Changchun Deng

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.

Preclinical Pharmacologic Evaluation of Pralatrexate and Romidepsin Confirms Potent Synergy of the Combination in a Murine Model of Human T-cell Lymphoma

Purpose: T-cell lymphomas (TCL) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in noninvasive imaging modalities, such as surface bioluminescence (SBL) and three-dimensional ultrasound (3D-US), are challenging conventional approaches in xenograft modeling relying on caliper measurements. The recent approval of pralatrexate and romidepsin creates an obvious combination that could produce meaningful activity in TCL, which is yet to be studied in combination. Experimental Design: High-throughput screening and multimodality imaging approach of SBL and 3D-US in a xenograft NOG mouse model of TCL were used to explore the in vitro and in vivo activity of pralatrexate and romidepsin in combination. Corresponding mass spectrometry–based pharmacokinetic and immunohistochemistry-based pharmacodynamic analyses of xenograft tumors were performed to better understand a mechanistic basis for the drug:drug interaction. Results: In vitro, pralatrexate and romidepsin exhibited concentration-dependent synergism in combination against a panel of TCL cell lines. In a NOG murine model of TCL, the combination of pralatrexate and romidepsin exhibited enhanced efficacy compared with either drug alone across a spectrum of tumors using complementary imaging modalities, such as SBL and 3D-US. Conclusions: Collectively, these data strongly suggest that the combination of pralatrexate and romidepsin merits clinical study in patients with TCLs. Clin Cancer Res; 21(9); 2096–106. ©2015 AACR.

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1–2 trial

BACKGROUND Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkins lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkins lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkins lymphoma and anaplastic large-T-cell lymphoma. METHODS In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkins lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331. FINDINGS Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkins lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths. INTERPRETATION This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkins lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant. FUNDING Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health.

A phase 1/2 trial of ublituximab, a novel anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL) or chronic lymphocytic leukaemia (CLL). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL. Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AEs) occurred. The most common AEs were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AEs were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.

Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study

BACKGROUND Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies. METHODS We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkins lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766. FINDINGS Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib. INTERPRETATION Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting. FUNDING TG Therapeutics.

The Novel IKK2 Inhibitor LY2409881 Potently Synergizes with Histone Deacetylase Inhibitors in Preclinical Models of Lymphoma through the Downregulation of NF-κB

Purpose: To evaluate the pharmacologic activity of a novel inhibitor of IκB kinase β (IKK2), LY2409881, in preclinical models of B- and T-cell lymphoma, as a single agent and in combination with histone deacetylase (HDAC) inhibitors. Experimental Design: The in vitro activity of LY2409881 was determined using an ATP-based growth inhibition assay and flow cytometric assay of apoptosis in lymphoma cell lines. The in vivo activity of LY2409881 was determined using SCID-beige xenograft mouse model. The mechanism of action was determined using immunoblotting, immuofluorescence, and electrophoretic mobility shift assay. Synergy of LY2409881 with other drugs active in lymphoma was determined by calculating relative risk ratio (RRR) and combination index (CI). Results: LY2409881 inhibited constitutively activated NF-κB, and caused concentration- and time-dependent growth inhibition and apoptosis in lymphoma cells. In models of diffuse large B-cell lymphoma (DLBCL), the cytotoxicity of LY2409881 correlated with the overall activation status of NF-κB, but not simply in a pattern predicted by the cell-of-origin classification of these cell lines. LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-κB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs. Conclusion: Collectively, these data strongly suggest that targeting the NF-κB pathway in combination with romidepsin could represent a novel and potent regimen for the treatment of B- and T-cell lymphoma. Clin Cancer Res; 21(1); 134–45. ©2014 AACR.

New Strategies in the Treatment of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of >90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease. Clin Cancer Res; 18(13); 3499–508. ©2012 AACR.

Brentuximab vedotin and bendamustine produce high complete response rates in patients with chemotherapy refractory Hodgkin lymphoma.

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Pralatrexate: a comprehensive update on pharmacology, clinical activity and strategies to optimize use

Abstract It has been nearly 8 years since pralatrexate became the first drug approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Like most drugs approved for a particular clinical indication, as much or more is learned once it enters mainstream use as in the years leading up to regulatory approval. Over the past several years, many diverse lines of research have shed new insight into both the agent, and the diseases it treats. In this review, we will bring the reader up to date on the many new aspects related to pralatrexate’s pharmacology, activity across the panoply of T-cell lymphoproliferative malignancies, as well as some new and emerging guidelines that are likely to improve its safety profile. Finally, the review will close with the many new lines of evidence building a rationale for the combination of these novels: novel combination, and the vision for new platforms in PTCL care.

Combination of ibrutinib and chemotherapy produced a durable remission in multiply relapsed diffuse large B-cell lymphoma leg type with mutant MYD88 and wildtype CD79

The mutant Myd88L265P protein promotes lymphoma cell survival in diffuse large B-cell lymphoma (DLBCL) by activating NF-κB via Irak-4. On the other hand, constitutively activated signaling of the B-cell receptor (BCR), encoded by CD79A/B , activates NF-κB via Bruton’s tyrosine kinase (Btk).