CD200 is a useful diagnostic marker for identifying atypical chronic lymphocytic leukemia by flow cytometry.

INTRODUCTION: Immunophenotyping by flow cytometry is routinely employed in distinguishing between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Inclusion of CD200 has been reported to contribute to more reliable differentiation between CLL and MCL. We investigated the value of CD200 in assessment of atypical CLL cases. METHODS: CD200 expression on mature B cell neoplasms was studied by eight-color flow cytometry in combination with a conventional panel of flow cytometry markers. The study included 70 control samples, 63 samples with CLL or atypical CLL phenotype, 6 MCL samples, and 40 samples of other mature B cell neoplasms. RESULTS: All CLL samples were positive for CD200, whereas MCL samples were dim or negative for CD200. Of the CLL samples, 7 were atypical by conventional flow cytometry, with Matutes scores ≤3. These cases were tested for evidence of a t(11;14) translocation, characteristic of MCL, and all were negative, consistent with their classification as atypical CLL. All these atypical CLL samples were strongly positive for CD200. CONCLUSION: CD200 proved to be a useful marker for differentiation between CLL and MCL by flow cytometry. In particular, CD200 was useful in distinguishing CLL samples with atypical immunophenotypes from MCL.

Second cancers and late mortality in Australian children treated by allogeneic HSCT for haematological malignancy.

We examined risk of second cancer and late mortality in a population-based Australian cohort of 717 pediatric allogeneic stem cell transplant (HSCT) recipients treated for a malignant disease during 1982-2007. Record linkage with population-based death and cancer registries identified 17 second cancers at a median of 7.9 years post HSCT; thyroid cancer being the most common malignancy (n=8). The cumulative incidence of second cancer was 8.7% at follow-up, and second cancers occurred 20 times more often than in the general population (standardised incidence ratio 20.3, 95% confidence interval (CI)=12.6-32.7). Transplantation using radiation-based conditioning regimens was associated with increased second cancer risk. A total of 367 patients survived for at least 2 years post HSCT and of these 44 (12%) died at a median of 3.1 years after HSCT. Relapse was the most common cause of late mortality (n=32). The cumulative incidence of late mortality was 14.7%. The observed rate of late mortality was 36 times greater than in the matched general population (standardised mortality ratio 35.9, 95% CI=26.7-48.3). Recipients who relapsed or who had radiation-based conditioning regimens were at higher risk of late mortality. Second cancers and late mortality continue to be a risk for pediatric patients undergoing HSCT, and these results highlight the need for effective screening and survivorship programs.

Second cancer risk in adults receiving autologous haematopoietic SCT for cancer: a population-based cohort study.

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992-2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.

Increased activity and improved outcome in unrelated donor haemopoietic cell transplants for acute myeloid leukaemia in Australia, 1992-2005.

BACKGROUND/AIM: Numbers of unrelated donor allogeneic haemopoietic cell transplants (HCT) for acute myeloid leukaemia have increased in Australia in recent years. The aims of this study were to investigate the components of this change and find contributing factors to changes in outcome. METHODS: The study method was a retrospective analysis of 213 consecutive first unrelated donor HCT for acute myeloid leukaemia performed within Australia for adult patients during the years of 1992-1997 (n= 43) and 1998-2005 (n= 170). RESULTS: The proportion of patients transplanted in first or second complete remission (CR) increased markedly from 21% in 1992-1997 to 52% in 1998-2005. The cumulative incidence of relapse at 1 year post HCT was significantly lower for the later cohort (22% vs 30%, P= 0.04) and for patients transplanted in CR compared with those not in CR (16% vs 31%, P= 0.01). The overall survival probability was significantly better at 5 years post HCT for patients transplanted in 1998-2005 compared with 1992-1997 (40% vs 21%, P= 0.04). Multivariate analysis identified five independent significant favourable factors for survival among the whole patient group: age under 40 years, transplant in CR1, CR2 or first relapse, patient CMV seronegativity, good performance status and year of transplant within 1998-2005. CONCLUSION: The later cohort of patients had improved survival even after allowing for the effects of age, remission status and other factors, which suggests a general improvement in the safety of the procedure over time, particularly for patients in early disease stages at transplant.

Haemopoietic stem cell transplantation in Australia and New Zealand, 1992-2001: progress report from the Australasian Bone Marrow Transplant Recipient Registry.

