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Snippets in haematology
  1. Scott McCloskey (scottmccloskey{at}doctors.org.uk),
  2. Mary Frances McMullin (m.mcmullin{at}qub.ac.uk)

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This section features synopses of pertinent practical publications that appear in pathology journals in the respective sub-specialties. The summaries are mere guidelines and personal opinions of the two authors. The articles selected are diverse but occasionally reflect the authors’ bias and are from the more widely read pathology journals. It is not intended to be an assiduous search of every publication in every pathology journal, but more of a general indication of some of the monthly highlights through the eyes of the authors.

Hopefully, these snippets will provide the reader with enough to glean some facts and tips, as well as encourage them to read the entire article if necessary.

New England Journal of Medicine

27 November 2008

Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313–23.

Gene expression signatures have been explored in many diseases to divide into diagnostic groups and predict prognosis. This group have identified three gene-expression signatures in pre-treatment biopsies of diffuse large-B-cell lymphoma. The three signatures termed “germinal-centre B-cell”, “stromal-1” and “stromal-2” from the training set predicted survival in the validation group. A “stromal-1” signature involved genes involved in extracellular matrix deposition and histolytic infiltration while a “stromal-2” signature reflected tumour blood-vessel density.

29 January 2009

Mulligan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukaemia. N Engl J Med 2009;360:470–80.

Genome wide analysis has identified a high frequency of DNA copy number abnormalities in acute lymphoblastic leukaemia (ALL). This genetic study of a cohort of over 200 children with high-risk progenitor B-cell ALL identified over 50 recurring copy-number abnormalities. PAX5 was involved in 31.7% and IKZF1 in 28.6%. A predictor of poor outcome in the independent validation cohort involved genetic alteration of IKZF1 a gene that encodes the lymphoid transcription factor IKAROS.

12 February 2009

Landgren O, Albitar M, Ma W, et al. B-cell clones as early markers for chronic lymphocytic leukaemia. N Engl J Med 2009;360:659–68.

This very large screening study of almost 80 000 healthy individuals included 45 who were later diagnosed with chronic lymphocytic leukaemia (CLL) up to 6.4 years later. Study of the screening samples identified a pre-diagnostic B-cell clone in 44 of the 45. Monoclonal B-cell lymphocytosis as indicated in the peripheral blood of a monoclonal B-cell population of less that 5×109/l is shown to be present in the majority of cases of CLL many months before diagnosis.

19 February 2009

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009;360:753–64.

Clinical and genetic information on over 4000 patients on warfarin was used to construct dosing algorithms. The algorithms were then tested in a further validation cohort of 1000 patients. The pharmacogenetic algorithm which included information on two polymorphisms in CYP2C9 and seven SNPs in VKORC1 and clinical information was the best for estimating the appropriate initial dose to produce a recommendation closer to the stable therapeutic required dose.

British Journal of Haematology

December 2008<1?tpb=8pt?>

Shi J, Tricot G, Szmania S, et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 2008;143:641–53.

In this interesting paper, NK cell allotransplantation is demonstrated to achieve graft-v-myeloma effect in a patient group which would be ineligible for a full matched allotransplant. There is a concise explanation of NK cell biology, and a clever application of this knowledge in a therapeutic procedure. Following conditioning, relapsed patients received haplo-identical KIR-ligand mismatched NK cells. Autologous stem cells were returned two weeks later with promising results in an otherwise poor prognostic group.

Amrein L, Hernandez TA, Ferrario C, et al. Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol 2008;143:698–706.

TP53 mutations, predominant expression of anti-apoptotic proteins and the deregulation of non receptor tyrosine kinases enhance the survival and chemoresistance of chronic lymphocytic leukaemia. Dasatinib opposes these survival mechanisms in vitro at clinically achievable concentrations, and induces apoptosis when used in combination with fludarabine and chlorambucil. Dasatinib sensitises or resensitises CLL cells to fludarabine and chlorambucil, providing a possible therapeutic avenue in the refractory patient.

