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Two important syndromes of hemophagocytic lymphohistiocytosis (HLH) have to be considered in infants and young children with recurrent fever, organomegaly and cytopenias. Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetically heterogeneous autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs and is currently curable only by bone marrow transplantation (BMT). Secondary HLH most commonly results from viral infections and some patients may be cured by treating the causative organism, others will need chemotherapy and immunosuppression. Since infections can also trigger disease episodes in FHLH, making the correct diagnosis can prove difficult. The published experience of BMT in HLH is reviewed. Taken together, cure of the majority of patients with HLH by matched related BMT, unrelated or haploidentical BMT is possible. Incomplete resolution of disease activity does not necessarily impede a successful outcome. Central nervous system involvement will eventually develop in many HLH patients and may cause considerable morbidity. Appropriate early treatment and a timely BMT will hopefully decrease mortality rates and improve neurodevelopmental outcome in this disease.

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, alpha-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid-reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) (n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) (n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% (p <. 02) and after TBI/VP/CY by 39% (p <.02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r =.80, p <.001; TBI/VP/CY: r =.84, p <.001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy (p <.02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = -.59, p <.001) and PUFA (in the radiochemotherapy group: r = -.67, p <.001). Whereas PUFA declined (p <.02 in both groups), TBARS increased (p <. 05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p <.02; ubiquinone-10/total coenzyme-Q10 ratio: p <.05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.

Haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a fivefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in five, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24.5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.

A five-agent GVHD prophylaxis programme consisting of cyclosporin A, methotrexate, anti-thymocyte-globulin, pentaglobin and metronidazol was given to 48 recipients of unrelated donor marrow with chronic myelogenous leukemia, acute leukemia, myelodysplastic syndromes, and familiar lymphocytic hemophagocytosis of an average age of 33.5 (0.6-56) years. GVHD grades II-IV occurred in 18 patients (39%) and grades III-IV in five patients (11%). Chronic GVHD developed in nine patients (23%), three limited and six extensive. Fifteen patients died. Clinical relapse was detected in eight patients. Four patients died as a consequence of the underlying disease and subsequent treatment, 11 patients died of transplant-related causes. After a median follow-up of 19 months, the overall and disease-free survival are 67% and 62%, respectively. Survival by age is as follows: 0-19 years: 12/13 patients; 20-39 years: 14/25 patients; 40-59 years: 7/10 patients. The five-agent GVHD prophylaxis regimen is effective. Matched-unrelated donor transplants can be carried out safely in patients younger than 50 years of age. The results in patients younger than 20 years of age should encourage matched-unrelated donor transplants at earlier stages of the disease.

Infections are a major cause of morbidity and mortality in patients undergoing high-dose therapy and subsequent autologous or allogeneic haemopoietic stem cell transplantation, despite the change from topical to systemic anti-infection prophylaxis and the introduction of growth factors and new antimicrobial drugs. We report our single centre experience with data from 409 patients treated at our unit from its opening in 1990 until May 1997. Three hundred and seventy-eight patients were transplanted for the first time, 12 patients were retransplanted or boosted and 19 patients were readmitted for miscellaneous reasons. 245 patients were allografted and 157 autografted. Antimicrobial prophylaxis was mainly quinolones, fluconazole plus amphotericin-B orally, aciclovir, and TMP/SMX or pentamidine. Three hundred and nineteen (78%) developed fever of significantly longer duration in the allogeneic setting with anti-CMV seropositivity. The most frequent infection was fever of unknown origin (50.6%), followed by septicaemia (12.5%) and pneumonia (11.0%). Pathogens isolated in 24.6% of the infections were mostly gram-positive bacteria (57.9%), followed by non-fermenting rods (11.2%), Aspergillus spp. and Candida spp. (10.3%, each). Cumulative response rate to antimicrobial therapy was 66.9%. Infections were responsible for 62.5% (25/40) of deaths after transplantation. Predominant pathogens were Aspergillus spp. (11), Candida spp. (four), and Pseudomonas spp. (three). None of the patients died from gram-positive bacterial infection. The risk of dying from infection was 11.2% after allografting and 0.8% after autotransplantation. Infections remain a major risk for early death after allogeneic transplantation of haemopoietic stem cells. Infection with gram-negative bacteria can be prevented by quinolone prophylaxis. Predominant pathogens are Aspergillus spp. Candida spp. and nonfermenting rods. Systemic infection with these pathogens is associated with a poor prognosis. Antimycotic prophylaxis and the therapy must be improved.

