High-dose Interferon Alfa Research Articles

PD-1 inhibitors versus conventional therapies for adjuvant treatment of resected acral melanoma: A systematic review and meta-analysis.

e21555 Background: Acral melanoma (AM) is a rare and aggressive melanoma subtype with unique characteristics in western Caucasian population, but mostly prevalent in Asian population. FDA has approved pembrolizumab and nivolumab for the adjuvant treatment of melanoma. However, its role in AM is still unclear. In US and mainland of China, high-dose interferon alfa was once approved, while in other part of the world, there was no standard treatment for adjuvant therapy of AM. Thus, we performed a meta-analysis to summarize the efficacy of anti-PD-1 monotherapy in patients with AM in adjuvant setting and derive implications for early-stage AM management. Methods: A systematic review of electronic databases was conducted to identify studies that assessed relapse-free survival (RFS) and overall survival (OS) between adjuvant PD-1 and conventional therapy (interferon (IFN) / chemotherapy) or observation alone in patients with AM. RFS was the primary endpoint, OS was the secondary endpoint. We estimated RFS/OS using the fixed-effect model. Statistical analyses in our study were carried out using Stata 12.0 (Stata Corp LP, College Station, TX, USA). Results: Five retrospective studies that totally involving 516 patients with AM were recruited, including 3 China studies and 2 non-China studies. Among them, there were 260 PD-1, 74 IFN, 178 OBS and 4 chemotherapy, respectively. Adjuvant PD-1 inhibitor achieved better efficacy than conventional therapy, showing significant improvement both in RFS (HR 0.76, 95%Cl 0.61-0.95) and OS (HR 0.57 0.37-0.88). This trend of RFS/OS benefit was observed in all subgroups, includes control treatment (OBS/IFN) or study region (China/non-China). Conclusions: Our data supports that patients with resected AM are more likely to derive benefit from adjuvant PD-1 comparing to conventional treatment or observation alone. Perspective studies are warranted to explore the role of adjuvant PD-1 in AM. [Table: see text]

Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary

BackgroundMelanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared...

Adjuvant nivolumab in high-risk stage IIb/IIc melanoma patients: Results from investigator initiated clinical trial.

9583 Background: Recent studies have shown 5-yr recurrence rates for Stage IIB and IIC melanoma of up to 46%. These high-risk patients currently have few options for adjuvant therapy to prevent this inevitable recurrence, with the only FDA approved therapy being high-dose interferon-alfa, which is quite toxic. However, there are now immunotherapies (anti-PD1) and targeted therapies (anti-BRAF and anti-MEK combinations) which are approved as adjuvants for Stage III patients, some of whom will have a lower baseline recurrence risk than those with Stage IIB/IIC melanoma. We sought to determine if adjuvant PD1 inhibition with nivolumab (N) would improve the recurrence free survival (RFS) compared to historical RFS rates. Methods: Our study (NCT03405155) is a single-arm, open label, multi-center, phase 2 clinical trial evaluating RFS at 24 months in patients with Stage IIB/IIC melanoma on treatment with N at 480 mg IV every 4 weeks for 12 cycles. Overall survival is a secondary endpoint. Associated translational research includes circulating tumor cell DNA and immune correlates. Results: Twenty three patients with Stage IIB and three patients with Stage IIC melanoma were enrolled onto the study and received at least one dose of N. At data cutoff, 22 patients remain in follow up, as four patients withdrew consent at different time points in the study – one patient after one dose who wished to discontinue, one due to concern for COVID and need for repeat visits, one due to insurance issues, and one due to recurrence and wish to discontinue (which was captured in study data and RFS calculations). Seventeen patients have been on the clinical trial for at least two years with nine patients having finished treatment but with less than two years follow-up; the median follow-up is currently 21.9 months. Two patients demonstrated melanoma recurrence, one after receiving cycle six of N and another one year after completing treatment, resulting in a 87.8% RFS (90% CI (64.2%-96.3%) at 2 years, compared to the historical RFS at 2 years of 70%. No N related serious adverse events (SAEs) were observed, with only 2% Grade 3 AEs observed (varied and unrelated to treatment) and all others were Grade 1-2, including 21% GI, 18% cutaneous, and 10% musculoskeletal, respiratory, and fatigue, each; overall, 2% of these Grade 1-2 AEs were treatment related. Conclusions: Our preliminary results show a trend towards improved RFS in patients with Stage IIB/IIC melanoma treated with nivolumab. The cohort has not reached a minimum follow up of at least 2 years for RFS; patients are continuing to be monitored. On study, we observed the expected adverse events, without evidence of new toxicities. Data maturation will reveal the full effect of adjuvant N on disease relapse and overall survival and distant metastasis-free survival in stage IIB/IIC melanoma patients. Clinical trial information: NCT03405155.

Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups

AbstractThe optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m2 daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 × 109/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P = .002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs. (Blood. 2004;103:4408-4415)

Unknown primary tumor high-risk melanoma as a unique patient population with distinct prognosis in the adjuvant setting: An ECOG-ACRIN E1609 study analysis.

e22090 Background: E1609 enrolled 1670 adult patients (pts) with resected AJCC7 stages IIIB, IIIC, M1a, M1b melanoma and compared adjuvant ipilimumab at 3 or 10 mg/kg (ipi3 and ipi10) to high dose interferon-alfa (HDI). With over 5 years of follow up, the risk of relapse and death by primary tumor status and by stage group is expected to inform the design of future adjuvant trials and ultimately, clinical practice. Methods: Unknown primary melanoma status was defined as initial presentation with cutaneous, nodal or lung metastasis that was completely resected without a history of known primary melanoma. We evaluated the pt distribution by the initial site of metastasis. Further, we evaluated the risk of relapse and death by primary tumor status and by stage group. Five-year relapse-free survival (RFS) and overall survival (OS) rates and 95% CIs were estimated by Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Two-sided p-values were derived. Results: Unknown primary melanoma represented 12.8% of the total study population including 11.7% on the ipi arms and 14.7% on HDI. Site of metastasis at initial presentation among unknown primary cases included cutaneous and nodal (97%) and lung (3%). Among the overall study population, M1a stage group included the highest proportion of pts with unknown primary (42.2%). Stratifying by stage, RFS (p = 0.001) and OS (p = 0.009) were significantly better for pts with unknown primary compared to known primary. Including only ipi3 and ipi10 pts, RFS (p = 0.005) and OS (p = 0.023) were consistently significantly better in favor of unknown primary. Five-year RFS and OS rates by primary tumor status and stage group among pts treated with ipi (ipi3 and ipi10) are summarized in Table. Conclusions: Unknown primary status represents a unique population among high-risk melanoma pts treated with ipi with improved RFS and OS outcomes that support their separate assessment in future immunotherapy adjuvant trials. In-depth analyses of the tumor biology and host immunology are ongoing. Outcome analyses by the overall study stage groups and the HDI arm will be reported at the meeting. Clinical trial information: NCT01274338. [Table: see text]

Systemic adjuvant therapy for adult patients at high risk for recurrent cutaneous or mucosal melanoma: an Ontario Health (Cancer Care Ontario) clinical practice guideline.

Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma. The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wild-type disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial.

Clonal expansion of tumor infiltrating lymphocytes (TILs) in the peripheral blood of metastatic melanoma patients is significantly associated with response to CTLA4 blockade-based immunotherapy.

2541 Background: Patients with metastatic melanoma were treated on a clinical trial with tremelimumab and High Dose Interferon-Alfa (HDI) (Tarhini. J Clin Oncol. 2012). We previously reported that patients who achieved disease control and clinical response had significantly greater T-cell clonality (p = 0.0008) and T-cell fraction (p = 0.044) respectively in their pretreatment tumor biopsy samples (Tarhini. J Clin Oncol. 2017). In this study, we further characterize T-cell repertoire clonality and clonal expansion in the peripheral blood at different time points to evaluate the association between repertoire features and clinical response. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks and HDI was given concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 33) were obtained at baseline, day 29, and day 85 (following tremelimumab-HDI treatment); tumor samples at baseline were also obtained (N = 18). The T-cell receptor beta chain (TCRB) repertoire of PBMCs and tumor samples was immunosequenced using the immunoSEQ assay (Adaptive Biotechnologies), and repertoire clonality was assessed at baseline, day 29, and day 85. Differential abundance analysis was used to detect and quantify peripheral clonal expansion pre- versus post-treatment and identify the subset of peripheral clones also detected in the tumor repertoire. The Morisita Index of repertoire similarity was also calculated to compare global repertoire changes between pre- and post-treatment PBMC samples. Results: T-cell repertoire turnover, as measured by the Morisita Index, showed a trend towards responders (CR/PR) having greater turnover (lower Morisita Index) post-treatment than non-responders (SD/PD). Similarly, the total number of clones expanding in the peripheral repertoire varied over time within an individual (p = 0.034) but was not significantly affected by response to therapy (p = 0.275) or by on-treatment time point (p = 0.768). When the analysis was restricted to peripherally expanded clones that were also found in the tumor repertoire, responders had significantly more TILs expanded in the periphery at day 29 than non-responders (p = 0.036). Conclusions: Our analysis of the peripheral T-cell repertoire following treatment showed that detection of TILs in early peripheral clonal expansion correlates with response to therapy.