January 2009

Turner ML, Ludlam CA. An update on the assessment and management of the risk of transmission of variant Creutzfeldt-Jakob disease by blood and plasma products. Br J Haematol 2009;144:14–23.

Variant Creutzfeldt-Jakob disease has affected a total 203 people, but despite the low incidence there have been major repercussions on surgical and transfusional practice and cost. Four individuals have contracted vCJD through non-leucocyte depleted blood transfusion, two of these from the same donor. The infectivity of blood donated by infected donors is high, but the incidence of the disease is low with only 70 further cases expected by mathematical projection. Strategies to reduce transmission include the importation of plasma for the young, and the development of prion assays and prion filters.

Hatfield K, Oyan AM, Ersvaer E, et al. Primary human acute myeloid leukaemia cells increase the proliferation of microvascular endothelial cells through the release of soluble mediators. Br J Haematol 2009;144:53–68.

The importance of the microenvironment in the survival and proliferation of malignant cells is increasingly appreciated. Endothelial cells contribute to this microenvironment and promote cell survival, proliferation and chemoresistance in acute myeloid leukaemia. This research paper demonstrates the secretion of numerous angiopoietic cytokines by leukaemic cells, and a role for the Ang-1/Tie2 system through STAT1, STAT3 and STAT5 phosphorylation. The mechanism of crosstalk between leukaemic cells and endothelial cells varies from one leukaemia to another, possibly eliminating the possibility of a single target for use in leukaemia therapy.

Schaar CG, le Cessie S, Snijder S, et al. Long-term follow-up of a population based cohort with monoclonal proteinaemia. Br J Haematol 2009;144:176–184.

This is one of only a few prospective studies which reports on 1464 patients recruited during a three year period from 1991 with newly diagnosed monoclonal gammopathy of undetermined significance (MGUS). During a median follow-up of nine years, the transformation rate to myeloma or lymphoma was lower than expected at 0.4% per annum. IgA and IgM paraproteins and rising paraprotein levels were associated with higher rates of transformation. The median survival was reduced in patients with hypoalbuminaemia. Patients without co-morbidity had lower overall survival than the matched control population, indicating the not-so-benign nature of the disease.

February 2009

Hancock BW, Qian W, Linch D, et al. Chlorambucil versus observation after anti-Helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial. Br J Haematol 2009;144:367–75.

Helicobacter pylori infection precipitates over 90% of gastric MALT lymphomas, and antibiotic eradication of the infection induces complete or partial remission in 60–80% of the lymphomas. Of those achieving complete remission, 10% will relapse. Evidence based guidelines are lacking for the role of adjuvant chemotherapy after eradication. In this study, Helicobacter pylori eradication produced 65% CR/PR with 95% 5-year survival. Adjuvant chlorambucil had no significant effect on 5-year progression free survival or overall survival. There remains a paucity of evidence for the use of other chemotherapies and rituximab as adjuvant therapy.

Rowe JM. Optimal management of adults with ALL. Br J Haematol 2009;144:468–83.

This excellent review begins with the two major dilemmas of ALL. The first is that paediatric survival has improved significantly, but adult survival has not. Secondly, despite a high remission rate following induction chemotherapy in adults, the relapse rate remains high and rapid. The author discusses MRD screening and current strategies and therapies to extend remission.

Papadaki C, Dufour A, Seibl M, et al. Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: clonal evolution is a limiting factor. Br J Haematol 2009;144:517–23.

Molecular monitoring has proven an invaluable tool in leukaemia for determining depth of remission and early relapse. NPM1 is a nucleolar protein which travels back and forth from the nucleus. Mutations of NPM1 occur in 60% of normal karyotype leukaemias, and in 80% of cases this mutation is the same. In this paper the authors develop a practical, sensitive and specific assay suitable for MRD detection.

Hematologica

December 2008

Malfuson JV, Etienne A, Turlure P, et al. Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia. Haematologica 2008;93:1806–13.

Acute myeloid leukaemia has a median age of presentation of 67 years. In older adults, the disease is often chemo resistant, treatment related mortality is high, and remission is often transient for those who achieve it. The difficulty is identifying the patients who will be harmed by intensive therapy, and those who will benefit. Here the authors propose a “decisional index” based on a standard multivariate analysis of 416 newly diagnosed patients of median age 72 years.

