Showing papers in "British Journal of Haematology in 2000"
TL;DR: The results suggest that preterm, as compared with term, cord blood is richer in mesenchymal progenitors, similar to haematopoietic progenitor cells.
Abstract: Haemopoiesis is sustained by two main cellular components, the haematopoietic cells (HSCs) and the mesenchymal progenitor cells (MPCs). MPCs are multipotent and are the precursors for marrow stroma, bone, cartilage, muscle and connective tissues. Although the presence of HSCs in umbilical cord blood (UCB) is well known, that of MPCs has been not fully evaluated. In this study, we examined the ability of UCB harvests to generate in culture cells with characteristics of MPCs. Results showed that UCB-derived mononuclear cells, when set in culture, gave rise to adherent cells, which exhibited either an osteoclast- or a mesenchymal-like phenotype. Cells with the osteoclast phenotype were multinucleated, expressed TRAP activity and antigens CD45 and CD51/CD61. In turn, cells with the mesenchymal phenotype displayed a fibroblast-like morphology and expressed several MPC-related antigens (SH2, SH3, SH4, ASMA, MAB 1470, CD13, CD29 and CD49e). Our results suggest that preterm, as compared with term, cord blood is richer in mesenchymal progenitors, similar to haematopoietic progenitors.
1,667 citations
TL;DR: The dyskeratosis congenita registry (DCR) has identified new features of DC and has been pivotal in the identification of the DKC1 gene which is mutated in X-linked DC.
Abstract: Classic dyskeratosis congenita (DC) is an inherited disease characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia (Zinsser, 1906; Engman, 1926; Cole et al, 1930). A variety of noncutaneous (dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal) abnormalities have also been reported (Sirinavin & Trowbridge, 1975; Drachtman & Alter, 1995; Dokal, 1996a; Knight et al, 1998a). Bone marrow (BM) failure is the principal cause of early mortality with an additional predisposition to malignancy and fatal pulmonary complications. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. Since the annotation (Dokal, 1996a), there have been significant advances in DC. These have been facilitated by the dyskeratosis congenita registry (DCR), established at the Hammersmith Hospital (London) in 1995. By November 1999, 92 DC families (Argentina, one; Australia, two; Austria, one; Belgium, two; Brazil, eight; Canada, two; Egypt, one; France, 11, Germany, three; Holland, two; Hong Kong, two; India, two; Ireland, five; Italy, four; New Zealand, one; Spain, two; Turkey, three; United Arab Emirates, two; UK, 14; and USA, 24) had been recruited. These 92 families from 20 different countries collectively comprised 148 (127 male and 21 female) patients. As well as confirming previous observations, the DCR has identified new features of DC and has been pivotal in the identification of the DKC1 gene which is mutated in X-linked DC.
508 citations
TL;DR: These revised guidelines on testing for the lupus anticoagulant have been prepared against this background and cover both clinical and laboratory aspects.
Abstract: In 1991, the Haemostasis and Thrombosis Task Force of the British Society for Haematology published guidelines on testing for the lupus anticoagulant (LA) (Machin et al, 1991). Since then there have been major developments in our understanding of the nature of `antiphospholipid antibodies' (aPLs) and improvements in our knowledge of the clinical course of the antiphospholipid syndrome. These revised guidelines have been prepared against this background. They cover both clinical and laboratory aspects.
439 citations
TL;DR: Morphological examination and haematopoietic colony‐forming assays for isolated TER‐ 119+ cells revealed that TER‐119 reacts with erythroid cells at differentiation stages from early proerythroblast to mature erythrocyte, but not with cells showing typical erythyroid blast‐forming unit (BFU‐E) and erystroid colony‐formed unit (CFU‐ E) activities.
