Showing papers in "British Journal of Haematology in 1986"

Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance.

Abstract: Summary. In 100 untreated patients with chronic lymphocytic leukaemia (CLL) lymphocyte doubling time (LDT) has been investigated in relationship with clinical stages, bone marrow histological patterns, treatment-free period and survival. Although partially correlated with clinical stages and bone marrow patterns. LDT has a clear prognostic significance by itself: whereas a LDT of 12 or less months identifies a population of patients with poor prognosis, a LDT higher than 12 months is indicative of good prognosis as substantiated by a long treatment-free period and survival. This simple parameter can be useful in the clinical management of CLL patients.

The role of platelet membrane glycoproteins Ib and IIb-IIIa in platelet adherence to human artery subendothelium

Abstract: Platelet adherence to human artery subendothelium in blood from eight normal subjects, four patients with Glanzmann's thrombasthenia (deficiency of platelet membrane glycoproteins IIb and IIIa: GPIIb-IIIa), two patients with Bernard-Soulier syndrome (deficiency of platelet membrane glycoprotein Ib: GPIb) and one patient with von Willebrand's disease (VWD subtype III. deficient in factor VIII-von Willebrand factor: FVIII-VWF) was compared at various wall shear rates (300, 500, 1000, 1800 and 2500 s-1). Platelet adherence in blood from the patients with Glanzmann's thrombasthenia was within the normal range at shear rates below 1000 s-1. There was some decrease in adhesion at higher shear rates and platelets were less spread out on the subendothelium than normally at all shear rates. Platelet aggregate formation was almost totally absent. Platelet adherence in blood from patients with the Bernard-Soulier syndrome was strongly impaired at all shear rates. Platelet adherence in blood from the patient with VWD subtype III was normal at shear rates of 300 and 500 s-1, but impaired at shear rates above 1000 s-1. Aggregate formation was also decreased at these shear rates. Platelet adhesion was strongly inhibited by a monoclonal antibody against glycoprotein Ib, which had previously been shown to inhibit ristocetin-induced aggregation, at shear rates of 500 and 1800 s-1 but not at 300 s-1. Platelet adhesion at 1800 s-1 was also inhibited, though to a lesser extent, by two antibodies against GPIIb-IIIa. These antibodies also inhibited platelet aggregate formation. The data indicates that GPIb is involved in adhesion at the same shear rates as von Willebrand factor. Absence or inhibition of GPIIb-IIIa primarily causes a defect of aggregate formation but GPIIb-IIIa may also play a role in adhesion, particularly at high shear rates. The defect of adhesion in the Bernard-Soulier syndrome may be dependent on factors other than a deficiency of GPIb alone.

Circulating transferrin receptor in human serum.

Abstract: Circulating transferrin receptor has been detected in human serum with a sensitive immunoassay. The mean concentrations of the serum transferrin receptor in healthy males and females were 251 +/- 94 (mean +/- SD) ng/ml and 256 +/- 99 ng/ml, respectively. The serum receptor concentration in patients with haematological malignancies, including acute leukaemia, multiple myeloma and malignant lymphoma, varied widely, from normal to 1100 ng/ml. A single band with an approximate molecular weight between 80,000 and 100,000 daltons was obtained by polyacrylamide gel electrophoresis-immunoblotting analysis of serum.

Use of leucocyte‐poor blood components and HLA‐matched‐platelet donors to prevent HLA alloimmunization

Abstract: Recent studies have shown that the incidence of alloimmunization due to repeated platelet transfusions from random donors may be reduced by the use of leucocyte-poor blood components. These results were confirmed by this study, where 16% of patients with acute leukaemia undergoing initial chemotherapy and receiving leucocyte-poor blood components developed lymphocytotoxic antibodies, compared with 48% of patients in a control group receiving standard (non-leucocyte-depleted) blood components. In a third group, who received leucocyte-poor blood components and HLA-matched platelets, none of the patients developed lymphocytotoxic antibodies. There was a low incidence of platelet-specific antibodies (8%) but no difference between the three groups. Improved methods of removing leucocytes from blood components appear to offer the best approach for minimizing HLA alloimmunization, as the provision of HLA-matched platelet donors for prophylactic platelet support of all patients is not feasible.

