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Background: Besides the extensively studied point mutations in the BCR/ABL TK domain as the clinically most important cause of imatinib (IM) resistance either in CML and Philadelphia-positive (Ph+) ALL, additional acquired genetic events contributing to resistance/disease progression are not fully understood. Many evidences suggest that the enhanced survival and differentiation arrest of the CML blast crisis (BC) cells depends on the cooperation of BCR/ABL with other genes deregulated during disease progression. A recent study has identified RUNX1/AML1 transcription factor gene as a modulator of the cellular response towards IM in vitro and in vivo in mice, suggesting its possible involvement in disease persistence in IM-resistant CML patients. Purpose: We investigated RUNX1 molecular abnormalities (point mutations or cryptic chromosomal RUNX1 translocation to a novel recently described gene partner PRDM16 at 1p36) in 18 Ph+ leukemias. The observation that RUNX1 mutated allele is frequently duplicated by acquired trisomy of the altered chromosome 21 in acute myeloblastic leukemias (AML) prompt us to focus our analysis on a selected cohort (1 CP-CML, 3 AP-CML, 8 myeloid BC, 1 lymphoid BC, 2 de novo Ph+ ALL-B, 1 de novo AML and 1 therapy-related- Ph+ ALL) presenting acquired trisomy 21 along disease course. Methods: From peripheral blood leucocytes, recurrent mutations were investigated by sequencing DNA PCR fragments corresponding to exon 3 to 8 of RUNX1. RUNX1-PRDM16 fusion was investigated by RT-PCR (i.e. RUNX1 exon 5-PRDM16 exon 2 junction) and by FISH using the TEL/AML1 dual color/dual fusion translocation probes (Vysis, Downer’s grove, IL, USA). Results: We report a high frequency (33%) of recurrent point mutations (4 in myeloid BC CML and 1 in CP-CML) within the DNA-binding region of RUNX1. We did not find any mutation in de novo BCR/ABL+ ALLs or lymphoid BC CMLs. Onset of RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21. We also report a high frequency of RUNX1-PRDM16 fusion for 3 out of 7 investigated patients: 2 CMLs and, for the first time reported to our knowledge, 1 therapy-related BCR/ABL+ ALL. RUNX1-PRDM16 is probably transcribed at low levels since only few bone marrow metaphases with trisomy 21 were t(1;21)(p36;q22) positive. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. All these events are associated with a poor survival: 14 out of 18 patients died with a median survival of 3 months after the diagnosis of the acquired clonal trisomy 21. Furthermore, none of the patients in our study raised durable optimal responses to IM. Conclusion: Our data support the concept of a cooperative effect of BCR/ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR/ABL+ ALL. Our findings also support that it may exist a heterogeneous genetic status at diagnosis of CML, underlying the need of further investigations able to define more precisely the molecular disease characteristics at diagnosis for better therapeutic decision adjustments.

The purpose of the registry is to collect existing cases of pts who failed imatinib therapy. Since the drug has been registered most of information on safety and efficacy were collected through clinical trials. Thus the true rate of failure is currently unknown. Members of the European LeukemiaNet agreed to establish a subregistry with the aim of collecting these cases. Failure is defined as efficacy failure i.e. no hematological response (HR) or cytogenetic response (CyR), unsatisfactory response, loss of response, according to the European Guidelines criteria (Baccarani et al, Blood 2006) and documented toxicity leading to discontinuation of imatinib. Objectives are to describe the sub-categories of failure and main toxicities, demographic patterns, clinical and biological profiles of pts (at diagnosis, at the beginning of imatinib therapy, at time of failure), dose and duration of imatinib therapy until failure was recorded, therapeutic decision after failure, and survival status. Eligibility criteria: To be included in the Registry, pts who failed imatinib therapy must be 18 years old or more with Ph+ CML in chronic phase at the onset of imatinib therapy. Pts are eligible, being included in prospective studies or not. Data collection: based on notification, data is prospectively centralized and quality controlled. The planned period for registration is 2005–2007 and 1000 cases are expected. Final analyses will be conducted overall, by groups: imatinib first line/not first line and by categories of failures. Results: As of July, 2006, 378 pts,(M: 56%, F 44%), were recorded. Median age at diagnosis was 51 (range 12–80). Participating countries were: Austria (4 pts), Denmark (13), Finland (18), France (236), Germany (39), Israel (34), Italy (10), Netherlands (11), Spain (13). Thirty seven percent of pts were never included in prospective studies at the time of failure. Reason for registration was no or unsatisfactory response in 30% of the cases including no complete HR (2%), not any CyR (12%), no major CyR (16%). Loss of responses occurred in 41% of the cases including hematological relapse (6%) cytogenetic relapse or progression (12%), progression to accelerated phase or blast crisis (23%). Discontinuation because of toxicity was recorded in 13% of the cases. Sixteen percent of the pts presented toxicity combined with unsatisfactory response. Policy: The IFP sub-registry is supported by a grant from the 6th European framework program “LifeSciHealth”. This collaborative study is linked with the European CML Registry (Work Package 4). This study is conducted in accordance with principles and guidelines of the European Community and Helsinki protocol and was approved by French authorities. In conclusion, this registry has been successfully established and already provides important information on subcategories of imatinib failure pts.