Abstract: The antigen specificity of a rat monoclonal antibody TER-119 was investigated. In adult mice, TER-119 reacted with mature erythrocytes, 20–25% of bone marrow cells and 2–3% of spleen cells but not with thymocytes nor lymph node cells. In fetal haematopoietic tissues, 30–40% of d 10 yolk sac cells, 80–90% of d 14 fetal liver cells and 40–50% of newborn liver cells were reactive with TER-119. TER-119+ cells in adult bone marrow expressed significant levels of CD45 but not myeloid (Mac-1, Gr-1) or B-cell (B220) markers. Morphological examination and haematopoietic colony-forming assays for isolated TER-119+ cells revealed that TER-119 reacts with erythroid cells at differentiation stages from early proerythroblast to mature erythrocyte, but not with cells showing typical erythroid blast-forming unit (BFU-E) and erythroid colony-forming unit (CFU-E) activities. Erythroleukaemia cell lines do not express the TER-119 antigen even after stimulation with dimethylsulphoxide. TER-119 immunoprecipitated protein bands with molecular masses of 110 kDa, 60 kDa, 52 kDa and 32 kDa from erythrocyte membrane, whereas only a 52-kDa band was detected by TER-119 in Western blot analysis. Further molecular and cellular analyses indicated that the TER-119 antigen is a molecule associated with cell-surface glycophorin A but not with glycophorin A itself.
380 citations
TL;DR: A sensitive, reliable and reproducible method, based on three multiplex PCR assays, for the rapid detection of seven common α‐thalassaemia deletions and one α‐globin gene triplication, which should greatly facilitate the genetic screening and molecular diagnosis of these determinants in populations where α‐halassaemias are prevalent.
Abstract: We describe a sensitive, reliable and reproducible method, based on three multiplex PCR assays, for the rapid detection of seven common alpha-thalassaemia deletions and one alpha-globin gene triplication. The new assay detects the alpha0 deletions - -SEA, - (alpha)20.5, - -MED, - -FIL and - -THAI in the first multiplex PCR, the second multiplex detects the -alpha3.7 deletion and alphaalphaalphaanti3.7 variant, the third multiplex detects the -alpha4.2 deletion. This simple multiplex method should greatly facilitate the genetic screening and molecular diagnosis of these determinants in populations where alpha-thalassaemias are prevalent.
346 citations
TL;DR: The results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.
Abstract: Thromboembolic phenomena have been described in patients with thalassaemia intermedia and major, although there are relatively few epidemiological data on the overall frequency of these complications. To obtain more insight into the risk and mechanism of venous thromboembolism in thalassaemia, the aims of this study were: (i) to establish retrospectively the prevalence of thromboembolic events in a large group of adults with thalassaemia intermedia and major during a follow up period of 10 years; (ii) to measure in subgroups of these patients sensitive markers of activation of coagulation and fibrinolysis enzymes; and (iii) to look for possible procoagulant mechanisms. A high prevalence of thromboembolic events was found, particularly in splenectomized patients with thalassaemia intermedia (29%). These patients had high plasma levels of markers of coagulation and fibrinolysis activation. Furthermore, thalassaemic red cells and erythroid precursors from splenectomized patients with thalassaemia intermedia had an enhanced capacity to generate thrombin. To evaluate the role of splenectomy per se on procoagulant activity, we evaluated the capacity to form thrombin in healthy individuals who had been splenectomized for trauma. They produced the same amount of thrombin as non-splenectomized controls. In conclusion, the results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.
302 citations
TL;DR: It is indicated that the P2T receptor plays a central role in amplifying platelet responses and demonstrate the clinical potential of P2 T receptor antagonists.
Abstract: Adenosine diphosphate (ADP) is an important platelet agonist and ADP released from platelet dense granules amplifies responses to other agonists. There are three known subtypes of ADP receptor on platelets: P2X(1), P2Y(1) and P(2T) receptors. Sustained ADP-induced aggregation requires co-activation of P2Y(1) and P(2T) receptors. AR-C69931MX, a selective P(2T) receptor antagonist and novel antithrombotic agent, was studied to characterize further the function of the P(2T) receptor. The roles of the P2Y(1) receptor and thromboxane A(2) were assessed using the selective P2Y(1) antagonist A2P5P and aspirin respectively. Aggregation was measured by whole blood single-platelet counting and platelet-rich plasma turbidimetry, using hirudin anticoagulation. Dense granule release was estimated using ([14)C]-5-hydroxytryptamine (HT)-labelled platelets. Ca(2+) mobilization, P-selectin expression, Annexin V binding and microparticle formation were determined by flow cytometry. P(2T) receptor activation amplified ADP-induced aggregation initiated by the P2Y(1) receptor, as well as amplifying aggregation, secretion and procoagulant responses induced by other agonists, including U46619, thrombin receptor-activating peptide (TRAP) and collagen, independent of thromboxane A(2) synthesis, which played a more peripheral role. P(2T) receptor activation sustained elevated cytosolic Ca(2+) induced by other pathways. These studies indicate that the P(2T) receptor plays a central role in amplifying platelet responses and demonstrate the clinical potential of P(2T) receptor antagonists.
