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.

Analgesic infiltration at the site of bone marrow harvest significantly reduces donor morbidity.

Little information has been published concerning the severity of pain experienced by bone marrow donors or the use of local analgesia following bone marrow harvesting procedures. The aims of this study were to assess duration and severity of pain experienced by bone marrow donors and the effectiveness of bupivacaine as a local analgesic agent following bone marrow harvest. During a single blinded randomised study of 24 bone marrow donors, 10 ml of 0.5% bupivacaine was infiltrated either into the right or left posterior iliac crest of the donor immediately following bone marrow harvest. Donors were requested to record the level of pain experienced at the right and left harvest sites on a pain rating score sheet (0-10) at time intervals of 4, 8, 12, 24, 48 and 72 h following harvest. A significant reduction in pain was experienced at the harvest site infiltrated with bupivacaine when compared with the control site during the first 3 days post-harvest. It is recommended that bupivacaine be infiltrated routinely into the harvest sites of all bone marrow donors to reduce the pain experienced in the 3 days following harvest.

The COBE Spectra cell separator is more effective than the Haemonetics MCS-3P cell separator for peripheral blood progenitor cell harvest after mobilization with cyclophosphamide and filgrastim.

BACKGROUND: Peripheral blood is rapidly replacing bone marrow as a source of hematopoietic progenitor cells for autologous transplantation. The advantages of peripheral blood progenitor cell transplantation are enhanced by the ability to collect sufficient progenitor cells to ensure rapid neutrophil and platelet recovery in a single procedure on some cell separators. STUDY DESIGN AND METHODS: A prospective randomized study was undertaken to compare peripheral blood progenitor cell yields from two cell separators (MCS-3P, Haemonetics and Spectra, COBE). Fifteen consecutive patients were mobilized with cyclophosphamide 2 g per m2 (Day 0) and filgrastim 10 micrograms per kg (Days 1-11). Consecutive collections (Day 10, Day 11) were performed with each machine once: patients were randomly assigned to either machine for the initial collection. RESULTS: Collection time was longer on the MCS-3P (p = 0.001), and the volume processed was greater with the Spectra (p < 0.0001). Despite similar nucleated cell yield (p = 0.62), the yield of CD34+ cells (p = 0.001) and colony-forming units-granulocytic-monocytic (p = 0.0001) was significantly higher with the Spectra. The yield of nucleated cells per unit of blood volume processed was higher for the MCS-3P (p = 0.0007), while the CD34+ cell yield (p = 1) and colony-forming units-granulocytic-monocytic yield (p = 1) per unit of blood volume processed were similar for the two machines. The collection of CD34+ cells at levels > 2 x 10(6) per kg (p = 0.063), 5 x 10(6) per kg (p = 0.031), and colony-forming units-granulocytic-monocytic > 1 x 10(5) per kg (p = 0.25) after a single collection was superior for the Spectra. CONCLUSION: The yield of progenitor cells after collection on the Spectra was superior to that achieved with the MCS-3P, because of the larger volume of blood processed per procedure. This would permit more patients to undergo only one collection.

Demonstration of late cardiotoxicity following bone marrow transplantation by assessment of exercise diastolic filling characteristics.

We evaluated the role of rest and exercise left ventricular diastolic filling parameters as a marker of cardiotoxicity in 25 consecutive patients 1 year following BMT. Ten age- and sex-matched subjects served as controls. Patients were evaluated in toto and in three sub-groups according to chemotherapy. Left ventricular ejection fraction (EF), peak filling rate (PFR) and time to peak filling (TTPF) were assessed at rest and at peak exercise. EF and PFR were similar at rest and at peak exercise in patients and controls. TTPF was significantly prolonged at rest in patients compared to controls (200 +/- 65 vs 131 +/- 26 ms, P = 0.003) and at peak exercise was markedly longer in patients (142 +/- 40 vs 54 +/- 19 ms, P < 0.001). Sub-group analysis demonstrated abnormal resting TTPF in those patients who had received either combination anthracycline and CY or anthracycline and melphalan, while those patients who received CY alone had normal resting TTPF. However, exercise TTPF was abnormally prolonged in all patient groups. While all controls demonstrated a normal decrease in TTPF during exercise, four of the 25 patients had a paradoxical increase in TTPF during exercise. Exercise diastolic function may provide evidence of cardiotoxicity in long-term survivors of BMT.

Efficacy of octreotide in controlling refractory diarrhea following bone marrow transplantation.

We report the use of octreotide in 10 patients with severe diarrhea, refractory to loperamide, following bone marrow transplantation (BMT). Five patients had regime-related toxicity (RRT) and 5 were suffering from acute intestinal graft versus host disease (GvHD). Complete responses were observed for all patients with RRT, with optimal response being observed in the patients with dose escalation to 250 micrograms tds. Only partial responses were observed in the patients with intestinal GvHD. Increased doses of systemically administered cyclosporin-A (CSA) were necessary to maintain therapeutic levels for 2 patients. Octreotide is very effective in controlling RRT diarrhea. It is less effective in the control of GvHD-related diarrhea. CSA levels require close monitoring, whether the drug is administered systemically or orally.

Aplastic anaemia in systemic lupus erythematosus: a cellular immune mechanism?

Aplastic anaemia is a rare complication of systemic lupus erythematosus (SLE). The mechanism is unclear but is thought to be related to an autoantibody to bone marrow precursors of haematopoiesis. We report a case of SLE related aplastic anaemia in which therapy with methylprednisolone and high dose cyclophosphamide followed by prednisolone and azathioprine resulted in complete clinical and haematological remission. Bone marrow cultures showed inhibition of erythropoiesis when incubated with acute and remission serum. Myeloid colony growth was not affected by either serum. The serum inhibitor we demonstrated was only active in vitro, and we postulate that the mechanism for marrow aplasia may have been an autoimmune cellular process.

