A phase I/II study of intensive dose escalation of cytarabine in combination with idarubicin and etoposide in induction and consolidation treatment of adult acute myeloid leukemia. Australian Leukaemia Study Group (ALSG).

To determine the safety and efficacy of the combination of idarubicin, cytarabine and etoposide ("ICE") for induction and consolidation treatment of acute myeloid leukemia (AML), and of dose-intensification of cytarabine in this setting, 54 previously untreated patients in three cohorts were studied by sequential dose escalation of cytarabine, in combination with standard doses of idarubicin and etoposide. Cytarabine was given to Cohort 1 at the conventional dosage of 100 mg/m2 per day by continuous infusion for 7 days in induction and 5 days in consolidation; to Cohort 2 at high-dose (HiDAC) (3 g/m2 intravenously twice daily on days 1, 3, 5 and 7) during induction with conventional dosage during consolidation; to Cohort 3 HiDAC was given for both induction and consolidation. In addition, Cohort 3 patients received lenograstim (Granocyte; rHuG-CSF) after both induction and consolidation courses. We found that there was no significant difference between the three cohorts in hematological toxicity in induction, but that HiDAC was associated with a greater incidence of gastro-intestinal toxicities. There was no difference in induction mortality between the three cohorts, which was 11% overall. Consolidation with HiDAC led to a significant increase in hematological toxicity. Overall, the complete remission (CR) rate was 80% with no significant difference between the three regimens. The estimated disease free survival at 3 years was 28%, 67% and 54% respectively for Cohorts 1, 2 and 3 with an estimated overall survival of 38%, 63% and 47%. We conclude that cytarabine dosage can be escalated safely in combination with idarubicin and etoposide in both induction and consolidation. The combination is effective for induction treatment of AML and its side-effects appear similar to those of standard regimens. Whether its use offers long-term benefits compared with standard regimens is the subject of ongoing controlled randomized studies.

Phase III efficacy study of interleukin-3 after autologous bone marrow transplantation in patients with malignant lymphoma.

We evaluated the efficacy of recombinant human interleukin-3 (rhIL-3) in reducing the number of platelet transfusions and major infections after autologous bone marrow transplantation (ABMT) in patients with malignant lymphoma. 198 patients with non-Hodgkin's lymphoma (NHL, n = 111) and Hodgkin's disease (HD, n = 87) were randomized to receive rhIL-3 10 microgram/kg/d (n = 130) or placebo (n = 68) for a maximum of 28 d after ABMT. Several well-known conditioning regimens were used. From day 1 after ABMT patients were treated with placebo or rhIL-3 at a dose of 10 microgram/kg/d by continuous i.v. infusion for 7 d and then by s.c. administration for 21 d or until platelet (50 x 109/l) and neutrophil (0.5 x 109/l) recovery had occurred. Treatment was completed in 54% of the patients in the rhIL-3 group versus 75% in the placebo group (P < 0.004). Adverse events were the main reason for premature discontinuation in the IL-3 group (23% IL-3 v 5% placebo). The median number of platelet transfusions was not significantly different between the IL-3 group and the placebo group (8.0 IL-3 v 6.0 placebo, P = 0.09). Platelet engraftment (>/= 20 x 109/l) was not significantly faster in the IL-3 group (28 d in the IL-3 and 27 d in the placebo group, P = 0.06) and the incidence of haemorrhagic complications was similar in both groups. In patients receiving the full intended dose of rhIL-3, platelet engraftment to >/= 20 x 109/l was delayed (P = 0.007). The median time to neutrophil engraftment was 23 d in the IL-3 and 25 d for the placebo group (P = 0.39). There was no difference in the incidence of major infections. We conclude that treatment with IL-3 has no clinical benefit in patients receiving ABMT for malignant lymphoma.

Mycobacterial central venous catheter tunnel infection: a difficult problem.

