Toby A. Eyre

Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies

Since the discovery of rapamycin in Easter Island soil in 1975, more has been learnt about the relevance and importance of the mammalian target of rapamycin (mTOR) pathway in cell signalling, proliferation and ultimately tumourigenesis. Rapamycin targets the mTORC1 complex alone. Despite initial excitement, rapamycin and its analogues, everolimus and temsirolimus, have displayed limited efficacy in the treatment of lymphoid malignancies. This review highlights the important and well‐described aspects of the critical phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K)/AKT/mTOR pathway and discusses the mechanisms of action of rapamycin, its clinical efficacy in lymphoid malignancies, and the mechanisms of resistance. Renewed interest in targeting the pathway has evolved through the discovery of mTORC2, a protein complex associated with a key mechanism of resistance to first generation mTOR inhibitors. As such, novel dual inhibitors of mTORC1 and mTORC2 have been developed, along with other dual inhibitors of the mTOR pathway. The evolution in the development of dual inhibitors is described herein, along with the burgeoning in vitro, pre‐clinical data and the early phase clinical data available. Although historically mTOR inhibitors have been used extensively in haematopoietic and solid organ transplant prophylaxis, this review will focus on developments of their use in lymphoid malignancies.

Incidence, management, and outcome of high-grade transformation of nodular lymphocyte predominant Hodgkin lymphoma: long-term outcomes from a 30-year experience.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare form of Hodgkin lymphoma that typically presents as early stage, indolent disease in young adult males. The relationship between NLPHL and DLBCL is incompletely understood, and there remains a paucity of data with regard the incidence and management of high‐grade transformation. We report the largest study to date describing the incidence, management and long‐term outcome of 26 cases of high‐grade transformation of NLPHL over a 30‐year period. We report a transformation incidence of 17.0%. Bone marrow, splenic, and liver infiltration with DLBCL was frequent. Patients with an aa‐IPI 2–3 have poorer OS and PFS (P = 0.034 and P = 0.009, respectively). Although the approach to treatment was somewhat variable, typically young, otherwise fit patients received anthracycline‐based induction, platinum‐based consolidation with stem cell harvesting, followed by autologous SCT with BEAM conditioning. Long‐term (5 year) PFS was over 60% with this approach, and comparable to our de novo DLBCL historical age and time period‐matched cohort largely treated with CHOP‐like chemotherapy alone. The transformation rate of 17.0% highlights the importance of accurate initial diagnosis, long‐term follow‐up, and re‐biopsy at relapse. Am. J. Hematol. 90:E103–E110, 2015.

Interventions to reduce wrong blood in tube errors in transfusion: A systematic review

This systematic review addresses the issue of wrong blood in tube (WBIT). The objective was to identify interventions that have been implemented and the effectiveness of these interventions to reduce WBIT incidence in red blood cell transfusion. Eligible articles were identified through a comprehensive search of The Cochrane Library, MEDLINE, EMBASE, Cinahl, BNID, and the Transfusion Evidence Library to April 2013. Initial search criteria were wide including primary intervention or observational studies, case reports, expert opinion, and guidelines. There was no restriction by study type, language, or status. Publications before 1995, reviews or reports of a secondary nature, studies of sampling errors outwith transfusion, and articles involving animals were excluded. The primary outcome was a reduction in errors. Study characteristics, outcomes measured, and methodological quality were extracted by 2 authors independently. The principal method of analysis was descriptive. A total of 12,703 references were initially identified. Preliminary secondary screening by 2 reviewers reduced articles for detailed screening to 128 articles. Eleven articles were eventually identified as eligible, resulting in 9 independent studies being included in the review. The overall finding was that all the identified interventions reduced WBIT incidence. Five studies measured the effect of a single intervention, for example, changes to blood sample labeling, weekly feedback, handwritten transfusion requests, and an electronic transfusion system. Four studies reported multiple interventions including education, second check of ID at sampling, and confirmatory sampling. It was not clear which intervention was the most effective. Sustainability of the effectiveness of interventions was also unclear. Targeted interventions, either single or multiple, can lead to a reduction in WBIT; but the sustainability of effectiveness is uncertain. Data on the pre- and postimplementation of interventions need to be collected in future trials to demonstrate effectiveness, and comparative studies are needed of different interventions.

Immune checkpoint inhibition in lymphoid disease.

It has long been understood that the immune system has intrinsic anti‐tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti‐tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death‐1 (PDCD1, PD‐1)/cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) ‘immune checkpoint’ pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti‐tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies.

A phase II trial of AZD1152 in relapsed/refractory diffuse large B-cell lymphoma

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Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter’s syndrome

BackgroundTransformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter’s syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly, immunosuppressed, possess co-morbidities and have a deteriorating performance status. TP53 disruption is a common molecular abnormality noted in RS and contributes to the tumour’s chemotherapy resistance. Ofatumumab is a fully human anti-CD20 monoclonal IgG1κ antibody that targets a unique epitope on B lymphocytes. It has displayed increased binding affinity and a longer dissociation time when compared to rituximab resulting in improved complement dependent cellular cytotoxicity (CDCC); a mechanism with the potential to overcome apoptosis-resistance in TP53 disruption. Given the prevalence of TP53 disruption in RS, Ofatumumab was considered a relatively non-toxic agent with a sound rationale to test in a prospective multicentre trial as an adjunct to CHOP induction and subsequent ofatumumab maintenance therapy in responding patients.Methods/DesignThe CHOP-OR study is a prospective phase II study to evaluate the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. The primary objective will be the overall response rate (ORR) in patients with RS after six cycles of CHOP-O. The secondary objectives include feasibility of recruitment, progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by exploratory analysis of the genomic landscape of RS in newly diagnosed patients.DiscussionThe CHOP-OR trial evaluates the safety, feasibility and activity of CHOP plus Ofatumumab induction and Ofatumumab maintenance in new RS patients. The study is currently recruiting and has met the interim analysis criteria, with more than 7 of the first 25 participants achieving a CR or PR after six cycles of CHOP-O. The study has the potential to identify predictive biomarkers for this treatment modality.Trial registrationNCT01171378.

An update for Richter syndrome – new directions and developments

High‐grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy‐resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics. Herein, we summarise what is known regarding the molecular drivers of RS and the existing clinical trial data, including the recently published CHOP‐OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial. We discuss novel agents in development with a focus on the second‐generation Bruton tyrosine kinase inhibitor acalabrutinib, checkpoint inhibition and the potential role of precision medicine in future trials of RS.

Multiple myeloma in the very elderly patient: challenges and solutions

Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life.

NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome.

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.

Obstructive sleep apnoea does not lead to clinically significant erythrocytosis

Keohane and colleagues report that obstructive sleep apnoea should be considered in the differential diagnosis of a secondary erythrocytosis.1 Obstructive sleep apnoea is also mentioned as a cause of secondary erythrocytosis in …