Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Tyrosine kinase inhibitors represent today’s treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

BACKGROUND/AIMS:The significance of interferon antibodies with respect to response to treatment in patients with chronic hepatitis C treated with interferon-alpha (INF-alpha) remains a matter of debate. The influence of ribavirin on IFN-antibody formation in combination therapy with IFN-alpha has not yet been studied. Therefore we evaluated the relationship between IFN-antibodies and response to ribavirin/IFN-alpha combination therapy and IFN-alpha monotherapy.METHODS:We studied 169 patients with chronic hepatitis C who were treated either with IFN alpha 2a (6 MU, thrice weekly) alone or in combination with ribavirin (14 mg/kg per day) for twelve weeks. Thereafter, patients who achieved a virological response (HCV-RNA-negative) were treated with 3 MU IFN-alpha thrice weekly for another 40 weeks. IFN antibodies were analyzed and quantified by a double-antigen sandwich enzyme immunoassay (EIA). In 86 patients two neutralization assays--an antiviral neutralization assay as well as an antiproliferative neutralization assay--were performed in addition. The relationship of the development of IFN-antibodies with the virologically defined response to treatment was analyzed.RESULTS:Ribavirin did neither influence the prevalence nor the level of IFN-antibodies. The frequencies of IFN-antibody formation did not differ in the response groups. However, patients with breakthrough showed significantly higher IFN-antibody titers as compared to responder at end of treatment (median 1,336 BU/ml vs. 148 BU/ml; p = 0.018). Among the breakthrough patients those with IFN-antibodies showed the reappearance of HCV-RNA during therapy significantly earlier (median week 24) than those without IFN-antibodies (median week 32; p = 0.03).CONCLUSION:The addition of ribavirin to IFN-alpha does not influence the formation of IFN-antibodies. The development of high-titer IFN-antibodies during IFN-alpha or ribavirin/IFN-alpha therapy of patients with chronic hepatitis C may account for the early occurrence of breakthrough in some patients, while other mechanisms seem to be responsible for this phenomenon in the majority of the afflicted patients.

Antibodies against interferon-alpha (IFN-alpha) may occur as natural or: spontaneous autoantibodies. More frequently, however, they will develop within weeks to months of initiation of IFN-alpha treatment and will disappear later on if IFN-alpha is continued for a long time. Frequencies of IFN-alpha binding antibodies as high as 60%; have been documented. The distinction of neutralizing anti-IFN-alpha antibodies, which depends on the assay format used, is rarely helpful. The clinical impact of spontaneous IFN-alpha antibodies is unknown. Treatment-induced IFN antibodies, however, may limit IFN efficacy in some patients, Antibody-mediated enhancement of IFN activity has rarely been documented. Rational IFN-alpha antibody monitoring and adjusted treatment strategies aid in optimizing the therapeutic benefit and cutting the costs of long-term IFN-alpha treatment.

Although several virus- and host-related predictive factors for the response to interferon alfa (IFN-alpha) have been defined in patients with chronic hepatitis C, no pretreatment parameter can definitely predict the response to antiviral treatment. Assessment of the initial response by quantification of serum hepatitis C virus RNA before and 4 weeks after initiation of therapy may be a clinically applicable and reliable parameter to predict long-term response. Therefore, the aims of the present study were to test the predictive value of a decline in HCV RNA of at least 3 log in the first 4 weeks of treatment (deltaHCV RNA) in patients treated with 3 x 10(6) units of recombinant IFN-alpha2a (rIFN-alpha2a) three times per week subcutaneously and to compare deltaHCV RNA with other established predictive factors, such as HCV genotype and pretreatment viremia. Serum HCV RNA was measured by a validated quantitative reverse transcription-polymerase chain reaction (RT-PCR). Geno/subtyping of HCV was performed by direct sequencing of the nonstructural (NS) 5B region of PCR-amplified isolates and subsequent phylogenetic analysis. Stable HCV RNA levels (deltaHCV RNA < or = 1 log) within the first 4 weeks of IFN-alpha treatment were present in 42 of 70 patients. A decline in HCV RNA levels between 1 to 3 log and more than 3 log was observed in 9 (13%) and 19 patients (27%), respectively. In 21 of 70 patients (30%), HCV RNA was not detectable at the end of 12 months' treatment. Three of 26 patients (11%) with a pretreatment viremia of < or = 10(6) copies/mL (all HCV subtype 3a) and 6 of 44 patients (14%) with a pretreatment viremia of > 10(6) copies/mL (HCV subtypes 1b, 2a, 2c, 3a [two patients], and 4) achieved a virological sustained response to interferon-alpha2a treatment. All patients with a virological sustained response had an initial deltaHCV RNA of more than 3 log. In a stepwise discriminant-function analysis, the initial deltaHCV RNA was confirmed as the strongest predictor of virological sustained response (P < .0001). In conclusion, the data of the present study suggest that IFN-alpha treatment can be terminated after 4 weeks in patients with a decrease in HCV RNA levels of less than 3 log, when apparent HCV eradication is considered the therapeutic target. The predictive value of deltaHCV RNA clearly exceeds the significance of HCV genotype and pretreatment viremia as predictors of successful IFN-alpha treatment.

