New England Journal of Medicine

25 June 2009

Pui C-H, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukaemia without cranial irradation. N Engl J Med 2009;360:2730–41.

Prophylactic cranial irradiation may prevent central nervous system (CNS) disease in acute lymphoblastic leukaemia but it has long-term effects. This study identifies children at risk of CNS disease and treats them with an intense and carefully administered intrathecal therapy as well as their systemic chemotherapy regimen but omitting prophylactic cranial irradiation. Compared with a historical control group this group had significantly longer continuous remissions. This trial suggests that prophylactic cranial irradiation can be safely omitted in the treatment of childhood acute leukaemia. In the small proportion who do develop CNS relapse this is eminently curable.

British Journal of Haematology

March 2009

Pettengell R, Bosly A, Szucs TD, et al. Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study. Br J Haematol 2009;144:677–85.

Febrile neutropenia is a common unwanted consequence of myelosuppressive therapy, and bears significant cost for the patient and for the NHS. This study identifies older age, chemotherapy dose, history of previous chemotherapy, recent infection and hypoalbuminaemia as risk factors for neutropenic infection. A scoring system is proposed to rationalise the decision process by which patients are commenced on G-CSF (granulocyte-colony stimulating factor).

Meklat F, Zhang Y, Shahriar M, et al. Identification of protamine 1 as a novel cancer-testis antigen in early chronic lymphocytic leukaemia. Br J Haematol 2009;144:660–6.

Immunotherapy possesses tremendous but elusive potential for the treatment of many forms of malignancy. An immune system sensitised to a tumour may synergise with chemotherapeutic agents to enhance remission, and may prolong that remission with antitumour activity after chemotherapeutic agents have stopped. Protamine (Prm) 1 can be detected in approximately 25% of patients with chronic lymphocytic leukaemia (CLL). Antibodies to Prm 1 are present in 50% of patients with CLL, in contrast to healthy individuals who do not possess these antibodies. Prm 1 may be a useful target for immunotherapy, and its upregulation may evoke an immune response within individuals. A bivalent vaccine against Prm 1 and SEMG 1 is proposed as an early therapy in CLL.

Siragusa S, Caramazza D, Malato A. How should we determine length of anticoagulation after proximal deep vein thrombosis of the lower limbs? Br J Haematol 2009;144:832–7.

This is a practical review of the literature informing the reader of the risk of recurrent thrombosis following discontinuation of anticoagulation. The reader is urged to risk stratify patients after 3 months to determine if anticoagulation should be continued or stopped. Clear guidance for the provision of anticoagulation is provided in tabloid form for the clinical management of deep vein thrombosis in low-risk and high-risk patients.

Baumann P, Muller K, Mandl-Weber S, et al. The peptide-semicarbazone S-2209, a representative of a new class of proteasome inhibitors, induces apoptosis and cell growth arrest in multiple myeloma cells. Br J Haematol 2009;144:875–86.

After decades of stagnation in available therapies for multiple myeloma, the past 10 years have witnessed exciting developments in non-genotoxic drugs such as thalidomide and the proteasome inhibitor bortezomib. Both of these drugs are frequently associated with adverse side-effects, and where second generation drugs are available for thalidomide, cleaner proteasome inhibitors are still required. S-2209 is the first of a new class of proteasome inhibitor that demonstrates potent anti-proliferative and anti-apoptotic effects in myeloma cell lines and patient samples. S-2209 is potent at nanomolar concentrations, at which it spares normal cells. Clinical trials are proposed to determine its clinical efficacy and safety profile.

April 2009

Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009;145:24–33.

This article is a must read as disseminated intravascular coagulation often presents as an enigmatic problem for clinicians of all specialties. The guideline provides a list of underlying conditions and a scoring system to make the diagnosis. Platelets and fresh frozen plasma should not be automatically prescribed when the platelet count is less than 50 and coagulation is deranged. Rather the risk of bleeding should be taken into account before blood product support is administered.

Stevens JM, Macdougall F, Jenner M, et al. Patterns of recruitment into acute myeloid leukaemia (AML) 15 and outcome for young patients with AML at a single referral centre. Br J Haematol 2009;145:40–4.

