A retrospective real-world study of the current treatment pathways for myelofibrosis in the United Kingdom: the REALISM UK study.

Background: Myelofibrosis (MF) is a blood cancer associated with splenomegaly, blood count abnormalities, reduced life expectancy and high prevalence of disease-associated symptoms. Current treatment options for MF are diverse, with limited data on management strategies in real-world practice in the United Kingdom. Methods: The REALISM UK study was a multi-center, retrospective, non-interventional study, which documented the early management of patients with MF. The primary endpoint was the time from diagnosis to active treatment. Discussion: Two hundred patients were included (63% [n = 126/200] with primary MF; 37% [n = 74/200] with secondary MF). Symptoms and prognostic scores at diagnosis were poorly documented, with infrequent use of patient reported outcome measures. 'Watch and wait' was the first management strategy for 53.5% (n = 107/200) of patients, while the most commonly used active treatments were hydroxycarbamide and ruxolitinib. Only 5% of patients proceeded to allogeneic transplant. The median (IQR) time to first active treatment was 46 days (0-350); patients with higher risk disease were prescribed active treatment sooner. Conclusion: These results provide insight into real-world clinical practice for patients with MF in the United Kingdom. Despite the known high prevalence of disease-associated symptoms in MF, symptoms were poorly documented. Most patients were initially observed or received hydroxycarbamide, and ruxolitinib was used as first-line management strategy in only a minority of patients. Plain Language Summary: Background: Myelofibrosis is a rare blood cancer associated with symptoms that can seriously affect a patient's daily life, such as enlarged spleen and decreased white and red blood cells. Although several treatments are available for patients with myelofibrosis, it is not clear which ones clinicians use most frequently.Methods: We aimed to review which treatments are usually given to patients with myelofibrosis in the UK, by collecting information from the medical records of 200 patients with myelofibrosis treated in different centres across the UK.Results: The results showed that the symptoms patients experienced were not always written down in the medical records. Similarly, clinical scores based on patient characteristics (which clinicians use to try to predict if a patient will respond to treatment well or not) were also missing from the medical records. Clinicians also rarely asked patients to complete questionnaires that try to measure the impact of myelofibrosis and its treatment on their health. The most common approach for patients with myelofibrosis in the UK was 'watch and wait', which over half of patients received. The most common drugs used for treatment were hydroxycarbamide and ruxolitinib; only a very small proportion of patients received a bone marrow transplant. On average, patients waited for 46 days before receiving a treatment, although patients considered to have a more aggressive type of disease received treatment sooner.Conclusion: The results of this study suggest that medical records can be missing key information, which is needed to decide which is the best way to treat a patient with myelofibrosis. They also suggest that clinicians in the UK prefer observation to treatment for a large number of patients with myelofibrosis. This could mean that the approach used for many patients with myelofibrosis does not help them to control symptoms that have an impact on their daily lives.

The not so innocent bystander: an unusual cause of progressive breathlessness.

This case report discusses a 76-year-old man who presented with symptomatic diffuse alveolar-septal and tracheobronchial amyloidosis with a low-grade monoclonal gammopathy. This patient had a combination of both symptomatic diffuse alveolar-septal interstitial disease and tracheobronchial amyloidosis, features that contradict the widely accepted presentations seen in this disease. First, tracheobronchial amyloidosis has been documented as localised disease without systemic involvement. Second, diffuse alveolar-septal interstitial disease is rarely identified with clinical symptoms unless there is significant cardiac involvement. This case highlights a number learning points in the diagnosis and management of systemic amyloid light chain amyloidosis;(1) There is a need for a high index of suspicion for diagnosis due to the potential subtlety of a plasma cell clone underlying AL amyloidosis, requiring serum-free light chain assays to increase sensitivity; (2) Haematological response and recovery of organ dysfunction are not a linear relationship due to the slower reversal of amyloid deposition; therefore, ongoing monitoring is required to identify those in need of repeated therapy. However, haematological response is a marker of overall survival and (3) Multisystem assessment and multidisciplinary collaboration are critical in optimising the care of patients with systemic AL amyloidosis.

Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia.

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0-4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

Toward the harmonization of result presentation for the eosin-5'-maleimide binding test in the diagnosis of hereditary spherocytosis.

