Deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and a-interferon. Huntly et al. (Blood 2003) suggest that der(9) deletions are associated with lower response rates and shorter time to progression. Quintas-Cardama et al. (Blood 2005) did not find any difference related with der(9) deletions. In these 2 studies, some patients received imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. European LeukemiaNet (ELN) recommendations include der(9) deletions among the warnings, requiring a careful monitoring of the patient. Aim. To investigate the prognostic value of der(9) deletions, we performed an analysis by age groups of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Methods. 559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. The presence of a der(9) deletion has been investigated by FISH in 521/559 at enrollment: 60 (12%) showed a der(9) deletion and 461 (88%) did not. The 2 groups, with/without deletions, were comparable (no significant difference in age, Sokal risk, imatinib dose). Median observation time is currently 42 (1-64) months. FISH analysis of bone marrow cells at diagnosis was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. Response monitoring was based on conventional cytogenetic examination every 6 months and quantitative molecular (Q-PCR) evaluations (PB) after 3, 6 and 12 months on imatinib (every 6 months thereafter). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+. Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1%IS . Events (ELN criteria for failure): no CHR at 6 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at 18 months, loss of CHR, loss of CCgR, progression and death. Results. Overall, the cumulative incidence of CCgR and MMR was 92%/91% and 88%/87% in patients with/without der(9) deletions. The probability of Event Free Survival, Progression Free Survival and Overall Survival was 82%/80%, 89%/90 and 93%/91 respectively. No difference was statistically significant. Conclusions. When investigated by FISH, the presence of der(9) deletions do not constitute a poor prognostic factor in early CP CML patients treated with imatinib: the cytogenetic and molecular response rates in the 2 groups, with and without der(9) deletions, are superimposable. No differences in outcome have been observed. This long-term outcome evaluation suggests that a redefinition of ELN warnings would be advisable.

DELETIONS OF THE DERIVATIVE CHROMOSOME 9 DO NOT INFLUENCE THE OUTCOME OF CHRONIC MYELOID LEUKEMIA IN EARLY CHRONIC PHASE TREATED WITH IMATINIB MESYLATE: A GIMEMA CML WP ANALYSIS OF 521 CONSECUTIVE PATIENTS

CUNEO, Antonio;
2009

Abstract

Deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and a-interferon. Huntly et al. (Blood 2003) suggest that der(9) deletions are associated with lower response rates and shorter time to progression. Quintas-Cardama et al. (Blood 2005) did not find any difference related with der(9) deletions. In these 2 studies, some patients received imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. European LeukemiaNet (ELN) recommendations include der(9) deletions among the warnings, requiring a careful monitoring of the patient. Aim. To investigate the prognostic value of der(9) deletions, we performed an analysis by age groups of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Methods. 559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. The presence of a der(9) deletion has been investigated by FISH in 521/559 at enrollment: 60 (12%) showed a der(9) deletion and 461 (88%) did not. The 2 groups, with/without deletions, were comparable (no significant difference in age, Sokal risk, imatinib dose). Median observation time is currently 42 (1-64) months. FISH analysis of bone marrow cells at diagnosis was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. Response monitoring was based on conventional cytogenetic examination every 6 months and quantitative molecular (Q-PCR) evaluations (PB) after 3, 6 and 12 months on imatinib (every 6 months thereafter). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+. Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1%IS . Events (ELN criteria for failure): no CHR at 6 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at 18 months, loss of CHR, loss of CCgR, progression and death. Results. Overall, the cumulative incidence of CCgR and MMR was 92%/91% and 88%/87% in patients with/without der(9) deletions. The probability of Event Free Survival, Progression Free Survival and Overall Survival was 82%/80%, 89%/90 and 93%/91 respectively. No difference was statistically significant. Conclusions. When investigated by FISH, the presence of der(9) deletions do not constitute a poor prognostic factor in early CP CML patients treated with imatinib: the cytogenetic and molecular response rates in the 2 groups, with and without der(9) deletions, are superimposable. No differences in outcome have been observed. This long-term outcome evaluation suggests that a redefinition of ELN warnings would be advisable.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1401605
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