We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30-45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2-93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan-Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18-58%) and 35% at 5 years (95% CI: 15-55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19-73%) and 34% at 5 years (95% CI: 17-51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P < 0.001). The bcr-abl fusion transcript (p210 vs p190 vs p210/190) did not affect disease-free or overall survival. In our experience, an intensified conditioning regimen seems to improve the results of bone marrow transplantation in patients with Ph+ acute lymphoblastic leukemia. However, the high relapse rate warrants novel approaches to enhance anti-leukemic efficacy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of infancy and young childhood. The clinical presentation includes recurrent unexplained fever with hepatosplenomegaly. Cytopenia, hypofibrinogenemia and/or hypertriglyceridemia and hemophagocytosis in bone marrow, spleen and lymphnode confirm the diagnosis. Hemophagocytosis may not be present at the beginning. In these cases, diagnosis is facilitated by a positive family history, a relapsing course of the disease, the frequent involvement of the central nervous system and positive findings on immunological work-up. Treatment by chemotherapy and immunosuppressants can achieve sustained remissions in most patients and reinduction of remission after relapse is possible. Most children however, eventually die from progressive disease. At present, allogeneic bone marrow transplantation is the only curative therapeutic option. Between August 1992 and May 1997 eleven consecutive patients with HLH received bone marrow from unrelated (n = 7) or matched sibling donors (n = 4). The conditioning regimen consisted of busulfan, VP-16 and cyclophosphamide. Patients engrafted after a median time of 16 days (13-43). Only one patient developed grade III acute GVHD, another patient, grade II acute GVHD. Although regimen-related toxicity was extensive, all patients have survived without signs of HLH after a median follow up of 20 months (8-63). One patient suffers from chronic GVHD, three patients reveal psychomotoric retardation and one patient has severe impairment with spastic tetraparesis, amaurosis and seizures. Our experience shows that HLH can be successfully treated by allogeneic BMT from unrelated donors.

Nontransferrin-bound iron (NTBI) and other parameters of iron status were measured in 40 patients undergoing bone marrow transplantation (BMT) prior to conditioning therapy (between day -10 and -7), at the time of BMT (day 0), and 2 weeks later (day + 14). Serum iron and transferrin saturation values were normal before conditioning therapy. At day 0 serum iron values were high and median transferrin saturation was 98% (changes in the values of both serum iron and transferrin saturation, p < .0001). Transferrin saturation values were still elevated 2 weeks posttransplant (day +14 vs. baseline values, p = .0001). Starting at low NTBI levels pretransplant (median 0.4 micromol/l, range 0-4.2 micromol/l, controls: < or = 0.4 micromol/l), all patients revealed high levels on day 0 (median 4.0 micromol/l, range 1.9-6.9 micromol/l, p < .0001) and 2 weeks posttransplant (median 2.7 micromol/l, range 0-6.2 micromol/l, p < .0001). These observations indicate that the plasma iron pool in patients undergoing BMT increases to a level at which the normal ability to sequestrate iron becomes exhausted and considerable amounts of NTBI appear in serum. This "free" form of iron can mediate the production of reactive oxygen species and may cause organ toxicity in the early posttransplantation period.

The biological properties of IL-6 include the induction of acute phase proteins, stimulation of hematopoietic stem cell growth and thrombopoiesis. Serum levels of IL-6 were closely monitored in 66 patients before and after allogeneic (n = 37), autologous bone marrow transplantation (n = 8) or autologous peripheral blood stem cell transplantation (n = 21). Almost every patient showed elevated IL-6 serum levels during the aplastic phase. Patients then suffered from mucositis, had elevated C-reactive protein (CRP) and usually body temperatures of above 38 degrees C. It was investigated whether IL-6 serum levels, apart from inducing acute phase reactions, correlated with transplant-related complications or leukocyte and thrombocyte engraftment. By statistical analysis, a correlation was found between IL-6 and CRP and between IL-6 and fever. In contrast, no correlation was found between IL-6 and elevated serum bilirubin as a marker for hepatotoxicity. IL-6 showed a weak negative correlation with leukocyte or platelet counts. In contrast, the day of platelet engraftment correlated with the day of peak serum IL-6 value, possibly indicating an influence of IL-6 on platelet engraftment.

Organ toxicity in BMT may in part be due to free radical damage. Therefore the 'Total Radical-trapping Antioxidant Parameter of plasma' (TRAP), individual plasma antioxidants, serum iron and linoleic acid, a main substrate of lipid peroxidation, were monitored before and after BMT, and they were compared with values obtained from healthy controls. Seven patients (3 AML, 3 CML, 1 multiple myeloma) receiving 16 mg/kg busulfan, 30-45 mg VP-16 and 120 mg/kg cyclophosphamide were investigated. TRAP values declined during chemotherapy by about 40% (day -9: 1019 +/- 245 mumol/l, mean +/- s.d.; day 0: 660 +/- 164 mumol/l; P < 0.05). The concentration of uric acid, one of the main antioxidants in plasma, decreased markedly (day -9: 339 +/- 108 mumol/l, day 0: 148 +/- 61 mumol/l; P < 0.05) and paralleled TRAP values. Vitamin E and bilirubin did not change from day -9 to 0 whereas vitamin C increased (day -9: 46 +/- 16 mumol/l, day 0: 89 +/- 44 mumol/l; P < 0.05). Serum iron rapidly increased within the pre-transplantation period, reaching values normally seen only in iron overload (day -9: 11.8 +/- 5.2 mumol/l, day 0: 40.6 +/- 6.5 mumol/l; P < 0.05). Linoleic acid levels were normal at the start and decreased substantially (27.0 +/- 1.6 wt% at day -9; 15.7 +/- 4.9 wt% at day 0; P < 0.05), indicating possible lipid peroxidation during high-dose chemotherapy. In conclusion, complex monitoring of the antioxidant status before and after BMT revealed a breakdown of plasma antioxidant defence and of radical-vulnerable lipids, which was associated with high circulating levels of iron.

We report on a patient suffering from multiple myeloma, for whom allogeneic bone marrow transplantation was planned. Donor workup revealed monoclonal gammopathy of unknown significance. We discuss this finding and stress the importance of performing complete donor examinations.