Immunological abnormalities in myelodysplastic syndromes. I. Serum immunoglobulins and autoantibodies.

Abstract: The immunoglobulin levels and autoantibody profiles of 104 patients with primary myelodysplastic syndromes (MDS), classified according to the FAB criteria, were analysed. Eight patients, four with coexistent non-Hodgkin's lymphomas, three with chronic lymphocytic leukaemia and one with a lymphoplasmacytoma, were excluded from the final analysis of immunoglobulin levels. Serum protein electrophoresis and immunoelectrophoresis revealed the presence of monoclonal gammopathy in 12 patients (12.5%). Of the remaining 84 patients, a polyclonal rise in serum immunoglobulins was present in 27 (32%) while a further 16 (19%) had low immunoglobulin levels. The direct antiglobulin test was positive in eight out of 98 patients tested (8.1%), and organ and non-organ specific autoantibodies were present in 15 out of 67 patients tested (22.3%). Two patients had associated pernicious anaemia (PA), two hypothyroidism, and one PA with hypothyroidism. Three patients had sero-negative rheumatoid arthritis. These results demonstrate that there is a high incidence of immunological abnormalities in MDS.

The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. II. Patterns of evolution of 'prolymphocytoid' transformation.

Abstract: A series of 55 patients with B-cell chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) was studied in order to investigate the evolution of prolymphocytoid transformation of CLL. Peripheral blood films were assessed for the percentages of prolymphocytes (%PROL) during a followup period of 2 months to 24 years. The majority of patients with typical CLL (less than or equal to 10% PROL) had minor variations or transient increases in %PROL throughout the course of the disease, but in one third of them a steady rise in the proportion of these cells was documented. Patients presenting with 11-55% PROL, referred to as CLL/PL, exhibited three patterns of evolution: half of them showed stability of the PROL counts, one third had unsustained increases in the %PROL and 18% showed definite progression to a PLL-like blood picture. Patients diagnosed as PLL (greater than 55% PROL) had maintained a high %PROL during the period of observation. Serial marker studies in some CLL and CLL/PL cases showed that the percentage of M-rosettes and the intensity of SmIg remained at the same initial levels in all but two cases. These two cases in the CLL/PL group showed a significant decrease in the percentage of M-rosettes and stronger SmIg staining associated with progressive prolymphocytoid transformation. Patients with CLL and CLL/PL who had a sustained rise in the %PROL responded poorly to treatment compared with those with stable disease.

Isolation of a new specific plasminogen activator in hibitor from pregnancy plasma

Abstract: Summary. A specific plasminogen activator inhibitor was isolated from the plasma of pregnant women by matrix-bound, cross reacting monoclonal antibodies against placental plasminogen activator inhibitor. The pregnancy plasma plasminogen activator inhibitor (PP-PA-I) was found to be immunologically different from the inhibitor produced by endothelial cells. Its molecular weight was 70 000 daltons. It formed complexes with urokinase (u-PA) and with plasminogen activator of the tissue type (t-PA), similar to those formed by the placental plasminogen activator inhibitor (Pl-PA-I). It did not inhibit plasmin. For measuring PP-PA-I, an enzyme-linked immunosorbent assay (ELISA) was designed using monoclonal and polyclonal antibodies against the placental inhibitor. Concentrations of PP-PA-I increased successively during pregnancy, and fell sharply after delivery. This inhibitor could not be detected in normal non-pregnancy plasma. The results indicate that the inhibitor isolated from pregnancy plasma is responsible for the depressed fibrinolytic activity during pregnancy, and that the placenta is the source of the inhibitor.