Santamaria C, Chillon MC, Garcia-Sanz R, et al. The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia. Haematologica 2008;93:1797–805.

This paper highlights that within a good prognostic group, it is not simply chance that dictates who will relapse and who will not, but the biology of the cell. High PRAME levels are associated with improved PFS in good prognosis APL, and may be useful as a secondary marker for monitoring the disease.

January 2009

Cornely OA, Bohme A, Buchheidt D, et al. Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica 2009;94:113–22.

This provides guidance on fungal prophylaxis in haematological malignancy and neutropenia based on best available evidence.

February 2009

Akagi T, Ogawa S, Dugas M, et al. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica 2009;94:213–23.

The mysterious nature of normal karyotype AML is under threat as we probe the underlying mechanisms of transformation in these patients. High-density genome-wide SNP-chip analysis identified genomic abnormalities in 49% of patients including deletions, mutations and copy number changes with loss of normal alleles.

Blood

1 December 2008

Lu S-J, Feng Q, Park JS, et al. Biological properties and enucleation of red blood cells from human embryonic stem cells. Blood 2008;112:4475–84.

Production of sufficient red cells of the appropriate type for clinical use is a problem requiring donors and industrial processes for the production of a safe blood supply. This group used human embryonic stem cells (hESCs) and a method to drive them down an erythroid pathway to produce red cells in large quantities. The resulting erythroid cells properties such as oxygen equilibrium curves, response to changes in pH and 2,3-diphosphglycerate comparable to normal red cells. It is therefore feasible to differentiate and mature hECSs into functioning erythrocytes on a large scale.

Sun J, Hakobyan N, Valentino LA, et al. Intraarticular factor IX protein or gene replacement protects against development of haemophiliac synovitis in the absence of circulating IX. Blood 2008;112:4532–41.

Congenital deficiency of factor VIII or IX in haemophiliacs results in recurrent intraarticular haemorrhage and destruction of the joints. Joint bleeding results in a chronic inflammatory disorder in the joints haemophiliac synovitis. The mainstay of treatment and prophylaxis of joint bleeding is clotting factor replacement. This study uses a different approach in a mouse model. Factor IX deficient mice were given intraarticular factor IX or intraarticular adeno-associated virus gene transfer vectors expressing factor IX. Both methods produced fewer pathological changes after injury compared to control injured joints. This should now be studied further in other models.

15 December 2008

Adamia S, Reichert AA, Kuppusamy H, et al. Inherited and acquired variations in the hyaluronan synthase 1 (HAS1) gene may contribute to disease progression in multiple myeloma and Waldenstrom macroglobulinemia. Blood 2008;112:5111–21.

Hyaluronan synthases are implicated in malignant transformation and hyaluronan synthase 1 (HAS1) over-expression has been found in many malignancies. In this study novel germ-line and somatic genetic variations in the region of the HAS1 gene involved in aberrant splicing are described in multiple myeloma and Waldenstrom’s macroglobulinaemia but not in chronic lymphocytic leukaemia, non-malignant diseases or healthy controls. These genetic variations occurred in all haematopoietic cells tested including normal CD34+ cells. Germ-line genetic variations may suggest some degree of risk of developing multiple myeloma and Waldenstrom’s macroglobulinaemia.

Gelebart P, Anand M, Armanious H, et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood 2008;112:5171–9.

Mantle cell lymphoma is characterised by a chromosomal translocation which involves the cyclin D1 gene and cyclin D1 over-expression is of importance in the pathogenesis of the disease. The Wnt canonical pathway (WCP) is a important pathway in normal cell growth and development. Normal process of this pathway inhibits β-catenin. If β-catenin is released it up-regulates a number of genes including cyclin D1. This study examined the WCP in mantle cell lymphoma cell lines and tumours. Wnt3 and Wnt10 were over-expressed. β-catenin was localised to the nucleus in cell lines and in a proportion of the tumours. This shows that the WCP is constitutively activated in a subset of mantle cell lymphoma.