BACKGROUND: The eosin-5'-maleimide (EMA) Binding test measures reduced mean channel fluorescence (MCF) reading of EMA-labeled red cells (EMA-RBCs) from patients with hereditary spherocytosis (HS). Reporting test results can be either in the actual MCF reading or as a ratio by normalization of the test MCF result to the mean MCF value of six normal controls. The latter format has potential for universal reporting. METHODS: We analyzed three years' archival MCF data from HS and non-HS patient groups for establishment of reference ranges of ratios for normal adults and HS. A prospective study used FC500 and FACS Canto II cytometers to analyze contemporaneously EMA-RBCs from several patient groups and normal donors. Statistical analyses of the prospective data determined the cut-off values, and the sensitivity and specificity for HS respectively for the MCF and the ratio result presentations. The effect of using fewer than six normal controls for the ratio denominator was explored. RESULTS: The FC500 gave a mean ratio of 0.782 (SD=0.086) in HS patients with an optimal cut-off ratio of 0.918 (98.7% specificity, 95.6% sensitivity), and gray area ratio of 0.868-0.918. The Canto II gave a mean ratio of 0.774 (SD=0.085) with an optimal cut-off ratio of 0.925 (97.1% specificity and 100% sensitivity), and gray area ratio of 0.859-0.925. CONCLUSION: Harmonization of result presentation is feasible with no apparent constraint by instrument design. Interpretation of gray-area data requires an assessment of patient's clinical presentation and family history or performing a family study.

Towards the harmonization of result presentation for the eosin-5'- maleimide (EMA) binding test in the diagnosis of hereditary spherocytosis.

Background: The EMA Binding test measures reduced mean channel fluorescence (MCF) reading of EMA-labeled red cells (EMA-RBCs) from patients with hereditary spherocytosis (HS). Reporting test results can be either in the actual MCF reading or as a ratio by normalization of the test MCF result to the mean MCF value of 6 normal controls. The latter format has potential for universal reporting. Methods: We analyzed three years' archival MCF data from HS and non-HS patient groups for establishment of reference ranges of ratios for normal adults and HS. A prospective study used FC500 and FACS Canto II cytometers to analyze contemporaneously EMA-RBCs from several patient groups and normal donors. Statistical analyses of the prospective data determined the cut-off values, and the sensitivity and specificity for HS respectively for the MCF and the ratio result presentations. The effect of using fewer than six normal controls for the ratio denominator was explored. Results:. The FC500 gave a mean ratio of 0.782 (SD = 0.086) in HS patients with an optimal cut-off ratio of 0.918 (98.7% specificity, 95.6% sensitivity), and grey area ratio of 0.868 - 0.918. The Canto II gave a mean ratio of 0.774 (SD = 0.085) with an optimal cut-off ratio of 0.925 (97.1% specificity and 100% sensitivity), and grey area ratio of 0.859 - 0.925. Conclusion: Harmonization of result presentation is feasible with no apparent constraint by instrument design. Interpretation of grey-area data requires an assessment of patient's clinical presentation and family history or performing a family study. © 2014 Clinical Cytometry Society.

Mesenteric and coeliac occlusions following heparin-induced thrombocytopenia after aortobiprofunda bypass surgery.

A 56-year-old man developed mid-gut bowel ischaemia following an elective aortobiprofunda bypass for short-distance claudication. The bowel was resected and he was commenced on lifelong total parenteral nutrition. He was found to have developed heparin-induced thrombocytopenia and thrombosis, confirmed by high levels of heparin-platelet factor 4-antibody on enzyme-linked immunosorbent assay (ELISA). He subsequently had foregut ischaemia with a second bout of thrombocytopenia despite not being on heparin. The case describes the first report of bowel ischaemia as a consequence of heparin-induced thrombocytopenia causing sequential superior mesenteric and coeliac arterial thrombosis in this scenario and highlights the importance of the awareness of the association of these pathological entities and subsequent management.

A monoclonal protein identified by an anomalous lipaemia index.

