In:
Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 921-921
Kurzfassung:
Abstract 921 This 3+3 dose escalation phase I trial by the German MDS study group aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of sequential azacitidine (AZA) 75 mg/m2 for 5 days followed by 14 days of up to 25 mg lenalidomide (LEN) in patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and del(5q) cytogenetic abnormalities. Twenty patients (median age 69 years) were enrolled, including 16 (80%) with complex cytogenetic abnormalities and 65% of patients harboring at least one TP53 mutation. Nine patients (45%) had no prior treatment while relapse or progression to single agent azacitidine or lenalidomide treatment (30%) and allogeneic HSCT (15%) were the most common regimens among previously treated patients. Three of 6 patients treated with LEN at the 25 mg dose level experienced DLTs, with 20 mg subsequently identified as MTD. All eligible patients experienced treatment-related Grade 3/4 thrombocytopenia and neutropenia. Hematologic responses occurred in 4 of 9 (44%) previously untreated patients with complex karyotypes, including 3 with a TP53 mutation and were preceded by a significant decrease of del(5q) CD34+ progenitor cells in the blood during cycle 1. In fact, compared with baseline, the percentage of peripheral blood CD34+ cells with del(5q) clone was decreased in the hematologic responders after 1 cycle of azacitidine followed by lenalidomide therapy (P = 0.001) (Figure 1A). In contrast, the percentage of peripheral blood CD34+ cells with del(5q) remained unchanged in hematologic non-responders (Figure 1B). By applying TP53 mutation directed deep-sequencing technology we observed a concomitant early reduction and disappearance of minimal residual disease in MDS patients achieving a complete cytogenetic response. In one patient, a reemergence of the TP53 clone was observed later despite continuation of the treatment but by consolidation (lower dose and every 8 weeks compared to 4 weeks with induction) and it preceded the hematologic and cytogenetic relapse by several months. In conclusion, in a population of higher-risk MDS/AML patients with del(5q) that included a high proportion of patients with complex karyotypes and mutations of TP53, the sequential combination of azacitidine and lenalidomide was shown to be a feasible and potentially effective treatment strategy, even in those patients with TP53 -mutated clones. We additionally observed a correlation between the percentage of peripheral CD34+ cells with del(5q) and hematologic response, suggesting that monitoring of this cell population may be a surrogate marker of response in this setting. Our results encourage an application of sequential azacitidine and lenalidomide as first line therapy for higher-risk MDS patients in future trials. (A) HEMATOLOGIC RESPONDERS (B) HEMATOLOGIC NON-RESPONDERS (A) HEMATOLOGIC RESPONDERS (B) HEMATOLOGIC NON-RESPONDERS Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V120.21.921.921
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2012
ZDB Id:
1468538-3
ZDB Id:
80069-7
