Andrew Will

The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology

The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMBASE were searched systematically for publications in English from 2002 using the key word Willebrand. The writing group produced the draft guideline, which was subsequently reviewed by the A United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) advisory committee, a British Committee for Standards in Haematology (BCSH) sounding board of approximately 50 UK haematologists, and the BCSH executive; comments were incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_ GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with von Willebrand disease.

Does isochromosome 7q mandate bone marrow transplant in children with Shwachman–Diamond syndrome?

Summary. We report on nine children with Shwachman–Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high‐risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4·5 years +). The six non‐transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.

Successful treatment of human metapneumovirus pneumonia using combination therapy with intravenous ribavirin and immune globulin.

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Association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia

Aims: To investigate the association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia. Methods: Cerebrospinal fluid (CSF) samples from patients with acute myelogenous leukaemia (AML) at diagnosis (n = 2) and acute lymphoblastic leukaemia (ALL) at diagnosis (n = 14) were analysed for parvovirus B19 DNA by means of nested polymerase chain reaction. In addition, samples from patients with benign intracranial hypertension (BIH) (n = 10) and hydrocephalus (n = 13) were tested as controls. Results: Four leukaemia cases were positive—common ALL (n = 2), null cell ALL (n =1), and M7 AML (n = 1)—whereas all controls were negative (Yates corrected χ2 value, 3.97; p = 0.046; odds ratio, 16.92; confidence interval, 1.03 to 77.18). All four patients were significantly anaemic, but none was encephalitic or had evidence of central nervous system leukaemia. In three of these patients, serum tumour necrosis α, interferon γ, interleukin 6, granulocyte–macrophage colony stimulating factor (range, 34.93–3800.06pg/ml), and macrophage chemoattractant protein 1 were detectable. All of these four patients carried at least one of the HLA-DRB1 alleles, which have been associated with symptomatic parvovirus B19 infection. Conclusion: Erythroid suppression and immune cell proliferation are both associated with B19 infection and may also be important in the pathogenesis of acute leukaemia.

Clearance of marrow infiltration after 1 week of therapy for childhood lymphoblastic leukaemia: clinical importance and the effect of daunorubicin

At the commencement of UKALL XI, a national MRC trial for childhood lymphoblastic leukaemia (ALL), the therapy included a bolus of daunorubicin (DR) on the first 2 d of the protocol. This component of treatment was subsequently withdrawn because of concern about long‐term cardiotoxicity. All children both before and after this change of policy had their marrow status at the end of the first week assessed by central review as part of the trial to examine the clinical importance of the rate of disease clearance. This also afforded an opportunity to observe the effect of DR on gross residual disease at an early stage of therapy.

Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.

The guideline group was selected to be representative of UKbased medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2013 under the heading: ‘tumour lysis syndrome’. The writing group produced the draft guideline. Review of the manuscript was performed by the British Committee for Standards in Haematology, BCSH Haemato-oncology Task Force, BCSH Executive Committee and by the haematooncology sounding board of the British Society for Haematology (BSH). This comprises over 50 members of the BSH who have reviewed the guidance and commented on its content and applicability in the UK setting. It has also been reviewed by representatives from Leukaemia and Lymphoma Research but they do not necessarily approve or endorse the contents. The ‘GRADE’ system was used to quote levels and grades of evidence (www.bcshguidelines.com). The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with tumour lysis syndrome (TLS). The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach.

The clinical management of tumour lysis syndrome in haematological malignancies.

Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent.

A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.

Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.

The impact of monitoring Epstein-Barr virus PCR in paediatric bone marrow transplant patients: can it successfully predict outcome and guide intervention?

Epstein–Barr virus (EBV) associated lymphoproliferative disease is a complication of haemopoietic stem cell transplantation (HSCT). In certain groups (unrelated and mismatched donor transplants, T‐cell depleted) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict the impending development of this disorder and allow early intervention have therefore assumed importance. We routinely screen the peripheral blood of all recipients of allogeneic HSCT to detect EBV DNA by quantitative polymerase chain reaction (PCR) technology and report here how this correlates with clinical disease and management.

A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross‐linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice‐site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA‐D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin‐3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA‐D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA‐derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA‐associated malignancies and might also play a role in the initiation and progression of cancer in the general population.