BACKGROUND: Bone marrow and blood stem cell transplantation is now used as curative therapy for a range of haematological malignancies and other conditions. The Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) has recorded transplant activity in Australia since 1992; transplant centres in New Zealand have corresponded with the Registry since 1998. AIM: To describe allogeneic and autologous bone marrow and blood stem cell transplantation activity and outcomes in Australia and New Zealand from 1992 to 2001. METHODS: Each haemopoietic stem cell transplant centre in Australia and New Zealand contributes information to the Registry via a single information form compiled when a transplant is performed. An annual follow-up request is then sent from the Registry to the contributing centre at the anniversary of each individual transplant. RESULTS: Haemopoietic stem cell transplants in Australia have increased in number from 478 in 1992 to 937 in 2001, whereas in New Zealand the number has grown from 91 in 1998 to 105 in 2001, mainly as a result of an increase in autologous blood stem cell transplants. The number of hospitals contributing to the ABMTRR has grown from 20 in 1992 to 37 in 2001. The most common indication for autologous transplantation in 2001 was non-Hodgkin's lymphoma, whereas for allogeneic transplants it was acute myeloid leukaemia. The 9-year actuarial disease-free survival probability for patients aged 16 and above between 1992 and 2000 was 37% for autologous, 39% for allogeneic related donor and 30% for allogeneic unrelated donor transplants. Recurrence of the underlying disease was the main cause of death post-transplant after both allogeneic (26.3% of deaths in the first year and 68.0% of deaths in the second year) and autologous transplants (59.0% and 86.2%). Treatment-related mortality was 16.9% after allogeneic transplantation and 2.1% after autologous transplantation in 2000. CONCLUSIONS: The ABMTRR provides a comprehensive source of information on the use of bone marrow transplant, and allows for continuing analysis of changes in the application of this high-cost technology and the outcome of patients undergoing these procedures. Registry data provide a means for directing future clinical research into perceived areas of priority for improvement of outcome, such as the reduction in the risk of disease recurrence post-transplant.

Posterior leukoencephalopathy in association with the tumour lysis syndrome in acute lymphoblastic leukaemia--a case with clinicopathological correlation.

We report a case and autopsy findings of posterior leukoencephalopathy (PL) developing during induction chemotherapy for B-cell acute lymphoblastic leukaemia (B-ALL) complicated by tumour lysis syndrome. PL may present with seizures, headache, altered mental status and occipital blindness, associated with transient parieto-occipital abnormalities on neuro-imaging studies. Precipitants include immunosuppressive agents, renal insufficiency, hypertension and fluid retention. It has also been reported in association with pre-eclamptic and eclamptic states, nephrotic syndrome and following liver and bone marrow transplantation. Only rare cases of PL developing during treatment for haematological malignancy have been reported and to our knowledge it has not been previously reported in association with tumour lysis syndrome. Since the condition is generally regarded as being fully reversible few autopsy findings have been reported.

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.

Unrelated volunteer bone marrow transplantation: initial experience at St Vincent's Hospital, Sydney.

BACKGROUND: Only 30% of patients with leukaemia have an HLA-compatible family member able to act as a marrow donor. The recent development of volunteer bone marrow donor registries has supplied HLA-matched donors for a number of such individuals. AIMS: To define the problem and outcome of the first cohort of patients given HLA-matched unrelated volunteer bone marrow transplants at St Vincent's Hospital, Sydney. METHODS: Post transplant outcome of patients with advanced leukaemia given HLA-identical unrelated donor marrow transplants was compared to that of patients transplanted concurrently from HLA-identical sibling donors, in terms of survival, leukaemia-free survival, incidence and severity of acute graft-versus-host disease (GVHD), duration of neutropenia, incidence of infection and duration of transplant hospitalisation. RESULTS: Sixteen patients with advanced leukaemia and without a histocompatible family member donor received unrelated donor bone marrow transplants. Actuarial survival at two years post transplant was 30%. Actuarial survival of 23 recipients of HLA-identical sibling bone marrow transplants with advanced leukaemia transplanted during the same time period was 17% (not significant). Actuarial disease free survival at two years was 30% and 13% respectively. Three of five long term survivors of the unrelated transplants had chronic myeloid leukaemia in blastic transformation at the time of transplant; thus blastic transformation should not preclude consideration of unrelated marrow transplantation. Recipients of unrelated allografts had a higher incidence of acute GVHD which occurred earlier and with greater severity than in recipients of sibling allografts, a longer duration of post transplant neutropenia (24 days to reach 0.5 x 10(9)/L versus 19.5, p = 0.07), a higher frequency of infection in the first 100 days post transplant (p = 0.0004) and a longer duration of transplant hospitalisation (p = 0.04). Transplant-related complications were the commonest cause of death in the unrelated donor recipients, while leukaemic recurrence was the commonest single cause of death in the HLA-identical sibling recipients. Improvements are needed in prophylaxis of infection and in prevention and treatment of acute GVHD in recipients of unrelated donor transplants. Nevertheless, this modality provides curative treatment for patients with otherwise incurable haematological malignancies and should no longer be considered experimental.

