Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group.

PURPOSE: Interferon alfa has shown significant activity in patients with low-grade malignant non-Hodgkin's lymphoma (NHL). In 1985, we initiated a prospective randomized study in which the potential benefit of interferon alfa given as maintenance treatment was investigated after tumor load reduction was achieved with chemoradiotherapy in patients with advanced low-grade malignant non-Hodgkin's lymphoma. PATIENTS AND METHODS: The study involved 347 patients with stage III or IV disease, 315 satisfying the eligibility criteria. All were treated with a regimen of cyclophosphamide, vincristine, and prednisone (CVP) given every 3 weeks for eight cycles. Thereafter, patients were eligible for iceberg irradiation. Finally, all patients were completely restaged, and responding and stable-disease patients were then randomized, 122 to interferon alfa-2a maintenance, 3 million U three times weekly for 1 year; and 120 to no further treatment. RESULTS: Seventy-nine percent of the patients response to CVP, ie, 45% complete remissions (CR) and 34% partial remissions (PR). In the group of randomized patients, the response rate after CVP plus or minus radiotherapy was 90%. As compared with control patients, patients in the interferon (IFN) maintenance group had a tendency toward a prolonged time to progression (TTP) (median, 132 v 87 weeks; P = .054, adjusted for response to CVP). However, overall survival was similar in both groups. Interferon was well tolerated. The median dose of IFN actually received corresponded to 90% of the planned cumulative dose. The treatment had to be stopped because of toxicity in 16 patients (15% of the patients in whom IFN was started). CONCLUSION: Interferon maintenance treatment in the phase of minimal residual disease of patients with advanced low-grade malignant NHL increased TTP at the borderline of statistical significance, without remarkable toxicity. However, overall survival was not influenced.

Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia.

MLLT10 (previously called AF10) is a moderately common MLL fusion partner predominantly occurring in acute monoblastic leukemia (AML-M5). 10;11 rearrangements require at least three breaks in order to generate an in-frame MLL-MLLT10 fusion as a result of the opposite orientations of both genes on the respective chromosome arms. In this study, we describe a detailed molecular cytogenetic analysis of MLL-MLLT10 positive 10;11 rearrangements in two patients. We observed an as yet unreported chromosomal mechanism with at least four breakpoints, leading to MLL-MLLT10 gene fusion in a 24-year-old male. An inversion of 11q13-q23 with a breakpoint in the MLL gene was followed by an additional break 3' of MLL prior to insertion of the 11q segment into MLLT10. In a second patient, a 37-year-old male with AML-M5b, molecular cytogenetic analysis of an apparent 10;11 reciprocal translocation showed an intrachromosomal inversion of 3'MLLT10followed by a reciprocal translocation between 10p12 and 11q23. Review of the literature showed that all cases were the result of an inversion of either 10p or 11q followed by translocation 10p;11q or insertion of the inverted segment into MLLT10 or MLL.

Karyotypic evidence for the leukemic involvement of the erythroblasts in erythroleukemia.

With the use of a monoclonal anti-glycophorin A antibody and flow cytometric cell sorting, an erythroleukemic bone marrow sample was separated in highly purified erythroblast and myeloblast fractions. Similar karyotypic anomalies were found in both cell populations as in the unseparated bone marrow. This study confirms that acute nonlymphocytic leukemia can originate at the level of a multipotential hemopoietic stem cell.

Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy.

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

Bone marrow cultures and prognosis in primary myelodysplastic syndromes.

Bone marrow cultures and survival time were studied in 39 patients with primary myelodysplastic syndromes. We divided the patients into two groups according to the CFU-GM numbers on day 10: type I with low colony (CFU-GM less than 30) and type II with normal to high colony formation (CFU-GM greater than or equal to 30). The median survival time was shorter for patients with an in vitro growth type II (5 months) than it was for patients with an in vitro growth type I (greater than 36 months). No relations was found between growth types and FAB-type, Bournemouth score or initial karyotype. The initial bone marrow blast percentage correlated well with the in vitro growth number.

Cytogenetic and DNA-flow cytometric studies of separated blasts.