286 citations
TL;DR: It is demonstrated that the FLT3 ITD mutation occurs in a significant percentage of adult AML cases and is an important adverse prognostic factor that appears independent of conventional karyotypic findings.
Abstract: Genomic DNA from 106 cases of adult de novo acute myeloid leukaemia (AML) was screened by polymerase chain reaction (PCR) and gel electrophoresis for FLT3 internal tandem duplication (ITD) mutations within the juxtamembrane (JM) domain. FLT3 mutations were detected in 14 cases (13.2%) and occurred in FAB types M1 (4 out of 14 cases), M3 (1 out of 10 cases), M4 (5 out of 37 cases) and M5 (4 out of 11 cases). Sequence analysis of four cases with abnormal PCR electrophoretic patterns revealed in frame duplications in the region of exon 11 of between 27 and 111 base pairs. Three are predicted to result in the tandem duplication of adjacent amino acid residues and one to result in a tandem duplication plus insertion of a novel amino acid motif. Statistical analysis showed the FLT3 mutations to be a strong prognostic factor, with patients lacking the mutation surviving significantly longer from diagnosis (mean 29.1 months) than those with an ITD (mean 12.8 months; P = 0.0002). Thirteen of the 14 patients with FLT3 mutations died within 18 months of diagnosis. FLT3 mutations were of prognostic significance in good risk disease (P = 0.04), as well as in patients with standard risk disease (P = 0.0096). This study demonstrates that the FLT3 ITD mutation occurs in a significant percentage of adult AML cases and is an important adverse prognostic factor that appears independent of conventional karyotypic findings.
285 citations
TL;DR: It is indicated that BCL‐HS is the equivalent of the Asian variant of IVL, and the clinical course was aggressive with a median survival of 7 months.
Abstract: Diffuse large B-cell lymphoma with haemophagocytic syndrome (BCL-HS) has been reported mainly in Asia and is regarded as a distinct variant of intravascular lymphoma (IVL). However, it is unclear whether all cases of BCL-HS fall within the framework of IVL and available clinical information is limited. We analysed 25 cases with BCL-HS, including 11 autopsied cases (median, 66 years; male-female ratio, 1.1:1). The patients presented with fever, anaemia, thrombocytopenia, hepatosplenomegaly, haemophagocytosis, bone marrow invasion, respiratory disturbance and disseminated intravascular coagulopathy, but usually lacked lymphadenopathy, mass formation, neurological abnormalities and skin lesions. The clinical course was aggressive with a median survival of 7 months. The morphological findings were uniform: large lymphoid cells infiltrated vessels and/or sinusoids of the liver, marrow, lung, kidney and other organs. They were positive for CD19, CD20, CD79a and HLA-DR, but negative for CD10, CD23 and CD30. CD5 was positive in five out of 17 cases. Our critical review indicates that BCL-HS is the equivalent of the Asian variant of IVL.
254 citations
TL;DR: Thalidomide may induce good partial remissions in advanced refractory Myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients.
Abstract: Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR, nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15- 50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.
248 citations
TL;DR: In this paper, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed.
Abstract: Recently, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed. However, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities for which real prognosis at present is uncertain. The main aims of this study were to evaluate in an independent series the prognostic value of the IPSS and to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in 640 patients. In univariate analyses, cases with single 1q abnormalities experienced poor survival, whereas those with trisomy 8 had a higher risk of acute leukaemic transformation than the remaining patients (P = 0.004 and P = 0.009 respectively). Patients with single del(12p) had a similar survival to patients with a normal karyotype and showed some trend for a better survival than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroup, proportion of bone marrow blasts and haemoglobin level were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk. A large international co-operative study should be carried out to clarify these findings.
TL;DR: Allogeneic stem cell transplantation from an HLA‐identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors.
Abstract: Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.