Changing results of HLA-identical sibling bone marrow transplantation in patients with haematological malignancy during the period 1981-1990.

During the years 1981-90 inclusive 227 patients with haematological malignancy received an HLA-identical sibling first transplant at St Vincent's Hospital, Sydney. Recipients with acute leukaemia in first remission or chronic myeloid leukaemia in first chronic phase were analysed as good risk, and those beyond these stages, as poor risk patients. Good risk patients transplanted in the years 1986-90 (n = 52) showed improved actuarial survival (74%) compared to those (n = 58) transplanted during 1981-85 (37%, p = 0.01). There was a suggestion that leukaemia-free survival was also improved in those transplanted during the later time period (62% versus 36%, p = 0.07). In contrast, poor risk patients transplanted during 1986-90 (n = 55) appeared to have worse leukaemia-free survival (15%) compared to those transplanted during 1981-85 (n = 62) (22%, p = 0.09). The incidence of acute graft-versus-host disease (GVHD) grades I-IV in all patients was 94% in those transplanted during 1981-85 (n = 120) and 86% in those transplanted during 1986-90 (n = 107) (p = 0.002). The incidence of acute GVHD grades II-IV was 37% during 1981-83, 20% during 1984-86, and 28% during 1987-90 (p = 0.1). The decrease in incidence and severity of acute GVHD correlated with the introduction of the cyclosporin/short methotrexate regimen in our practice. The incidence of cytomegalovirus (CMV) pneumonitis was 18% in 1981-85, and 11% in 1986-90 (p = 0.09). In 1989 and 1990 no cases of CMV pneumonitis occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

High dose chemotherapy and autologous bone marrow transplantation in advanced Hodgkin's disease.

OBJECTIVE: To present the use of high dose chemotherapy with autologous bone marrow transplantation as salvage therapy for advanced Hodgkin's disease in Australia. DESIGN: A prospective open study for patients whose disease was resistant to conventional treatment. SETTING: The bone marrow transplantation units of four Australian tertiary hospitals. PATIENTS: Seventeen patients (median age 30 years) entered and completed the study. The stage of the disease at initial diagnosis was I or II (seven patients), III (seven patients) and IV (three patients). Histological types were lymphocyte predominant (one), nodular sclerosis (12), mixed cellularity (three) and unknown (one). Therapy before consideration for transplantation included radiotherapy (13), mustine, vincristine, procarbazine and prednisone (MOPP--17 patients) or doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD--13 patients) and other chemotherapy regimens (five). The median interval from diagnosis to transplantation was 29 months (range, 9-178 months). The patient's disease was classified as sensitive (nine) or resistant (eight) to treatment, depending on the response to the most recent course of chemotherapy. INTERVENTIONS: Morphologically normal autologous bone marrow was harvested and cryopreserved. The conditioning regimen given was cyclophosphamide, carmustine and etoposide (14) or busulphan and cyclophosphamide (three). The marrow was then infused. MAIN OUTCOME MEASURES: Remission (complete or partial), disease-free survival and overall survival. RESULTS: Over all, 10 of 17 patients (59%) entered or remained in complete remission and four of 17 (24%) achieved partial remission. The overall actuarial survival at 30 months was 70%. Eight of the nine patients with treatment-sensitive disease (89%) remain disease-free at a median of 22 months (range, 18-29 months) after transplantation. Two of the eight patients with resistant disease (25%) are disease-free at 20 and 28 months. There was one procedure-related death from haemorrhage and four disease-related deaths at six, seven, eight and 13 months after transplantation. CONCLUSION: Autologous bone marrow transplantation may provide an effective salvage therapy in advanced Hodgkin's disease, particularly for patients with treatment-sensitive disease and a low tumour burden.

Peripheral blood and bone marrow findings in patients with acquired immune deficiency syndrome.

In 4 years (1984-1987), 183 bone marrow examinations were performed on 155 human immunodeficiency virus (HIV) antibody positive patients. One hundred and fifty three had category IV AIDS. One-third of the marrows yielded specific information. This included opportunistic infection, in particular Mycobacterium Avium Intracellulare Complex (MAI) (24%), malignancy (4%), consistent with ITP (9%) and iron deficiency (1%). In the remaining two thirds of the bone marrows the most frequent non-specific abnormalities were dyserythropoiesis, erythroid hypoplasia, reticuloendothelial iron block, granulomas, lymphoid aggregates, plasmacytosis and histiocytosis. Common peripheral blood findings were anemia, lymphopenia, anisocytosis, rouleaux and atypical lymphocytes. Peripheral blood and bone marrow examinations on 16 patients on AZT are included. These patients have more pronounced blood and bone marrow abnormalities. The causes of these abnormalities are multifactorial and include low T4 levels, severe viral and other infections and therapy with marrow toxic drugs.

