SummaryThe guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the 'GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post-PV MF) and post-thrombocythemic myelofibrosis (post-ET MF) in both adult and paediatric patients.

The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein alpha). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases.

With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient–physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Interleukin (IL)-12 is expressed mainly in antigen-presenting cells after challenge with microbial material or after CD40 activation. Although IL-12 was cloned from human Epstein-Barr virus (EBV)-transformed B cell lines, surprisingly, CD40 ligation on murine B cells did not lead to IL-12 production, suggesting that murine B cells do not produce IL-12. Here we demonstrate that a subset of human tonsillar B cells can be induced to express and secrete bioactive IL-12. The major stimulus to produce IL-12 in human B cells was CD40 ligation. In contrast, B cell receptor cross-linking did not induce IL-12. Expression of IL-12 after CD40 activation was restricted to CD38−IgD± non-germinal center (non-GC) B cells. CD40 ligation and interferon (IFN)-γ exhibited synergistic effects on IL-12 production, whereas IL-10 abrogated and IL-4 significantly inhibited IL-12 production by these B cells. In contrast to IL-12, production of IL-6 is conversely regulated, leading to significant increase after CD40 ligation in the presence of the T helper type 2 (Th2) cytokine IL-4. Cord blood T cells skewed towards either a Th1 or a Th2 phenotype maintained their cytokine expression pattern when restimulated with allogeneic resting B cells. Blockade of CD40 and/or IL-12 during T–B interaction significantly reduced IFN-γ production by the T cells. This suggests a model whereby B cells produce either IL-12 or IL-6 after contact with T cells previously differentiated towards Th1 or Th2. Furthermore, IL-12 and IL-6 might provide a positive feedback during cognate T–B interactions, thereby maintaining T cells' differentiation pattern during amplification of the immune response.