Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia

Abstract

Purpose Chronic lymphocytic leukemia (CLL) patients refractory to fludarabine based therapies have poor outcomes with currently available therapies. Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients and Methods Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. Results One hundred and sixty five patients were enrolled at 34 centers, and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Conclusion Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Clinical responses were observed in patients with high risk clinical and genomic features. With careful monitoring, alvocidib has a manageable safety profile. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

“…The drug concentrations tested in our validation studies were in the range of clinically achievable concentrations for each of the KIs, with achievable plasma concentrations of 0.25 mM, 0.5 mM, and up to 1.1 mM reported for sunitinib, [56][57][58][59][60] ibrutinib (NCT01105247), 66 and idelalisib (NCT00710528, NCT01090414), 48 respectively. P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 sunitinib Other KIs such as dasatinib [67][68][69][70][71] and flavoperidol [72][73][74] were identified as having a high total kill with venetoclax ( Figure 3A, arrow and arrowhead, respectively). In combination with venetoclax in vitro, dasatinib ranked in position 10 of 31 licensed drugs and its venetoclax-enhanced effect was intermediate and detected in only 5 of 13 patients ( Figure 3A-B, arrow).…”

“…Alvocidib had high clinical activity in patients with advanced fludarabinerefractory CLL; however, acute tumor lysis syndrome limited its use clinically. 74 Given that tumor lysis syndrome is associated with both alvocidib and venetoclax, 9,74 combining the 2 agents might be too toxic. DMSO venetoclax P34 P35 P36 P37 P38 P39 P34 P35 P36 P37 P38 P39 P34 P35 P36 P37 P38 P39 sunitinib A1210477 Unstimulated 2S stimulated navitoclax P34 P35 P36 P37 P38 P39 P34 P35 P36 P37 P38 P39 P34 P35 P36 P37 P38 P39 sunitinib A1210477 Our results suggest that a personalized drug selection based on screening may identify clinically relevant drugs that can overcome resistance to venetoclax by altering microenvironmental signaling pathways (Figure 7Biii).…”

Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia

“…[2][3][4] Despite these advances, 5-year overall survival (OS) remains dismal (;20%) among adults age $60 years treated at academic centers and on multiinstitutional clinical trials by using established first-line regimens. 5,6 European population-based analyses have similarly revealed suboptimal outcomes in this population. [7][8][9][10] Emerging novel agents provide substantial antileukemic effect with manageable toxicity and may represent attractive therapeutic strategies for older patients with ALL, either as components of initial therapy or as treatment at relapse.…”

“…3 The pan-CDK inhibitor flavopiridol demonstrated clinical efficacy 4,5 but was associated with tumor lysis syndrome (TLS), which occurred in 25% of patients, some of whom required hemodialysis. 6 Dinaciclib is a novel, potent, small-molecule CDK inhibitor that selectively inhibits CDK1, 2, 5, and 9 at 50% inhibitory concentration values in the 1-to 4-nM range. 7,8 In in vitro studies, dinaciclib induced apoptosis and/or cell growth arrest in various solid and hematopoietic tumor cell models.…”

Cell cycle proteins as promising targets in cancer therapy

“…Although flavopiridol exhibited significant anti-tumour activity in preclinical studies 111 , clinical phase II studies reported insufficient efficacy for solid cancers. However, some evidence for clinical activity was observed in haematological malignancies (TABLE 2) 113, 114 .…”