The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes

Abstract: Fifteen patients with the initial diagnosis of myelodysplastic syndrome (MDS) received aggressive chemotherapy with high dose cytarabine or with a standard acute myeloid leukaemia (AML) regime. Cases treated with aggressive chemotherapy were either younger individuals with refractory anaemia with excess of blasts (RAEB) or patients, irrespective of age in advanced stages of MDS (RAEB in transformation or after evolution to frank AML), who did not have a major infection at the time of presentation. Age seemed to be the most important factor in determining the outcome of aggressive remission induction chemotherapy in MDS: 86% of the patients less than 50 years entered complete remission, compared to only 25% in the older age group. In spite of intensive consolidation therapy the duration of complete remission was short. We conclude that young patients (less than 50 years) with excess of bone marrow blasts should be treated with aggressive chemotherapy even in the early stages of the disease. Elderly patients in advanced stages of MDS should be treated with less aggressive chemotherapy.

Haemoglobin gene frequencies in the Jamaican population: a study in 100,000 newborns.

Abstract: The gene frequencies of abnormal haemoglobins have been determined in a group of 100,000 Jamaican newborns screened over a period of 8 1/2 years. The population is predominantly of West African origin and the survey represents approximately one quarter of all island deliveries within the period of the study. The common beta globin chain abnormalities beta s and beta c occurred with gene frequencies of 0.055 and 0.019 respectively; beta thalassaemia was relatively rare. In contrast, alpha thalassaemia was quite common, occurring with a gene frequency of 0.183. In addition to these common abnormalities, the frequencies of 256 rare abnormal haemoglobins are described. This survey thus represents a complete and accurate documentation of the alpha and beta globin variants that occur in the Jamaican population.

Post‐transfusion purpura

Abstract: In 1959, van Loghem et al described a 51-year-old woman, Zw, who developed severe thrombocytopenia and purpura 7 d after elective myomectomy, did not respond to repeated blood transfusions and recovered spontaneously after about 3 weeks. Her serum contained a strong antibody which enabled the definition of the 6rst platelet-specific antigen Zwa. However, the patient's thrombocytopenia was not attributed to platelet alloimmunization, and it was Shulman and associates (Shulman & Jordan, 1982) who 6rst established their causal relationship and coined the term post-transfusion purpura (PTP). New immunological data and therapeutic achievements warrant a review of this rare, but serious iatrogenic complication of transfusion therapy.

Surface marker analysis in acute myeloid leukaemia and correlation with FAB classification.

Abstract: The immunological phenotype of blast cells in 102 patients with acute myeloid leukaemia (AML) was analysed with a panel of 20 monoclonal antibodies and the enzyme terminal transferase, and correlated with the FAB classification. Although a partial correlation between these two approaches could be observed, almost every morphological group contained patients from more than one immunological phenotype. The M1 and M5a leukaemias showed the most undifferentiated phenotype, often lacking in specific myelomonocytic antigens. The M3 formed a uniform group defined as My7+, Ia-, FMC8+, a phenotype which was also observed in two cases of the microgranular variant. The granulocytic (CDw15) and monocytic (CDw14) antibodies crossreacted with some M5b and M2 leukaemias, respectively. Compared with M5a, the M5b leukaemias showed a large increase in the expression of CDw14 antigen, confirming the validity of the morphological differentiation. Glycophorin-A was present in four out of five M6 leukaemias. TdT activity was demonstrated in 10% of AML cases, with a higher incidence among the monocytic variants: M4 and M5-. Eleven AML were considered as unclassifiable according to the FAB criteria and in seven of them a megakaryoblastic cell population (GP IIb/IIIa+, GPIb+) was demonstrated; this confirms the need to include the subgroup of megakaryoblastic leukaemias within the AML. Finally, a possible immunological classification for AML is proposed.

Immunological abnormalities in myelodysplastic syndromes. II. Coexistent lymphoid or plasma cell neoplasms: a report of 20 cases unrelated to chemotherapy.

Abstract: We report a series of 20 patients with the myelodysplastic syndrome (MDS) each with a coexistent lymphoid or plasmacytic neoplasm. In none of the patients did chemotherapy play a part in the pathogenesis. The possible reasons for the coincidence of these conditions are discussed. The frequency and variety of associated neoplasms reinforces the idea that in MDS there are genetically unstable progenitor cells liable to clonal differentiation along a variety of pathways given appropriate stimuli.

The morphological spectrum of T-prolymphocytic leukaemia.