The use of vidarabine in the treatment of human polyomavirus associated acute haemorrhagic cystitis.

The human BK and JC polyomaviruses are known to be reactivated and excreted in the urine following bone marrow transplantation (BMT). A proportion of patients who excrete BK virus following BMT experience a haemorrhagic cystitis (HC), which may persist for many months. We report a case of human polyomavirus-associated HC, in whom treatment with vidarabine was associated with a dramatic response.

Plasma erythropoietin levels and acquired cystic disease of the kidney in patients receiving regular haemodialysis treatment.

Acquired cystic disease of the kidney (ACDK) in patients with end-stage renal failure can be associated with development of polycythaemia. The relationship between plasma erythropoietin levels and ACDK in 17 patients on long-term haemodialysis treatment was studied. There was a significantly higher level of plasma erythropoietin in patients with multiple renal cysts than in those patients with less than five cysts or no cysts. Haemoglobin tended to be higher in the ACDK group, but the difference was not significant. These results indicate that the development of renal cysts results in increased secretion of erythropoietin.

The clinical relevance of plasma viscosity in Hodgkin's disease.

The erythrocyte sedimentation rate has previously been identified as an important prognostic factor in Hodgkin's disease. The plasma viscosity has replaced the ESR measurement in many laboratories, but doubts exist about its clinical relevance. In this study plasma viscosity at presentation/diagnosis was studied in 107 patients with Hodgkin's disease. A multivariate analysis of factors influencing prognosis and relapse-free survival identified plasma viscosity and number of disease sites as being highly significant. The risk of relapse increases initially with a rise in plasma viscosity, but after a value of about 2.0 mPa.s no further increase in risk is observed. When all of the prognostic factors are made available to the proportional hazards model, treatment modality and plasma viscosity are selected as the best set for predicting time to first relapse. This study demonstrates that measurement of plasma viscosity at presentation is an important prognostic factor in Hodgkin's disease, in terms of predicting outcome or risk of relapse.

Histiocytic cytophagic panniculitis.

A 33 year old man developed fever, malaise, jaundice, pancytopenia, coagulation abnormalities, hepatomegaly, pleural effusions and a subcutaneous lump. Biopsies revealed a lobular panniculitis with the presence of cytophagic histiocytes; erythrophagocytosis was also demonstrated in the liver and bone marrow. Despite the use of chemotherapy (CHOP) his clinical condition deteriorated and he died 5 months after presentation. This illness is consistent with the recently described syndrome of histiocytic cytophagic panniculitis.

Antibody-mediated pure neutrophil aplasia, recurrent myasthenia gravis and previous thymoma: case report and literature review.

We describe a case of neutrophil aplasia in a woman with recurrent myasthenia gravis and a past history of thymoma. Bone marrow showed virtually absent granulopoiesis but normal erythropoiesis and megakaryopoiesis. Bone marrow cultures showed no growth of granulocyte/mononuclear cell progenitors (CFU-GM). She was treated with immunosuppression including azathioprine, and her neutrophil count returned to normal. Serum before treatment, and also an IgG fraction thereof, inhibited CFU-GM growth both in autologous 'remission' marrow and in allogeneic marrow. She remains in complete remission 36 months after starting azathioprine. This association is extremely rare, and was formerly associated with a grim prognosis.

In situ hybridization detection of light chain mRNA in routine bone marrow trephines from patients with suspected myeloma.

A method for the detection of immunoglobulin light chain mRNA by situ hybridization has been applied to routine bone marrow trephines, from patients suspected of having multiple myeloma. The principle aim was to define monoclonal populations even in cases lacking a paraprotein or an obvious atypical plasma cell proliferation. The expression of light chain mRNA in plasma cells in routine bone marrow trephines from 14 patients with suspected myeloma was studied. Plasma cells in the marrow ranged from 4% to 99%. Clonal populations based on light chain restriction were delineated in 12 patients, using biotinylated probes to kappa and lambda mRNA and visualized using an alkaline phosphatase/fast red naphthol capture method. Normal tonsil and bone marrow trephines were used as controls. In situ hybridization was found to be a specific, safe and rapid technique. It could be applied to both fixed and fresh tissue. It was found to lack the background staining of interstitial immunoglobulin, particularly in sclerotic cases, which is so often encountered with immunocytochemistry. Additionally, this technique will type plasma cell neoplasms (undetected by routine immunocytochemistry) in post-transcriptional block or non-secretory myeloma.

Zygomycosis in aplastic anaemia: response to a combined regimen of amphotericin B and antilymphocyte globulin.

A 22-yr-old man with aplastic anaemia was treated with high dose methylprednisolone. A month later he developed severe epistaxis which was not controlled by regular platelet transfusions. A balloon catheter inserted into the left nostril caused necrosis of the left ala nasi accompanied by gross facial oedema. He received treatment with horse ALG for aplastic anaemia but developed gross facial oedema and anaesthesia of incisor and canine teeth on the right side. Radiographs initially showed thickening of the maxillary antral mucosa and later erosion of the maxilla over the anaesthetic region. A biopsy specimen of this region contained hyphae of zygomycetes. He was treated with amphotericin B and a second course of antilymphocyte globulin followed by oxymetholone. He has made a satisfactory clinical and haematological recovery.