Coexistence of rheumatoid arthritis and a monoclonal CD4 T cell lymphoproliferative disorder.

A 33-year-old man developed seropositive rheumatoid arthritis (RA) followed soon after by a monoclonal lymphoproliferative disorder characterized by CD4 positive T lymphocytes in his peripheral blood, bone marrow and lymph nodes. Previous reports of polyarthritis in association with a T cell lymphoproliferative disorder have all involved the CD8 phenotype.

The development of the acquired immunodeficiency syndrome after bone-marrow transplantation.

Since bone-marrow transplant recipients receive considerable quantities of packed-cell, platelet and sometimes leukocyte transfusions, as well as the donor marrow infusion, it would be predictable that acquired immunodeficiency syndrome (AIDS) by blood-product transfusion would occur in this patient population. We report here two patients who received HLA-identical sibling bone-marrow transplants for acute non-lymphoblastic leukaemia during their first remission. Both developed category-A AIDS at days 342 and 546 after transplantation, respectively. Neither patient belonged to any known high-risk group for AIDS, other than having received a blood-product transfusion. One of the two patients is now known to have received blood from a donor who was human immunodeficiency virus (HIV) seropositive. Both patients developed Pneumocystis carinii pneumonia and other opportunistic infections, and both have died of AIDS without evidence of recurrence of their leukaemia. One patient had no chronic graft-versus-host disease (GVHD) and the other had mild chronic GVHD of the mouth. Since severe opportunistic infections are rare after transplantation in the absence of GVHD, their late occurrence after transplantation should raise the suspicion of AIDS. This complication is likely to have an adverse impact on the long-term survival of patients who received bone-marrow transplants between 1981 and the introduction of effective screening tests for HIV infection in blood donors.

Red cell alloantibodies produced after bone marrow transplantation.

This article describes the production of red cell alloantibodies in 13 of 150 patients after bone marrow transplantation. New alloantibodies appeared 12 days to 11 months after the transplantation. The specificities of these antibodies were anti-N, -Jka, -E-like, -Kell-like, -M, -Leb, -Hl, -H and -A1. The posttransplantation production of antibody could be due to either the transfusion of mature lymphocytes along with the marrow, the ability of the grafted immune system to produce alloantibodies, or the viable immunocompetent cells remaining despite high-dose chemotherapy and irradation.

Aplastic anemia: analysis of two methods of treatment.

Between 1981 and 1985, 27 patients with aplastic anemia have been treated by immunosuppression with antilymphocyte globulin and prednisolone or allogeneic bone marrow transplantation. Fifteen have undergone bone marrow transplantation and have an actuarial survival at 54 months of 65% +/- 12% (95% confidence limits). There have been four deaths from graft rejection, septicemia (two), and graft-versus-host disease. Twelve have received antilymphocyte globulin and have an actuarial survival at 56 months of 67% +/- 21%. Five of these now have a normal blood count and two have had good partial responses and are self supporting. Of the five non-responders, three survived, two with persistent aplasia and one after allogeneic bone marrow transplantation. Two are dead, one of hemorrhage and one after mismatched bone marrow transplantation. In this study antilymphocyte globulin produced survival equivalent to bone marrow transplantation although only 58% of patients had a response to the antilymphocyte globulin. The advantages and disadvantages of these two methods of treatment are discussed.

Red cell deformability and other haemorheological variables in stable coronary artery disease.

In this study, red cell deformability and other haemorheological variables were measured in 40 patients who underwent cardiac catheterization for the investigation of chest pain. The patients were divided into two groups - those with extensive disease and those with less extensive or no disease. Deformability was assessed by a filtration method. There were no significant differences in filterability, haematocrit, plasma viscosity or plasma fibrinogen between the two groups of patients. However, those with extensive disease had significantly higher blood viscosity than those with less extensive disease. Thus the study was able to demonstrate an association between blood viscosity and extent of coronary artery disease but not between the individual determinants of blood viscosity (red cell deformability, plasma fibrinogen and haematocrit) and extent of disease.

The provision of blood for elective surgery.

The improvement in efficiency of blood use within a hospital is a major responsibility of the hospital blood bank. Such an improvement can be brought about by introducing a group and antibody screen system or by limiting the amount of blood routinely cross-matched for any procedure. Data to justify this can be best provided with the use of a blood bank microcomputer. Although autologous blood transfusion is the ideal it is difficult to implement in many situations and so homologous blood is used. The use of red cell concentrates in elective surgery has not been shown to be inferior to whole blood in most procedures.