Abstract: The morphology of the cells from 29 cases of T-prolymphocytic leukaemia (T-PLL) was studied by light (LM) and transmission electron microscopy (TEM) and was compared with that of 33 B-cell PLL. The membrane phenotype of T-PLL cells was T4+, T8- in two-thirds of the cases, others being T4- T8+ or T4+ T8+. Two morphological types of T-PLL were defined according to the nuclear features: regular (55% of cases) and irregular (45% of cases). T-PLL cells with a regular, round or oval, nuclear outline resembled B-PLL cells but had less abundant cytoplasm and a higher nucleo-cytoplasmic ratio. Irregular T-prolymphocytes displayed a distinct convoluted nucleus. A 'small-cell' variant of T-PLL was recognized by TEM in six cases in which the diagnosis was uncertain by LM. A characteristic of all types of T-prolymphocytes by LM was the presence of a deep basophilic cytoplasm which by TEM corresponded to clusters of ribosomes and endoplasmic reticulum. No differences in clinico-haematological features or membrane markers were apparent between the morphological types of T-PLL, although it was noted that the three T4- T8+ cases had irregular cells and four of the small cell variant were T3- T4+. TEM permits a more precise assessment of the cytoplasmic organelles and nucleolus than LM analysis and facilitates the distinction between T-PLL and other leukaemias with a mature T-cell phenotype, namely adult T-cell leukaemia/lymphoma. Sezary syndrome and T-chronic lymphocytic leukaemia.

Changes in fluidity and composition of erythrocyte membranes and in composition of plasma lipids in Type I diabetes

Abstract: Summary. Changes in the fluidity and composition of human erythrocyte membranes and in the composition of plasma in Type I (insulin-dependent) diabetes were investigated. The increased microviscosity of diabetic erythrocyte membranes provide unambiguous proof of the structural deterioration of erythrocyte membranes in diabetes. It seems most likely that enhancement of the membrane cholesterol/phospholipid ratio is the main reason for decreased membrane fluidity in diabetes. A distinct correlation between membrane cholesterol/phospholipid ratio, plasma cholesterol content and membrane fluidity was found. Composition and structural changes in erythrocyte membranes and compositional changes in plasma lipids may contribute to the development of diabetic complications in diabetes.

Diagnostic significance of detecting pseudo-Pelger-Huët anomalies and micro-megakaryocytes in myelodysplastic syndrome.

Abstract: To investigate the kind of morphological dysplastic changes important in the diagnosis of myelodysplastic syndrome (MDS), we examined 50 patients with MDS and 86 control subjects. Micromegakaryocytes and pseudo-Pelger-Huet anomalies were detected in 46 patients (92%) with MDS, and were also found in the differentiated types of acute myeloid leukaemia and chronic myeloid leukaemia, but not in other haematological disorders, or healthy subjects. We believe that evaluation of these changes would be helpful in diagnosing MDS.

Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells.

Abstract: Summary. A patient with agranulocytosis and myeloid marrow hypoplasia following a second exposure to propylthiouracil (PTU) was studied for antibodies against mature blood cells and bone marrow precursor cells. During the acute phase of the agranulocytosis, significant growth inhibition of the myeloid committed progenitor cells (CFU-GM) was found following incubation with complement, indicating the presence of in-vivo cell bound cytotoxic antibodies. Using immunofluorescence and complement dependent cytotoxicity techniques it was demonstrated that acute phase and recovery phase sera contained circulating antibodies, reactive not only with differentiated granulocytes and monocytes but also with myeloid and erythroid (BFU-E/CFU-E) progenitor cells. Complement dependent lysis of the progenitor cells was facilitated by preincubation with PTU. These results indicate that the agranulocytosis was mediated by a PTU dependent antibody that affected both mature blood cells and bone precursor cells.

The haemorrhagic and antithrombotic effects of dermatan sulphate.

