Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia : results from a randomized, placebo-controlled trial
Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary ob…
Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).
Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferat…
Clinical Course and Significance of the Novel FLT3-Y842C Mutation in a Patient with AML Treated with PKC412 Monotherapy.
Abstract We recently identified a novel mutation (Y842C) within the tyrosine kinase domain of FLT3 in a patient treated with PKC410 monotherapy (ASH 2003, # 4681). Here, we present follow up studies including the clinical course of the patient and frequency analysis in 110 patients with AML. In addition, we characterized the novel mutation using overexpression of FLT3-Y842C in 32D cells. AML M2 was diagnosed in a 63 year old, male patient in 1993. After having experienced his second relapse upon standard therapy the patient was refractory to alemtuzumab treatment. Due to reduced performance status the patient was not eligible to standard chemotherapy and was enrolled into a phase II trial i…
Sorafenib In Combination with Standard Induction and Consolidation Therapy In Elderly AML Patients: Results From a Randomized, Placebo-Controlled Phase II Trial
Abstract Abstract 333 Background: Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemotherapy is feasible (Ravandi F JCO 2010; 28:1856). Sorafenib is a potent Raf, c-Kit and FLT3 inhibitor that may also affect AML blasts and bone marrow (BM) stroma cells via VEGFR and PDGFR-β inhibition. Therefore, we performed a multicenter, randomized, placebo-controlled, double-blind phase II trial in elderly (>60 y) AML pa…
Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN).
PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene ( FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD–positive AML in complete hematologic remission after HCT were r…
Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
Contains fulltext : 218279.pdf (Publisher’s version ) (Open Access) Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (>/=0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 …
Real Life Experience with ATRA-Arsenic Trioxide Based Regimen in Acute Promyelocytic Leukemia - Updated Results of the Prospective German Intergroup Napoleon Registry
Abstract Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany …
Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain.
Activating mutations in the FLT3 tyrosine kinase (TK) occur in approximately 35% of patients with acute myeloid leukemia (AML). Therefore, targeting mutated FLT3 is an attractive therapeutic strategy, and early clinical trials testing FLT3 TK inhibitors (TKI) showed measurable clinical responses. Most of these responses were transient; however, in a subset of patients blast recurrence was preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is unclear but is of major significance for the development of future therapeutic strategies. We searched for mechanisms of resistance in 6 patients with AML who had relapses upon PKC412 treatment. In an …
Phase I/II Study of the Deacetylase Inhibitor Panobinostat As Maintenance Therapy after an Allogeneic Stem Cell Transplantation in Patients with High-Risk MDS or AML: The Panobest-Trial
Abstract Background: Leukemic relapse and graft-versus-host disease (GvHD) remain major obstacles after an allogeneic stem cell transplantation (HSCT). Panobinostat is a potent inhibitor of class I, II and IV deacetylases and has shown antileukemic as well as immunomodulatory activity. The hypothesis of our phase I/II PANOBEST trial was that panobinostat can effectively prevent relapse in patients (pts) with high-risk (HR) myeloid diseases while simultaneously reducing GvHD. We aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of panobinostat in adult pts with HR acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS…
Enhancing the Activation and Releasing the Brakes: A Double Hit Strategy to Improve NK Cell Cytotoxicity Against Multiple Myeloma
Natural killer (NK) cells are innate lymphocytes with a strong antitumor ability. In tumor patients, such as multiple myeloma (MM) patients, an elevated number of NK cells after stem cell transplantation (SCT) has been reported to be correlated with a higher overall survival rate. With the aim of improving NK cell use for adoptive cell therapy, we also addressed the cytotoxicity of patient-derived, cytokine-stimulated NK cells against MM cells at specific time points: at diagnosis and before and after autologous stem cell transplantation. Remarkably, after cytokine stimulation, the patients' NK cells did not significantly differ from those of healthy donors. In a small cohort of MM patients…
AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations
Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein α (c/EBPα) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D ce…