A randomized phase II study of ipilimumab at 3 (ipi3) or 10 mg/kg (ipi10) alone or in combination with high dose interferon-alfa (HDI) in advanced melanoma (E3611).

9542 Background: Interferon-α (IFN) favors a Th1 shift in immunity. Combining CTLA4 blockade with IFN may downregulate CTLA4 suppressive elements. Prior data from a phase II of tremelimumab and HDI showed promising efficacy supporting the current study. Methods: E3611 had a 2x2 factorial design (A: ipi10 + HDI; B: ipi10; C: ipi3 + HDI; D: ipi3) to evaluate (i) no HDI vs. HDI (across ipi doses) and (ii) ipi3 vs. ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months (mos) with HDI vs. no HDI and with ipi10 vs. ipi3. Based on the log-rank test for 80 patients (pts) these comparisons would have 82% power at 2-sided type I error of 0.10. Results: Median follow up 26.4 mos. PFS and overall survival (OS) (eligible and treated pts; N = 80: 18 III/M1a, 24 M1b, 38 M1c) are shown in Table 1. There were no significant differences in PFS or OS when evaluating HDI vs. no HDI or ipi10 vs. ipi3 (Table 1). Response (RECIST) among response evaluable pts (and 4 pts with early death) (N = 76) is shown in Table 1. Stable disease (SD) in 7 (A), 6 (B), 8 (C) and 6 (D). Adverse events (AEs) were consistent with the toxicity profiles of ipi and HDI and included 3 grade 5 AEs considered at least possibly related: 1 in A (suicide), 1 in B (lung infection and hemorrhage) and 1 in C (adult respiratory distress syndrome). One patient in B died of gastrointestinal bleed and cardiac arrest while on corticosteroids to treat temporal arteritis and vision loss. Conclusions: Within the limitations of the sample size, there were no significant differences in PFS with HDI vs. no HDI or ipi10 vs. ipi3. Response and PFS with ipi10 were superior to historical controls and similar to the combination. Correlative studies are ongoing. Clinical trial information: NCT01708941. [Table: see text]

A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.

9500 Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]

CO10. Importance of duration of high-dose interferon-alfa in the adjuvant therapy of melanoma

Melanoma Research: June 2011 - Volume 21 - Issue - p e6-e7 doi: 10.1097/01.cmr.0000399444.81116.73

Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma

A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively. We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m2 IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B). Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment.

Cost Effectiveness of Adjuvant Interferon in Node-Positive Melanoma

To assess the benefits of adjuvant high-dose interferon alfa (HDI) treatment for patients with high-risk melanoma. We designed a decision-analytic probabilistic Markov model to simulate the natural history of patients with stage IIIA, IIIB, and IIIC melanoma and evaluate the outcomes with and without HDI treatment. Outcomes were in quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Probability estimates and costs were derived from primary patient level data, while the efficacy of HDI and associated utilities were determined from published reports. The base-case analysis was a cohort of 50-year-old patients. HDI increased the median life expectancy in patients with stage III melanoma from 3.75 years in the observation cohort to 4.42 years in the HDI cohort. The difference in QALYs ranged from 0.31 years for stage IIIA patients to 0.60 years for stage IIIC patients treated with HDI. HDI was cost effective in patients with stage IIIB and IIIC melanoma, with ICERs of $95,304 and $76,068 per QALY gained, respectively. Using a threshold of $100,000 per QALY gained, HDI was cost effective for all stage III patients younger than 52 years. HDI was not cost effective for patients with stage IIIA disease and for subsets of patients older than 63 years with stage IIIB disease. Our model demonstrates that the probability of HDI being cost effective varies substantially by melanoma substage. HDI showed the greatest benefit in terms of QALYs and was most cost effective in patients younger than 60 years with stage IIIC disease.

