Advanced Systemic Mastocytosis with associated haematological neoplasm: Treatment with avapritinib can facilitate successful bridge to allogeneic haematopoietic cell transplant.

Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, with approximately 70% patients having an associated haematological neoplasm (AHN). Avapritinib, a selective tyrosine kinase inhibitor targeting KIT D816V, has shown potent activity translating clinically into durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies. We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.

Immune reconstitution inflammatory syndrome in a patient with HIV presenting as severe mixed haemolytic anaemia.

A patient with a delayed diagnosis of vertically transmitted HIV presented with a rare form of severe warm and cold (mixed) autoimmune haemolytic anaemia, six months after starting antiretroviral therapy. The CD4 count had responded rapidly to introduction of antiretroviral therapy, rising from 5 cells/µL to 93 cells/µL over the course of six months. The haemolysis was resistant to immunoglobulin therapy, eventually responding to corticosteroids. On careful scrutiny of the case, we found the features to be in keeping with immune reconstitution inflammatory syndrome; thorough investigations revealed no other trigger for haemolysis in this case.

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth.

Proteomic-based drug testing is an emerging approach to establish the clinical value and anti-neoplastic potential of multikinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC(50) values. Midostaurin and CGP62221 also produced growth inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, which accumulates in vivo, showed no substantial effects. Chemical proteomic profiling and drug competition experiments revealed that midostaurin interacts with KIT and several additional kinase targets. The key downstream regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgE receptor downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation, which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia.

Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4-specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100-500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET-bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated.

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis.

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.

Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal.

Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.

Skeletal muscle mass reference curves for children and adolescents.

BACKGROUND: Skeletal muscle is key to motor development and represents a major metabolic end organ that aids glycaemic regulation. OBJECTIVES: To create gender-specific reference curves for fat-free mass (FFM) and appendicular (limb) skeletal muscle mass (SMMa) in children and adolescents. To examine the muscle-to-fat ratio in relation to body mass index (BMI) for age and gender. METHODS: Body composition was measured by segmental bioelectrical impedance (BIA, Tanita BC418) in 1985 Caucasian children aged 5-18.8 years. Skeletal muscle mass data from the four limbs were used to derive smoothed centile curves and the muscle-to-fat ratio. RESULTS: The centile curves illustrate the developmental patterns of %FFM and SMMa. While the %FFM curves differ markedly between boys and girls, the SMMa (kg), %SMMa and %SMMa/FFM show some similarities in shape and variance, together with some gender-specific characteristics. Existing BMI curves do not reveal these gender differences. Muscle-to-fat ratio showed a very wide range with means differing between boys and girls and across fifths of BMI z-score. CONCLUSIONS: BIA assessment of %FFM and SMMa represents a significant advance in nutritional assessment since these body composition components are associated with metabolic health. Muscle-to-fat ratio has the potential to provide a better index of future metabolic health.

Relationship between periparturient management, prevalence of MAP and preventable economic losses in UK dairy herds.

Johne's disease (JD) is an infectious, progressive, gastrointestinal disease affecting ruminants. Calves are mostly infected in their first six months of life, or in utero. We investigated the impact of specific periparturient management practices on within-herd JD prevalence and economic losses foregone in UK dairy herds by means of data synthesis (systematic appraisal of published evidence and expert elicitation) and use of a pre-existing simulation model. Our results show the scarcity of accurate estimates of the impact of specific periparturient management practices on within-herd JD prevalence, which could, in part, be explained by challenges associated with the chronic nature of JD. Management practices aiming to limit the faecal-oral transmission route of Mycobacterium avium subspecies paratuberculosis (MAP) were found to be most effective at reducing within-herd prevalence of JD. Practices aiming to limit MAP transmission via colostrum and milk were found to be less effective. Losses foregone for a hypothetical herd of 200 milking cows were considerable; based on the assumptions, it is reasonable to expect between £7000 and £11,000 of losses foregone when management practices are implemented as a package of measures. The findings of this study are envisaged to enable farmers and veterinarians to make more informed decisions on changes to periparturient management to control JD.

Family-based behavioural management of childhood obesity: service evaluation of a group programme run in a community setting in the United Kingdom.

A service evaluation of a pilot of a family-based behavioural management group programme for childhood obesity was conducted in a community setting in the United Kingdom. A total of 17 families with children aged 7.5-14 years completed the programme, which was delivered in 15 sessions over 6 months. Behavioural and psychological measures and age- and sex-adjusted z-body mass index (BMI) were assessed before and after programme. z-BMI was maintained. There was a significant increase in the amount of high-fibre foods and a decrease in the amount of low-fibre foods consumed and in sedentary behaviours. There were significant decreases in depression, abnormal dieting behaviour and bulimia and food preoccupation, and an increase in self-worth related to physical appearance. These positive behavioural and psychological changes suggest that this is a promising programme.

Comparison of children's body fatness between two contrasting income groups: contribution of height difference.

OBJECTIVE: To compare measures of growth and body fatness (body mass index (BMI) and % body fat) in children from two contrasting income backgrounds and to examine the contribution of height difference to these measures. DESIGN: Cross-sectional study. SETTING: Schools in inner East London ('low income') and West London, Hertfordshire and Cambridgeshire ('high income'), UK. PARTICIPANTS: A total of 2298 children aged 5-14 years. MAIN OUTCOME MEASURES: Height, weight, BMI (weight per height(2)) and percentage body fat (%BF, by bioelectrical impedance analysis). RESULTS: Children from the 'lower income' background were significantly shorter, heavier and fatter (%BF) with a higher BMI for their age compared with those from a 'higher income' background. Prevalence of overweight/obesity was greater in the 'lower income' group children, assessed on the basis of BMI, and this income group difference was magnified when based on %BF (overfat/obese). Irrespective of the assessment tool used, overweight/overfat/obese children as a group were significantly taller for their age compared with children categorized as normal weight/normal fat. Despite the overfat/obese children being taller for their age, an 'income group' difference in height remained within this category. CONCLUSION: These findings confirm the income group influence on obesity prevalence. They also illustrate that BMI underestimates the true number of children having excess body fat, particularly in 'low income' children. Exactly why BMI seems to function differently along income group divisions in unclear, but a shorter height-for-age of the 'lower income' group children could be one explanation. These findings raise important questions about the causes and consequences of obesity in children from 'lower income' backgrounds.

British Society for Haematology, Slide session, Annual Scientific Meeting, Bournemouth, 2007.

Eight cases discussed by experts at the 2007 Annual Scientific Meeting of the British Society of Haematology are presented as at the meeting, with a discussion of the morphological features, digital information and differential diagnosis being followed by further information and a final diagnosis. Additionally, digital slides of two of the cases were available to be viewed by the internet with the opportunity for delegates to suggest diagnoses.

Second autologous transplant with cyclosporin/interferon alpha-induced graft versus host disease for patients who have failed first-line consolidation.

The prognosis for patients with non-Hodgkin's lymphoma (NHL) and advanced Hodgkin's disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon alpha to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkin's lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.

High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.

T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.