Abstract: Heparin and dermatan sulphate are effective antithrombotic agents but the clinical use of heparin is complicated by haemorrhage. The haemorrhagic effect of dermatan sulphate is unknown. In this study we compared the antithrombotic, haemorrhagic and anticoagulant effects of heparin and dermatan sulphate in rabbits. The antithrombotic effect was measured as prevention of venous thrombus formation. The haemorrhagic effect was measured as 51Cr-blood loss from standardized cuts in rabbit ears. The anticoagulant effect was measured as changes in the APTT, TCT and circulating anti-factor Xa level, and the formation of 125I-thrombin/inhibitor complexes ex vivo. The effect of heparin and dermatan sulphate on collagen-induced platelet aggregation was measured ex vivo. Maximal antithrombotic effects of heparin and dermatan sulphate were achieved with 70 and 500 micrograms/kg respectively. A 20-fold increase in heparin dose caused an 8-fold increase in blood loss and higher doses (40- and 80-fold increases) caused further dose-related increases in blood loss (13- and 35-fold increases respectively). In contrast, a 20- to 40-fold increase in the antithrombotic dose of dermatan sulphate did not increase blood loss and an 80-fold dose increase caused only a 7-fold increase in blood loss. There was no relationship between the antithrombotic and haemorrhagic effects of either heparin or dermatan sulphate and their anticoagulant activities. In contrast, there was a relationship between the dose-related enhancement of blood loss by these glycosaminoglycans and the inhibition of collagen-induced platelet aggregation ex vivo. These results suggest that dermatan sulphate is less haemorrhagic than heparin at equivalent antithrombotic doses, and that the haemorrhagic effect is associated with a glycosaminoglycan-induced platelet defect.

Primary thrombocythaemia treated with busulphan

Abstract: Summary. Thirty-seven patients with primary thrombocythaemia (PT) treated with busulphan have been followed for periods up to 25 years. Reduction of the platelet count to less than 400 × 109/l resolved vascular occlusive symptoms, but haemorrhagic symptoms often remained unaltered. Cox regression analysis indicated that there were only two prognostically important presenting features; age had a strong inverse correlation with survival and vascular occlusive symptoms correlated with a better survival. Median duration ofsurvival on treatment was 9·8 years. The number of deaths was 2·1 times that of a comparable control group, with deaths from myelofibrosis markedly increased. Deaths from thrombosis and malignant diseases, including leukaemia, were not significantly different from the number expected. which emphasizes the efficacy and the relative safety of busulphan for the long-term treatment of PT. Progression of PT into myelofibrosis occurred in 24% of cases and 9% became polycythaemic. Two additional cases of ‘thrombocythaemia'with a Philadelphia chromosome (and no overt evidence of chronic granulocytic leukaemia) are also presented.

The natural anti‐α‐galactosyl IgG on human normal senescent red blood cells

Abstract: Summary A highly sensitive antiglobulin test based on rosette formation due to the interaction between IgG bearing red blood cells (RBC) and Fc receptors on K562 cells, was used to study the immunoglobulin molecules present on human senescent RBC Normal human RBC were separated into young and senescent subpopulations on the basis of age-dependent differences in density by centrifugation on a discontinuous density Percoll gradient, and by flotation on phthalate ester mixtures The senescent but not the young RBC were found to bear membrane bound IgG Most of the bound IgG molecules could be specifically eluted by galactose in its α-anomeric form Antigalactosyl (anti-Gal) IgG antibodies with similar reactivity were found to be present in high titres in every one of the 400 normal human sera tested The natural anti-Gal antibodies isolated from normal sera by affinity chromatography could bind to IgG depleted senescent RBC but not to young RBC Erythrophagocytosis experiments indicated that the anti-Gal bound to the senescent RBC induced their destruction by macrophages It is suggested that the natural anti-Gal antibodies interact with cryptic α-galactosyl residues which are exposed in the course of the RBC senescence and mediate the removal of these RBC from circulation by cells of the reticuloendothelial system

Features affecting outcome during remission induction of acute myeloid leukaemia in 619 adult patients.

