Abstract
Welcome to the August 2012 issue of Therapeutic Advances in Hematology. We have a number of comprehensive reviews in this issue with a strong focus on two areas: first, therapeutics for lymphoid neoplasms, specifically antibody therapies and antifolates; second, the nonmalignant hematologic issues of heparin-associated thrombocytopenia and veno-occlusive disease (VOD) of the liver and their management and treatment. I, as always, need to thank the editorial team and contributors for their ongoing efforts on behalf of our journal. Look for focused ‘theme issues’ forthcoming and other new features as we continue to expand our horizons, reach, and the impact of Therapeutic Advances in Hematology.
The first paper by Prof. Dyer of Leicester University, United Kingdom, looks critically at the choices of antibody therapy in chronic lymphocytic leukemia (CLL) and tries to clarify the role of one newer agent, ofatumumab. Highlighting its strengths (entirely human, increased CD20 recognition, enhanced complement-directed cytotoxicity) and limitations of efficacy data known to date and the difficulties of properly identifying anti-CD20/chemotherapy failure to test such agents, this review thoughtfully generates pause as such agents continue in development. Continuing in the realm of antibody therapy for lymphoid neoplasms, Dr Vaklavas and Prof. Forero-Torres from the University of Alabama review the profile and data for bretuximab vedotin, an anti-CD30/microtubule inhibitor conjugate. They meticulously present the mechanism of action and approach of anti-CD30 directed therapy and contrast the early data of the ‘naked’ antibody and the subsequent improvement with the conjugate with monomethyl auristatin E (MMAE). The authors then cover nicely the significant activity in Hodgkin’s lymphoma and anaplastic large cell lymphoma patients heavily pretreated and with limited alternatives, and the ongoing research and toxicity concerns (peripheral neuropathy) with this agent.
Continuing focus on lymphoid neoplasms, now specifically T-cell lymphomas, Dr Marchi and Prof. O’Connor from Columbia University Medical Center, New York, cover the development and study of the novel antifolate agent pralatrexate. They review the compound’s early development and increased potency over conventional methotrexate and early study in lung cancer and mesothelioma followed by study in lymphomas. They cite the avoidance of antifolate toxicity (mucositis/stomatitis, cytopenias) based on correction of homocysteine and methylmalonic acid with folic acid and vitamin B12 and marked efficacy in peripheral T-cell lymphoma in the PROPEL trial leading to FDA approval. They close by covering development for cutaneous T-cell lymphomas and combination approaches in ongoing trials.
Switching gears to nonmalignant hematology, Dr Bakchoul and Prof. Greinacher of the Ernst-Moritz-Arndt University, Greifswald, Germany then cover for us recent advances in heparin-induced thrombocytopenia (HIT). They remind us of the mechanism HIT is based on, platelet factor 4 (PF4)/heparin complex immunization, and the challenge of identifying, sourcing, and implicating these antibodies in patients at risk or with thrombocytopenia. An algorithm is provided for our referral and management is then reviewed, covering the novel injected and oral anticoagulants directed against activated factor X/Xa and thrombin as well as the transition to vitamin K antagonists.
Finally we have a review of VOD of the liver and the use of defibrotide, an antithrombotic polydisperse oligonucleotide, led by Drs. Richardson and Soiffer of the Dana Farber Cancer Institute, Boston, and co-authored by an outstanding group of transplant hematologists. The authors carefully dissect the incidence, pathogenesis, and risk factors for VOD followed by delving into the prevention and treatment of VOD. They explain the antithrombotic, anti-inflammatory, and other properties of defibrotide and review data from trials in the treatment and prophylaxis with this agent and the effect on morbidity and development of VOD, closing with hints at a future optimized use of this agent in the transplant population.
Enjoy this issue as well as your summer (in the Northern Hemisphere at least)!