TL;DR: The ability of APC to inhibit LPS‐induced translocation of NF‐κB is likely to be a significant event given the critical role of the latter in the host inflammatory response.
Abstract: Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor α (TNF-α) production and on the activation of the central proinflammatory transcription factor nuclear factor-κB (NF-κB) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 µg/ml, 100 µg/ml and 20 µg/ml) before addition of LPS (100 ng/ml and 10 µg/ml). APC inhibited LPS-induced production of TNF-α both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-κB, with APC (200 µg/ml) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-κB is likely to be a significant event given the critical role of the latter in the host inflammatory response.
TL;DR: The current management strategy for these disorders, with few exceptions and considerable caution, is simple: in TMD, do nothing'; in AML, `do less'; and in ALL, ` do more'.
Abstract: Down's syndrome (DS) is the most common factor predisposing to childhood leukaemia. Children with DS have a 10to 20-fold excess risk of developing leukaemia (Table I) (Krivit & Good, 1957; Stewart et al, 1958; Wald et al, 1961; reviewed in Fong & Brodeur, 1987; Levitt et al, 1990; Robison, 1992; Zipursky et al, 1992; Avet-Loiseau et al, 1995). Roughly 1% of children with DS develop one or more of the following distinctive types of leukaemia: (i) a spontaneously regressing congenital or neonatal myeloproliferative disorder (TMD) (also known as transient myeloproliferative syndrome, congenital transient leukaemia, congenital leukaemoid reaction, transient leukaemoid proliferation and transient abnormal myelopoiesis); (ii) acute myeloid leukaemia (AML), usually acute megakaryoblastic leukaemia (AMKL) (or erythro/megakaryoblastic leukaemia before the age of 5 years); or (iii) common B-lineage acute lymphoblastic leukaemia (ALL) (for a review, see Zipursky et al, 1987; Robison, 1992; Avet-Loiseau et al, 1995). The current management strategy for these disorders, with few exceptions and considerable caution, is simple: in TMD, `do nothing'; in AML, `do less'; and in ALL, `do more'. The rationale for this approach is the subject of this review.
TL;DR: The data show that quantitation of liver iron from a single liver biopsy has little value in long‐term monitoring of iron stores, and most complications can be avoided if ferritin levels can be brought down to <1500 μg/l.
Abstract: Clinical complications of transfusional iron overload are still common in patients with thalassaemia major (TM) and it is not clear how best to monitor body iron stores during long-term follow-up to anticipate tissue damage. In this study, we have reviewed a group of 32 patients who underwent liver biopsy between 1984 and 1986. We developed a method of assessing the trend in serum ferritin (TSF) during long-term monitoring and compared this with mean serum ferritin (MSF) and initial liver iron (LI) concentration to determine whether, individually or in combination, they were accurate in predicting clinical outcome. LI levels were low ( 15 mg/g dry weight) in 15, 7 and 10 patients respectively. MSF was low ( 2500 μg/l) in 10, 14 and 8 patients. TSF was low, medium and high risk in 9, 9 and 11 out of 29 evaluable patients. During a median follow-up of 13·6 years (range 2·3–14·8 years) after biopsy, nine patients died and an additional three patients developed heart failure. Hypothyroidism developed in five, hypoparathyroidism in four, and diabetes mellitus in seven patients. Cirrhosis developed in four of 10 evaluable patients. The clinical end-point of death or cardiac failure was significantly associated with increasing iron load using all three means of assessment. Although numbers were insufficient for statistical analysis, MSF or TSF were more closely associated with complications of iron overload than LI. There was no clear additional value in combining LI with MSF or TSF. The data show that quantitation of liver iron from a single liver biopsy has little value in long-term monitoring of iron stores. Most complications can be avoided if ferritin levels can be brought down to <1500 μg/l.
TL;DR: The results suggest that the chemical blocking of the gp130 signalling pathway at the JAK level could be a relevant therapeutic approach to MM.
Abstract: Cytokines of the interleukin 6 (IL-6) family, which activates the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp130 involves the Janus tyrosine kinases (JAK) JAK1, JAK2 and Tyk2 and then the downstream effectors comprising the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. We evaluated the effects of the JAK2 inhibitor tyrphostin AG490 on MM cells. We found that AG490 suppressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited. These results suggest that the chemical blocking of the gp130 signalling pathway at the JAK level could be a relevant therapeutic approach to MM.