1 January 2009

van Doom R, van Kester MS, Dijkman R, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood 2009;113:127–36.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma is a malignancy of mature T cells affecting the skin. Sezary syndrome (Sz) is a triad of erythroderma, lymphadenopathy and circulating malignant T cells. It is often thought to be a leukaemia phase of MF. This study carries extensive genetic studies, comparative genomic hybridisation and gene-expression profiling on a group of well characterised MF samples which were compared with a group of samples of Sz patients. A number of gains and losses of chromosomal material were found. Chromosomal alterations in 9p21, 8q24 and 1q21–1q22 were associated with poor prognosis in MF. There were genomic differences between MF and Sz, suggesting that they may be distinct diseases and should not necessary be included in one group.

8 January 2009

Saumet A, Vetter G, Bouttier M, et al. Transcriptional repression of microRNA by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood 2009;113:412–21.

Micro (mi)RNAS are small non-coding RNAs that orchestrate the expression of genes in many key aspects of cell physiology. Deregulation of miRNAs has been linked to diseases including malignancy. In acute promyleocytic leukaemia (APL) chromosomal translocations implicate the gene retinoic acid receptor alpha (RARA) which is most frequently fused with the promyelocytic leukaemia gene (PML). Pharmacological doses of retinoic acid receptor agonists such as all-trans-retinoic acid (ATRA) overcome PML-RARA repression and cells then differentiate normally. This study identifies the miRNAs repressed by the PML-RARA oncogene and shows that they are released after treatment with ATRA.

15 January 2009

Stamataki Z, Shannon-Lowe C, Shaw J, et al. Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells. Blood 2009;113:585–93.

Hepatitis C virus (HCV) replicated within the liver. An association of the virus with B cells is suggested as the infection is associated with B cell abnormalities. This paper shows that an infectious strain of HCV JFH-1can bind immortalised B cells but fails to establish productive infection but B cell associated virus infect hepatoma cells. The relationship between the B cell associated transfer of HCV to hepatoma cells is investigated and it is shown that HVC promoted that adhesion of primary B cells to HUH-7 hepatoma cells. B cells may be a vehicle for HCV to persist and transmit in the liver.

22 January 2009

Yong A, Keyvanfar K, Hensel N, et al. Primitive quiescent CD34+ cells in chronic myeloid leukaemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood 2009;113:875–82.

In chronic myeloid leukaemia (CML), primitive quiescent CD34+ cells remain a reservoir of disease and these quiescent stems cells are more resistant to tyrosine kinase inhibitors. In this study it is shown that CD34+ CML stem cells have increased surface expression of tumour necrosis factor-related-apoptosis-inducing ligand (TRAIL). Natural killer (NK) cell populations from donor samples were expanded in vitro. Treatment of CD34+ CML cells with the proteosome inhibitor bortezomib up-regulated TRAIL receptor expression and enhanced the CD34+ cell susceptibility to killing by expanded NK cells. This may be a method to use expanded NK cells from donors to help eliminate residual leukaemia with the aid of bortezomib at standard doses.

29 January 2009

Fehniger TA, Byrd JC, Marcucci G, et al. Single-agent lenalidomide induces complete remission of acute myeloid leukaemia in patients with isolated trisomy 13. Blood 2009;113:1002–5.

Lenalidomide has been shown to be efficacious in the treatment of multiple myeloma and patients with myelodysplastic syndromes with the 5q-abnormality. It has been evaluated for the treatment of other myelodysplastic syndromes and acute myeloid leukaemia. As part of such studies these investigators identified two patients, who had sustained remissions of 9 months, treated with lenalidomide alone. Both patients had a trisomy 13 clone which is present in 3% of cases of acute myeloid leukaemia. Only 2 of 31 non-trisomy 13 patients treated achieved a complete response on lenalidomide. This agent appears to have specific clinical activity in this poor risk subset.

Katzenberger T, Kalla J, Leich E, et al. A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood 2009;113:1053–61.

