A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia

This phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n=252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.     

A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia

Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.     

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.     

A multivariate model for predicting induction response and prognosis in core binding factor acute myeloid leukemia

正Objective To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities,therefore optimizing the treatment strategies.Methods Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification.Complete remission (CR) rate,disease-free survival (DFS) and overall survival (OS) were assessed by     

Spontaneous molecular response of IDH2 acute myeloid leukemia

Annals of Hematology -     

Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.     

A phase 2 study of vorinostat in acute myeloid leukemia

Background

This two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia.

Design and Methods

Patients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest.

Results

Data from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment.

Conclusions

Vorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients’ and physicians’ preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00305773","term_id":"NCT00305773"}}NCT00305773.     

A critical role for Lyn in acute myeloid leukemia

Receptor or nonreceptor tyrosine kinases (TKs) are known to play an important role in leukemogenesis. Here we studied the level of protein tyrosine phosphorylations in a series of fresh AML samples and evaluated the effect of TK inhibitors. Compared with normal hematopoietic progenitors, a high level of tyrosine phosphorylation was detected in most acute myeloid leukemia (AML) samples. The Src family kinases (SFKs) appeared constitutively activated in most cases, including in the CD34(+)CD38(-)CD123(+) compartment as revealed by the level of phosphorylated tyrosine 416. Lyn was the major SFK family member expressed in an active form in AML cells where it was abnormally distributed throughout the plasma membrane and the cytosol as opposed to normal hematopoietic progenitors. The SFK inhibitor, PP2, strongly reduced the global level of tyrosine phosphorylations, inhibited cell proliferation, and induced apoptosis in patient samples without affecting normal granulomonocytic colony forming units. Moreover, silencing Lyn expression by small interfering RNA in primary AML cells strongly inhibited proliferation. Interestingly, a link between Lyn and the mTOR pathway was observed as PP2 and a Lyn knockdown both affected the phosphorylation of mTOR targets without inhibiting Akt phosphorylation. Lyn should be considered as a novel pharmacologic target for AML therapy.     

Network pharmacology-based strategy for predicting therapy targets of Tripterygium wilfordii on acute myeloid leukemia

This is a study on the potential therapeutic targets and pharmacological mechanism of Tripterygium wilfordii (TW) in acute myeloid leukemia (AML) based on network pharmacology.Active components of TW were obtained by network pharmacology through oral bioavailability, drug-likeness filtration. Comparative analysis was used to investigate the overlapping genes between active ingredient''s targets and AML treatment-related targets. Using STRING database to analyze interactions among overlapping genes. Both KEGG pathway analysis and Gene Ontology enrichment analysis were conducted in DAVID. These genes were analyzed for survival in OncoLnc database.We screened 53 active ingredients; the results of comparative analysis showed that 8 active ingredients had an effect on AML treatment. On the basis of the active ingredients and overlapping genes, we constructed the Drug-Compounds-Genes-Disease Network. Survival analysis of overlapping genes indicated that some targets possessed a significant influence on patients’ survival and prognosis. The enrichment analysis showed that the main pathways of targets were Toll-like receptor signaling pathway, NF-kappa B signaling pathway, and HIF-1 signaling pathway.This study, using a network pharmacologic approach, provides another strategy that can help us to understand the mechanisms by which TW treats AML comprehensively.     

Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC(50) values; 100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.     

急性髓性白血病的靶向治疗

目前,急性髓性白血病(AML)传统化疗的疗效已难以提高.在慢性粒细胞白血病确定了BCR-ABL可以作为有效的靶点,并合成了特异针对该靶点的药物伊马替尼,伊马替尼在临床上取得了非常好的疗效.通过研究AML的分子生物学、免疫表型和细胞生物学异常,从而确定有效的治疗靶点,合成特异的靶向治疗药物,可能会进一步提高白血病疗效.过去的十年,在AML的靶向治疗领域取得了巨大的进展,本文将对这些进展进行简述.