This article addresses the peddled rumour that patients in trials do better. Outcomes of patients entered into the AML15 trial from one centre are reported. Patients who refused trial entry had similar outcomes to patients entered into the trial. Where all patients were considered for trial entry, doctors’ bias was identified as precluding trial entry for some patients, based on their clinical condition. These patients fared worse than those entered. This distortion may enhance the outcome of trials over the clinician’s experience.

Flight SM, Johnson LA, Du QS, et al. Textilinin-1, an alternative anti-bleeding agent to aprotinin: importance of plasmin inhibition in controlling blood loss. Br J Haematol 2009;145:207–11.

Aprotinin is a plasmin inhibitor that is used in surgery to arrest bleeding. Paradoxically, aprotinin also inhibits the intrinsic pathway of coagulation, raising the activated partial thromboplastin time (APTT), which may contribute to bleeding. Textilinin-1 is derived from Pseudonaja textilis venom, and is a selective inhibitor of plasmin, with no effect upon the APTT. In mouse models, aprotinin and textilinin-1 reduced blood loss, but textilinin-1 achieved haemostasis in a shorter time. Textilinin-1 awaits clinical trials, but may prove to be a safer anti-fibrinolytic.

May 2009

Habermann TM, Lossos IS, Justice G, et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 2009;145:344–9.

Mantle cell lymphoma often presents as an indolent chemosensitive lymphoma, but quickly relapses, becomes chemorefractory and has a poor prognosis. There has been little improvement in the median survival and there remains a need for effective and durable therapies. In this article, lenalidomide was administered to 15 patients who had mantle cell lymphoma for approximately 5 years and had received a median of four previous treatments. Responses, of median duration 13.7 months, were observed in 50% of patients. Complete remission was observed in 20% of patients. Lenalidomide may be another step towards improving outcome in this difficult set of patients.

Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol 2009;145:318–32.

This report of the AML14 trial reinforces the need for new anti-leukaemic treatments for AML in older patients. Outcomes are not improved by dose escalation, increasing courses or PSC-833.

Marin D, Khorashad JS, Foroni L, et al. Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? Br J Haematol 2009;145:373–5.

Historically relapse is diagnosed and treatment offered when disease becomes symptomatically or clinically manifest. Molecular monitoring is now practiced in a number of malignancies, but what constitutes relapse and what triggers should there be for treatment. In this study, a doubling of minimal residual disease (as measured by BCR-ABL PCR) carried no prognostic value when transcript levels were below 0.05%. However, a doubling in transcript level above 0.05% carried a relative risk of relapse of 8.3.

Kato GJ, Wang Z, Machado RF, et al. Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. Br J Haematol 2009;145:506–13.

Sickle cell disease is a multisystem disease producing significant morbidity, disability and mortality. This paper improves our understanding of the non-occlusive mechanisms inducing vasculopathy in sickle cell patients. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and is significantly elevated in sickle cell disease. ADMA therefore compounds the detrimental effect of plasma haemoglobin and elevated arginase on nitric oxide levels.

Haematologica

March 2009

Terpos E, Katodritou E, Tsiftsakis E, et al. Cystatin-C is an independent prognostic factor for survival in multiple myeloma and is reduced by bortezomib administration. Haematologica 2009;94:372–9.

Serum cystatin-C levels inversely reflect renal function and correlate strongly in myeloma with advanced ISS stage, extensive bone disease, and high β₂-microglobulin. Cystatin-C in conjunction with the lactate dehydrogenase (LDH) provides useful prognostic information for myeloma. Where both serum cytstatin-C and LDH are elevated at diagnosis, the survival is 24 months. Survival rises to 48 months when only one is elevated and survival has not yet been reached when neither is elevated. Bortezomib causes cystatin-C levels to fall in parallel with tumour burden, revealing the need for pre-treatment analysis.

Tang H, Chen S, Wang H, et al. TAM receptors and the regulation of erythropoiesis in mice. Haematologica 2009;94:326–34.

TAM receptors have recently been shown to be involved in megakaryocytopoiesis. The receptors are also present on erythropoietic cells. Using mouse knockout models, erythropoiesis was impaired in the absence of two TAM receptors (Axl and Mer). GATA-1 and EpoR mRNA levels were significantly reduced in the absence of TAM receptors, but elevated in the presence of the receptors and their ligand Gas6. These results indicate a new tier in the regulation of erythropoiesis that is independent of erythropoietin.