The majority of cases of follicular lymphoma (FL) have uniform morphological features, a distinct and immunophenotype and the t(14;18)(q32;q21) translocation. This paper draws together a series of 35 cases which have distinct and different features. They have disuse FL with low clinical stage but large localised inguinal tumours and an immunophenotype with expression of CD10, BCL6 and CD23 (a germinal centre B-cell phenotype). Genetically they were negative for the t(14;18)(q32;q21) translocation but were characterised by a deletion of the short arm of chromosome 1, del(1p36). This is a previously unrecognised subtype of FL.

5 February 2009

Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009;113:1315–25.

Aberrant DNA methylation, cytogenetic instability and mutational instability are the main processed that can silence tumour suppressor genes. This study looked at the extent of DNA methylation and chromosome aberrations in bone marrow samples from 184 patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with known outcomes. Aberrant methylation was seen in all samples. The most frequently aberrantly methylated genes identified FZD9 on chromosome 7, a receptor for Wnt in the Wnt pathway, as a possible tumour suppressor gene. Deletion of FDZ9 on one allele and aberrant methylation of the other allele was associated with poor outcome. This study supports the development of agents which reverse hypermethylation for treatment of MDS and AML.

Bruce LJ, Guizouarn H, Burton NM, et al. The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood 2009;113:1350–7.

Overhydrated hereditary stomatocytosis (OHSt) is characterised by an invaginated cell shape which suggests inward binding of the red cell membrane. The red cells leak cations at 20 to 40 times the normal rate. Mutations in the SLC4A1 gene which codes for the band 3 anion exchanger were found in the related condition cryohydrocytosis. Band 3 is part of a complex with Rh-associated glycoprotein (RhAG) which prompted study of RhAG in 7 OHSt kindreds. Two novel heterozygous mutations were discovered which lead to substitution on two highly conserved amino acids (Ile61Arg, Phe65Ser). Expression of the mutants on oocytes induced a large monovalent cation leak and modelling of RhAG suggested that these mutations would lead to an open pore structure. This paper therefore shows that these mutations in RhAG lead to the large cation leak in OHSt.

12 February 2009

Heddle NM, Cook RJ, Tinmouth A, et al. A randomised controlled trial comparing standard and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 2009;113:1564–73.

Prophylactic platelet transfusions are given to patients with chemotherapy induced thrombocytopenia. The dose of platelets administered depends on custom and practice and availability. This paper presents the results of a randomised double blind trial of two platelet doses, standard-dose 300−600×109 platelets or low-dose 150−300×109 platelets. A total of 119 patients were analysed, 58 in the low dose group and 61 in the standard risk group. The trial was stopped because of an excess of grade 4 bleeding in the low risk group, with three patients having grade 4 bleeds. This study cannot make a conclusion about non-inferiority of low-dose platelet transfusion but there were no benefits.

19 February 2009

Janin A, Murata H, Leboeuf C, et al. Donor-derived oral squamous cell carcinoma after allogeneic bone marrow transplantation. Blood 2009;113:1834–40.

Squamous cell carcinomas (SCCs) are well recognised complications following allogeneic bone marrow transplantation. This study investigated tumour tissue from 8 patients with SCC by two independent methods. In 4 of the 8 cases, all with chronic graft versus host disease, it was clear that the SCC arose from cells of donor origin that is the engrafted bone marrow. Thus donor derived bone marrow cells are recruited to sites of chronic mucosal inflammation and yield epithelial tumours.

26 February 2009

Schaub FX, Jager R, Looser R, et al. Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F. Blood 2009;113:2022–7.

Patients with myeloproliferative disorders (MPD) have deletions of the long arm of chromosome 20 (del20q). In MPD the mutation JAK2 V617F is now known to be common. Previous studies form this group suggested that the del20q preceded the acquisition of the JAK2 V617F mutation. This expanded study of a large number of patients and analysis of large numbers of individual colonies did not support this sequence of events. There events in colonies suggested that either event could have occurred first and did not support the thesis that del20q was a predisposing event for JAK2 V617F.

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Footnotes

  • Provenance and peer review Commissioned; not externally peer reviewed.