Search

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.Janssen ResearchDevelopment, LLC.

Background/Aims: Acute myeloid leukemia (AML) is an aggressive cancer with limited treatment options outside of chemotherapy. Improved therapies with novel mechanisms of action are desperately needed to fill this need. Both hTERT, the catalytic subunit of telomerase, and BCL-2, an apoptotic regulator, are overexpressed in AML, correlating with disease severity and poor prognosis respectively. Imetelstat is a novel, first-in-class competitive inhibitor of telomerase with clinical activity in hematologic malignancies. Venetoclax, an approved BCL-2 inhibitor for CLL, has shown a promising clinical benefit in AML patients. Preclinical evidence shows that downregulation of hTERT induces apoptosis via disruptions of hTERT and BCL-2 interaction; we hypothesize that inhibiting both targets would yield greater anti-tumor activity in AML compared to treatment with either agent alone. Methods: AML cell lines and AML patient’s PBMC samples were treated with imetelstat or venetoclax alone, or in combination, and viable and apoptotic populations of cells were evaluated by flow cytometry. Telomerase activity, hTERT expression and mitochondrial dysfunction were investigated for mechanism of action. Furthermore, an in vivo study in the MOLM-13 AML disseminated model was conducted to assess efficacy and survival. Results: A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. Similarly enhanced apoptotic activity was also observed in PBMCs purified from 4 AML patient whole blood samples. Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone. Furthermore, in vivo studies showed all mice tolerated the combination of imetelstat with ABT-199 well, with increased life span as compared to the vehicle control (68.1%, p=0.0001), to imetelstat (39.6%, p=0.0011) alone, or to venetoclax (23.3%, p=0.0001) alone. In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit. Conclusions: To our knowledge, this is the first investigation combining imetelstat with venetoclax in AML, and the results demonstrated a synergistic effect on induction of apoptosis in cell lines and patient samples in vitro, which translated into prolonged survival in xenograft models, thus providing a strong rationale for clinical exploration of this combination. Citation Format: Joshua J. Rusbuldt, Leopoldo Luistro, Diana Chin, Melissa Smith, Amy Wong, Margarita Romero, Aleksandra Rizo, Jacqueline Bussolari, Fei Huang, Amy (Kate) Sasser. Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1101. doi:10.1158/1538-7445.AM2017-1101

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by 1 or more peripheral blood cytopenias.Anemia is the most common cytopenia associated with low-grade MDS (based on the International Prognostic Scoring System). Erythropoiesis-stimulating agents (ESA) are commonly used as frontline treatment of anemia in patients (pts) with low-grade MDS; red blood cell transfusions are also important in supportive care. The present database analysis was conducted to understand the transfusion burden and outcomes among pts in the United States who were diagnosed with low- or unspecified-grade MDS and treated with ESA. Methods: A retrospective analysis of theOptum integrated claims and Electronic Medical Record database ("Optum Database") identified pts aged ≥ 18 years with an index diagnosis of MDS (low-grade, ICD 9 code: 238.72; high-grade, ICD 9 code: 283.73; del(5q), ICD 9 code: 238.74; or unspecified-grade, ICD 9 code: 238.75) between 2006 and 2014 who had 365 days of retrospective data preceding index diagnosis. Pts with baseline acute myeloid leukemia were excluded. Demographics and clinical outcomes were analyzed by descriptive summary. Kaplan-Meier survival analysis was performed to define overall survival (OS) and time to transfusion dependence or transfusion independence. Results: Among the 8,493 pts in the Optum Database who met the inclusion criteria, MDS was categorized as low-grade in 2,136 (25.2%), high-grade in 367 (4.3%), del(5q) in 198 (2.3%), and unspecified-grade in 5,792 (68.2%); median follow-up was 2.3 years. In each MDS category, roughly half of pts were male, and the majority were white and non-Hispanic. Median ages at diagnosis were 75, 74, 74, and 76 years, and 977 (46%), 224 (61%), 83 (42%), and 2,071 (36%) received ≥ 1 treatment in the low-grade, high-grade, del(5q), and unspecified-grade MDS categories, respectively. Frontline therapy with ESA was the mainstay of treatment for pts with low-grade (n = 732; 75%) and unspecified-grade (n = 1,284; 62%) MDS. Average durations of frontline treatment with ESA were 228.1 and 204.5 days in pts with low-grade and unspecified-grade MDS, respectively. Median OS among low- and unspecified-grade MDS pts receiving frontline ESA was 5.4 and 4.6 years, respectively. Of the pts who received frontline ESA, 53 (7.2%) with low-grade and 107 (8.3%) with unspecified-grade MDS were transfusion dependent (≥ 2 transfusions in the 16 weeks prior to treatment initiation). Transfusion dependence in pts receiving frontline ESA was associated with shorter median OS vs transfusion independence (1.7 years vs 5.7 years in low-grade MDS, P < 0.0001; 1.7 years vs 5.2 years in unspecified-grade MDS, P < 0.0001;Figure 1). Among the 160 frontline ESA pts with low-/unspecified-grade MDS who were transfusion dependent, 108 (68%) became transfusion independent (defined as ≥ 60 days without transfusion; 37 of 53 with low-grade MDS; 71 of 107 with unspecified-grade MDS); median time to transfusion independence was 137 and 139 days in pts with low-grade and unspecified-grade MDS, respectively. Most pts with low- or unspecified-grade MDS who received frontline ESA (52% and 51%, respectively) went on to receive second-line treatment, and treatment with ESA was the most common second-line therapy (42% and 40%, respectively). 163 (8.7%) of post-front-line ESA pts were transfusion dependent. Among pts with low-/unspecified-grade MDS who received second-line therapy, median OS was shorter for those who were transfusion dependent after frontline treatment with ESA vs those who were transfusion independent (1.97 years vs 4.5 years, respectively, P < 0.001). 92 (56%) of these transfusion-dependent pts became transfusion independent in a median of 181 days. Conclusions: ESA therapy was the most common treatment approach, both frontline and second-line, for pts with low- or unspecified-grade MDS; however, treatment with ESA did not always eliminate the need for transfusion. Similar to previous reports in pts with low-grade MDS, survival outcomes were substantially worse if pts were transfusion dependent prior to frontline or second-line treatment or became transfusion dependent following frontline treatment. These data indicate the critical importance for treatments to reduce transfusion burden among pts with MDS, in both the frontline and relapsed settings. Disclosures Mehra: Janssen: Employment, Equity Ownership. Potluri:Janssen Research & Development, LLC: Other: Contracted to perform research; SmartAnalyst, Inc.: Employment. He:Janssen Global Services, LLC: Employment, Equity Ownership. Rizo:Janssen Research & Development, LLC: Employment, Equity Ownership. Mundle:Janssen Research & Development, LLC: Employment, Equity Ownership. Bussolari:Janssen Research & Development, LLC: Employment, Equity Ownership.