Abstract
Welcome to issue number three of Therapeutic Advances in Hematology for 2012! In the spirit of covering ‘all the bases’ of hematology, this issue brings in needed insight into the world of non-malignant hematology; specifically we have insightful information to bring to you regarding one of the newer drugs for ITP and the complex question of managing anemia in the oncology patient. The advances in understanding and the developments in therapeutics have been parallel in malignant and non-malignant hematology and our mission at TAH is to cover it all. We again thank the editorial board and staff of the journal for their commissioning and critical reviews as well as thank the authors for a multitude of tour de force reviews for this issue. We continue to look forward to bringing you not only excellent summary and review work, but original research, perspectives, and case reports/ brief reports when appropriate; please enquire with your efforts!
This issue commences with Harper Hubbeling, Drs. Frank and Hexner from the University of Pennsylvania providing a comprehensive and detailed review of the ‘state of myelofibrosis’. Highlighting the description of the discovery of JAK2 mutation, the paper reviews pathologic considerations, including the distinctions between essential thrombocytosis (ET) and prefibrotic myelofibrosis (MF), the development and evolution of prognostic models for MF, the effect of JAK2 gene ‘dose’ and ‘myelodepletive’ versus ‘myeloproliferative’ MF and the important developments in mouse models to corroborate gene dose effect on phenotype. The also cover in this broad review the identification of 46/1 JAK2 haplotype single nucleotide polymorphism (SNP) based predisposition to mutation acquisition, and alternate mutations/alterations in MPL, LNK, and TET2. They then turn to therapeutic considerations and the limitations of JAK2 inhibitors with a bit of debate on specificity (‘clean versus dirty’), the recognized potential for IFN (allele burden reduction), the potential of HDAC inhibitors and HSP90 inhibitors, and of course the complex role of transplant highlighting the benefit of reduced intensity conditioning and role of splenectomy. They close with a word on monitoring minimal residual disease after therapy; a review worth reading and referring to…
This is followed by Dr. Sopena and colleagues from Universidad Complutense de Madrid, Spain, bringing us an interesting and critical review of the proteosome inhibitor bortezomib and its schedule when used in elderly patients with multiple myeloma (MM). With an eye towards proving the case that less key toxicities such as peripheral neuropathy and thrombocytopenia occur with weekly schedules, the authors reviewed seven trials in addition to the phase III randomized VISTA (adding bortezomib to melphalan plus prednisone in untreated MM) trial as a reference. The authors show that intended ‘conventional’ (twice weekly) bortezomib is often not achievable with high fractions of patients with dose reductions / discontinuation, and that studies using weekly schedule showed equal efficacy and allowed for bortezomib maintenance to improve CR rates. Next we hear from Dr. Cheng from the Dr. Stanley Ho Medical Development Foundation, Macau providing a comprehensive review of the thrombopoietin receptor agonist eltrombopag. He sets its place amongst the spectrum of other therapies for ITP including steroids, splenectomy, IVIG, rituximab, and others; reviews its development in clinical trials; and as well its mechanism of action and safety profile / administration. Key studies are covered in detail, including the phase II dose-finding study and the initial phase II study, as well as the randomized phase III RAISE trial and the EXTEND extension study- all of which Dr. Cheng has participated / published on.
The final two papers are from Drs. Knobe and Berntorp of the Malmö Centre for Thrombosis and Haemostasis, Sweden, producing a primer on hemophilia A and B. Their review begins with descriptions of the subgroups and complications as well as current available therapies (factor VII and IX replacement therapy types, products used to overcome inhibitors, timing and strategy for prophylaxis, recognizing the complexity of lifelong intravenous access and therapy, etc.). The authors then go on to review the latest pursuits in modification and optimization of therapy for hemophilia A & B covering pegylation and Fc or albumin fusion as means to prolong factor half-life; activity-enhancing modifications to recombinant factors; gene therapy; and tissue factor pathway inhibitor blockade. The paper is written with clear sensitivity to the ultimate goal of preserving the quality and extending the life of those afflicted with these not-so-uncommon inherited disorders.
The issue then closes with Dr.Steinmetz from the Praxis für Hämatologie und Onkologie, Cologne, Germany and a provocative look at the role of iron therapy in the treatment of anemia in the cancer patient. We are first helped to understand the etiology and differences between ‘AID’ (acquired iron deficiency) and ‘FID’ (functional iron deficiency) and reminded of how therapy with erythropoiesis-stimulating agents (ESAs) proceeded with insufficient thought as how to set the stage for utility and efficacy of these agents. The author then provides a concise review of trials showing the benefit of adjunct iron therapy with erythropoiesis-stimulating agents (ESAs) as well as trials using iron therapy to reduce transfusion requirements in oncology patients generally receiving cytotoxic chemotherapy. Importantly, the paper ends with advice regarding the proper work-up and treatment (oral versus IV iron, dose, and preparations for use) for the patient who develops anemia in association with cancer and cancer therapy; another paper to have at the clinic/bedside for use in practice…
Enjoy!