Abstract: Summary. Six hundred and nineteen patients with de novo acute myeloid leukaemia, entered into the Medical Research Council's eighth trial of therapy have been studied. All patients were treated with the same remission induction regimen. Pretreatment variables comprising age, clinical status, haematologi-cal status and a detailed marrow cytology and cytochemistry score have been analysed. Poorer remission rates have been found in older patients, in those with lower Karnofsky scores and in patients with a platelet count of less than 25 × 109/1. Leukaemias showing evidence of cytoplasmic maturation along the granulocyte and monocyte lines, as evidenced by granules, Auer rods, a high percentage of Sudan black positive blast cells and morphological and cytoche-mical abnormalities of neutrophils were associated with a higher remission rate. Marrow eosinophilia was a good prognostic feature. Nuclear features of immaturity, i.e. increasing numbers and prominence of nucleoli were associated with a low remission rate. Abnormalities of the erythroid series, notably Periodic acid-Schiff positivity which was present in 13 3 cases (22% of the total), was associated with a low remission rate. Patient age and pretreatment Karnofsky score were the most useful predictors of treatment outcome.

Disappearance of factor VIII:C antibodies in patients with haemophilia A upon frequent administration of factor VIII in intermediate or low dose.

Abstract: Summary. In 18 haemophilia A patients with antibodies against factor VIII:C (F VIII:c) the effect of regular treatment with factor VIII (F VIII) in intermediate or low dose was studied. All patients with previous maximal F VIII:c antibody levels between 5 and 60 Bethesda Units per millilitre (BU/ml) showed a decrease of antibody level and normal F VIII recovery within 1-2 months. From nine patients with previous maximal antibody levels above 60 BU/ml four showed a decrease of antibody level within 2-26 months. In four young patients F VIII prophylactic therapy was started or continued as soon as there was evidence of F VIII:c antibody activity. In three of these patients F VIII recovery normalized within a few months.

A murine monoclonal IgM antibody specific for blood group P antigen (globoside)

Abstract: A murine monoclonal IgM erythrocyte antibody appeared to have anti-P (anti-globoside) specificity The antibody was a relatively weak cold agglutinin, but a strong haemolysin and its reactivity with red cells was markedly enhanced by enzyme treatment This antibody was used to study the cell and tissue distribution of globoside Globoside was not only detectable on red cells and erythroblasts, but also on endothelial cells and on subsets of platelets, megakaryocytes and fibroblasts It was not detectable on granulocytes, monocytes and most peripheral blood lymphocytes Neither was it present on erythroblast precursors (CFU-E, BFU-E), pro-erythroblasts or on the cells of the pro-erythroblastic cell lines K562 and HEL However, K562 cells expressed globoside when induced to mature into erythroblasts by sodium butyrate Cells of patients with various leukaemias were also tested A significant number of positively reacting cells was frequently (six out of 18) seen in cases with a CML blast crisis (CML-BC) and rarely in AML (four out of 37 cases) In CML-BC the P-positive cells were probably erythroblasts and/or megakaryoblasts Thus, globoside appeared to be an interesting marker in CML-BC of the erythroblastic or mixed erythroblastic-megakaryoblastic type

Treatment of adult patients with idiopathic thrombocytopenic purpura with intravenous immunoglobulin: effects on circulating T cell subsets and PWM-induced antibody synthesis in vitro.

Abstract: Summary. Eight adult patients with idiopathic thrombocytopenic purpura (ITP) were given two 5-d courses of intermediate (250 mg/kg body weight/d) to high dose (400 mg/kg body weight/d) intravenous infusions of human plasmin-cleaved Ig, at 15–30 d intervals. Three patients also were given single booster infusions (400 mg/kg body weight for 1 d) of a different preparation, S-sulfonated Ig. As expected, significant though transient rises in the platelet count were consistently observed in all patients. The mean platelet count increase was 95 600/mm3 after the first course, and 143 500/mm3 after the second course. Similar effects of lower magnitude were obtained several times in the patients given single booster doses. In three patients, platelet-bound IgG levels were decreased in association with Ig therapy. Phenotypic analysis of T cell subsets before starting Ig therapy and at the end of the second high dose course of intravenous Ig treatment revealed significant reductions in the proportion of T4 + lymphocytes in five patients and relative increases in the percentage of T8 + cells after therapy. As the overall proportion of T3 + cells remained unchanged, the T4 +/T8 + ratio was therefore decreased. The total number of circulating lymphocytes was also decreased following therapy. In addition, PWM-driven Ig biosynthesis in vitro was significantly impaired after therapy in most patients, the capacity to synthesize IgG being mainly affected. It is concluded that, in addition to the reported transient blockade of the reticuloendothelial system, non-specific suppression of polyclonal Ig biosynthesis induced by the high dose Ig infusions also contributes to the net increase in platelet count.