Background/Aims: A causative role of hepatitis C virus infection (HCV) has been discussed in the pathogenesis of mixed cryoglobulinaemia and in B-cell non-Hodgkin's lymphoma, No data are available concerning the newly discovered hepatitis G virus (HGV) and extrahepatic manifestations such as haematological malignancies, But, HCV and HGV most probably belong to the same family of Flavivirus, Consequently, we looked for the prevalence of HCV, HGV and cryoglobulins in patients with B-cell non-Hodgkin's lymphoma,Methods: Serum samples from 69 patients with non-Hodgkin's lymphoma were studied, Diagnosis of non-Hodgkin's lymphoma was established according to the Kiel classification, Active HCV-and HGV infections were investigated using polymerase chain reaction for detection of viral RNA, Cryoglobulins were detected from serum and monoclonal immunoglobulin components were analysed with immunofixation electrophoresis, In addition, we assessed the clinical course of HCV-and HGV-infected patients under chemotherapy,Results: Three of 69 (4.3%) patients with B-cell non-Hodgkin's lymphoma were HCV-infected and nine non-Hodgkin's lymphoma patients (13.0%) were positive for hepatitis G virus RNA, All HGV infected patients were suffering from low-grade non-Hodgkin's lymphoma, No HGV-infected patient was co-infected by HCV and neither HCV-nor HGV-infected patients showed clinical signs of chronic liver disease before, during or after chemotherapy. Serum samples from all patients were devoid of cryoglobulins,Conclusions: HCV seems to have no significance for the pathogenesis of non-Hodgkin's lymphoma in Germany The increased prevalence of hepatitis G (16.3%) in patients with low-grade non-Hodgkin's lymphoma could suggest a pathological consequence of HGV infection outside of the liver, Evidence of clinically relevant hepatic disease in HGV infected patients was not obtained, Further, chemotherapy does not seem to affect the subsequent clinical course of HGV infection.

Among 13 patients with pemphigus or bullous pemphigoid, high titers of anti-interferon-alpha (IFN-alpha) antibodies were present in all serum samples of one patient suffering from pemphigus foliaceus. This patient was characterized by a relatively benign course of the disease. The IFN antibodies were of oligoclonal or polyclonal origin, predominantly of the IgG subtype, and displayed a broad spectrum of specificity including various natural and recombinant IFN-alpha subtypes as well as recombinant IFN-omega 1. In vitro, these antibodies neutralized both the antiviral and antiproliferative activities of the respective IFN types. Recognition of the patient's endogenous IFN-alpha demonstrated their autoantibody nature. The IFN antibodies were present at diagnosis and resistant to continued immunosuppressive treatment. Despite clinical remission, the IFN antibodies persisted, suggesting that they were not pathogenically related to the skin manifestations of the pemphigus. There were no sings of immune complex-mediated organ damage. IFN antibodies constitute a new class of autoantibodies that may occur in conjunction with pemphigus and likely interfere with the endogenous IFN system.

Antibodies to IFN-alpha have been recognized as a novel type of autoantibody developing after allogeneic BMT. Ninety-six patients undergoing BMT for various hematologic disorders were followed for the presence of spontaneous IFN-alpha antibodies until 12 years after transplantation. Seven of them (7.3%) developed IFN-alpha antibodies occurred late after BMT (> or = 15 months), rose to very high titers in some patients, and persisted for years despite combined immunosuppressive treatment. They were oligo- or polyclonal in nature, predominantly IgG with a broad IgG subclass distribution, and neutralized the antiviral and antiproliferative activity of various natural and recombinant IFN-alpha types including the patients' endogenous IFN-alpha in vitro. All antibody-positive recipients suffered from chronic GVHD (n = 5) or chronic viral hepatitis (n = 2), but the only significant association was with prior severe aplastic anemia (3/9, 33%; P = 0.022). There was no discernible HLA association of IFN antibody development. Although the clinical relevance of the IFN-alpha antibodies is uncertain they may interfere with cellular defence mechanisms and immune regulation after BMT.

