Alpha Combination Therapy Research Articles

DOP75 Loss-of-response and immunogenicity following immunomodulator withdrawal from anti-tumour necrosis factor alpha combination therapy: Results from a large retrospective cohort study

Abstract Background Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels. Methods This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated >4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for >30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure. Results We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal. Conclusion Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.

Behandlung von Miktionsstörungen bei BPS

Benign prostatic syndrome (BPS) is considered a diagnosis of exclusion and needs a thorough work-up. One of the pitfalls for a tailored medical treatment scheme is the objective evaluation of benign prostatic obstruction. Characteristics of the various medical therapy options and the multifactorial origin of LUTS in BPH patients imply an individualized approach. LUTS involving mostly urine storage disorders and a small prostate are suitably managed with alpha(1)-receptor antagonists, which may be combined with antimuscarinics if OAB symptoms predominate. Long-term treatment addressing clinical progression may favor combination therapy of alpha(1)-receptor antagonists with 5alpha-reductase inhibitors if prostate size is sufficient. Age, symptom severity at baseline, a large prostate volume, or a high PSA value are indicative of progression. However, combination therapy aggravates side effects, and thus a risk-benefit analysis is essential. The potential of any medication for BPS to treat obstruction is rather low. If deobstruction is the main aim of therapy, medical treatment is not suitable.

Kombinationstherapie bei LUTS: Wann Pillen und wann nicht?

To improve the efficacy of medical treatment of patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), studies on combination treatment with alpha(1)-blockers and 5alpha-reductase inhibitors, alpha(1)-blockers and muscarinic receptor antagonists, and alpha(1)-blockers and 5-phosphodiesterase inhibitors are increasingly performed. The most substantial data are available on the combination of alpha(1)-blockers and 5alpha-reductase inhibitors. This combination is not suitable for symptom improvement alone but for inhibition of progression. A combination therapy of alpha(1)-blockers and muscarinic receptor antagonists cannot be recommended as routine because of the still limited, although promising, data. Only preliminary data are available for the combination of alpha(1)-blockers and 5-phosphodiesterase inhibitors, which do not show convincing advantages over other combinations.

The role of combination medical therapy in benign prostatic hyperplasia

To review key trials of monotherapy and combination therapy of alpha(1)-adrenergic receptor antagonists (alpha(1)-ARAs), 5alpha-reductase inhibitors (5alphaRIs) and anti-muscarinic agents in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). To assess the safety and efficacy of combination therapies for LUTS associated with BPH, a search of the MEDLINE and Cochrane databases (1976-2008) was conducted for relevant trials and reviews using the terms benign prostatic hyperplasia, lower urinary tract symptoms, alpha(1)-adrenergic receptor antagonists, 5alpha-reductase inhibitors, anti-muscarinics, anticholinergics, combination therapy, alfuzosin, doxazosin, tamsulosin, terazosin, dutasteride, finasteride, tolterodine, flavoxate, propiverine, oxybutynin, erectile dysfunction, sildenafil, vardenafil and tadalafil. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study indicated a role for long-term use of alpha(1)-ARAs and 5alphaRIs in combination. In the MTOPS study, combination therapy with the alpha(1)-ARA doxazosin and the 5alphaRI finasteride was significantly more effective than either component alone in reducing symptoms (P=0.006 vs doxazosin monotherapy; P<0.001 vs finasteride monotherapy) and in lowering the rate of clinical progression (P<0.001 vs either monotherapy). These findings were confirmed by the 2-year preliminary results of the Combination of Avodart and Tamsulosin study. In this study, combination therapy of the alpha(1)-ARA tamsulosin and the 5alphaRI dutasteride resulted in a significantly greater decrease in International Prostate Symptom Score (IPSS) when compared with either monotherapy. Several recent trials have studied the efficacy of combining alpha(1)-ARAs and anti-muscarinic agents in the treatment of BPH. These studies have found this combination to result in statistically significant benefits in quality of life scores, patient satisfaction, urinary frequency, storage symptoms and IPSS scores. Studies have not shown an increased risk of urinary retention associated with the use of anti-muscarinics in a highly select cohort of men with BPH. The available data suggest that combination therapy can be beneficial in the treatment of BPH and associated LUTS. The greatest efficacy for the alpha(1)-ARA and 5alphaRI combination was shown in patients with larger prostate size and more severe symptoms. The combination of alpha(1)-ARAs and 5alphaRIs appears to prevent disease progression in these patients. The combination of alpha(1)-ARAs with anti-muscarinic agents is useful for relieving symptoms of bladder outlet obstruction and detrusor overactivity. Theoretic concerns regarding the risk of acute urinary retention have been refuted in several recent clinical trials; however, it must be noted that the patients in these trials were a highly select cohort of men. Men with overactive bladder and BPH who are not receiving adequate alleviation of symptoms from the first-line alpha(1)-ARAs may benefit from the addition of an anti-muscarinic agent.