Reaching First Base in the Treatment of Metastatic Melanoma

Reaching First Base in the Treatment of Metastatic Melanoma

Severe rhabdomyolysis associated with pemetrexed-based chemotherapy

Pemetrexed is an antifolate metabolite that inhibits several enzymes involved in the folate pathway. It has activity against various solid tumours, and has been approved for treatment of malignant pleural mesothelioma on the basis of fi ndings from a randomised phase III trial. The main toxic eff ects noted for pemetrexed have been rash, myelosuppression, diarrhoea, mucositis, and reversible elevation of liver enzymes—eff ects that are preventable partly by vitamin supplementation. A 68-year-old man with malignant pleural mesothelioma had extrapleural pneumonectomy followed by external mediastinal radiotherapy (50 Gy total dose, completed in March, 2003). Because of distant disease progression involving supradiaphragmatic and infradiaphragmatic lymph nodes and a biopsy-confi rmed metastatic nodule in the mammary gland, he received 500 mg/m2 pemetrexed, given as an intravenous infusion over 10 min followed at least 45 min later by carboplatin (AUC [area under the curve] 5, given as an intravenous infusion over 60 min) in the setting of an expanded access trial in January, 2004. As requested per protocol, he was given full vitamin supplementation (ie, 400 μg folic acid a day orally and 1 mg vitamin B12 as one intramuscular injection every 9 weeks), starting 14 days before fi rst trial treatment. The patient was given 4 mg dexamethasone twice a day intramuscularly on the day before chemotherapy and the day after chemo therapy; on the day of chemotherapy, he received 16 mg dexamethasone, 50 mg ranitidine, and 8 mg ondansetron intravenously. No acute toxic eff ects were reported. On day 2 after chemotherapy, he developed severe and gradually worsening myalgias, weakness of the arms and legs, and abdominal tenderness. On day 4 after chemotherapy, he was therefore admitted to the accident and emergency department. Physical examination showed a severely ill patient with weakness in both arms and both legs. Laboratory tests on admission showed substantially increased serum concentrations of creatine kinase (21 530 U/L), myoglobin (3000 μg/L), aspartate aminotransferase (453 U/L), and alanine aminotransferase (159 U/L); serum electrolytes and renal-function tests were normal. The patient was diagnosed with rhabdomyolysis. The patient was treated with vigorous fl uid replacement with the addition of sodium bicarbonate, methylprednisolone, and furosemide. On the third day in hospital, concentration of creatine kinase decreased to 1835 U/L, and the weakness improved slowly during the following weeks. However, the patient was unable to do his normal daily activities, and 1 month later he was transferred to a long-term hospital clinic for muscular rehabilitation, at which stage serum concentrations of creatine kinase and transaminases were normal. Drug-induced rhabdomyolysis is a fairly common and potentially life-threatening syndrome associated with several drugs, including chemotherapeutic agents. In patients with cancer, rhabdomyolysis has been reported in association with exposure to high-dose interferon alfa, vancomycin after high-dose chemotherapy with peripheralblood stem-cell transplantation, and the combination of cyproterone and statins. To our knowledge, this is the fi rst report of severe and life-threatening rhabdomyolysis during pemetrexed-based chemotherapy. Moreover, to our knowledge, no cases of rhabdomyolysis have been reported as a consequence of exposure to other structurally related drugs such as methotrexate and raltitrexed. The causal association of rhabdomyolysis with pemetrexed in our patient is suggested by a temporal relation and by the absence of concomitant exposure to any other drugs potentially involved with this clinical syndrome, including statins. Although to our knowledge no cases of rhabdomyolysis have been reported with carboplatin-based regimens, with the exception of a patient with a testicular germ-cell tumour given high-dose ifosfamide, carboplatin, and etoposide and peripheralblood stem-cell transplantation, we cannot presently rule out its involvement in the pathogenesis of this particular patient. Nevertheless, we think that clinicians should be aware of this possible, although rare, complication of pemetrexed-based treatment to recognise promptly and treat successfully the potentially life-threatening disorder of rhabdomyolysis.

Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial

Individuals affected by melanoma with thick primary tumours or regional node involvement have a poor outlook, with only 30-50% alive at 5 years. High-dose and low-dose interferon alfa have been assessed for the treatment of these patients, with the former having considerable toxicity and a consistent effect on disease free survival, but not on overall survival, and the latter no consistent effect on either. Our aim was, therefore, to assess the effect of two regimens of interferon of intermediate dose versus observation alone on distant metastasis-free interval (DMFI) and overall survival in such patients. We did a randomised controlled trial in 1388 patients who had had a thick primary tumour (thickness > or = 4 mm) resected (stage IIb) or regional lymph node metastases dissected (stage III) and had been assigned to 13-months (n=553) or 25 months (n=556) of treatment with subcutaneous interferon alfa 2b, or observation (n=279). Treatment comprised 4 weeks of 10 million units (MU) of interferon alfa (5 days per week) followed by either 10 MU three times a week for 1 year or 5 MU three times a week for 2 years, to a total dose of 1760 MU. Our primary endpoint was DMFI. Analyses were by intent to treat. After a median follow-up of 4.65 years, we had recorded 760 distant metastases and 681 deaths. At 4.5 years, the 25-month interferon group showed a 7.2% increase in rate of DMFI (hazard ratio 0.83, 97.5% CI 0.66-1.03) and a 5.4% improvement in overall survival. The 13-month interferon group showed a 3.2% increase in rate of DMFI at 4.5 years (0.93, 0.75-1.16) and no extension of overall survival. Toxicity was acceptable, with 18% (195 of 1076) of patients going off study because of toxicity or as a result of refusal of treatment because of side-effects. Interferon alfa as used in the regimens studied does not improve outcome for patients with stage IIb/III melanomas, and cannot be recommended. With respect to efficacy of the drug, duration of treatment seemed more important than dose, and should be assessed in future trials.

Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin

The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C (CHC) and response of both viruses to combination therapy with high-dose interferon-alfa (IFN) plus ribavirin remain uncertain and are being investigated. Total 164 (97 males and 67 females, the mean age 48.1+/-11.4 years, range: 20-73 years, 128 histologically proved) naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method. Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay (COBAS AMPLICOR HCV Test, version 2.0). HCV genotypes 1a, 1b, 2a, 2b, and 3a were determined by using genotype-specific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay (Quantiplex HCV RNA 3.0). There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined. Sixty-one (37.2%) patients were positive for SENV-D DNA and had higher mean age than those who were negative (50.7+/-10.6 years vs 46.6+/-11.6 years, P = 0.026). The rate of sustained viral response (SVR) for HCV and SENV-D were 67.3% (105/156) and 56.3% (27/48), respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b (P<0.001), younger ages (P = 0.014), lower pretreatment levels of HCV RNA (P = 0.019) and higher histological activity index (HAI) score for intralobular regeneration and focal necrosis (P = 0.037). By multivariate analyses, HCV genotype non-1b, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR (odds ratio (OR)/95% confidence interval (CI): 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively). The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy (P = 0.04). Coexistent SENV-D infection, apparently associated with higher ages, is found in more than one-third Taiwanese CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.

Successful treatment of systemic mastocytosis with high-dose interferon-alfa: long-term follow-up of a case

Daily treatment of systemic mastocytosis with high-dose interferon-alfa often is not tolerated because of clinical or hematologic side effects. We report successful treatment of a patient with systemic mastocytosis, who was positive for the D816V mutation, with interferon alfa-2b at 10 million units three times per week. During 5 years of treatment, bone marrow infiltration by mast cells decreased from 50 to ≤5%, and there was a decrease (urinary N-methylhistamine excretion, 75%; serum tryptase concentration, 98%) or normalization (serum calcitonin value, urinary prostaglandin F 2α excretion) of mast cell mediators. Side effects included mild depression (untreated) and biochemical hypothyroidism easily managed with supplemental levothyroxine.