April 2009

Wang X, Ottosson A, Ji C, et al. Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica 2009;94:470–8.

Bortezomib was recently shown to sensitise tumour cells to natural killer (NK) cell mediated lysis in addition to inducing apoptosis directly. The authors demonstrate that bortezomib is equally toxic to NK cells in a dose-dependent and time-dependent manner. As bortezomib is also toxic to T cells and dendritic cells, it may actually reduce tumour recognition and targeting rather than enhance it.

May 2009

Gaymes TJ, Shall S, MacPherson LJ, et al. Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukaemia and myelodysplastic syndromes. Haematologica 2009;94:638–46.

Acute myeloid leukaemias and myelodysplastic syndromes often have defective DNA repair. Poly ADP-ribose polymerase (PARP) inhibitors target cells with defective double-stranded DNA break repair, and have been shown to be effective in inducing apoptosis in solid tumour cell lines. The authors demonstrate that the PARP inhibitors KU-0058948 and PJ34 induce cell cycle arrest and apoptosis in primary myeloid leukaemia cells and leukaemic cell lines. This effect is enhanced by histone deacetylase inhibitors. Therapeutic testing in leukaemia and myelodysplastic syndromes is proposed.

Van den Biggelaar M, Bouwens EA, Kootstra NA, et al. Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells. Haematologica 2009;94:670–8.

Previous attempts at gene therapy in haemophilia A patients have been disappointing. Factor VIII levels have been poor and of short half-life because production has been independent of von Willebrand factor (vWF; a FVIII carrier molecule). In this clever study, the endothelial cells have been transfected with FVIII. Subsequent production is in conjunction with vWF and storage is in the Wiebel-Palade bodies. The paper concludes with strategies to enhance FVIII:vWF binding.

Blood

5 March, 2009

Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161–71.

Romiplostin is a thrombopoiesis-stimulating protein composed of two IgG Fc domains coupled with four copies of a thrombopoietin mimetic peptide. It has already been shown to raise the platelet count in those with immune thrombocytopenic purpura and is administered by a once weekly by subcutaneous injection. This study shows that romiplostin is safe and efficacious over the long term in a group of 142 patients. Patients were treated with the drug for up to 156 weeks. Platelet counts were above 50×10⁹/l in 87% and remained above this level on average 67% of the time in responding patients. Severe bleeding episodes occurred in 9% and thrombotic events (many of which had other causes than the drug) occurred in 5%. Eight patients were noted to have reticulin present in bone marrow biopsies performed for various reasons but there was no evidence of chronic idiopathic myelofibrosis. Bone marrow biopsies were not preformed in the majority of patients or in a systematic fashion so this needs further investigation.

12 March, 2009

Kim DH, Xu W, Ma C, et al. Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. Blood 2000;113:2517–34.

The cellular events which drive the BCR/ABL translocation and initiate leukaemogenesis in chronic myeloid leukaemia (CML) are unclear. This study looked at single nucleotide polymorphism (SNP) markers in the main pathways that have been proposed as possible contenders for the provocation of leukaemogenesis. In the comparison between 170 patients with CML and 182 healthy controls, only a BCL2 SNP in the apoptosis pathway was associated with susceptibility to CML. This association between BCL2 SNP and CML susceptibility was also shown with haplotype analysis where a BCL2 haplotype block was associated in those who had developed CML. Therefore BCL2 SNP is associated with increasing susceptibility to CML in single marker and haplotype analysis.

19 March, 2009

Ohnmacht C, Voehringer D. Basophil effector function and homeostasis during helminth infection. Blood 2009;113:2816–25.

Basophils are a morphologically familiar cell but much about the function of the cell is not clear. This study, in mice, establishes that the life-span of basophils is about 60 h. Basophils are produced at least in part by the bone marrow. It was possible to deplete the mice of basophils. Such mice also had significantly reduced numbers of eosinophils in the lung, spleen and blood. When mice were infected by the worm Nippostrongylus brasiliensis, basophil-depleted mice showed impaired worm expulsion whereas it was efficient in non-basophil-depleted mice indicating that basophils have a major role to play in worm expulsion and play a crucial role as effector cells in type 2 immune responses.

