Ahmed Sawas

New therapeutic targets and drugs in non-Hodgkin's lymphoma

Purpose of reviewAlthough enormous progress has been made in treating non-Hodgkins lymphoma (NHL), and some patients can be cured with combination immunochemotherapy, patients with relapsed and refractory lymphoma often succumb to their disease. Advances in our understanding of lymphoma biology and molecular pathogenesis are yielding new therapeutic targets. Recent findingsThis article reviews NHL biology and describes how our understanding of molecular pathogenesis is leading to the discovery of many therapeutic targets, including the cell signaling and cell cycle regulatory proteins, pro-apoptotic family members, the B-cell antigen receptor (BCR), and histone deacetylase. Recent preclinical and clinical data with inhibitors of phosphatidylinositol 3-kinase, AKT, mammalian target of rapamycin, histone deacetylase, bcl-2, and the Brutons tyrosine kinase, a pivotal enzyme in the BCR pathway, are discussed. SummaryUnderstanding these novel targets in the context of NHL biology will bring new therapies and allow us to develop new therapeutic platforms for the treatment of relapsed and refractory NHL, and will hopefully improve the clinical outcome for these patients.

Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review

Peripheral T-cell lymphoma (PTCL) is a disease with poor prognosis and limited treatment options. Recent advances in cancer biology suggest that PTCL may be characterized by gross epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors. HDAC inhibitors have demonstrated significant activity in T-cell neoplasms and recently, the BELIEF trial evaluated belinostat leading to its approval in the US. This review discusses the development of belinostat, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for patients with relapsed or refractory PTCL. Key clinical trials covered include phase I/II evaluation of belinostat in hematologic malignancies, cutaneous T-cell lymphoma (CTCL) and PTCL. In addition, the BELIEF trial in PTCL leading to FDA approval of belinostat is reviewed in detail.

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.

Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.

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.

Will new drugs change the standard of care for patients with mantle cell lymphoma

ABSTRACT Mantle Cell lymphoma is a heterogeneous malignancy that has different subtypes with variable levels of aggressiveness. Research on the pathobiology of this disease is helping us understand the etiology for this heterogeneity and has the potential to guide future therapeutic options. The availability of the Ki67 proliferation index and the use of the MIPI score can help determine which of the numerous therapeutic options might be utilized. Minimal Residual Disease testing can act as a guide as to the potential benefit of maintenance therapy. This article discusses the current standard of care for Mantle Cell lymphoma and our current understanding of the pathobiology of the disease leading to strategies to improve patient outcomes with some of the newer targeted agents.

Abstract 2709: Evaluation of CD37 expression and binding of AGS67E, an antibody-drug conjugate (ADC) against CD37, on white blood cells (WBCs) collected from phase I non-Hodgkin lymphoma (NHL) patients

AGS67E is an antibody drug conjugate (ADC) against CD37 conjugated to monomethyl auristatin E (MMAE). CD37 is expressed on normal WBCs, but is also highly expressed in NHL, CLL and AML (Pereira et al., 2015). A phase I study is currently evaluating the safety, PK and anti-cancer activity of AGS67E with or without growth factor (GF) in subjects with relapsed/refractory NHL. To assess CD37 expression on WBCs, binding of AGS67E, and potential pharmacodynamic effects, samples from subjects were collected at pre-dose, D2, D8, and D15 and analyzed by flow cytometry. CD37 expression on subject tumor samples was also evaluated by immunohistochemistry (IHC). Our results demonstrated that CD37 was highly expressed in tumor samples and that AGS67E binds to WBCs causing down-regulation of CD37, achieving saturation of binding at 24 hours post-treatment (earliest time measured) at or above 0.9 mg/kg. A dose-dependent decrease in the number of all cell types examined was observed with a nadir occurring at D8, with partial or full recovery at D15, except for neutrophils. NK and T cell counts appeared to be least impacted while neutrophils were most affected. B cell counts were extremely low pre-dose for some patients, presumably from prior therapies. In patients treated at 0.9 mg/kg and higher without GF, recovery of neutrophils was delayed beyond D15. At doses of 1.2 mg/kg and higher, use of GF resulted in a significant recovery of neutrophils by D15. The extent of cell count decreases did not correlate to the proportion of cells expressing CD37. For example, decreases in NK cells, monocytes, and, in some cases, T cells, were much greater than the proportion of cells expressing CD37. Furthermore, mature WBCs are unlikely to be affected by AGS67E. This raises the possibility that the main effect of AGS67E may be on rapidly growing precursor cells and that cells with low, or no, CD37 expression may be impacted by the membrane permeable MMAE through a by-stander effect. The effect of AGS67E on neutrophils was investigated in an in vitro assay where hematopoietic stem cells were differentiated into neutrophils. Using this method, we showed that when AGS67C antibody was conjugated to a non-cleavable, membrane impermeable auristatin (mcMMAF) less cytotoxicity to differentiating neutrophils was observed compared to AGS67E. Previously, we have shown that neutrophils secrete proteases that can liberate MMAE from ADCs (Zhao et al, 2016). These results suggest that AGS67E contributes to neutropenia through a by-stander effect, in addition to the CD37-mediated internalization of the ADC. In conclusion, the results showed that AGS67E bound to its target CD37, modulated its expression, achieved saturation of binding at doses at or above 0.9 mg/kg, and reversibly depleted WBCs, with the exception of neutrophils for which GF administration appeared to significantly improve recovery rate. Citation Format: Sher Karki, Hector Avina, Jacqueline Lackey, Ahmed Sawas, Kerry J. Savage, Raymond Perez, Ranjana Advani, Jasmine Zain, Owen A. O9Connor, Sara Gulesserian, Hui Zhao, Peng Yang, Karen Morrison, Leonard Reyno, Fernando Donate. Evaluation of CD37 expression and binding of AGS67E, an antibody-drug conjugate (ADC) against CD37, on white blood cells (WBCs) collected from phase I non-Hodgkin lymphoma (NHL) patients [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 2709. doi:10.1158/1538-7445.AM2017-2709

Belinostat for the treatment of T-cell lymphoma

Introduction: T-cell lymphomas are a rare and heterogeneous group of malignant diseases that, for the most part, are associated with a very poor prognosis. Advances in understanding lymphoma biology and molecular pathogenesis coupled with interesting empiric observations have yielded many promising new therapeutic targets. Histone deacetylase (HDAC) inhibitors represent an emerging class of anticancer agents with great promise in the treatment of T-cell lymphoma. Areas covered: This paper focuses predominantly on the emerging data on belinostat, including its clinical development and unique pharmacologic properties. Expert opinion: Belinostat has demonstrated marked single-agent activity in patients with refractory and relapsed T-cell lymphoma comparable to what has been observed with other HDAC inhibitors. However, its safety profile may provide advantages over other agents within its class, especially with regard to its manageable hematologic toxicity, affording more opportunities to combine it with current and emerging therapies for T-cell lymphoma. Presently, clinical trials are exploring the integration of belinostat with other conventional agents to improve the response rates and to increase the duration of response, in the hope of moving belinostat to the frontline setting and into a potentially curative regimen for T-cell lymphoma.