P. J. Hamilton

Guidelines on the management of massive blood loss

The guideline group was selected to be representative of UKbased medical experts and included the authors of previous recommendations. Preparation of the guidelines included a review of key literature, including Cochrane Database and MEDLINE and consultation with representatives of relevant specialties. Recommendations are based on appraisal of the relevant literature and expert consensus. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Transfusion Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 100 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http:// www.bcshguidelines.com/process1.asp#App3). The objective of this guideline is to provide healthcare professionals with clear guidance on the management of massive blood loss. They do not address the specific problems associated with major obstetric haemorrhage; these are being addressed by the Royal College of Obstetricians. In all cases individual patient circumstances may dictate an alternative approach.

The relationship between bcl‐2 expression and response to chemotherapy in acute leukaemia

Summary. Immunocytochemistry was used to assess bcl‐2 expression in blasts obtained from the bone marrow of 28 patients with acute lymphoblastic leukaemia (ALL) (16 children and six adults at presentation and three children and three adults on relapse) and 20 with acute myeloid leukaemia (AML) (19 adults and one child, 13 with de novo AML, 11 at presentation and two on relapse, and seven secondary to myelodysplasia or chronic myeloid leukaemia). Slides were examined both for the percentage of positive cells and for the intensity of staining using a five‐point scale. There was a statistically significant increase in both the percentage of positive cells seen (P < 0.002) and the intensity of staining (P < 0.01) between samples obtained at relapse and those at presentation in ALL. There was a significantly greater intensity of staining in cells from patients with ALL (P < 0.05) and AML (P < 0.05) who failed to achieve remission after chemotherapy than in those who responded. The intensity of staining in cases of secondary AML was lower than that in de novo disease (P < 0.01). These results suggest that expression of bcl‐2 may be an important prognostic feature in both de novo AML and in ALL, but not in secondary AML.

Transfusion‐associated graft‐versus‐host disease in fludarabine‐treated B‐chronic lymphocytic leukaemia

Summary. Transfusion‐associated graft‐versus‐host disease (TA‐GVHD) is a rare but serious complication of blood component therapy in patients with haematological malignancies. B‐chronic lymphocytic leukaemia (B‐CLL), however, has rarely been associated with TA‐GVHD. We report three patients with advanced B‐CLL who developed TA‐GVHD. All these had been treated with fludarabine. Suppression of T cells by fludarabine may have contributed to an increased susceptibility to TA‐GVHD. The use of irradiated blood products to prevent this complication should be considered for patients with advanced B‐CLL treated with fludarabine or other purine analogues.

Class Ii Antigen Expression By Keratinocytes And Enterocytes—an Early Feature Of Graft-versus-host-disease

HLA-DR expression by keratinocytes and enterocytes was studied in 23 patients undergoing BMT (12 autologous; 11 allogeneic). Two monoclonal antibodies were used to detect the HLA-DR antigen. Only in two patients before transplant and in one following autologous BMT was HLA-DR expressed on keratinocytes. Of 11 allogeneic recipients, 7 developed clinical GVHD, and HLA-DR-positive keratinocytes were seen in 6 of these. HLA-DR was expressed by enterocytes in 5 patients with GVHD and 4 of these also showed HLA-DR expression by keratinocytes. HLA-DR expression by keratinocytes correlated well with clinical GVHD. Expression of this antigen by enterocytes was associated with characteristic histological appearances of GVHD, even in the absence of intestinal symptoms. A combination of traditional and immunocytochemical techniques offers a sensitive and accurate method of confirming GVHD before it becomes florid.

Histological features of skin and rectal biopsy specimens after autologous and allogeneic bone marrow transplantation.

The histological appearances of skin and rectal biopsy specimens were studied in 31 bone marrow transplant recipients (13 autologous, 18 allogeneic) before transplant, at 28 days, at six months, and as soon as graft versus host disease (GVHD) was clinically suspected. Grades I and II skin changes were commonly seen in patients before transplant and in the autologous group after transplant, as well as in most of the allogeneic recipients with suspected GVHD. Epidermal lymphocytic infiltration was seen only in allogeneic recipients, with clinical GVHD following transplant, but this was not a consistent finding and no other histological features were seen which would distinguish early GVHD from changes caused by cytotoxic agents. Rectal biopsy specimens, however, were normal in patients before transplant and in autologous recipients at 28 days; single cell necrosis of crypt cells was seen only in six of 13 allogeneic recipients studied after transplant with clinical skin GVHD but no gastrointestinal symptoms. Skin changes greater than I and II are required for the histological diagnosis of GVHD. Rectal changes are more specific and may be present despite a lack of intestinal symptoms.

Factor II, VII, IX and X concentrations in patients receiving long term warfarin.

Using standard one stage clotting assays the concentrations of factors II, VII, IX and X were determined in 37 patients stabilised on warfarin for between three months and 17 years. Contrary to popular belief, the concentrations were not equally depressed, with factor X the lowest, factor II at intermediate value, factors VII and IX the highest. Some 71% of the variance of the British corrected ratio (BCR) could be accounted for by measurement of the factors assayed. Analysis of this variance showed 91% of the explained variance attributable to factor II, 7% to factor VII, 1.6% to factor IX and 0.4% to factor X. With the sudden and recent withdrawal of human thromboplastin, investigation of the sensitivities of the animal thromboplastins to changes in vitamin K dependent factors in orally anticoagulated patients is needed to ensure that the potentially alarming falls in factors II and X in these patients are being adequately detected.

The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56–81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.

Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow.

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin’s disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin’s disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02–4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.

Familial myelodysplasia: progressive disease associated with emergence of monosomy 7

. Two brothers developed hypoplastic anaemia with the development in one of refractory anaemia with excess blasts (RAEB) accompanied by emergence of monosomy 7. Both brothers have a constitutional inversion of chromosome 1. Neither shows the increased chromosomal fragility of Fanconis anaemia or its variants. This family is the third reported in which monosomy 7 has been found when leukaemic or preleukaemic transformation has occurred in patients with familial hypoplastic anaemia.

Virus infections in bone marrow transplant recipients: a three year prospective study.

Over three years 81 consecutive bone marrow transplant recipients (32 allogeneic and 49 autologous) who received prophylaxis with acyclovir, were studied for symptomatic virus infection. Thirty nine infections were documented in a total of 28 patients. Thirty two infections were mild, five were moderately severe, and two were severe. Cytomegalovirus infection occurred in only six allogeneic recipients. Herpes simplex virus and varicella zoster virus infections occurred infrequently. Seven patients who were considered at the time of death to have died due to an infectious cause were studied virologically at necropsy. In only one patient was a virus infection thought to have been the cause of death. Prophylaxis with acyclovir may have influenced the rate and clinical prominence of herpes virus infections. In this study viruses were considered to have had a relatively minor role in causing morbidity and mortality.