Defective Hepatic Response to Interferon and Activation of Suppressor of Cytokine Signaling 3 in Chronic Hepatitis C

Approximately half of hepatitis C virus (HCV)-infected patients do not respond to current interferon (IFN)-alpha combination therapy. To understand IFN-alpha resistance in vivo, we examined the dynamic responses to both type I and type II IFNs, human IFN (hIFN)-alpha, -gamma, and consensus IFN, in the chimpanzee model. Naive and HCV-infected chimpanzees were treated with 3 forms of hIFNs in vivo. Quantitative real-time polymerase chain reaction was performed to evaluate the expression of IFN-stimulated genes (ISGs) in both peripheral blood mononuclear cells and liver to compare the responses to hIFN between naive and infected chimpanzees. The hepatic expression of IFN signaling components and inhibitory regulators including suppressor of cytokine signaling 3 (SOCS3) were assessed. SOCS3 expression was also evaluated in the liver of HCV-infected patients undergoing IFN treatment. The in vivo responses to all 3 hIFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. This defect was particularly evident in the liver because induction of hepatic ISGs was barely detectable in the infected animals. Following IFN administration, the expression of SOCS3 was significantly up-regulated, possibly through induction of interleukin-6, in the liver of HCV-infected chimpanzees. HCV-infected humans also showed a differential pattern of hepatic SOCS3 expression in response to IFN that is associated with treatment response. Our data indicate a predominantly defective hepatic response to IFN in HCV-infected chimpanzees, which is probably mediated through the activation of SOCS3 and may explain the nonresponse of many HCV patients to IFN-based therapy.

Ｃ型慢性肝炎患者に対するインターフェロンα単独療法とリバビリン併用療法における血球変動の比較

Ｃ型慢性肝炎患者に対するインターフェロンα単独療法とリバビリン併用療法における血球変動の比較

Ifosfamide, Mesna, and Interferon-Alpha2A Combination Chemoimmunotherapy in Malignant Mesothelioma: Results of a Single Center in Central Anatolia

Our aim was to determine the efficacy of ifosfamide, mesna, and interferon alpha combination therapy in malignant mesothelioma (MM) patients. Fourty-two patients (39 evaluable) with histologically proven MM were enrolled into this study from January 1999 to October 2002. The drug schedule consisted of a combination of ifosfamide, 3000 mg/m2 1-3 d intravenous infusion (iv), the uroprotective agent mesna, 3000 mg/m2 1-3 d iv every 3 wk, and interferon alpha2a, 4.5 MU subcutaneously (sc) 3 d/wk for 6 mo as first-line chemotherapy. Overall, 140 cycles were administered to the 39 patients (median, 3.5 cycles; range, 1 to 6 cycles). Among the 39 patients, 8 partial remissions (PR) (21%) were observed. Thirteen patients (33%) had stable disease for at least 8 wk and 18 (46%) had progressive disease. Overall survival (OAS) and progression free survival (PFS) for all patients were 10.0 +/- 2.9 mo (95%CI 4.3-15.7) and 5.0 +/- 1.9 mo (95%CI 1.38-8.62), respectively. One and two year survival rates were calculated as 39% and 5%, respectively. All of the PR patients had the epithelial type of MM. Their survival time was 21.0 +/- 5.7 mo (95% CI 9.9-32.1) and significantly longer than that of nonresponders (p=0.0061). The toxicity of the drug combination was mild and well tolerated. There were no treatment-related deaths. Grade 3-4 neutropenia and febrile neutropenia were seen in 10 patients (26%) and 3 patients (8%), respectively. Chemotherapy was stopped in three patients because of renal function deficiency. One of these patients who had peritoneal MM required hemodialysis. In conclusion, this combination therapy showed encouraging antitumor activity with modest toxicity.