The prevalence and clinical characteristics of coinfection of SENV-H among Taiwanese chronic hepatitis C patients with combination therapy of high-dose interferon-alfa and ribavirin

The clinical significance of coinfection of SENV-H among patients with chronic hepatitis C (CHC) and the response to combination therapy with high-dose interferon-alpha (IFN) plus ribavirin in Taiwan are uncertain. A total of 151 (120 histologically proved) naı̈ve CHC patients who received 6 MU IFN thrice a week plus ribavirin for 24 weeks therapy were enrolled in this study. SENV-H DNA was tested by PCR method. Of 151 patients, 29 (19.2%) were positive for SENV-H DNA. The positive SENV-H DNA was significantly associated with HCV genotype 1b than non-1b infection (69.0% versus 43.4%; P = 0.011). No other clinical, histopathological and virological factor was related to positive SENV-H DNA. After combination therapy, the rate of sustained viral response (SVR) of HCV and SENV-H were 66.9 and 78.3%, respectively. By multivariate analyses, the significant factors associated with HCV SVR after combination therapy were HCV genotype non-1b, pretreatment HCV RNA levels less than 200,000 IU/mL, and younger age. We conclude that coexistent SENV-H infection, apparently associated with HCV genotype 1b, is found among 19.2% of Taiwanese CHC patients. Both HCV and SENV-H are highly susceptible to combination therapy with high dose IFN and ribavirin and SENV-H coinfection does not affect the HCV response.

Successful treatment of systemic mastocytosis with high dose interferon alfa: Long-term follow-up of a case

Rationale Interferon alfa-2b (IFN-a) has been used to treat systemic mastocytosis for over 10 years. The dosage used, frequency of administration, and responses to therapy have varied widely in reported series. Here we report sustained response to high dose IFN-a given for 5 years. Methods A 44 year-old man with urticaria pigmentosa developed weight loss, anemia and leukocytosis. Bone marrow biopsy was positive for mastocytosis with 50% involvement by mast cells. Treatment was begun with IFN-a 6 million units (MU) subcutaneously 3 times/week and prednisone 10 mg on the alternate days. After 4 weeks the dose of IFN-a was increased to 10 MU 3 times/week and the dose of prednisone was tapered and discontinued. Treatment with IFN-a 10 MU 3x/week continued for the next 5 years. Results The patient re-gained his weight loss and the urticaria pigmentosa lesions faded and disappeared over 2-3 years. During 5 years of treatment the following biochemical improvements were observed: normal (initial value–> present value): Tryptase <11.5 ng/ml (>200–>37); Calcitonin 0-15.9 pg/ml (15–>9.3); Urinary prostaglandin F2a </=1000 ng/24 hr (2869–>807); Urinary N-methyl histamine 30-200 ug/g Cr. (1038–>262). Repeat bone marrow biopsy was negative for mastocytosis, and immunophenotyping of bone marrow cells was normal. Side effects included mild depression and biochemical hypothyroidism treated with levothyroxine. Conclusions For this patient, chronic treatment with IFN-a 10 MU 3x/wk, a dose higher than commonly used in other series, led to continued clinical and biochemical improvement. High-dose, prolonged treatment with IFN-a should be considered a treatment option for patients with systemic mastocytosis.

Metastatic melanoma in pregnancy: risk of transplacental metastases in the infant.

Although metastases to the fetus via the placenta are rare, melanoma is the most common culprit. When it occurs, maternally derived melanoma metastasis in the infant is almost invariably fatal. This article reviews current guidelines for placental evaluation in pregnant women with metastatic melanoma and presents surveillance recommendations for their infants. Comprehensive literature reviews were performed on melanoma in pregnancy and melanoma metastasis to the placenta and fetus. The use of interferon alfa in the pediatric population was also reviewed. A comprehensive search of the MEDLINE database (1966 to 2002) was performed. Articles were reviewed and additional references were obtained from the bibliographies. Translation of non-English articles was performed, and authors of previous publications were contacted. Eighty-seven patients with placental or fetal metastasis were identified. Twenty-seven occurrences were attributed to melanoma (31%). The fetus was affected in six of 27 melanoma patients (22%), with five of six infants dying of disease. The use of high-dose interferon alfa adjuvant therapy in pediatric patients has not been reported. The placentas of women with known or suspected metastatic melanoma should be carefully examined grossly and histologically by pathologists. With placental involvement, fetal risk of melanoma metastasis is approximately 22%. Neonates delivered with concomitant placental involvement should be considered a high-risk population. The risk-benefit ratio of adjuvant treatment for a potentially affected infant should be carefully weighed.