Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children's Oncology Group.

Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3-25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day -1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day -1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.

Interleukin-1 production following T-cell-depleted and unmodified marrow grafts.

Interleukin-1 (IL-1) production by endotoxin-stimulated cultured monocytes from 31 participants in grafts of marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep red blood cells (SBA-E-) and 12 recipients of unfractionated bone marrow were studied and compared with normal controls. Patients were studied prior to marrow transplant (BMT) and at 1 month, 2 to 4 months, and 5 to 6 months post-transplant. Deficiencies in IL-1 production (<50 units) were detected in both transplant groups prior to and at 1 month post-BMT. From 2 to 4 months post-transplant, 67% of the recipients of unmodified marrow and 45% of the recipients of SBA-E- marrow grafts produced a normal level of IL-1. By 5 to 6 months post-transplant and thereafter, the proportions of patients exhibiting deficiencies in IL-1 production in each group were equally low. We also evaluated the impact of early deficiencies of IL-1 on engraftment, hematopoietic function, and immunological reconstitution. Deficiencies in IL-1 production persisting to 2 to 4 months post-BMT did not significantly affect the degree of chimerism or the time to recovery of neutrophil counts to 500/mu l in recipients of either unmodified or T-cell-depleted marrow. Platelet recovery during the first 50 days post-transplant was significantly slower in the IL-1-deficient group, but thereafter rebounded, so that by 4 months post-BMT patients with initial deficiencies in IL-1 production achieved levels comparable with those attained by patients with normal production of IL-1. When we looked at the lymphocyte response to phytohemagglutinin (PHA), there was no difference detected among patients with or without IL-1 deficiency receiving unmodified transplants. In contrast, recipients of T-cell-depleted grafts exhibiting a prolonged deficiency of IL-1 experienced a slower rate of recovery of PHA responses. Our results suggest that IL-1 may play an important role in the early expansion of megakaryocytic precursors following an allogeneic marrow transplant and may facilitate the functional development of allogeneic lymphoid progenitors following a T-cell-depleted marrow graft.

Continuous fetal heart rate monitoring during bone marrow harvesting in pregnancy.

To date, our computer-assisted search failed to report any case involving a gravid patient donating her bone marrow for harvesting. It is known that bone marrow harvesting causes a significant decrease in the donor's blood volume and therefore this can be potentially detrimental to both the mother and the fetus. We report the first case of the gravid donor in which fetal heart rate (FHR) during bone marrow harvesting has been studied. Decreased beat to beat variability and disappearance of accelerations were noted. The FHR returned to normal shortly after the procedure was terminated.

Transformation of congenital neutropenia into monosomy 7 and acute nonlymphoblastic leukemia in a child treated with granulocyte colony-stimulating factor.

A cytogenetically normal infant with Kostmann syndrome (severe congenital granulocytopenia) was treated with granulocyte colony-stimulating factor, which resulted in a rapid improvement in his neutrophil count and a resolution of recurrent infections. After 11 months of therapy, splenomegaly developed, with thrombocytopenia, anemia, circulating nucleated erythrocytes, and acquired monosomy 7, which evolved during a period of 7 months into acute nonlymphoblastic leukemia. The use of granulocyte colony-stimulating factor in patients with congenital marrow failure disorders may induce or hasten the onset of a malignant transformation.

Primary ocular recurrence of leukemia following bone marrow transplant.

A patient with acute lymphoblastic leukemia (ALL) who had undergone an allogeneic bone marrow transplant that included high-dose chemotherapy and total body radiation without eye shielding, sustained an isolated relapse of her disease in the iris. A review of ocular leukemic disease is discussed.

Intraperitoneal production of erythropoietin with continuous ambulatory peritoneal dialysis.

Higher hematocrit and serum erythropoietin (EPO) levels have previously been shown in end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis (CAPD) compared with hemodialysis. We investigated whether EPO was produced intraperitoneally in CAPD patients. EPO concentration was 3.5 +/- 0.3 mU/ml by radioimmunoassay in 26 samples of peritoneal dialysis effluent obtained from 15 CAPD patients. EPO was not detectable in the fresh unused dialysate. No correlation was observed between EPO levels in the serum and dialysis effluent. Peritoneal macrophages were isolated from the dialysis effluent of 9 CAPD patients after an overnight dwell. The culture supernatant obtained after 24 h of in vitro culture of a million cells yielded EPO of 3.5 +/- 0.3 mU/ml. Our study demonstrated that peritoneal macrophages from CAPD patients produce EPO on in vitro stimulation, and EPO is present in the dialysis effluent of CAPD patients.

Allogenic bone marrow transplantation in severe Gaucher disease.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.

High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates.

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.

Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation.

A 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure was treated with high-dose cyclophosphamide, busulfan, and antithymocyte globulin followed by an infusion of human leukocyte antigen-identical, mixed lymphocyte culture (MLC) non-reactive sibling bone marrow. He developed cardiac arrhythmias and intractable hypotension and died on day 23 posttransplant. Autopsy findings were consistent with cyclophosphamide-induced pancarditis. The bone marrow showed signs of early engraftment. Allogeneic bone marrow transplantation may be a treatment alternative for Shwachman-Diamond syndrome with severe bone marrow failure. However, fatal posttransplant pancarditis due to doses of cyclophosphamide not usually associated with cardiac death may be an unanticipated problem. Further trials of bone marrow transplantation as therapy for this syndrome may be warranted, perhaps using lower doses of cyclophosphamide or substituting for it other immunosuppressive and myelosuppressive agents.

Correlation between interleukin-1 production and engraftment of transplanted bone marrow stem cells in patients with lethal immunodeficiencies.

Interleukin-1 (IL-1) production by endotoxin-stimulated, cultured monocytes from 19 patients with lethal congenital immune disorders were studied and compared with normal controls. Lipopolysaccharide (LPS) stimulated IL-1 production was normal in three of three patients with Wiskott Aldrich syndrome (WAS), two of three combined immunodeficiency with T-cell predominance (CIDTP) and nine of 13 with severe combined immunodeficiency (SCID). Monocytes deficient in IL-1 production could be restored to normal production after incubation with indomethacin in three of five deficient patients. Monocytes from the other two patients could not be induced to generate IL-1, suggesting either an intrinsic deficiency or an alternate inhibitory mechanism as the basis for the IL-1 deficiency observed. In patients with SCID who were transplanted with HLA-haplotype disparate, T-cell depleted marrow without preparative chemotherapy, deficiency of monocyte IL-1 production was correlated with graft failure. Immune reconstitution was achieved in IL-1 deficient patients only when donor monocytes were also engrafted. We hypothesize that deficiencies of IL-1 production may contribute to the heterogeneous expression of combined immunodeficiencies, and may also restrict the engraftment and functional development of allogeneic lymphoid progenitors from a T-cell depleted marrow graft.

Long survival in Philadelphia-chromosome-positive acute leukemia.

A case of Philadelphia (Ph)-chromosome-positive acute leukemia (AL) is presented who went into remission with disappearance of the Ph1 chromosome and later on developed the chronic phase of chronic granulocytic leukemia (CGL) with reappearance of the Ph1 chromosome. The patient is alive 6+ years following the diagnosis. The entity of Ph1-positive AL is discussed. It is suggested that the patients with Ph1-positive AL who develop CGL have a better prognosis than previously described.