The treatment of hairy-cell leukaemia with 2'-deoxycoformycin.

Abstract: Summary Eight patients with hairy-cell leukaemia (HCL) complicated by pancytopenia were treated with low dose regimens of the adenosine deaminase (ADA) inhibitor 2′-deoxycoformycin (DCF). All patients had significant haema-tological and clinical improvement. One patient who had been splenectomized and five patients with mild to moderate splenomegaly achieved normal blood counts within 2 months, which have been maintained for up to 18 months. Complete remissions occurred in two patients and four patients had 50–95% marrow clearance of hairy cells. The initial DCF treatments produced a 1–3 g/dl fall in the haemoglobin levels and one patient had a temporary reduction in granulocyte and platelet counts. Five patients had nausea/vomiting, and/or lethargy following DCF, but there was no correlation between the plasma levels of deoxyadenosine and adenosine and the incidence or severity of these side effects. An increased incidence of infection and drug hypersensitivity may reflect the effects of DCF on the immune system. Low dose DCF is a highly effective agent in HCL.

Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance

Abstract: We performed 221 marrow trephine biopsies in 139 patients with Ph1-positive (Ph1+) chronic granulocytic leukaemia (CGL) in order to assess the incidence, degree and prognostic significance of marrow fibrosis (MF) at various stages of the disease. We also attempted to elucidate the relationship between development of MF and the various clinical and haematological features of CGL. A significant correlation was found between the amount of fibrosis (graded from 0 to 3) and the stage of CGL, indicating that major fibrotic changes are associated with accelerated or blastic disease. Survival studies performed to assess the prognostic significance of the various degrees of MF, showed a progressively worse life-expectancy from grade 0 to grade 3 fibrosis. Multivariate regression analysis indicated Hb level, age, number of marrow megakaryocytes (MKs), time from diagnosis as the features most significantly correlated with the degree of MF. This study demonstrates that the natural history of CGL involves a progressive increase in reticulin deposition towards severe MF, although the rate of this progression varies widely. Monitoring changes of fibrosis with sequential biopsies could give a measure of the rate of progression of the disease and help in prognostic assessment of CGL patients. Our findings also confirm that among marrow features the number of MKs is the cytological variable most significantly correlated with MF.

The influence of oxygen tension on the long-term growth in vitro of haematopoietic progenitor cells from human cord blood.

Abstract: Growth of low density human cord blood cells in long-term suspension culture was evaluated at incubation conditions of 5% carbon dioxide in approximately 20% (normal incubator) oxygen tension or in 5% (low) oxygen tension. During the first 5 weeks there was no difference in the numbers of morphologically recognizable cells grown at either oxygen tension, while growth was superior from weeks 5 to 8 at approximately 20% oxygen tension. For the first 5 weeks, growth of granulocyte-macrophage progenitors (CFU-GM) was superior at 5% oxygen tension during the long-term and semi-solid culture phases and least impressive in the long-term and semi-solid cultures incubated at approximately 20% oxygen. This trend was reversed after 5 weeks and after 8 weeks there were no detectable CFU-GM in suspension cultures at 5% oxygen while steady state levels of CFU-GM were maintained for greater than 12 weeks in suspension cultures at approximately 20% oxygen. Semi-solid cultures for erythroid (BFU-E) and multipotential (CFU-GEMM) progenitors were incubated at approximately 20% oxygen only. During the first 4 weeks, the growth of BFU-E and CFU-GEMM was superior at 5% oxygen during long-term culture. Numbers of these cells decreased by week 5 and at this time growth was better in the long-term cultures grown at approximately 20% oxygen. By week 6, no BFU-E or CFU-GEMM were detectable. Thus, growth of cord blood at low oxygen tension gives an initial enhancement in output of progenitor cells, but this appears to be at the expense of continued production.