TL;DR: Three cases of iatrogenic parvovirus B19 infection resulting from the use of the same batch of fibrin sealant under operation are reported, suggesting that infection may occur from blood products contaminated with it.
Abstract: Human parvovirus B19 infection has been shown to be transmissible by blood and blood products and to result in transient aplastic crisis in patients with rapid red cell turnover. We report three cases of iatrogenic parvovirus B19 infection resulting from the use of the same batch of fibrin sealant under operation. Fibrin sealant, which is a typical haemostatic agent produced from blood, has been used during surgery. Human parvovirus is resistant to existing virus-inactivating techniques, suggesting that infection may occur from blood products contaminated with it. Use of recombinant products for these proteins may thus be necessary.
TL;DR: Four hundred and twenty‐nine patients received myeloablative chemotherapy for solid and haematological malignancies in a bone marrow transplantation unit and Multivariate analysis showed that the only independent risk factor for mucositis was the conditioning regimen.
Abstract: Four hundred and twenty-nine patients received myeloablative chemotherapy for solid and haematological malignancies in a bone marrow transplantation unit. Regimens appropriate to the tumour type were administered and haemopoietic reconstitution was achieved with peripheral blood progenitor cells (PBPC; n = 275), autologous bone marrow (auto-BMT; n = 69) or allogeneic bone marrow (allo-BMT; n = 85). World Health Organization (WHO) oral mucositis scores were collected prospectively from the start of chemotherapy (d 1) until d 28 or discharge. Oral mucositis (OM) was experienced by 425 (99%) patients and in 289 (67.4%) this was grade III or IV. Strong opiate analgesia was prescribed for a median of 6 d to 47% of patients. Univariate analysis suggested that the area under the OM curve (AUC; sum of daily mucositis grades, d 1-28) was associated with the myeloablative regimen, haemopoietic progenitor source (PBPC > allo-BMT > auto-BMT), use of myeloid growth factors and age. Multivariate analysis showed that the only independent risk factor for mucositis was the conditioning regimen (P < 0.00005). The mean OM AUC for high-dose melphalan (HDM) regimens (52 grade-days) exceeded busulphan (41), busulphan-cyclophosphamide (35), cyclophosphamide-total body irradiation (TBI) (34), cyclophosphamide-carmustine (BCNU) (20) and cyclophosphamide-etoposide-carmustine (CVB) (19). HDM regimens resulted in the highest mean peak OM (3.6), followed by busulphan regimens (2.6), cyclophosphamide/TBI (2.3) and cyclophosphamide-carmustine and CVB (1.4). Busulphan produced significantly delayed OM (median 3 d; P < 0.00005). There was a linear association between the area under the OM curve for each treatment group and the time to reach grade 3 OM (P < 0.00005), but no association with the time to reach grade 4 neutropenia (P = 0.24) or thrombocytopenia (P = 0.73), implying that haematological and mucosal toxicity are not associated. The cytotoxic regimen is the most significant determinant of OM. Studies investigating agents to ameliorate mucosal toxicity should be stratified according to cytotoxic regimen.
TL;DR: Data indicate that immunotherapy with Id‐pulsed DCs in MM patients is feasible and safe, and DC generated from CD34+ progenitor cells can serve as a natural adjuvant for the induction of clinically relevant humoral and cellular idiotype‐specific immune responses in patients suffering from advanced MM.