A-52-year-old patient presented with a 2-year history of multiple myeloma, recurrent episodes of hypercalcemia, and extensive bone involvement. She developed pulmonary infiltrates, initially misdiagnosed as interstitial pneumonia. High-resolution computed tomography and bone scintiscanning indicated pulmonary calcification, which was confirmed by a transbronchial biopsy. Cytostatic treatment of multiple myeloma in combination with repetitive i.v. administration of bis-phosphonates over a period of 6 months led to a significant improvement of clinical symptoms. Regression of pulmonary infiltrates was demonstrated by chest radiograph and computed tomography. There are only a few reports on pulmonary calcification in patients with multiple myeloma; the condition was associated mostly with progressive disease, kidney failure, adult respiratory distress syndrome and bad prognosis. In our patient isolated calcification of the lungs without involvement of other organ systems was successfully treated. These findings suggest that interstitial pulmonary calcinosis in multiple myeloma can be reversed by normalization of serum calcium levels using bisphosphonates combined with cytostatic treatment.

Interferon-α combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-α antibodies (IFN ab) occur regularly during IFN-α treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subeutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg body weight) daily or with 5-methoxypsoralen (1.2 mg/kg body-weight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of β2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

Abstract. We report a case of a patient with systemic mastocytosis who was treated with interferon‐γ. Because of severe diarrhoea, nausea and weight loss due to mast cell infiltration of the gastric mucosa the patient received 150μg d‐1 interferon‐γ subcutan‐eously for 10 months. During therapy, the plasma concentrations of IL‐3, IL‐4 and GM‐CSF, which seem to play a role in mast cell growth and differentiation were monitored. The patient had good symptomatic relief and the initially very high eosinophil counts in the pripheral blood showed a partial reduction. However, after 4 months of therapy the patient relapsed. In serum obtained after the relapse, but not in stored serum from the beginning of the therapy, neutralizing antibodies against interferon‐γ were found. Therefore an initial response to the therapy and a secondary failure mediated by treatment‐induced antibodies against recombinant interferon‐γ might be suggested. Interferon‐γ may be a well tolerated therapeutic option in systemic mastocytosis. However, treatment‐induced neutralizing antibodies against recombinant interferon‐γ should be considered if secondary treatment failure occurs.

In a patient undergoing allogeneic BMT for chronic phase CML, de novo chronic GVHD developed within 80 days after transplantation. Eighteen months post-BMT, high serum levels of neutralizing interferon-alpha (IFN-alpha) antibodies were detected, which persisted despite continuous immunosuppressive treatment. The antibodies were of oligoclonal or polyclonal origin, predominantly of the IgG1 type, and reacted broadly with various human IFN-alpha types, including the patients endogenous IFN-alpha, but failed to recognize natural IFN-beta and recombinant IFN-gamma. Pathogenesis and clinical impact of the IFN-alpha antibodies are unknown. Antibodies of cytokines are a novel class of autoantibodies that may develop after allogeneic BMT and interfere with cytokine homeostasis and immune regulation.

The pathophysiological mechanisms involved in the development of a spontaneous systemic capillary leak syndrome (CLS) are unknown. In contrast, CLS is a well-known side effect of high-dose interleukin-2 (IL-2) therapy in solid tumors. We report on a patient who developed CLS with high serum levels of endogenous IL-2 under immunosuppressive therapy for chronic graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation (BMT). Generalized edema persisted for 10 weeks. The condition resolved after antibiotic therapy of a septic shock withβ hemolyzing streptococci group A. Thus, a latent infection may alter cytokine homeostasis and may cause CLS in BMT patients.

Background: In advanced renal cell cancer (RCC) interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) have shown modest clinical activity as single agents, substantial toxicity being associated with IL-2. For development of a therapeutically active but less toxic regimen a phase II trial of subcutaneous recombinant IL-2 (rIL-2) and low-dose recombinant IFN-alpha 2a (rIFN-alpha 2a) was initiated in unselected patients with advanced RCC.Patients and Methods: From 26 patients stratified to 2 prognostic subsets differing in ECOG status and risk factors, 16 patients were eligible. One treatment cycle consisted of 18x10(6) IU rIL-2 and 3x10(6) IU rIFN-alpha 2a on days 1-3 of weeks 1-3 with the 4th week off therapy. Toxicity led to dose reductions of rIL-2 (day 1: 18x10(6) IU, day 2: 12x10(6) IU, day 3: 6x10(6) IU). Circulating cytokines were determined by sandwich enzyme immunoassays during the first 3 days of treatment.Results: 63 treatment cycles were given to 16 patients. The toxicity of the reduced regimen allowed an outpatient therapy (44 treatment cycles). No tumor remission occurred. Stable disease after 2 treatment cycles was observed in 44% of all patients and in 70% of low-risk patients. Median survival was 496 days for low-risk patients and 57 days for high-risk patients. Immunological monitoring revealed a treatment-related enhancement of interleukin-6 serum levels (days 1-3) and of tumor necrosis factor-alpha and interferon-gamma serum levels (day 1).Conclusion: No effect on tumor remission was observed by this treatment regimen of subcutaneous rIL-2 combined with low-dose rIFN-alpha 2a in unselected patients with advanced RCC. Toxicity necessitated a dose reduction of rIL-2 for outpatient therapy.