Autologous bone marrow transplantation for acute leukaemia in remission.

Abstract: Between 1980 and 1985, 175 patients with acute leukaemia in first or subsequent complete remission (CR) were treated by chemotherapy or chemoradiotherapy followed by transfusion of autologous bone marrow cells that had been collected days or months previously. In 85 cases, autologous marrow cells were treated ex vivo with cytotoxic drugs or monoclonal antibodies with the intention of removing residual leukaemic cells. The actuarial relapse-free rate was 52% at 2 years. Of 89 patients autografted for acute non-lymphocytic (myeloid) leukaemia (ANLL), 60 were treated in first remission and 18 in second CR; their relapse-free rates at 2 years were 67% and 41% respectively (P less than 0.001). In contrast, of 77 patients autografted for acute lymphoblastic leukaemia (ALL), 32 were treated in first CR and 28 in second CR and their actuarial relapse free rates at 2 years were 56% and 55% respectively (P = NS). There was no significant difference in leukaemia relapse rates between patients autografted with purged and those autografted with non-purged marrow cells. These preliminary results suggest that autologous bone marrow transplantation may be valuable if offered to patients with ANLL in first CR or to patients with ALL in first or second CR but the need for marrow purging remains uncertain.

Treatment of acute lymphoblastic leukaemia in adults.

Abstract: Between 1972 and 1982, 112 consecutive previously untreated adults (aged 15-69 years, median 26) commenced therapy for acute lymphoblastic leukaemia (ALL) at St Bartholomew's Hospital. The first 63 patients entered into the study received initial treatment which comprised four cycles of adriamycin and vincristine, prednisolone and L-asparaginase with the first cycle (OPAL). In 1978, six cycles were given, with escalating doses of adriamycin and cyclophosphamide from cycle 3 (HEAV'D). Central nervous system (CNS) prophylaxis incorporated intrathecal methotrexate and cytosine arabinoside with cranial irradiation. Maintenance chemotherapy consisted of 6-mercaptopurine, cyclophosphamide and methotrexate for 3 years. Results obtained with the OPAL and HEAV'D regimens were not significantly different. The overall complete remission (CR) rate was 66% (73/111), factors correlating unfavourably with achievement of CR being advanced age (P less than 0.001) and L3 morphology/B-ALL immunophenotype (P less than 0.01). Fifty-three patients have relapsed, the bone marrow being the primary site in 43. Extramedullary relapse alone occurred in 10 (seven CNS, two testicular and one skin). Only three of the 64 patients who had complete CNS prophylaxis subsequently relapsed in the CNS as an isolated site. One patient died in CR, 19 remain in continuous CR between 2.5 and 10.5 years. The median duration of remission of the 73 patients who achieved CR was 18.5 months, factors correlating favourably with duration of CR being low blast cell count at presentation (P less than 0.002) and common ALL immunophenotype (P less than 0.04). Twenty-four patients remain alive, with a median survival of all patients of 18 months. Long-term survival is possible for approximately 20% of adults with ALL treated relatively intensively.

Orally active α‐ketohydroxy pyridine iron chelators intended for clinical use: in vivo studies in rabbits

Abstract: Summary Increased daily iron excretion from iron overloaded, 59Fe lactoferrin labelled rabbits was observed following the intragastric administration of 1,2-dimethyl-3-hydroxy pyrid-4-one (L1) or 1-ethyl-2-methyl-3-hydroxy pyrid-4-one (L1-NEt) at doses of 200 mg/kg. 59Fe excretion induced by these drugs was predominantly faecal and was comparable to that caused by similar doses of subcutaneous or intramuscular desferrioxamine. The effectiveness of the two α-ketohydroxy pyridine chelators was confirmed by repeated administration, intragastrically or by subcutaneous or intramuscular injection, to the same or other rabbits. Examination of the urine during the administration of the chelators revealed their high specificity for iron but not for copper, zinc, calcium or magnesium.