26 March, 2009

Roudaia L, Cheney MD, Manuylova E, et al. CBFβ is critical for AML 1-ETO and TEL-AML1 activity. Blood 2009;113:3070–9.

The translocations t(8;21)(9q22;q22) in acute myeloid leukaemia and t(12;21)(p13;q22) in acute lymphocytic leukaemia both involve the RUNX1 gene. These translocations generate the fusion proteins AML1-ETO and TEL-AML1. The Runt domain of AML1 mediates DNA binding and heterodimerisation of the core binding factor β (CBFβ) in both proteins. This study introduces changes in the Runt domain so that heterodimerisation of CBFβ but not DNA binding is disrupted. In the mouse bone marrow many of the clonogenic activities of AML1 are disrupted. These studies show that CBFβ is essential for the activity of the AML1 fusion proteins. The Runt domain/CBFβ is therefore a valid therapeutic target.

2 April, 2009

Jackson SC, Sinclair GD, Cloutier S, et al. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with VWFV1316M mutation. Blood 2009;113:3348–51.

One family has been described with the Montreal platelet syndrome where there is hereditary thrombocytopenia, muocutaneous bleeding, giant platelets and spontaneous platelet aggregation in vitro. In von Willebrand disease type 2B there is also macrothrombocytopenia and spontaneous platelet aggregation in vitro. This paper revisits the original family, described initially in 1963, and shows that affected individuals with the Montreal platelet syndrome had borderline von Willibrand factor antigen and discrepantly low ristocetin cofactor activity. They were shown to be heterozygotes for a V1316M VWF mutation, which is described in type 2B von Willibrand disease.

9 April, 2009

Ludwig H, Hajek R, Tothova E, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009;113:3435–42.

Multiple myeloma has a median survival of 6.5 years with high-dose therapies but only 3.5 years in less-fit older patients treated with conventional therapy. This study is a trial that compares thalidomide plus dexamethasone to standard melphalan and prednisolone in 289 older patients. When patients had stable disease or better, they were then randomised to thalidomide and interferon maintenance or interferon only maintenance. Time to progression and progression-free survival was similar with both regimens but overall survival was significantly less with the thalidomide–dexamethasone treatment. Toxicity was higher with this treatment in patients over the age of 75 years with poor performance status. Toxicities with new drugs may have significant disadvantages particularly in frail older populations.

16 April, 2009

Margaritis P, Roy E, Alijamali MN, et al. Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 2009;113:3682–9.

A factor VII transgene has been engineered to be secreted in the activated form. FactorVIIa has been shown to correct the haemostatic parameters in mouse models of haemophilia A and haemophilia B. This study uses this system in a large animal model. An engineered canine FactorVIIa transgene was delivered in an adeno-associated viral vector delivered via the portal vein in haemophilia A and haemophilia B dogs. This was well tolerated and resulted in correction of clotting parameters and complete absence of spontaneous bleeding. There was no hepatotoxicity or thrombotic complications noted. This study provides proof-of-concept for this gene transfer method demonstrating in vivo efficacy and safety for continuously expressed factor VIIa in a large animal model. This system avoids the risk of inhibitor formation that occurs with conventional bolus administration of clotting factors.

23 April, 2009

Ku GH, White RH, Chew HK, et al. Venous thromboembolism in patients with acute leukaemia: incidence, risk factors, and effect on survival. Blood 2009;113:3911–7.

Thrombosis is a common complication in patients with cancer. It has been thought that this is more common with solid tumours than in haematological malignancies. This large population study looks at the incidence of venous thromboembolism (VTE) in a cancer registry in a 6-year period in the 1990s. In acute myeloid leukaemia the 2-year cumulative incidence of VTE was 5.2%. Of these events, 64% occurred within 3 months of diagnosis. In acute lymphoblastic leukaemia the 2-year cumulative was 4.1%. In both groups, perhaps not surprisingly, presence of a central catheter, older age and comorbidities were associated with VTE. This study shows that the incidence of VTE with acute leukaemia is significant and similar to that in solid tumours.

30 April, 2009

Guo Y-H, Herndandez I, Isermann, et al. Caveolin-1-dependent apoptosis induced by fibrin degradation products. Blood 2009;113:4431–9.

