Interferon-alpha Group Research Articles

Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial

Background There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir–ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19. Method In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion. Results A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups. Conclusions and relevance rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied. Key messages There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.

Pharmacological interventions for acute hepatitis C infection.

Pharmacological interventions for acute hepatitis C infection.

Pharmacological interventions for acute hepatitis C infection: an attempted network meta-analysis.

Pharmacological interventions for acute hepatitis C infection: an attempted network meta-analysis.

Interferon-Alpha With Or Without Rituximab Achieves a High Response Rate and Durable Responses In Relapsed FL: 17 years' Experience In a Single Centre

BackgroundMaintenance interferon-alpha (IFNa) immunotherapy after induction chemotherapy prolongs progression-free survival (PFS) in untreated follicular lymphoma (FL). Little information is available about IFNa use in relapsed FL. ObjectivesTo evaluate the benefit of IFNa as treatment for low-burden FL relapse. MethodsIn this single-centre retrospective study, we analysed all patients with molecular or clinical relapsed low- burden FL who received 3MIU IFNa three times a week alone (16 times) or in combination with 4-weekly rituximab (R) (11 times), without chemotherapy, according to the institution's policy. All responses were evaluated according to the IWG 1999 criteria, except for molecular relapses which are described separately. Results20 patients (13 men, 7 women), treated for a total of 27 times with IFNa were identified, with a median follow-up of 85 months. At diagnosis, 17 patients had advanced III-IV stage and 5 of them a high tumour burden, according to GELA criteria. 5 patients were treated for molecular IGH-BCL2 relapses. The FLIPI score was intermediate or high risk in 37% of patients. The median age of patients at the first IFNa +/- R treatment was 51 years (range: 30-65). Patients had previously received a median of three lines of treatment (range: 1-6) and 59% had received anthracycline-based chemotherapy. In the 22 situations with measurable disease, the overall response rate (OR) was 70%, with 59% complete responses (CR). For patients with only detectable molecular disease (n=5), IFNa was used alone for a median duration of 15 months (range: 12- 21 months), MRD becoming negative in 4 patients. The only factor significantly correlated with maximum response was low FLIPI score calculated at study entry (p=0.02). Median PFS was 56.9 months, (95% CI: 0.8-113). The R-IFNa and IFNa subgroup outcomes did not statistically differ in response or PFS. The FLIPI score calculated at initiation of IFNa treatment was predictive of time to relapse (P=0.014). The overall survival at 5 years was 95 % (95%CI: 91-99): 100% in the IFNa group and 91% (95%CI: 82-100) in the R-IFNa group. Reported toxicity was low. ConclusionInterferon alpha with or without rituximab achieve high response rates in relapsed low burden follicular lymphoma. These results compare favorably with previous reports of the efficacy of R alone, and of R with IFNa in relapse. Further research is required to explore the role of IFNa in the management of FL. Disclosures:Gyan:Roche: Research Funding.

Involvement of dynamic HBeAg quantitation and response during chronic hepatitis B treatment

To observe the changes in quantity of serum HBeAg and the Correlation with response during chronic hepatitis B treatment using interferon-alpha or nucleotside analogue, evaluate the predictive value of dynamic HBeAg quantitation to antiviral response. 53 cases treated with interferon-alpha and 70 cases treated with nucleotide analogue for 48 weeks. Used the Electro chemiluminescence immunoassay (ECLIA) to measure the quantity of the serum HBeAg before treatment and 12 weeks, 24 weeks and 48 weeks after treatment, analysis the correlation of dynamic HBeAg quantitation with antiviral response. After 48 weeks treatment, whether interferon-alpha group or nucleotide analogue group, the complete responser quantity of HBeAg before treatment was no significant correlation compared with non-complete responser (P > 0.05), but at treatment weeks 12 and 24 had correlation with the serum HBeAg level and HBeAg decline degree (P < 0.05), deferent HBeAg titer and HBeAg quantatition decline degree during treatment achieved deferent complete response rate, HBeAg titer lesser than 100 U/ml and HBeAg quantatition decline degree higher than 90% at treatment weeks 24 achieved more complete response rate After 48 weeks treatment. During the treatment CHB with interferon-alpha or nucleotside analogue, the dynamic changes in quantity of serum HBeAg has a relationship with response.