We report our experience of non-tuberculous mycobacterial infection associated with the tunnel of Hickman-Broviac central venous catheters in immunosuppressed patients with haematological malignancies undergoing high-dose chemotherapy supported by BMT. The problem is rare and difficult to treat. Our cases are unique in developing tunnel site mycobacterial infection well after the tunnelled catheters were removed. We diagnosed one case of Mycobacterium chelonae, which is a well-documented cause of such infections, and two cases of Mycobacterium haemophilum, which are the first reported cases in this setting. Early wide surgical excision of the infected tunnel site and prolonged antibiotic therapy is necessary. Despite these measures recurrence occurred in two cases. Close liaison with the microbiology laboratory is needed to ensure the appropriate culture media and conditions are used for these fastidious organisms. Empiric antibiotic regimens should be based on the likely organism. Drugs active against M. chelonae and M. haemophilum should be included.

Infections in patients managed at home during autologous stem cell transplantation for lymphoma and multiple myeloma.

A group of 51 patients with multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's disease receiving high-dose chemotherapy and autologous peripheral blood stem cell rescue received chemotherapy and clinical care in the peritransplant period at home. This group was compared with 88 cases with the same diagnoses, receiving the peripheral stem cell transplant over the same time period as an inpatient in a high efficiency particulate air filtered bone marrow transplant unit. Patients were treated at home based on choice, geographic accessibility, availability of an educated care giver and a clean home environment, and comprehension of the concepts of infection and aseptic techniques. Febrile neutropenia and sepsis were not increased in the home group and no episodes of septic shock were seen in this group. Patients at home received prophylactic oral ciprofloxacin and roxithromycin during the phase when the absolute neutrophil count was < 1 x 10(9)/l. Fewer gram-negative infections, but no diminution in gram-positive infections or in the rate of fever were seen in patients at home. Empiric therapy with a third generation cephalosporin, teicoplanin and tobramycin was instituted in 31 patients who developed a fever greater than 38.5 degrees C. Of this group of 31, 18 required admission to hospital, 12 because of febrile neutropenia which persisted or was considered unsuitable for management at home due to sepsis. The remaining 13 with febrile neutropenia remained at home throughout, as did the 20 cases not developing neutropenic fever. This study demonstrates the feasibility of managing carefully selected patients in their home environment when at risk from febrile neutropenia or other septic complications following autologous peripheral stem cell support.

Clinical care for patients receiving autologous hematopoietic stem cell transplantation in the home setting.

PURPOSE/OBJECTIVES: To undertake a pilot study of autologous hematopoietic stem cell transplantation (HSCT) in the patient's home to improve satisfaction of care, reduce financial costs, and relieve pressure on inpatient accommodation. DESIGN: Descriptive, cross-sectional, qualitative. SETTING: Patients' homes within the metropolitan area of Perth, Australia. SAMPLE: 25 Caucasian adults with recurrent multiple myeloma, non-Hodgkin's lymphoma, or Hodgkin's disease requiring autologous HSCT. METHODS: A program was developed to use the bone marrow transplant team from a major tertiary hospital to permit home visiting, treatment with cytotoxic chemotherapy at home, treatment of complications at home, and an integrated home/hospital caring facility to expedite hospital admission if complications developed. FINDINGS: The program was practical to administer, improved overall patient satisfaction, and was significantly less costly than inpatient transplantation. Fifteen patients (60%) of the total study group of 25 required hospital admission for a median of five days (range 1-13 days) for management of complications, predominantly febrile neutropenia. Nineteen (76%) of the 25 patients received i.v. antibiotic therapy at home during the period of neutropenia. Two patients died of transplant-related complications--one from respiratory syncytial virus infection and one from veno-occlusive disease of the liver. These complications were not attributable to the home setting. IMPLICATIONS FOR NURSING PRACTICE: This program increased the responsibility and sense of autonomy of advanced practice nurses and developed their counseling skills as well as their ability to participate more actively in the decision-making process of those involved. MAIN RESEARCH VARIABLES: Participation in the home transplant program, patient satisfaction, nursing development, and cost-effectiveness of the program.

The synthesis of a peanut agglutinin-ricin A chain conjugate: potential as an in vitro purging agent for autologous bone marrow in multiple myeloma.

