In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2608-2608
Abstract:
Abstract 2608 Aim. CBF-AML is a favorable AML subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, respectively responsible for RUNX1-RUNX1T1 (CBFα) or CBFB-MYH11 (CBFβ) gene fusion. Nonetheless, relapse incidence may reach 30–40% in these patients. The tyrosine kinase (TK) receptor KIT is expressed in the vast majority of CBF-AML and activating KIT gene mutations, including exon 8 del/ins and exon 17 point mutations, have been reported in both CBF-AML subtypes. These mutations have been retrospectively associated with a higher risk of relapse. Dasatinib is a TK inhibitor active on both wild-type and mutant KIT isoforms. These observations led several groups to initiate prospective trials testing dasatinib/chemotherapy combinations in newly diagnosed CBF-AML patients. The aim of the present Phase 2 DASA-CBF trial (EudracCT 2006-00655-12) was to search for a positive signal by treating CBF-AML patients in first complete remission (CR), but with persistent or re-appearing molecular minimal residual disease (MRD), by the single-agent dasatinib. Prevention of further hematological relapse was the primary endpoint. Methods. Eligible patients (18–60y) had to have been previously enrolled and treated in the CBF-2006 study (Jourdan et al. this meeting). MRD was quantified by RQ-PCR and results were expressed as 100 × CBF fusion gene/cABL ratios. Patients in first CR were eligible if: 1) MRD ratio reduction less than 3-Log before the second consolidation cycle (refractory Mol-REF patients); or 2) MRD ratio re-increase more than 1-Log on two successive evaluations (relapsing Mol-REL patients). Patients with a sibling or unrelated donor and no contra-indication to allogeneic stem cell transplantation (SCT) were not eligible. Dasatinib was administered orally at 140 mg once daily for a total duration of 12 months. In case of grade 3 adverse event (AE), treatment was discontinuated until AE resolution to grade 0–1. In case of grade 4 AE or AE reappearance, dose reduction to 100 mg/d was allowed. Dose escalation to 90 mg bid was allowed in case of stable or increasing MRD after 2 months of therapy without toxicity. Results. Between June 2008 and June 2011, 26 CBF-AML patients (median age, 44y) were included. They were 12 CBFα patients (6 Mol-REF, 6 Mol-REL) and 14 CBFβ patients (12 Mol-REF, 2 Mol-REL). Seven patients had a KIT mutation (4 exon 8 and 3 exon 17; 3 CBFα and 4 CBFβ). The median time between CR achievement and DASA-CBF enrollment was 161 days (106–406) in Mol-REF patients and 413 days (167–530) in Mol-REL patients. Overall, dasatinib was well tolerated. Two grade 3 AEs (hypertension, headache) led to dasatinib dose reduction without further reoccurrence. Dose escalation was performed in two patients. With the exception of one patient (without KIT mutation) still alive in CR1 at 929 days, 7 of the 8 Mol-REL patients had rapid hematological relapse under dasatinib treatment after a median time of 60 days (52–120). In the 18 Mol-REF patients, the probability of persistent hematological remission was 65% (95% CI, 38–82) at 12 months and 45% (95% CI, 20–67) at 24 months, with a trend for shorter remission duration in the 6 patients with KIT mutation (P=0.07). These 18 Mol-REF patients were compared to the 37 other Mol-REF patients from the CBF-2006 trial not enrolled in the DASA-CBF trial (9 SCT in CR1, 28 without further therapy). Both series were comparable in terms of age, WBC, baseline fusion transcript ratio, MRD ratio Log-reduction after induction and first HDAC consolidation, as well as additional cytogenetic anomalies and KIT, FLT3 and RAS gene mutations. Despite dasatinib treatment, the probability of persistent hematological remission was not higher in the 18 DASA-CBF patients than in the 28 patients who received no further therapy (45% versus 53% at 24 months, P=0.91). Conversely, only one hematological relapse was observed in the 9 patients who received SCT in CR1, the remaining 8 patients being alive in continuous CR. Conclusion. This Phase 2 trial failed to show a significant effect of single-agent dasatinib in the prevention of hematological relapse in CBF-AML patients in first CR after standard therapy, but at high risk of relapse because of persistent or re-appearing MRD. Moreover, no trend towards a preferential effect was observed in KIT mutated patients. This observation does not preclude any dasatinib activity in CBF-AML patients when combined with conventional chemotherapy. Disclosures: Off Label Use: Dasatinib is not approved for AML patients. Mohamed:Bristol-Myers Squibb: Employment.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.2608.2608
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