Interferon alpha for chronic hepatitis D

Hepatitis D virus is a small defective RNA virus that requires the presence of hepatitis B virus infection to infect a person. Hepatitis D is a difficult-to-treat infection. Several clinical trials have been published on the efficacy of interferon alpha for hepatitis D virus (HDV) infection. However, there are few randomised trials evaluating the effects of interferon alpha, and it is difficult to judge any benefit of this intervention from the individual trials. To evaluate the beneficial and harmful effects of interferon alpha for patients with chronic hepatitis D. We identified relevant for the review randomised clinical trials by electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until May 2011. We also checked the bibliographic references of identified randomised trials, textbooks, and review articles in order to find randomised trials not identified by the electronic searches. Randomised clinical trials evaluating interferon alpha versus placebo or no intervention for patients with chronic hepatitis D infection. Two authors assessed the trials and extracted data on mortality, virologic, biochemical, and histological response as well as adverse events at end of treatment and six months or more after completing treatment. The analyses were performed using the intention-to-treat principle including all randomised participants irrespective of follow-up. Drop-outs, withdrawals, and non-compliance were considered as treatment failures. Data were analysed with fixed- and random-effects models. Reported results were based on fixed-effect model except in cases where statistical significance varied between the two models. Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high. Five trials compared interferon alpha with no treatment in the control group. One of these trials had two treatment arms with a higher dose and lower dose of interferon alpha and a no-treatment control group. We analysed both treatment regimens as a single group in a primary analysis and as separate groups in the subgroup analysis of different interferon dosages. The sixth trial compared only a higher dose of interferon alpha with a lower dose.Meta-analysis of five trials comparing interferon alpha with no-treatment control group included 169 participants. There were seven drop-outs in the treatment group and nine in the control group. One patient out of 92 (1.1%) died in the interferon alpha group compared with zero out of 77 (0.0%) in the no-intervention control group (risk ratio (RR)) 3.00; 95% confidence interval (CI) 0.14 to 66.5). Interferon alpha led to failure of end of treatment virological response in 62/92 (67.4%) of the patients compared with 71/77 (92.2%) in the untreated controls (RR 0.76, 95% CI 0.66 to 0.87, P = 0.0001 by fixed-effect model and RR 0.71, 95% CI 0.43 to 1.16, P = 0.17 by random-effects model). Failure of normalisation of alanine aminotransferase (ALT) at the end of treatment was seen in 60/92 (65.2%) patients treated with interferon alpha versus 76/77 (98.7%) in the control group (RR 0.69, 95% CI 0.59 to 0.80, P < 0.00001). Sustained virological response was not achieved in 76/92 (82.6%) of patients on interferon compared with 73/77 (94.8%) of controls (RR 0.89, 95% CI 0.80 to 0.98, P = 0.02). Serum alanine aminotransferase was abnormal in 81/92 (88.0%) treated with interferon alpha patients at six months post-treatment follow-up compared with 76/77 (98.7%) in controls (RR 0.92, 95% CI 0.84 to 0.99, P = 0.04). There was no significant histological improvement in 67/92 (72.8%) patients treated with interferon alpha compared with 65/77 (84.4%) in controls (RR 0.86, 95% CI 0.74 to 1.00, P = 0.06).Two trials comparing a higher dose of interferon alpha with the lower dose showed no significant difference in sustained virological response (76.7% compared with 90.0%) (RR 0.85, 95% CI 0.68 to 1.07, P = 0.16). Adverse events such as flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all these trials and the adverse events were related to interferon alpha. These were common and sometimes severe. One patient in the treatment group was reported to have died by suicide towards the end of the study period. Interferon alpha does not seem to cure hepatitis D in most patients. The agent seems effective in suppressing viral and liver disease activity in some patients, but this improvement is not sustained in the majority of patients. We cannot exclude overestimation of benefits and underestimation of harms due to high risk of bias (systematic errors) and high risk play of chance (random errors). Therefore, more randomised trials with large sample sizes and less risk of bias are needed before interferon can be recommended or refuted.

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BackgroundType I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.Methods/Principal FindingsUsing a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNα group for an additional 3.5 years. Significant telomere loss in naïve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8+CD45RA+CD57+ memory T cells and an inverse correlation of alanine aminotransferase levels with naïve CD8+ T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.Conclusions/SignificanceSustained interferon-alpha treatment increased telomere loss in naïve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.

Analysis of PTEN and HIF‐1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon‐α

Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN). Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry. There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.

Chronic Myeloid Leukemia Stem Cells and Their Differentiated Progeny Display Divergent Drug Sensitivities to Imatinib Mesylate and Interferon-Alpha.

