Showing papers by "Stefan Faderl published in 2016"
TL;DR: Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission.
Abstract: Nucleoside analogues are highly active in patients with hairy cell leukaemia (HCL); however, patients continue to relapse. This phase II study evaluated the efficacy and safety of cladribine followed by rituximab in patients with untreated HCL (N = 59), relapsed HCL (N = 14) and HCL variant (HCLv, N = 7). Cladribine 5·6 mg/m(2) was given intravenously (IV) daily for 5 d and was followed approximately 1 month later with rituximab 375 mg/m(2) IV weekly for 8 weeks. Complete response rate in patients with untreated HCL, relapsed HCL and HCLv was 100%, 100% and 86%, respectively. With a median follow up of 60 months, 5-year failure-free survival (FFS) in patients with untreated HCL, relapsed HCL and HCLv was 95%, 100% and 64%, respectively. Median duration of response to the cladribine followed by rituximab was significantly longer than the first-line cladribine single agent in patients who received this treatment as second-line treatment (72 months vs not reached, P = 0·004). Almost all patients (94%) achieved negative minimal residual disease (MRD) after the treatment. Positive MRD during the follow up did not necessarily result in clinically relevant relapse. Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission.
64 citations
TL;DR: Hypoxia markers HIF‐1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy, which has shown limited activity in heavily pretreated leukemia patients.
Abstract: Tumor hypoxia causes resistance to radiation and chemotherapy Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915) In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11) Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL Patients had received a median of five prior therapies In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) The continuous infusion MTD was a daily dose of 330 mg/m(2) Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A Evofosfamide has shown limited activity in heavily pretreated leukemia patients Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted Am J Hematol 91:800-805, 2016 © 2016 Wiley Periodicals, Inc
30 citations
TL;DR: It is found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells.
Abstract: In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3 However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells.
29 citations
Harvard University1, Roswell Park Cancer Institute2, Sarah Cannon Research Institute3, Fred Hutchinson Cancer Research Center4, City of Hope National Medical Center5, Duke University6, Cleveland Clinic7, Albert Einstein College of Medicine8, Yale University9, University of Michigan10, University of Texas MD Anderson Cancer Center11
TL;DR: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2); preliminary assessment of efficacy including changes in MRD burden and response duration.
26 citations
TL;DR: The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL, suggesting a role of competent immune system in supporting the efficacy of this treatment.
Abstract: Purpose: We evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment. Experimental Design: Thirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3–6, and once every other course during courses 7–24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed. Results: The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders. Conclusions: The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359–67. ©2016 AACR .
23 citations
TL;DR: Among patients with CLL receiving first-line FCR, the best pre-treatment predictor of achieving MRD-negativity and subsequent longer PFS was IGHV-M, and patients with IGHv-M who achieved MRD -negativity after 3 courses had a particularly favorable outcome, even after abbreviation of therapy.
6 citations
TL;DR: This data indicates that whileparenteral hypomethylating agents induce hematologic response in ~50% of pts with IPSS higher-risk MDS, options are very limited for nonresponding pts who are at high risk of MDS.
Abstract: TPS7078Background: Whileparenteral hypomethylating agents (HMAs) induce hematologic response in ~50% of pts with IPSS higher-risk MDS, options are very limited for nonresponding pts who are at high...
1 citations