytarabine. 9 We have treated with imatinib a series of patients with CML in chronic phase who were resistant to or intolerant of IFNa. We have tried to identify those patients most likely to benefit from continuing imatinib therapy by construct- ing a scoring system based on criteria defined after 3 months of treatment. The system has been validated with an independent cohort of patients. Patients and methods Patients Between January 2000 and January 2003, 145 patients with CML in chronic phase who had failed IFNa (defined as refractory to or intolerant of IFNa 10 ) were treated with imatinib (previously STI571, Glivec s ) at the Hammersmith Hospital as part of various multicentre phase II clinical studies. Written informed consent was obtained from all patients before enrolment. Blood samples were taken for analysis weekly for the first 6 weeks and then at monthly intervals. Bone marrow samples for morphology and cytogenetics were taken at baseline and thereafter at 3- month intervals. The characteristics of the patients were typical of those with IFNa-treated ‘late’ chronic phase (Table 1). The median interval from diagnosis to starting imatinib was 4.2 years. The median follow-up after starting imatinib was 734 days; 98% of the patients were followed for at least 365 days. Imatinib was administered as described by others. 7,10 Briefly, a single oral dose of 200–800 mg daily was given according to tolerance and response. Doses were reduced in the presence of grades III–IV thrombocytopenia or neutropenia or if there was grades II–IV nonhaematological toxicity; wherever possible doses were maintained above 300 mg/day. If a patient failed to achieve or lost a complete haematological response or a CCR, the dose of imatinib was increased in 200 mg steps to a maximum of 800 mg daily. Definitions of disease phase and cytogenetic response Chronic phase was defined as fulfilling all the following criteria: (a) peripheral and marrow blasts both less than 15%, (b) peripheral or marrow blasts plus promyelocytes less than 30%, (c) peripheral or marrow basophils less than 20%, and (d) platelets greater than 100  10 9 /l. 7,10 Disease progression was defined as progression to advanced phase (accelerated phase or blastic transformation as defined by Kantarjian et al. 8,10,11 Clonal evolution alone (ie the presence of any new cytogenetic abnormality) in the absence of features of advanced phase was not considered evidence of disease progression. 7,10 Cytogenetic Received 17 December 2002; accepted 25 March 2003 Correspondence: Professor JM Goldman, Department of Haematol- ogy, Imperial College London at Hammersmith Hospital, Du Cane Road, London W12 0NN, UK; Fax: +44 20 8749 2748 Leukemia (2003) 17, 1448–1453 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu SPOTLIGHT