Imatinib has largely replaced interferon-alpha (IFN) as front-line therapy in the treatment of chronic myeloid leukemia (CML) because of its favorable toxicity profile and superior initial response rate. However, recent laboratory data demonstrating that CML stem cells may have limited susceptibility to imatinib brings into question the potential durability of these responses. In contrast, responses to IFN often take place over months or years, but extensive long-term clinical data indicate that they are often long lasting. In order to determine if the differences in clinical response kinetics could be explained by the activity of imatinib and IFN against CML stem cells or their differentiated progeny, we examined the effects of each agent on distinct cellular subsets in vitro. CD34+ CML progenitors were isolated from 4 patients with newly diagnosed chronic phase CML and incubated with IFN (1000U/ml) or imatinib (10μM) for 96 hours followed by long-term liquid culture over 1-3 weeks to assay more primitive CML stem cells. The effects of each drug on CML progenitors was determined by calculating the number of CFU-GM positive for BCR-ABL by FISH and comparing these values to the bcr-abl+ CFU-GM formed by untreated control cells. Initially, the CML CFU-GM recovery immediately following 96 hours of drug treatment was 62.7 ± 8% and 9.7 ± 2% from IFN and imatinib-treated groups, respectively. After 3 weeks of long-term culture, CML CFU-GM recovery was 23.4 ± 2.6% following IFN treatment and 57.3 ± 22% after imatinib. Thus, imatinib was significantly more toxic to committed CML progenitors than primitive CML progenitors responsible for the maintenance of long-term liquid cultures (p = 0.04). Conversely, IFN had significantly greater activity against primitive CML progenitors than committed progenitors (p = 0.05). Although IFN has diverse biological properties, the mechanisms responsible for its antileukemic activity are unknown. Treatment of the human CML cell line KT-1 with IFN resulted in increased expression of the myeloid antigens CD33 and myeloperoxidase as well as the inhibition of clonogenic growth demonstrating that IFN induced terminal differentiation. Furthermore, several groups have shown that myeloid growth factors also induce differentiation of CML cells in vitro and clinically enhance the activity of IFN; accordingly, the addition of GM-CSF (200U/ml) augmented the differentiation of KT-1 cells. Moreover, myeloid growth factors were required for differentiation as neutralizing antibodies against GM-CSF and IL-3 inhibited the activity of IFN. The addition of GM-CSF to IFN produced similar effects on clinically derived CD34+ CML cells. Although imatinib is a potent inhibitor of committed CML progenitors, it is relatively ineffective against more primitive CML stem cells. In contrast, IFN appears to act primarily against CML stem cells by inducing terminal differentiation that is dependent on the activity of myeloid growth factors. Imatinib and IFN have divergent effects on CML progenitors at different stages of maturation that may correlate with clinical response kinetics and durability.

Prospective randomized trial of natural interferon-alpha (IFN) versus IFN + cimetidine in advanced renal cell carcinoma with pulmonary metastasis

4676 Background: In the preliminary non-randomized study, combination therapy with natural IFN plus cimetidine showed high response rate in 15 out of 37 patients (41%) for advanced renal cell carcinoma. A prospective randomized multiinstitutional clinical trial to compare the effect of IFN alone to IFN + cimetidine in patients with advanced renal cell carcinoma with pulmonary metastasis was performed. Methods: Patients received IFN (5 megaunits) 5 times a week, or the IFN regimen plus daily oral cimetidine (800 mg). The primary end point was response rate, and time to progression (TTP). The secondary end point was overall survival. Results: Between April 1998 and March 2002, 71 patients from 32 institutions were randomly assigned to the two treatment groups. One patient in each group was found to be ineligible because they did not receive IFN at all. Two patients in IFN alone group stopped the treatment on day 9 and on day 10. Among 36 patients in IFN alone group, one CR, 4 PRs, 16 NCs, and 12 PDs were shown, with a response rate of 15.2%. Of 35 patients in IFN + cimetidine group, two CRs, 8 PRs, 13 NCs, and 11 PDs were observed, with a response rate of 29.4%. The difference was not significant (P=0.34). TTP ranged from 9 to 2307 days (median 179 days) in the IFN alone group, and from 31 to 3030 days (median 178 days) in IFN plus cimetidine group (p=0.86). The overall survival between the two groups was not significantly different either. The responses in pulmonary site were 1 CR, 3 PRs, 20 NCs, and 9 PDs in the IFN alone group, and 2 CRs, 7 PRs, 17 NCs, and 7 PDs in the combination therapy group (P=0.13). Conclusions: The combined treatment with IFN + cimetidine for advanced renal cell carcinoma could not have shown significant improvement in response rates or survival compared to IFN alone therapy. No significant financial relationships to disclose.