Abstract: Multiple myeloma (MM) is characterized by a clonal proliferation of malignant plasma cells in the bone marrow secreting a monoclonal immunoglobulin (paraprotein) with specific antigenic determinants, the idiotype (Id), which can be regarded as a tumour-associated antigen (TAA). In order to analyse the impact of a dendritic cell (DC)-based vaccine, 11 patients with advanced MM were treated with CD34 stem cell-derived dendritic cells that were pulsed with Id peptides. Subsequently, the patients received three boost immunizations every other week with a combination of Id and granulocyte-macrophage colony-stimulating factor (GM-CSF) (nine patients) or with Id peptide-pulsed dendritic cells again (two patients). The treatment was well tolerated with no side-effects. The present clinical study was a proof of concept analysis of dendritic cell-based vaccines in MM. The capacity of the dendritic cells to activate idiotype-specific T cells was verified by in vitro stimulation experiments before the vaccination therapy. Immunological effects of the Id vaccination were analysed by monitoring changes in anti-idiotype antibody titres and idiotype-specific T-cell activity. After vaccination, three out of 10 analysed patients showed increased anti-idiotype antibody serum titres, indicating the induction of an idiotype-specific humoral immune response. The idiotype-specific T-cell response analysed by ELISpot was increased in four out of 10 analysed patients after vaccination, and one patient had a decreased plasma cell infiltration in the bone marrow. In conclusion, five out of 11 patients showed a biological response after vaccination. Thus, our data indicate that immunotherapy with Id-pulsed DCs in MM patients is feasible and safe. DC generated from CD34+ progenitor cells can serve as a natural adjuvant for the induction of clinically relevant humoral and cellular idiotype-specific immune responses in patients suffering from advanced MM.
TL;DR: It has become clear that the high-dose therapy does not eradicate the malignancy in many patients and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versusmalignancy effect.
Abstract: Allogeneic bone marrow transplantation was initially considered as a means of delivering supralethal doses of chemotherapy and total body irradiation (TBI) for the treatment of malignancy (Thomas, 1969, 1983). Many malignancies exhibit a steep dose±response relationship to chemoor radiotherapy, with higher doses producing greater cytoreduction. Bone marrow transplantation (BMT) enables the escalation of doses of many agents beyond those producing severe bone marrow toxicity. The marrow transplant was considered a supportive care modality to restore haematopoiesis. It has become clear, however, that the high-dose therapy does not eradicate the malignancy in many patients and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versusmalignancy effect.
TL;DR: The long‐term outcome of the 114 patients included in the HU trial is reported, with 56 patients randomized to receive HU and 58 patients to receive no cytoreductive therapy.
Abstract: We have previously demonstrated that hydroxyurea (HU) reduces the rate of vascular complications in patients with essential thrombocythaemia (ET) at high risk of thrombosis. However, the relatively short follow-up (median 27 months) did not enable the evaluation of the risk of developing secondary malignancies. In this study, we report the long-term outcome of the 114 patients included in the trial: 56 patients randomized to receive HU and 58 patients to receive no cytoreductive therapy. Before randomization, 15 patients had been treated with busulphan. During the observation period, 29 patients (50%) shifted from the control to the HU group mainly because of thrombosis. Median follow-up was 73 months (range 3-94). Analysis was by intention to treat and, when indicated, by treatment. When analysed by intention to treat, 46 out of 54 patients (85%) originally randomized in the HU group are alive, compared with 49 of 58 patients (84%) in the control group [not significant (n.s.)]. Five patients (9%) in the HU group and 26 patients (45%) in the control group had thrombosis (P < 0.0001). Seven patients (13%) in the HU group developed secondary acute leukaemia, myelodysplastic syndromes or solid tumours, compared with only one of the control group patients (1.7%) (P = 0.032). The occurrence of secondary malignancies was also analysed by treatment: none of the 20 patients who had never been treated with chemotherapy developed neoplasia vs. three of the 77 patients given HU only (3.9% n.s.) and five of the 15 patients given busulphan plus HU (33% P < 0. 0001). This study showed that: (a) HU reduced the risk of thrombosis in ET patients; (b) the sequential use of busulphan and HU significantly increased the risk of second malignancies; and (c) overall survival was not affected by HU therapy.
TL;DR: Blood transfusion was widely practised for a variety of medical conditions from the time of Hippocrates through to the nineteenth century in Europe and yet transfusion only became a commonplace therapeutic intervention less than 100 years ago.