The lectin peanut agglutinin (PNA) and CD19 monoclonal antibody have been covalently linked to magnetic beads and utilized in an in vitro purging system for autologous bone marrow in multiple myeloma (MM). An alternative to mechanical purging involves the use of immunotoxins to provide specifically targeted cellular toxicity; however, no studies to date have examined the utility of a lectin-ricin A chain (RCA) combination as a purging agent in MM. Initially, we studied the internalization of PNA by target cells (Raji) using flow cytometry. The surface fluorescence intensity of PNA-treated Raji cells was reduced upon incubation at 37 degrees C, and subsequent studies with fixed cells detected the endocytosed PNA. Complete internalization occurred within 120 minutes, indicating the potential of PNA as a purging agent. We manufactured a novel PNA-RCA conjugate and demonstrated its strong and specific binding to PNA reactive cell targets. Subsequent experiments assessed the toxicity of the conjugate to Raji cells and normal bone marrow progenitor cells. 3H-leucine uptake assays showed that PNA-RCA was capable of reducing protein synthesis in Raji cells and that the toxic effects were specific. In addition, at concentrations of conjugate achieving greater than 99% selective cytotoxicity for Raji cells, adequate CFU-GM were preserved in normal marrow. These studies suggest that PNA-RCA may be of value as an in vitro purging agent for MM.

Immunohistochemical changes in sigmoid colon after allogeneic and autologous bone marrow transplantation.

AIM: To determine whether there are characteristic immunohistological changes in the colonic mucosa in acute graft versus host disease (GvHD). METHODS: Consecutive allogeneic (n = 11) and autologous (n = 11) bone marrow transplant recipients underwent endoscopic biopsy of sigmoid mucosa before transplant and on day 30 post-transplant. Immunohistochemical staining and quantitation of intraepithelial and lamina propria mononuclear cells were undertaken using a panel of monoclonal antibodies and a Streptavidin-biotin alkaline phosphatase staining technique. RESULTS: In the allogeneic group (nine of whom had clinical acute GvHD) there was a fivefold increase in lamina propria CD16+ mononuclear cells (3.1 +/- 4.3 to 17.0 +/- 12.2 per 100 lamina propria nucleated cells), compared with autologous transplant recipients in whom this rise was twofold (5.5 +/- 4.6 to 10.6 +/- 7.1 per 100 lamina propria nucleated cells). The CD16+ mononuclear cells had morphological appearances of tissue macrophages, but in neither the allogeneic nor autologous groups was there an increase in total macrophage numbers (CD14+). In patients with acute GvHD the lamina propria CD4+:CD8+ lymphocyte ratio fell (1.97 +/- 1.12 to 1.07 +/- 1.01), primarily because of a fall in the number of lamina propria CD4+ lymphocytes. In both allogeneic and autologous groups there was a fall in intraepithelial lymphocyte numbers, but there was no change in CD19+ (B cell), CD25+ (interleukin-2 receptor positive) or CD56+ (natural killer) cell numbers. CONCLUSION: Following bone marrow transplantation, there appears to be upregulation of lamina propria tissue macrophage CD16 (an Fc receptor for IgG), a change which is more noticeable after allogeneic transplantation and which may be related to the development of acute GvHD. In patients with acute GvHD there was a fall in the lamina propria CD4+:CD8+ lymphocyte ratio. If these changes are functionally important, they may have significant implications for understanding the pathogenesis of GvHD.

A prospective study of screening upper gastrointestinal (GI) endoscopy prior to and after bone marrow transplantation (BMT).

