Low CD49d expression in newly diagnosed chronic lymphocytic leukaemia may be associated with high-risk features and reduced treatment-free-intervals.

This study was carried out to assess the prognostic power of low CD49d expression (≥10%) in newly diagnosed CLL patients using a previously described cohort. Eighty-five patients were included. Median age at diagnosis; 70 years (43-88); CD49d was expressed in 33/85 (38.8%); 23/33 (69.7%) at ≥30% referred to as 'HiCD49d' and 10/33 (30.3%) between 10 and 30% with a bimodal pattern on scatterplot analysis referred to as 'LoCD49d'. Eleven patients (12.9%) presented as Binet stage B, of whom 8 (72.7%) were CD49d+ (HiCD49d 7/8; LoCD49d 1/8). Seven of 81 patients (8.6%) were NOTCH1 mutated and all were CD49d+ (p ≤ .01). IgVH analysis was performed on 29 (87.8%) of the CD49d+ cases, of whom 21 (72.4%) were unmutated and 8 (27.6%) were mutated. CD38+/CD49d+ accounted for 11/20 (55%) (CD38+/HiCD49D: 9/11; CD38+/LoCD49D: 2/11). At 42 months, treatment had been initiated in 18/85 (21%) patients, of these 10/33 (30.3%) were CD49d+ versus 8/52 (15.4%) of the CD49d- group. The median treatment free interval for the CD49d+ group was 11 months (HiCD49d; 14.5 months, LoCD49d; 11 months) compared to 21.5 months for the CD49d- group. These findings suggest that the predictive value of CD49d expression is retained at expression levels down to 10%.

Phase 2 studies of lenalidomide, subcutaneous bortezomib, and dexamethasone as induction therapy in patients with newly diagnosed multiple myeloma.

There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.

Transcultural care and individuals with an intellectual disability.

Healthcare delivery today reflects a history of change, which has responded to lifestyle changes, cultural diversity, population needs and expectations. In today's health-care environment it is crucial for health-care professionals to be mindful of cultural factors that affect health. These factors include the intricate interdependent biological, intellectual, psychological, social and spiritual needs of the individuals they work with. However, challenges exists for those who provide healthcare to people with intellectual disability. This article presents the transcultural care challenges for people with intellectual disability, through highlighting the biomedical/sociocultural perspectives of healthcare, communication and inequality experienced by those with intellectual disability. As a population group, people with intellectual disability can often be considered part of a larger culture rather than a culture within itself, and this article endeavours to emphasize that intellectual disability is in itself a coterminous culture. By highlighting intellectual disability as a cultural community within a larger community, requiring a transcultural response to care on several levels health-care professionals can provide culturally compatible care to those with intellectual disability within a transcultural framework to augment a person-centred approach to care.

Aggressive behaviour and its prevalence within five typologies.

Crucial to understanding an individual, presenting with intellectual disability and the management of their challenging behaviours, is the knowledge of the types of those specific behaviours. The term aggressive behaviour is a universal term that embraces many aspects of behaviour that vary in terms of severity, frequency and seriousness for the individual and those around them. Hence, greater consideration regarding intervention, management, person-centred strategies and prevalence and frequency rates are required in service provision for individuals with intellectual disability and aggressive behaviour. This review presents the context of aggressive behaviour and its prevalence within the five typologies of aggressive behaviour: verbal aggression, aggression against others, sexually inappropriate behaviour, self-injurious behaviour and aggression against property, as identified by Crocker et al. (2007). The focus of this review is to report on the prevalence of aggressive behaviour reported for individuals with intellectual disability and consider the ambiguity in defining aggressive behaviour.

Biclonal lymphoproliferative disorders: another association with NOTCH1-mutated chronic lymphocytic leukaemias.

INTRODUCTION: Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. METHODS: We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. RESULTS: Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. CONCLUSION: In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide.

INTRODUCTION: Lenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting. PATIENTS AND METHODS: Patients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator's routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration. RESULTS: In total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively. CONCLUSION: No new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials.

Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL.

Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.

Nonfamilial, MPL S505N-Mutated Essential Thrombocythaemia.

Mutations of MPL are present in a significant proportion of patients with the myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF), and essential thrombocythaemia (ET). The most frequent of these mutations, W515L and W515K, occur in exon 10 of MPL, which encodes the receptor for thrombopoietin. Another exon 10 mutation, MPL S505N, has been shown to be a founder mutation in several pedigrees with familial thrombocythaemia where it is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Rare cases of sporadic, nonfamilial, MPL S505N MPN have been documented, but the presenting laboratory and clinical features have not been described in detail. The diagnosis and clinical course of a case of MPL S505N-positive MPN are presented with diagnostic features and treatment response resembling typical ET but with evidence of increasing bone marrow fibrosis. Further MPN cases possessing this genotype require reporting in order to ascertain whether any particular morphological or clinical features, if present, determine clinical course and aid the refinement of therapeutic options.

Evaluation of bone marrow examinations performed by an advanced nurse practitioner: an extended role within a haematology service.

PURPOSE: Traditionally, medical personnel have undertaken bone marrow (BM) examination. However, specially trained nurses in advanced practice roles are increasingly undertaking this role. This paper presents the findings from an audit of BM examinations undertaken by an advanced nurse practitioner (ANP) at a regional haematology specialist centre. METHODS: The audit evaluated the quality of BM examinations performed by the ANP over the past two years (September 2007-September 2009). Over the two year period, 324 BM examinations were performed at the centre of which 156 (48.1%) were performed by the ANP. A random sample of 30 BM examinations undertaken by the ANP were analysed by the consultant haematologist. RESULTS: All 30 BM examinations undertaken by the ANP were sufficient for diagnosis. CONCLUSIONS: The ANP is capable and competent to obtain BM samples which are of a sufficient quality to permit diagnosis.

Large granular lymphocyte leukemia: natural history and response to treatment.

Large granular lymphocyte leukemia (T-LGL) is an indolent T lymphoproliferative disorder that was difficult to diagnose with certainty until clonality testing of the T cell receptor gene became routinely available. We studied the natural history and response to treatment in 25 consecutive patients with T-LGL diagnosed between 2004 and 2008 in which the diagnosis was confirmed by molecular analysis, to define an effective treatment algorithm. The median age at diagnosis was 61 years (range 27-78), with a male to female ratio of 1:1.8 and presenting features of fatigue (n = 13), recurrent infections (n = 9), and/or abnormal blood counts (n = 5). Thirteen patients with symptomatic disease were treated as follows: pentostatin (nine patients), cyclosporine (six patients), methotrexate (three patients), and alemtuzumab in two patients in whom pentostatin was ineffective. Pentostatin was the single most effective therapy, with a response rate of 75% and minimal toxicity. The overall survival (OS) and progression-free survival (PFS) 37 months from diagnosis were 80% and 52%, respectively. Treatment of T-LGL should be reserved for patients with symptomatic disease, but in this series, pentostatin treatment was less toxic and more effective than cyclosporine or methotrexate.