Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).
University Research Compliance Office and informed consent was obtained from all subjects involved in the study. The clinical research was conducted in accordance with the Declaration of Helsinki. The trial was registered at www.ClinicalTrials.gov as # NCT00890929.
The primary objective of this study was to determine the vorinostat dose with the most favorable efficacy and toxicity when combined with azacitidine and GO. Methods Study population
3288 Introduction: The elderly constitute the majority of patients (pts) with AML. Effective and tolerable therapeutic alternatives are necessary for these pts, in whom outcomes with standard induction therapy are poor. Azacitidine (AZA), a DNA methyltransferase inhibitor, decreases methylation of tumor suppressor gene (TSG) promoters, which correlates with clinical responses. Lenalidomide (LEN), an immunomodulatory and anti-angiogenic agent, has anti-leukemic activity when used as a single agent. We hypothesized that combining these two agents would decrease promoter methylation and upregulate TSG expression. We present the Phase I results of a Phase I/II clinical trial that sequentially combines AZA with LEN in elderly, previously untreated AML pts. Methods: Eligible pts were ≥ 60 years, had a World Health Organization-confirmed diagnosis of non-M3 AML, a performance status (PS) ≤ 2, adequate organ function, no prior leukemia therapy and were not candidates for standard induction. All pts had a white blood cell count ≤ 10,000/mm3 at the time of study entry; the use of hydroxyurea to attain this was permitted. Pts were enrolled into 4 cohorts using a 3+3 dose escalation design. In cohort 1, pts received 75 mg/m2 AZA SC/IV on d 1–7, followed by 21 days of observation for a 28-day cycle. At the completion of this “cycle 0,” pts were escalated to cycle 1, in which they received the same dose and schedule of AZA followed by LEN 5 mg PO daily on d 8–28, and then observation on d 29–42. Cohorts 2, 3 and 4 received the same dose and schedule of AZA with LEN doses of 10, 25 and 50 mg respectively, at the same schedule described for cycle 1. Intra-cohort dose escalation after cycle 0 was not permitted. Baseline bone marrow biopsies were compared to biopsies obtained after cycles 0, 1, 3, 6 and 12, and response assessments were based on International Working Group criteria. Adverse events (AEs) were graded according to the NCI CTCAE v 3.0. Pts were eligible for a maximum of 12 cycles, provided they tolerated therapy and achieved a response (defined as a complete response [CR], a CR with incomplete recovery of blood counts [CRi] or a partial response [PR]). Result: Eighteen pts were enrolled between April 2009 and July 2010. The median age was 72 years (64-86), 67% were male and 94% were Caucasian. The median PS was 1 (0-2) and the median hematopoietic cell transplant comorbidity index score was 0.5 (0-4). Six of 18 (33%) required hydroxyurea prior to enrollment. Seven of 18 (39%) had de novo AML and 11/18 (61%) had secondary AML (1 therapy-related, 1 evolved from primary myelofibrosis and 9 with myelodysplasia-related changes). The median bone marrow blast percentage was 63.5% (21-91%). Three of 18 (17%) pts had adverse cytogenetics, while 15/18 (83%) pts exhibited intermediate grade cytogenetics (11/15 with normal karyotype). Grade 3 serious AEs with a suspected relationship to treatment included neutropenic fever (NF) (n=5), fatigue (n=3), renal insufficiency (n=2), hyponatremia (n=1) and bleeding (n=1). In Cohort 4, 1/6 pts experienced grade 4 NF; however, 5/6 did not experience DLT, and therefore, the MTD was not reached. Pts have completed a median of 2 treatment cycles (0-6), with a median follow up of 94 days (21-275). Presently, of the 17 evaluable pts, 9/17 (53%) are alive. The overall response rate (ORR; defined as CR+CRi+PR) is 8/17 (47%) and the CR+CRi rate is 4/17 (24%). Thirty-day mortality was 12% (2/17); both deaths occurred in the first cohort in pts who had not received the drug combination, and were related to disease progression. Of the 5 pts enrolled in cohort 1, none responded, and all ultimately died of disease progression. However, among those in cohorts 2–4, 9 of 12 (75%) evaluable pts are alive with an ORR of 67% (CR+CRi= 4/12 [33%]), a median of 104 days after initiation of treatment (42-275). No responder has relapsed to date. Of the 3 post-cohort 1 deaths, 1 was from disease progression and 2 were from infectious complications. Conclusion: The sequential combination of AZA and LEN was well tolerated in elderly, untreated AML pts. The MTD was not reached at the highest dosing cohort, and the Phase II dose and schedule is AZA 75 mg/m2 d 1–7 and LEN 50 mg d 8–28, on a 6-week cycle schedule. The preliminary ORR of 47% is encouraging, as is the 67% ORR in pts who received ≥10 mg of LEN. Six month follow up will be presented. This trial was registered at ClinicalTrials.gov as NCT00890929. Disclosures: Off Label Use: Azacitidine and lenalidomide for AML. Liedtke:Celgene: Lecture Fee, Research Funding.
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