The paper describes a new pathway linking fibrin degradation to apoptosis which may have a role in physiological and pathophysiological systems. Fibrin degradation products (FDPs) but not fibrinogen, fibrin or fibrinogen degradation products have been shown to induce DNA fragmentation and cell death of placental trophoblast cells. The original studies were carried out with mouse FDPs and in mouse cells. This study shows that human FDPs and human cells behave in the same fashion. The apoptotic activity was only associated with fibrin fragment E (FnE). The pro-apoptotic activity has a requirement for internalisation of FnE mediated by an epitope within fibrinopeptide Aα52–81. This is dependent on caveolin-1. Apoptosis-inducing activity is found to be located in fibrinopeptide Aα17–37. Observations then suggest that FnE induces cell death by activating the mitochondrial apoptosis pathway dependent of capases 9 and 3. This FDP-induced apoptosis pathway could account for trophoblast cell death, placental insufficiency and pregnancy loss in situations of increased FDP generation.

7 May, 2009

McCann KJ, Ashton-Key M, Smith K, et al. Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence of separate development. Blood 2009;113:4677–80.

Primary central nervous system (CNS) lymphomas are malignant large B-cell non-Hodgkin lymphomas, which by definition are confined to the CNS. This study uses immunoglobulin variable (V)-gene analysis to define and track clones in tumour and in the peripheral blood and bone marrow in the three patients with full sample sets. Tumour-derived sequences were detected in the bone marrow of all three patients. There was increased diversification of clones at the peripheral blood sites than in the CNS tumour. As there is no malignant growth at peripheral sites and limited diversity in the brain it is indicated that there is little or no re-entry into the brain. Tumour clones in the CNS may undergo a final transforming event or environmental stimulus leading to their malignant behaviour.

14 May, 2009

Warkentin TE, Sheppard JI, Moore JC, et al. Studies of the immune response in heparin-induced thrombocytopenia. Blood 2009;113:4963–9.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies to complexes of platelet factor 4 bound to heparin. This study examined the nature and sequence of development of anti-PF4/heparin antibodies in 12 patients who developed HIT and 36 who formed antibodies but did not develop HIT. In those with HIT, antibodies were detectable 4 days after starting heparin and their presence preceded the fall in platelet count by 2 days. This implies that those with a fall in platelet count but no antibody detected are unlikely to have an “incipient HIT”. Thrombotic events occurred unpredictably. Rapid formation of IgG antibodies with simultaneous IgM and IgA occurred unlike a classical immune response where IgM antibodies would occur first.

21 May, 2009

Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009;113:5277–86.

Hepcidin is a master regulator of iron homeostasis. It binds to ferroportin, an iron export protein, results in internalisation of the transporter and then blockage of iron export from the enterocytes and macrophages to the circulation. Hepcidin synthesis can be induced by cytokines. In the anaemia of chronic disease (ACD) iron is retained in the mononuclear phagocytic system but patients with ACD may also be iron deficient, and the differentiation between ACD and need for iron can be difficult. This study addresses this issue in a mouse model of ACD where the animals are also made iron deficient by venesection, and in a patient cohort with both disorders.

In ACD in both systems hepcidin levels were elevated, whereas in combined ACD and iron deficiency hepcidin levels were lower. Hepcidin levels seem to reflect erythropoietic demands for iron and may be an aid in selecting appropriate therapy for patients.

28 May, 2009

Stabach PR, Simonovic I, Ranieri MA, et al. The structure of the ankyrin-binding site of β-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties. Blood 2009;113:5377–84.

Ipsaro JJ, Huang L, Mondragon A. Structures of the spectrin–ankyrin interaction binding domains. Blood 2009;113:5385–92.

The skeleton of the red cell is composed of spectrin tetramers, which associate with actin and other proteins, and ankyrin, which forms a bridge to the anion exchanger. These two papers both explore the link between spectrin and ankyrin. Using different approaches they resolve the crystal structure of the crucial repeats of 14 and 15 of B-spectrin. One paper found 14 critical residues for ankyrin binding at the end of helix C of repeat 14 the linker region and B-C loop of repeat 15. The other paper found a negatively charged patch on one side of repeat 14 that may bind to a positively charged region of ankyrin. These may all contribute to a flexible area in spectrin that associates with ankyrin. Spectin–ankyrin function defects are implicated in many pathologies; therefore these studies elucidating the interaction are of importance to human disease.