Prospective randomized trial of natural interferon-alpha (IFN) versus IFN + cimetidine in advanced renal cell carcinoma with pulmonary metastasis

4676 Background: In the preliminary non-randomized study, combination therapy with natural IFN plus cimetidine showed high response rate in 15 out of 37 patients (41%) for advanced renal cell carcinoma. A prospective randomized multiinstitutional clinical trial to compare the effect of IFN alone to IFN + cimetidine in patients with advanced renal cell carcinoma with pulmonary metastasis was performed. Methods: Patients received IFN (5 megaunits) 5 times a week, or the IFN regimen plus daily oral cimetidine (800 mg). The primary end point was response rate, and time to progression (TTP). The secondary end point was overall survival. Results: Between April 1998 and March 2002, 71 patients from 32 institutions were randomly assigned to the two treatment groups. One patient in each group was found to be ineligible because they did not receive IFN at all. Two patients in IFN alone group stopped the treatment on day 9 and on day 10. Among 36 patients in IFN alone group, one CR, 4 PRs, 16 NCs, and 12 PDs were shown, with a response rate of 15.2%. Of 35 patients in IFN + cimetidine group, two CRs, 8 PRs, 13 NCs, and 11 PDs were observed, with a response rate of 29.4%. The difference was not significant (P=0.34). TTP ranged from 9 to 2307 days (median 179 days) in the IFN alone group, and from 31 to 3030 days (median 178 days) in IFN plus cimetidine group (p=0.86). The overall survival between the two groups was not significantly different either. The responses in pulmonary site were 1 CR, 3 PRs, 20 NCs, and 9 PDs in the IFN alone group, and 2 CRs, 7 PRs, 17 NCs, and 7 PDs in the combination therapy group (P=0.13). Conclusions: The combined treatment with IFN + cimetidine for advanced renal cell carcinoma could not have shown significant improvement in response rates or survival compared to IFN alone therapy. No significant financial relationships to disclose.

Cotreatment with interferon-alpha and -gamma reduces liver fibrosis in a rat model.

Background/Aims: Interferon-alpha is used widely to treat viral hepatitis. Interferon-gamma modulates a system attacking infected cells and also has an anti-fibrotic effect. A treatment with interferon-alpha and -gamma has undergone trials in eliminating hepatitis C virus. We investigated effects of cotreatment in a liver fibrosis model to explore anti-fibrotic effects. Methods: Rats were assigned to groups including normal controls (NC), CCl(4) controls, rat interferon-alpha treatment, rat interferon-gamma treatment, and cotreatment. All groups except normal controls received CCl(4) orally for 8 weeks. At the beginning of the third week of exposure, 6 weeks of treatment were initiated according to interferon group. Digitally analyzed immunohistochemistry, biochemical assays, and Northern analysis were performed. Results: Pixels (x10(5)) per field containing immunoreactive type III collagen (fibrotic density) in CCl(4) controls, interferon-alpha, interferon-gamma, and cotreatment groups respectively were [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. Liver hydroxyproline content correlated with fibrotic density, and was significantly low in the cotreatment group. Plasma hyaluronate and transaminase were significantly low in cotreatment and interferon-alpha groups. Northern blotting showed lowest mRNA expression for type I collagen, desmin, transforming growth factor (TGF)-beta1, and matrix metalloproteinase-2 mRNA in the cotreatment group; tissue inhibitor of metalloproteinase-1 and -2 mRNAs were significantly low in the interferon-gamma group. Conclusions: Cotreatment can suppress collagen and transforming growth factor-beta1 and has an overall anti-fibrotic effect without exacerbating inflammation.