With Percoll density gradients, blasts from peripheral blood and bone marrow could be separated with a significant enrichment, and very often with a high degree of purity. This allowed a study of selected cases, where the separated sample exhibited chromosome abnormalities and/or an abnormal DNA content distribution (as measured by DNA-flow cytometry). The anomalies were shown to be associated with the separated blast fraction.

Epidemiology of invasive fungal infections in bone marrow transplantation. EORTC Invasive Fungal Infections Cooperative Group.

Infections and graft-versus-host disease are the major causes of morbidity and mortality in bone marrow transplantation (BMT). Bacterial infections can nowadays be treated effectively in most instances. The prophylactic and therapeutic armamentarium for viral infections is improving. Fungal infections on the contrary remain a major obstacle for successful outcome in the transplant situation. Invasive fungal infections are mainly caused by Candida and Aspergillus spp. and more seldom by Mucor, Trichosporon and Fusarium. Invasive fungal infections are notoriously difficult to diagnose early and effective non-toxic treatments are still out of reach. Prophylaxis for Candida albicans has become more effective with new triazoles but for species other than albicans and for Aspergillus spp. prophylaxis still remains a major problem. Better treatment modalities, more effective prophylaxis and better knowledge of risk factors are urgently needed. The recently created Invasive Fungal Infections Cooperative Group of the EORTC chaired by Professor F. Meunier runs different surveys to investigate the incidence and nature of invasive fungal infections in cancer patients and in BMT. The group runs different clinical trials on the prophylaxis and treatment of invasive fungal infections.

Practices for cytomegalovirus diagnosis, prophylaxis and treatment in allogeneic bone marrow transplant recipients: a report from the Working Party for Infectious Diseases of the EBMT.

During the past few years major progress has been made in the diagnosis and therapy of CMV infection after allogeneic BMT. The aim of this survey was to investigate the use of diagnostic techniques, use of prophylaxis and the therapeutic strategies among members of the EBMT. Seventy centers from 20 countries responded to the survey. Sixty-seven centers (96%) routinely tried to diagnose CMV from the blood. Fifty-seven centers used standard or rapid isolation techniques. Thirty-seven centers used one of the newly developed techniques, antigenemia detection in leukocytes or PCR together with isolation, while 10 centers used one of these two techniques without standard isolation. Fifty-five centers regularly performed bronchoscopy and bronchoalveolar lavage on the suspicion of CMV pneumonia but only 12 centers required detection of CMV in specimens from the lavage or lungs as the indication to start therapy; 31 centers started therapy on symptoms of pneumonia combined with CMV detection from any site. Prophylaxis was used in 54 centers (84%). The most commonly used regimen was high-dose acyclovir which was used by 42 centers, while seven centers used ganciclovir. The strategy of early therapy was used by 53 centers (76%) and was most frequently based on detection of viremia or CMV antigen in the blood. CMV pneumonia was treated by a combination of ganciclovir and i.v. immunoglobulin by 64 centers, by foscarnet and immunoglobulin in 5 centers and by ganciclovir alone in 5 centers. CMV gastrointestinal disease was treated by antiviral therapy alone in 18 centers and by a combination of antiviral therapy and iv immunoglobulin in 46 centers.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of liver disease and hepatitis infections on allogeneic bone marrow transplantation in Europe: a survey from the European Bone Marrow Transplantation (EBMT) Group--Infectious Diseases Working Party.

This survey investigated allogeneic bone marrow transplantation (BMT) policy in European BMT units by questionnaire, in relation to pre-transplant liver disease. It also assessed diagnostic standards for viral hepatitis infections and their prevalence in BMT candidates. Sixty-three EBMT centers from 22 countries participated in the survey. Median pre-transplant prevalences of HBsAg and anti-HCV positivity were 3.5% (range 0-15%) and 5% (range 0-45%), respectively. Forty-six (73%) centers adopt the policy of cancelling or postponing BMT in patients with ALT abnormalities but in four of these centers, BMT is not delayed when progressive disease or acute leukemia is present. In 17 institutions (27%) BMT was reported to be carried out irrespective of transaminase values. Data on fatal post-BMT liver disease were provided by 45 centers. The overall mortality rate for liver failure was 4.5% (258 of 5788) with no differences between centers performing or not performing BMT in cases of ALT elevation. These results indicate that there is strong concern in most European BMT units about performing BMT in the presence of ALT elevation and prospective studies on its real impact on fatal post-BMT liver disease should be conducted.