Abstract: The basic techniques involved in this life-saving procedure are relatively simple and it is thus perhaps surprising that blood transfusion only became a part of routine clinical practice relatively recently. Blood-letting (venesection) was widely practised for a variety of medical conditions from the time of Hippocrates (<430 bc) through to the nineteenth century in Europe and yet transfusion only became a commonplace therapeutic intervention less than 100 years ago. This is because both an understanding of the nature of blood as well the physiology of the circulation were required as a foundation for the development of blood transfusion and these were not forthcoming until the middle of the seventeenth century. The views of the Romans and ancient Greeks exerted a profound influence on both the traditions and practise of Western medicine for nearly 2000 years. The principal beliefs of the ancient Greeks and Romans were based on the writings of Hippocrates. The central doctrine of the humoral theory is set out in the treatize entitled `On the nature of man', in which it was proposed that all living matter is composed of four basic ingredients, namely blood, phlegm, yellow bile and black bile (Lloyd, 1978). Although recognized as a vital element in the constitution of man, blood was certainly not viewed as being more or less important than the other humours. Differences in personality were viewed as reflecting different mixes of humours in people and this belief extended well into the Renaissance period (Fig 1). Indeed, words still used today such as `sanguine', `phlegmatic', `melancholic' and `choleric' can be considered to be linguistic fossils from that era. An important consequence of the acceptance of the humoral theory was that it encouraged a holistic approach to medicine, in which illness came to be regarded as being due to an imbalance of the four humours. Correction of the imbalance was thus required for restoration of health and this could be achieved by attention to diet and environment, although medical procedures such as dieting, purging and blood letting could also be used. Anatomical knowledge was also required for an understanding of the circulation of the blood, the cornerstone for the practice of transfusion. The anatomical knowledge of the Greeks was very limited and they believed that blood simply ebbed and flowed through the peripheral veins with some blood passing through the pores of the interventricular septum to mix with the `pneuma' (or vital spirit) that was inspired with the air and which fed the brain. William Harvey (1578±1657), who studied medicine in Padua after graduating from Cambridge, was the first to understand the circulation of the blood and his treatize entitled `Exercitatio anatomica de motu cordis et sanguinis in animalibus' was first published in 1628.
TL;DR: It is demonstrated that agranulocytosis is less common than previously predicted and, under the specific conditions of monitoring, the safety profile of deferiprone is characterized, and it is shown that neutropenia resolved after interruption of therapy.
Abstract: In previous trials, the orally active iron chelator deferiprone (L1) has been associated with sporadic agranulocytosis, milder forms of neutropenia and other side-effects. To determine the incidence of these events, we performed a multicentre prospective study of the chelator. Blood counts were performed weekly, and confirmed neutropenia mandated discontinuation of therapy. Among 187 patients with thalassaemia major, the incidence of agranulocytosis (neutrophils 2500 μg/l. This study characterized the safety profile of deferiprone, and, under the specific conditions of monitoring, demonstrated that agranulocytosis is less common than previously predicted.
TL;DR: Clinical evidence of the preterm neonate's immune incompetence is the pattern of bacterial infections which closely parallels that seen in patients with profound neutropenia and the frequent development of neutropania in response to bacterial sepsis.
Abstract: Bacterial infection is a major cause of death and long-term morbidity in preterm neonates. Infection rates among neonates undergoing intensive care range from 25% to 50% (Stoll et al, 1996; Cooke et al, 1997; Fanaroff et al, 1998) and, in spite of effective antibiotic therapy, sepsisrelated mortality has remained constant at 15±20% for nearly two decades (Gladstone et al, 1990). The reason for such high sepsis rates and attendant mortality are largely due to the immaturity of bactericidal mechanisms. Clinical evidence of the preterm neonate's immune incompetence is the pattern of bacterial infections which closely parallels that seen in patients with profound neutropenia (Stoll et al, 1996) and the frequent development of neutropenia in response to bacterial sepsis (Engle et al, 1984; Gessler et al, 1995). These two phenomena can be directly related to immaturity of neutrophil function and production.
TL;DR: Data show that haemorrhage and abnormal coagulation are common in AL‐amyloidosis and are multifactorial in origin, and evidence is provided suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT.
Abstract: Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light-chain (AL)-amyloidosis, in whom whole-body serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0.0012), but this was independent of the whole-body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0.00001), with proteinuria (P < 0.001) and low serum albumin (P < 0.00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2.5, range 0.81-9.25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0.96, range 0.65-1.29, n = 28, P < 0.0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL-amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag.
TL;DR: Mucosal tract haemorrhages such as epistaxis and menorrhagia were the most prevalent symptoms in type 3 VWD and increased bleeding occurred at parturition when affected women were treated with replacement therapy for less than 3-4 d.