BACKGROUND: Upper gastrointestinal (GI) endoscopic abnormalities are common in symptomatic bone marrow transplant (BMT) recipients but the incidence of occult gastrointestinal disease in these patients is unknown. AIMS: To examine the role of screening upper GI endoscopy before and after BMT. METHODS: Endoscopy was performed routinely on allogeneic (n = 24) and autologous (n = 17) BMT patients before transplant and at 30 and 120 days after transplant. RESULTS: Twenty-one of 41 patients (51%) had an endoscopic abnormality on one or more occasions which necessitated a change in treatment. These abnormalities were present in ten of 41 (24%) pre-transplant endoscopies, ten of 32 (31%) endoscopies at day 30 after BMT, and in seven of 22 (32%) day 120 endoscopies. Abnormalities included mucosal erosions or ulcers n = 22 endoscopies), infections (n = 5) or previously undiagnosed GI graft-versus-host disease (n = 3). Mucosal erosions or ulcers were present in eight of 28 endoscopies despite regular anti ulcer drug therapy. CONCLUSIONS: Screening upper GI endoscopy before and after BMT is generally safe and detects a high yield of significant GI abnormalities. However, it remains to be demonstrated that treatment of these lesions will improve the clinical outcome in BMT recipients without GI symptoms.

Liver disease complicating bone marrow transplantation: a clinical audit.

Hepatic dysfunction following bone marrow transplantation (BMT) may present complex management issues. The incidence and aetiology of abnormal liver function following allogeneic and autologous BMT was reviewed over a 2 year period in Royal Perth Hospital and these findings were related to management decisions and patient outcome. Abnormal serum liver biochemistry during the first 12 post-transplant months occurred in all allogeneic (n = 31) and 14 of 23 (61%) autologous transplant patients; 13 (41%) allogeneic and three (13%) autologous patients developed severe hepatic dysfunction. In allogeneic transplants, the most common causes of liver disease were graft-versus-host disease (33%), drug hepatotoxicity (19%) and posttransplant viral hepatitis (15%); in autologous patients, disease recurrence (28%) and sepsis (17%) were the most frequent identifiable cause of abnormal liver function. The aetiology of abnormal liver biochemistry was not determined in 13 instances, but this did not adversely affect patient outcome. Percutaneous liver biopsy or endoscopic cholangiography were only required in three patients. Liver disease contributed to death in two allogeneic patients with multiple causes for liver dysfunction, and in one patient with refractory severe hepatic graft-versus-host disease. It was concluded that hepatic dysfunction is common after BMT, the cause of which can be determined in many cases with simple non-invasive tests used in conjunction with the clinical setting. Specific treatment, where necessary, is then able to be commenced in a majority of patients without the need for invasive investigation.

Iron deficiency. Current trends and fads.

Anaemia due to iron deficiency remains the commonest form of anaemia world-wide, predominantly due to blood loss, either associated with infestations such as hook worm or menstrual blood loss, or malnutrition. In Australia, iron deficiency anaemia is the commonest form of anaemia and is seen in pregnant and breastfeeding females where the iron balance is often in a negative state. Fads and fallacies abound, particularly in this group. Despite extensive knowledge of iron metabolism, diagnosis of iron deficiency often remains a difficult problem. The use of diagnostic tests available is discussed in this article.

Cross-matched platelets in bone marrow transplantation.

Antibodies to HLA-antigens remain a problem in multiply-transfused patients. Over a 2 yr period 44 bone marrow transplant recipients were screened at weekly intervals for the presence of HLA-antibodies using a solid phase red cell adherence technique. An adaptation of this method was used to provide cross-matched random donor platelets (XMRDP) when screening proved positive. Twelve of the 44 patients were antibody positive, 6 prior to transplantation and 6 following the transplant. Those 4 patients who developed an antibody following the transplant had a significant increase in platelet increments following the change from random donor platelets (RDP) to XMRDP even though only one patient was refractory to platelets at the time the antibody was first detected. No significant bleeding occurred during the study period. The use of routine platelet antibody screening followed by platelet cross-matching allows excellent support of thrombocytopenic patients without requiring HLA-typed blood donors and avoiding clinical platelet refractoriness.

The MHC influences acute graft versus host disease in MHC matched adults undergoing allogeneic bone marrow transplantation.

To determine whether the MHC plays an antigen non-specific role in the development of acute GVHD, the prevalence of acute GVHD in relation to MHC genotype was examined in 51 adult patients undergoing allogeneic BM grafting. The majority of patients received grafts from HLA-identical siblings. HLA-B7 haplotypes were associated with a decreased risk of acute GVHD (2 of 15, p = 0.005) whereas HLA-B44 haplotypes were associated with a higher risk of acute GVHD (11 of 14, p = 0.02). As these alleles have been reported previously as having opposite effects in relation to inflammatory mediators, these findings may have important implications with respect to donor selection and patient management.