We describe a patient being investigated for anaemia where the lipaemia index on a Beckman Coulter DxC800 analyser was markedly elevated and out of keeping with the visual appearance of the serum. Subsequent investigation revealed a monoclonal IgM kappa immunoglobulin with type I cryoglobulin behaviour. The patient was then diagnosed with a non-Hodgkin B-cell lymphoma. We later identified a second patient with a similar anomalous index with an IgM lambda paraprotein, and a known marginal zone splenic lymphoma but were unable to confirm cryoglobulin behaviour prior to treatment. A review of 50 consecutive IgM paraproteins revealed no other anomalous lipaemia indices. We postulate that it is the properties of the paraprotein that determine its cryoglobulin behaviour that also render it susceptible to precipitation in the index diluent, not the fact of it being an IgM paraprotein per se. This appears to be the first reported case of a paraprotein identified following an anomalous lipaemia index.

Lymphomatoid granulomatosis of the uterine cervix.

Lymphomatoid granulomatosis is an Epstein-Barr virus-driven lymphoproliferative disorder, usually with a prominent pulmonary involvement and occasional extrapulmonary manifestations. Here, we present a case of lymphomatoid granulomatosis confined to the uterine cervix at the initial diagnosis. The disease was preceded by an immunosuppressive condition, namely low-grade lymphoplasmacytic lymphoma treated with chemotherapy. This is the first report of lymphomatoid granulomatosis at this site and emphasizes that it can present at unusual sites, such as the female genital tract in immunosuppressed patients.

Can serum free light chains replace urine electrophoresis in the detection of monoclonal gammopathies?

BACKGROUND: We investigated how sensitive serum free light chain (FLC) analysis was for the detection of Bence-Jones protein (BJP) and whether a serum kappa/lambda ratio could replace urine electrophoresis as part of the investigation algorithm for monoclonal gammopathy. METHODS: Serum kappa and lambda FLC analysis was performed on 932 consecutive patients investigated for monoclonal gammopathy, along with serum electrophoresis, serum immunofixation where appropriate, and in 483 individuals urine immunofixation. A reference interval for the kappa/lambda ratio was derived from all patients who had normal serum and urine electrophoresis and no B-cell dyscrasia (n = 312). RESULTS: The 100% reference interval was 0.21-1.44 (median 0.50), lower than that previously published. From the 483 patients who provided urines, BJP was detected in 34, with an abnormal kappa/lambda ratio in 26 of these. Using the reference interval, sensitivity, specificity, negative and positive predictive values of an abnormal kappa/lambda ratio for the presence of BJP were 0.76, 0.96, 0.98 and 0.59 respectively. Seven patients had an abnormal kappa/lambda ratio with no paraprotein. CONCLUSION: All kappa/lambda results should be interpreted against a reference interval appropriate for the analyser in use and the population under study. Some urines will be positive for BJP when the serum kappa/lambda ratio is normal, but there is little difference in outcome whether urine for BJP or serum FLC analysis is included in the screening strategy for monoclonal gammopathies. On balance, we believe that it is not yet time to dispense with urine BJP in the investigation of patients with suspected monoclonal gammopathy.

Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission.

Many solid tumours have been shown to lack expression of either of the immune co-stimulatory molecules CD80 (B7.1) or CD86 (B7.2), which is thought to be one of the ways in which tumours may escape immune recognition. We have examined the surface expression of CD80, CD86, human leucocyte antigen (HLA) class I and II, CD11a, CD54, and CD58 on the blast cells from patients with acute myeloid leukaemia (AML) at presentation. CD80 was only rarely expressed on AML blasts and, in those leukaemic cells expressing CD80, the level of expression was low. In contrast, expression of CD86 was detected on the AML blasts in more than half of the samples tested and, in some cases, the level of expression was equivalent to that of mature monocytes and activated B lymphocytes. The percentage of leukaemic blasts expressing CD86 was higher in the M4 and M5 French-American-British (FAB) types, and expression of CD11a and HLA class II was higher in the M4 FAB type. There was no difference in expression of CD80, CD54, CD58, or HLA Class I between different FAB subgroups. There was no significant difference in duration of first remission with expression of CD80, CD86, CD11a, CD54 or HLA class II. However, when expression of CD80 and CD86 were considered together, a significantly longer duration of remission was found. We suggest that these molecules may play a role in immunosurveillance, resulting in prolonged remission in some patients treated for AML.