Abstract: Type 3 is the most severe form of von Willebrand disease (VWD) transmitted as an autosomal recessive trait We collected data on the clinical manifestations of type 3 VWD by examining 385 patients from 300 Iranian kindreds, who were compared with 100 age-matched patients with severe haemophilia A Joint and muscle bleeding was less frequent than in haemophiliacs, perhaps because factor VIII levels were in general higher (median value 4% vs 1% or less) Mucosal tract haemorrhages such as epistaxis and menorrhagia were the most prevalent symptoms in VWD Post-circumcision and oral cavity bleeding occurred frequently when prophylactic replacement therapy was not carried out or was inadequate The course of pregnancy was usually uneventful, but increased bleeding occurred at parturition when affected women were treated with replacement therapy for less than 3-4 d Ten of 385 (26%) of these multitransfused patients developed an alloantibody to VWF and 55% are chronically infected with the hepatitis C virus
TL;DR: It is demonstrated that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.
Abstract: Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as ‘poor-risk’. DF was commenced intravenously at a median of 14 d (range, −2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2–71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34·2 μmol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40–70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21–51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.
TL;DR: One‐third of patients undergoing allogeneic BMT report a poor quality of life (QOL), factors associated with poor QOL are older age, presence of long‐term sequelae, chronic GVHD and short follow‐up, and BMT affects different aspects of life in males and females.
Abstract: The number of long-term survivors after allogeneic bone marrow transplantation (BMT) has been increasing over the past years, and quality of life (QOL) has become an important end-point. We studied 244 patients undergoing an allogeneic BMT to identify factors and events influencing psychosocial outcome. Patients enrolled received the Psychosocial Adjustment to Illness Scale (PAIS) questionnaire assessing psychological and social adjustment to chronic illness or its sequelae. Eighty-two per cent of patients had a haematological disease. The median age was 28 years at BMT, and the median follow-up was 61 months. The median overall PAIS score for all patients was 56 (range 22-76): 25% (n = 61) of patients were considered to have a good QOL ( 75 percentile score). Factors associated with a poor QOL in multivariate analysis were: patients' age at BMT (> 25 years, P < 0.01); presence of long-term sequelae (P < 0.01); chronic graft-versus-host disease (GVHD) (P < 0.05); and a short interval from BMT (< 5 years; P < 0.05). The QOL improved with time: 12% of patients reported a good QOL within 5 years compared with 38% after this time point and, conversely, 38% reported a poor QOL within 5 years compared with 24% after this time point (P < 0. 0001). Older patients had significantly poorer QOL compared with younger patients (< or = 25 years; P = 0.01). Females had significantly poorer scores when compared with males in the sexual (P < 0.0001) and psychological domains (P = 0.001). The data suggest that (i) one-third of patients undergoing allogeneic BMT report a poor QOL; (ii) factors associated with poor QOL are older age, presence of long-term sequelae, chronic GVHD and short follow-up; (iii) QOL is superior in long-term survivors; and (iv) BMT affects different aspects of life in males and females. A longitudinal study is ongoing to prove the effect of time on quality of life.
TL;DR: It is suggested that a careful search for T‐lymphocyte clonality and cytogenetic changes should be included in the work‐up of HES for adequate management.
Abstract: Idiopathic hypereosinophilic syndrome (HES) and Gleich's syndrome are related disorders characterized by persistent or recurrent hypereosinophilia of unknown origin. Elevated IgE levels and polyclonal hypergammaglobulinaemia are considered as markers of benign outcome in this setting as they are generally associated with predominant cutaneous manifestations and favourable response to glucocorticoid therapy. In a previous study, we identified a clonal population of CD3-CD4+ Th2-like lymphocytes secreting interleukin (IL)-5 and IL-4 in peripheral blood of a patient fulfilling the diagnostic criteria of HES with associated serum hyper-IgE. We now extend this observation by describing identical findings in three additional patients, and we compare their clinical and biological parameters with five other patients with HES. Chromosomal abnormalities were detected in purified CD3-CD4+ Th2 cells from three patients, among whom one developed anaplastic null cell lymphoma. We therefore suggest that a careful search for T-lymphocyte clonality and cytogenetic changes should be included in the work-up of HES for adequate management.