Urate metabolism during bone marrow transplantation.

We studied urate metabolism in 36 patients undergoing both allogeneic and autologous bone marrow transplantation (BMT) without allopurinol. Most patients had low tumour burdens. Three different preparative regimens were used; busulphan/cyclophosphamide (BUCY); BCNU, etoposide, ara-C and melphalan (BEAM) and cyclophosphamide/total body irradiation (CY/TBI). Urate excretion rose during each of the regimens but the pattern of excretion varied with each regimen. Urate excretion remained elevated 72 h after completion of BEAM and BUCY, possibly reflecting the prolonged action of some of the agents used, e.g. melphalan, busulphan and etoposide. Urinary urate concentrations were unchanged compared with pre-chemotherapy levels reflecting the adequacy of the hydration protocol. No significant rise in creatinine was seen and no cases of tumour lysis syndrome occurred. Serum uric acid levels were a poor reflection of urate production, falling in most patients, and are an unreliable end-point for decisions regarding prophylaxis. BMT can be safely undertaken in patients with low tumour loads without allopurinol if an adequate urine volume is maintained. In this series, high levels of urate excretion often persisted for 72 h after the completion of conditioning and adequate hydration should be ensured during this period.

Prompt haemopoietic reconstitution following hyperthermia purged autologous marrow and peripheral blood stem cell transplantation in acute myeloid leukaemia.

We report a case of acute myeloid leukaemia in a 35-year-old woman where marrow and chemotherapy-mobilized peripheral blood stem cells (PBSC) were obtained in first complete remission and heat treated at 42 degrees C for 1 h to minimize the likelihood of leukaemic relapse. Transplantation of marrow and PBSC was undertaken following busulphan/cyclophosphamide conditioning 9 months after diagnosis in CR1. Hyperthermic purging did not impair the rate of engraftment and the patient was independent of blood product support by day 21. Studies on this patient's committed normal granulocyte-macrophage progenitor cells (CFU-GM) on samples from marrow and peripheral blood following treatment at 42 degrees C for 1 h, showed minimal and acceptable loss of activity comparable with the loss seen in other marrow progenitor activity treated in a similar fashion in our laboratory. We conclude that hyperthermia-purged PBSC can be used to hasten recovery in autologous haemopoietic progenitor transplantation without compromising rate of engraftment. This is part of an ongoing pilot study to evaluate the role of hyperthermic purging to reduce the risk of leukaemic relapse.

Peanut agglutinin (lectin from Arachis hypogaea) binding to hemopoietic cells: an immunophenotypic study using a biotin streptavidin technique.

The lectin peanut agglutinin (PNA) was used to study the surface carbohydrate expression of galactose beta 1, 3, N-acetylgalactosamine by normal and malignant hemopoietic cells. Immunostaining was performed using biotinylated PNA and a streptavidin-alkaline phosphatase staining technique on 78 patients. The study was undertaken to enlarge on previous reports of lectin binding to cells of hemopoietic origin and to establish the potential role of biotinylated PNA as a component of an immunotoxin for in vitro purging of bone marrow in patients with multiple myeloma. In normals only monocytes, macrophages, centroblasts and plasma cells showed reactivity. Of the hematological malignancies, all cases of multiple myeloma were positive and non-Hodgkin's lymphoma cases with a large cell component had positive centroblasts. Two of 5 cases of acute myelomonocytic leukemia, one case of chronic myelomonocytic leukemia and one case of pleomorphic T cell non-Hodgkin's lymphoma showed PNA positive neoplastic cells. The reactivity of biotinylated PNA with centroblasts and plasma cells suggests that it may be of potential value when linked to a streptavidin-ricin conjugate in the in vitro purging of bone marrow of patients with multiple myeloma prior to autologous bone marrow transplantation.