High‐dose interferon α‐2a with ribavirin and amantadine in naïve chronic hepatitis C patients — results of a randomized, prospective, pilot study

Hepatitis C viral kinetic studies have demonstrated the increased anti-viral effect of higher than standard dosages of interferon and of daily treatment schedules. To compare, in a prospective, randomized, controlled trial, the efficacy and safety of high-dose interferon-alpha therapy vs. standard-dosage interferon-alpha therapy, in a triple therapy combination with ribavirin and amantadine. Previously untreated patients with chronic hepatitis C were randomized to the standard interferon-alpha group (n = 15), receiving thrice weekly 6 MU interferon-alpha for 12 weeks, followed by 3 MU interferon-alpha for 36 weeks, or the high-dose interferon-alpha group (n = 15), receiving daily 9 MU interferon-alpha for 4 weeks, followed by 6 MU (weeks 5-8), 3 MU (weeks 9-12) and 1.5 MU (weeks 13-48) interferon-alpha. All patients were given ribavirin (1000-1200 mg) and amantadine (200 mg) daily for 48 weeks. At the end of treatment and after the 24-week follow-up period, serum hepatitis C virus RNA was undetectable in eight (53%) and six (40%) patients treated with standard-dosage interferon-alpha, respectively, compared with 11 (73%) and 10 (67%) treated with high-dose interferon-alpha, respectively (not significant). The safety profile of both treatment regimens was similar. Severe adverse events leading to withdrawal from the study occurred in one patient (7%) in each group, and in both groups one patient (7%) was lost during therapy for unknown reasons. The findings suggest that, although the difference between the response rates of standard and high-dose interferon-alpha regimens (within a triple anti-viral therapy combination) did not reach statistical significance, there was a clear trend towards a higher response with high-dose interferon-alpha therapy and an equal safety profile.

A randomized comparative dose‐ranging study of interferon‐α and mitomycin‐C as an internal control in primary or recurrent superficial transitional cell carcinoma of the bladder

To compare, in a phase II study, the activity and toxicity of three dose levels of interferon-alpha, and of mitomycin-C given intravesically (as an internal control to validate the results), the primary objective being to investigate the percentage of complete responses (complete disappearance of a marker lesion) induced by the three interferon-alpha dose levels on a marker lesion; a secondary objective was to compare the interferon-alpha doses for toxicity. In all, 115 patients were enrolled, with the inclusion criteria being multiple grade 1 or 2, stage Ta or T1, primary or recurrent transitional cell carcinoma of the bladder. Interferon-alpha (30, 50 and 80 MU) and mitomycin-C (40 mg) intravesical treatments were given as follows. Patients randomized to one of three interferon-alpha dose levels were treated weekly for 12 weeks. However, in week 9 (first cystoscopy after baseline) interferon-alpha treatment was stopped if there was a complete response or disease progression. Patients randomized to mitomycin-C were treated weekly for 8 weeks only and in week 9 underwent follow-up cystoscopy. Interferon-alpha at doses of 30, 50 and 80 MU gave response rates at 13 weeks of 19%, 33% and 41%, respectively. Although the response rates were higher for 50 and 80 MU than for 30 MU, the differences were not statistically significant. All three interferon-alpha groups had significantly lower response rates than the internal control, mitomycin-C (72%). The safety analysis showed that most of the adverse events were of mild to moderate severity. Adverse events were experienced by 37%, 37% and 48% of patients receiving 30, 50 and 80 MU interferon-alpha, respectively, and by 55% of patients receiving mitomycin-C. The corresponding rates for severe adverse events related to treatment were 9% for interferon-alpha and 10% for mitomycin-C. Ablative therapy with interferon-alpha was less effective than mitomycin-C in patients with superficial bladder cancer. Both drugs were well tolerated, although interferon-alpha appeared to have a slightly better overall safety profile.

Interferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial

BACKGROUND: Metastatic renal carcinoma has a 2-year survival of around 20% and is largely resistant to chemotherapy. The use of interferons in the treatment of metastatic renal carcinoma remains controversial. Although non-randomised studies suggest that biological therapy with interferons produces a small number of tumour responses, most clinicians judge such treatment to be ineffective. We have investigated the effect of treatment with interferon-alpha on survival in patients with metastatic renal carcinoma. METHODS: In a multicentre, randomised trial, patients with metastatic renal carcinoma were randomly assigned subcutaneous interferon-alpha (three doses--5 MU, 5 MU, 10 MU--for the first week, then 10 MU three times per week for a further 11 weeks; n=174) or oral medroxyprogesterone acetate (MPA; 300 mg once daily for 12 weeks; n=176). The primary endpoint was overall survival. Analysis was by intention to treat. The trial used a triangular sequential design for early termination as soon as results were conclusive. The trial was stopped in November, 1997, when data were available for 335 patients (167 interferon-alpha, 168 MPA). FINDINGS: A total of 111 patients have died in the interferon-alpha group, and 125 patients have died in the MPA group. There was a 28% reduction in the risk of death in the interferon-alpha group (hazard ratio 0.72 [95% CI 0.55-0.94], p=0.017). Interferon-alpha gave an improvement in 1-year survival of 12% (MPA 31% survival, interferon-alpha 43%), and an improvement in median survival of 2.5 months (MPA 6 months, interferon-alpha 8.5 months). INTERPRETATION: The benefit of treatment with interferon-alpha should be weighed against the drug's toxic effects. Combination regimens of biological therapy and chemotherapy should now be compared with interferon-alpha monotherapy in randomised controlled trials.

