与急性粒细胞白血病

Todd A Fehniger Hematology Grand Round March 13, 2009,Lenalidomide therapy for untreated acute myeloid leukemia in older adults ( 60 years of age),Disclosure,Clinical study funded in part by Celgene Non-FDA approved use of Revlimid (lenalidomide),Case,71 yo M presented with dyspnea, fatigue, and pancytopenia Performance status: ECOG 1 PMH: HTN, GERD, BPH PE: petechiae, pale CBC WBC 1900/uL (ANC 190/uL) Hgb 6.7 g/dL Plts 74,000/uLf Differential: 33% blasts,Blood 113: 1002, 2009,Case,Bone marrow biopsy and aspirate 30% cellular 90% myeloblasts FAB M0 (undifferentiated) Flow: CD34+CD33+CD13+CD117+ Routine cytogenetics: trisomy 13 47,XY+135/46,XY15 FLT3ITD: Positive,Blood 113: 1002, 2009,Case: Dx Bone Marrow and Cytogenetics,BM Aspirate,Leder stain,Acute Myeloid Leukemia in patients 60 year old,Median age of AML is 65-70 13, 410 new AML cases / 8,990 deaths in 2007 14.5/100,000 in adults 60 years 0.7/100,00 in adults 60 years Majority of patients do not receive specific therapy (best supportive care) Median survival 1 year,Older AML: Prognosis and Standard Therapies?,7+3: median survival 8-13 months Low dose ara-c: 9 months NCCN: Investigational agents recommended as 1st line therapy Prognosis, Results with current therapy options, and overview of investigational agents Summarized in Mike Martins WashU Heme/Onc grand rounds presentation from February 2008 Martin and Abboud. Bood Rev 22:311, 2008 Eliah Estey J Clin Oncol 25:1908, 2007,Older AML biology: continuum with myelodysplastic syndrome (MDS),Cytogenetics in older AML lower percentage of favorable risk cytogenetics t(8;14), t(15;17), inv(16) Higher percentage of unfavorable cytogenetics -5, -7, +8, complex Frequently arises from MDS or initial diagnoses as AML with multilineage dysplasia Resistant to traditional chemotherapy (MDR1) Presentation with a hypoproliferative, MDS type picture common,MDS and lenalidomide,Efficacy of lenalidomide in MDS. List A et al. NEJM 352:549 2005 Lenalidomide in MDS with 5q deletion. List A et al. NEJM 355:1456,2006 Phase 2 study of lenalidomide in transfusion-dependent, low and int-1 risk MDS with karyotypes other than deletion 5q. Blood 111:86, 2008. A small number of patients with clonal cytogenetic abnormalities (non-5q-) and excess blasts had cytogenetic responses and CRs,(I presented this topic at WashU Heme/Onc Grand Rounds 6/10/2005 as a fellow: my interest led to the current study!),Hypothesis: Lenalidomide has activity in acute myeloid leukemia,One of my fellow clinical protocols (with Ravi Vij),Study design,Phase II, single-institution, investigator-initiated, prospective, open-label study Simon 2 stage design (n=12 evaluable in stage 1) Primary Endpoint: CR (CRc/CRm/CRi) IWG criteria with addition of SD Secondary Endpoints: safety, IWG response criteria, overall survival, event-free survival, and duration of remission Eligibility: Untreated AML age 60 yo (prior MDS, therapy related, de novo all eligible) Exclude: 5q- and favorable risk cytogenetics,Stage 1 / Cohort 1 Schema,Cheson JCO 2007,IWG Criteria for AML,06-0907: Stage 1 (Cohort 1) Results,WHO IWG Criteria: (n=15 total patients) CRc: 1 (duration: 9 months) PR: 2 (duration: 6 and 12 months - ongoing) SD: 4 (duration: 3, 3, 4, 7 months) Treatment failure indeterminate cause: 6 Rash, Sepsis, Cardiac Arrest Progressive disease 2 cycles Len (n=3) Morphologic leukemia free BM at d15 w/ PD at d30 Treatment failure resistant disease: 2,Len,(No Len),Stage 2 / Cohort 2 Schema,Stage 2 = Cohort 2 N=27 patients Independent analysis,Preliminary Results Cohort 2 (n=25 so far),Unpublished,Case: Clinical Course Pt. 007,Case: Follow-up,BM (%),0,20,40,60,80,100,Day 0,Day 15,Day 30,Day 75,LD,cycle 1,BM blasts,BM cellularity,WBC count,Hemoglobin (g/dL),0,2,4,6,8,10,12,Day 0,Day 15,Day 30,Day 75,LD,cycle 1,Hemoglobin,Platelets,0,2.0,4.0,6.0,8.0,10.0,0,50,100,200,250,300,Platelets (x103/L),WBC (x 103/L),150,CR Aspirate 100X,CR Leder 10X,CR Leder 100X,Lenalidomide: Mechanism?,Block Angiogenesis,Direct Effects on tumor,Alter cytokine profiles,Immune modulation,Phosphatase modulation,Lenalidomide (Revlimid),Multiple Myeloma,Lymphoma,MDS (w/ 5q-),Activity,Potential Mechanism(s),CLL,AML,Lenalidomide has activity in AML how does it work?,Modulation of NK cell responses? Correlative studies evaluating NK cells prior to, during, and after therapy Direct effects on AML? BM blasts at Dx: In vitro lenalidomide exposure, follow blast cell death compared to vehicle; correlation to response? Leukemia microenvironment? Flow for CXCR4 on AML blasts,This would be a great project for a fellow!,Acknowledgments,Ravi Vij Alissa Nelson Kim T