Immunisations after bone marrow transplantation: results of a European survey and recommendations from the infectious diseases working party of the European Group for Blood and Marrow Transplantation.

Increased numbers of recipients of BMTs and autologous BMTs are becoming long-term survivors. Existing data support that loss of protective immunity to agents such as tetanus and poliovirus is common in patients who received BMTs and autologous BMTs. Thus, a reimmunisation programme is needed to ensure immunity. A questionnaire concerning immunisation practices was sent to EBMT member centres. The immunisation practices varied extensively in the 59 responding BMT and 48 responding autologous BMT centres. Sixty five per cent of responding centres routinely immunise patients who received allogeneic BMTs whereas 37% were routinely immunising recipients of autologous BMTs. Tetanus toxoid and inactivated poliovirus vaccine were the most frequently used vaccines in both BMT and autologous BMT centres. Immunisations of recipients of both BMTs and autologous BMTs with tetanus toxoid, diphtheria toxoid, inactivated poliovirus vaccine and influenza vaccine are recommended. Other vaccines, and in particular live attenuated vaccines, may be considered on an individual basis.

Febrile neutropenia in allogeneic transplantation.

Infections post allogeneic bone marrow transplant (BMT) are a major problem. Post BMT, three periods with infectious complications are discerned: pre-engraftment and early recovery, mid recovery and late recovery. In the first period mucosal damage and neutropenia are the major host defence deficits. Bacterial infections with Gram-positive and Gram-negative organisms, and fungal infections are seen in this period. In the mid recovery phase graft versus host and its treatment contribute to diminished host defences. Viral infections and fungal infections predominate. In the late recovery phase chronic graft versus host reaction impairs the monocyte macrophage function and CD4 counts are low. In this phase patients are at risk for infections with encapsulated bacteria, fungi, Pneumocystis carinii and Toxoplasma. Strategies for the management of febrile neutropenia are similar to those in 'high risk' neutropenic patients: immediate broad spectrum I.V. antibiotics (3rd or 4th generation cephalosporin+/-aminoglycoside or carbapenem) and early amphothericin B (lipid formulation) if fever persists beyond 5 days despite adequate I.V. antibiotics. Cytomegalovirus (CMV) prophylaxis or better preemptive therapy guided by viraemia is accepted practice. Prevention of infection measures, antimicrobial, antifungal and viral prophylaxis are generally accepted strategies but would differ from center to center. The post transplant infection history will change with different transplant techniques and evolving prophylactic and preemptive treatments.

Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult.

A man without a history of porphyric attacks developed a subacute motor neuropathy at the age of 63. At the same time the first signs of a myeloproliferative disorder were found. He had a homozygous deficiency of erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) with autosomal recessive inheritance. Treatment with parenteral glucose and with hematin had a beneficial influence on the plasma ALA levels. The finding of a motor neuropathy with increased plasma levels of ALA but not of porphobilinogen (PBG) supports the potential role of ALA in the pathogenesis of porphyric neuropathy.

[Sulfasalazine allergy: fever, skin rash, hepatitis and T-lymphocytes]. / Sulfasalazine-allergie: koorts, huidrash, hepatitis en T-lymfocytose.

We describe a case of severe sulfasalazine allergy. Exacerbation of the symptoms occurred after unintentional rechallenge with co-trimoxazole, indicating that the reaction was triggered by the sulphonamide component. The clinical picture consisted of generalised adenopathy, hepatitis, high fever and a maculopapular skin rash. A bone marrow biopsy and skin biopsy both showed noncaseating granulomas. The white blood cell count rose to 90.10(9)/l with 40% atypical lymphocytes (plasmacytoid). They were identified by flow cytometry as activated T lymphocytes.

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP.