Abnormal Patterns of Immunoglobulin Heavy Chain Gene DNA Fingerprinting During Chronic Phase Chronic Myeloid Leukemia

Using IgH DNA fingerprinting we have previously demonstrated clonal immunoglobulin heavy chain (IgH) gene rearrangements during chronic phase (CP) chronic myeloid leukemia (CML) in patients destined to develop lymphoid blast crisis (L-BC). In view of this we decided to follow a cohort of CP CML patients to determine the frequency with which abnormal IgH fingerprints are found and their relationship, if any, to treatment regimen. Thirty three, initially CP, CML patients were studied on 111 occasions over a 16 month period using consensus PCR amplification of the third complementarity determining region (CDR3) of the IgH gene and high resolution polyacrylamide gel electrophoresis (IgH DNA fingerprinting). Of these 33 patients, thirteen received interferon-alpha (IFN) containing regimens and 15 non-IFN containing regimens throughout the study period. Five patients received variable therapy. During the period of observation 7 patients experienced disease progression: 5 accelerated phase, 1 L-BC and 1 myeloid blast crisis (M-BC). Abnormal IgH fingerprints were seen in 29 of the 111 (26%) specimens analysed. The 28 patients who received uniform therapy (IFN or non-IFN) over the 16 months were classified as “normal” (n=18, normal pattern on all occasions) or “abnormal” (n=10, abnormal on 1 or more occasions). Analysis by patient group (normal vs abnormal) showed that fingerprint abnormalities were associated with an elevated peripheral blood lymphocyte count (p=0.0001) but not with changes in the total white cell count. Comparison of the IFN vs non-IFN groups showed the former all had normal patterns whereas 10 of 15 non-IFN therapy patients were abnormal (p=0.00023). The peripheral blood lymphocyte counts in the normal vs abnormal patients within the non-IFN group were not significantly different. The patient who developed L-BC demonstrated a persistent IgH fingerprint pattern abnormality from 7 months prior to the diagnosis of L-BC. The M-BC patient had a normal pattern at all times. We conclude that: (1) abnormal IgH fingerprints are found in a significant number of CP CML patients; (2) in this cohort the use of IFN was associated with normal CP CML IgH fingerprints, and (3) detection of abnormal IgH fingerprints may be highly predictive for the lineage of impending blast crisis.

Clinical significance of serum beta-2 microglobulin levels in hematological malignancies.

The clinical significance of serum beta-2 microglobulin (Sβ2M) levels in hematological malignancies and of the ratio of measured β2M value to calculated β2M (β2M M/CTD ratio) from the serum creatinine level for assessing renal function were examined. The levels of Sβ2M in patients with multiple myeloma (MM), polycythemia vera (PV), and renal failure were markedly increased. The β2M M/CTD ratio was increased in MM and PV patients, but was not increased in renal failure patients, suggesting that the β2M M/CTD ratio is useful for distinguishing between MM and renal failure.In the MM group, the mean Sβ2M level did not significantly differ between the patients who received chemotherapy with/without interferon and those who were not treated. However, the mean β2M M/CTD ratio of the chemotherapy plus interferon-alpha group was significantly higher than that of the non-treated group (p <0.01) and that of the chemotherapy-only group (p < 0.02). In the group with chronic myelogenous leukemia, both the mean Sβ2M level and the mean β2M M/CTD ratio were significantly different in the non-treated patients compared with the interferon therapy patients (p <0.02, p <0.05).We speculate that the evaluation of prognosis and tumor mass by the level of Sβ2M should be performed at the time of diagnosis, before the administration of chemotherapy with interferon.

The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses.

The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine.

Randomized Comparison of Interferon-α With Busulfan and Hydroxyurea in Chronic Myelogenous Leukemia

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.