The treatment of diffuse large B-cell lymphoma with chemotherapy was retrospectively evaluated in 348 patients who had received at least three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like, ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone)-like or CHVmP-BV (cyclophosphamide, hydroxorubicin, Vm-26, prednisone, vincristine and bleomycin) treatment in Belgium between 1995 and 2000. In our sample, the proportion who received each of the three regimens was 78.4, 16.4, and 5.2%, respectively. Of those prescribed CHOP-like regimens, 15% received <80% average relative dose intensity (ARDI). In 210 patients treated with CHOP-21 (77% of the CHOP-like group), median survival was 7.08 years in those who received >90% of the ARDI, significantly longer than in those who received < or = 90% of the ARDI (p = 0.002). Dose reductions and/or delays, mainly due to hematological toxicities, resulted in a reduction in treatment intensity. These data indicate that patient outcome is improved when the intensity of chemotherapy treatment is optimal.

Pulmonary aspergillosis complicated by osteomyelitis.

We report on a patient with aplastic anaemia and an invasive aspergillosis of the lung with subsequent osteomyelitis of the ribs. Diagnosis was made by puncture of the soft tissues and isolation of Aspergillus fumigatus. Treatment with amphotericin B induced renal function disturbances. It was successfully replaced by AmBisome. Healing occurred with recovery of the immunity of the patient. The literature on Aspergillus osteomyelitis is reviewed.

Clinical trial of low-dose Ara-C in the treatment of acute leukemia and myelodysplasia.

In a multicenter analysis, the effect of low-dose cytosine arabinoside (Ara-C)(10 mg/ m2q 12 h subcutaneously for a minimum of 15 days) has been assessed in 13 patients with acute leukemia (10 myeloid-AML-, 3 lymphocytic-ALL-) and 7 patients with dysmyelopoietic syndromes (DMPS), conditions classified as refractory anemia with an excess of blasts ( RAEB ). Seven patients suffering from acute leukemia and 1 with DMPS in blastic transformation displayed a leukocytosis of more than 10 X 10(9)/1. Three out of 7 DMPS, 1 out of 10 AML achieved a complete remission, 1 out of 3 ALL-patients reached a partial remission twice. Seven patients showed a blast clearing in the bone marrow and peripheral blood, in another 7 instances examination of the bone marrow was not performed after therapy because of early death. The majority of patients were in their late phase of disease and refractory to conventional chemotherapy. Only 5 patients had no pretreatment at first presentation before low-dose Ara-C was initiated. At least for the DMPS-group, this therapeutic approach seems to be of some benefit.

Increased tumor necrosis factor alpha (TNF alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF alpha and IL-6 levels and febrile transfusion reactions.

Increased interleukin 6 (IL-6) levels were found in 8 of 12 platelet concentrates (PCs) after 3 days of storage and in 10 of 12 PCs after 5 and 7 days of storage. Most of the PCs with an increased IL-6 level also showed increased tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) levels. Levels of IL-6 increased by 3 log10 over the base level during storage. Increased levels were found when the PC white cell count exceeded 3 x 10(9) per L. A linear correlation was found among the levels of TNF alpha, IL-1 beta, IL-1 alpha, and IL-6 in the PCs (r > 0.885). Comparison of the TNF alpha, IL-1 beta, and IL-6 levels in samples taken at various storage times indicates that the increased levels are the result of an active synthesis and release of interleukins during storage. In a second part of the study, 45 transfusions of white cell-reduced PCs were studied. Six transfusions were complicated by a febrile reaction. These reactions were related to high levels of IL-6 and TNF alpha in the PCs (p < 0.0001). These cytokines are known as endogenous pyrogens. These findings indicate that transfusion reactions might be due to the intravenous administration of plasma with high cytokine levels and might not always result from an antigen-antibody reaction.

Surface and cytoplasmic immunoglobulin distribution during treatment of a non-excretory myeloma.

A patient with non-excretory myeloma with severe clinical signs, has been assessed for cytoplasmic and surface immunoglobulins on peripheral mononuclear cells and bone marrow cells. A clearcut monoclonal pattern was found. During treatment with melphalan, methotrexate and prednisolone a clinical remission was obtained. The immunological studies were repeated during this remission and were in accordance with the clinical improvement, however the monoclonality persisted and indicated an intracellular dissocitaion of light and heavy chains. The patient died with broncho-pneumonia and marrow failure.