A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C

One of the major side effects of ribavirin/interferon alpha combination therapy for chronic hepatitis C is hemolytic anemia. One of the causes of hemolytic anemia is considered to be decreasing deformability of erythrocytes resulting from the accumulation of phosphorylated ribavirin in erythrocytes. The administration of eicosapentaenoic acid (EPA), which has a wide variety of pharmacological actions, increases the deformability of erythrocytes. We conducted an uncontrolled pilot study of EPA therapy for patients with ribavirin-related anemia. Six patients with chronic hepatitis C, who had developed anemia while receiving combination therapy, were treated with an oral ethyl ester of EPA (1800 mg/day) for two months. The hemoglobin level of all six patients increased following EPA therapy. The mean hemoglobin level significantly increased from 10.8 g/dl to 11.4 g/dl one month after therapy was initiated (P<0.05), and this level was obtained again one month later (11.5 g/dl). None of the patients developed an adverse reaction. These findings suggest that EPA has a beneficial effect in patients with ribavirin-related anemia. Further study is required to confirm our results.

298 Effects of ribavirin and interferon alpha combination therapy on T cell-dependent immune responses to HCV proteins in patients chronically infected with HCV

298 Effects of ribavirin and interferon alpha combination therapy on T cell-dependent immune responses to HCV proteins in patients chronically infected with HCV

Influence of TT virus co-infection on IFN-beta therapy in patients with chronic hepatitis C.

Although results of IFN alpha therapy in chronic hepatitis C (C-CH) patients co-infected with TT virus (TTV) have been reported, no results of IFN beta therapy or IFN beta and alpha combination therapy have been reported. In this study, we retrospectively investigated whether co-infection with TTV affects the results of IFN therapy by using stored sera from 60 C-CH patients co-infected with TTV who underwent IFN beta therapy or IFN beta and alpha combination therapy. The stored sera were from 29 complete responders, 10 incomplete responders, and 21 non-responders, and they were used for qualitative and quantitative analysis of HCV RNA, HCV genotype analysis, and qualitative and quantitative analyses of TTV DNA. TTV DNA was detected in 23 (38.3%) of the 60 C-CH sera. The TTV DNA-positive rate was 17.2% among the complete responders to IFN therapy, versus 58.1% in the incomplete responders and non-responders, and the difference was significant (p < 0.01). While the complete response prediction rate based on two factors, HCV RNA level and HCV genotype, was 80.8% (21/26) in the C-CH patients, the prediction rate based on three factors, these two factors plus TTV DNA, was higher, 90.0% (18/20). It was concluded that determination of HCV RNA concentration, HCV genotype, and TTV DNA, before IFN beta therapy or IFN beta and alpha combination therapy is useful for predicting the results of treatment of C-CH patients.

Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha: evidence of a risk/benefit advantage of subcutaneous therapy.

Systemic immunotherapy with recombinant interleukin-2 (rIL-2) via intravenous (i.v.) and subcutaneous (s.c.) administration produces objective responses in a proportion of advanced cancer patients. While most of the previous investigations chose the i.v. route for cytokine application, there is an increasing number of trials employing s.c. rIL-2 therapy. The comparison of reported response rates for i.v. versus s.c. therapy reveals no significant differences between these modalities. In an effort to describe systemic toxicities of s.c. cytokine therapy with regard to renal, metabolic, and hemodynamic abnormalities and to compare these effects to toxicities reported upon i.v. therapy, we retrospectively evaluated 148 treatment cycles of s.c. immunotherapy given to 107 outpatients. Our study cohorts consisted of 15 patients who received s.c. rIL-2 at doses of (4.8-14.4) x 10(6) IU m-2 day-1 5 days/week for a total of 8 weeks, 20 patients who received rIFN alpha 2b at (3.0-6.0) x 10(6) m-2 day-1 thrice weekly for a total of 6 weeks, and 72 patients who were given s.c. rILFN alpha 2b at 6.0 x 10(6) U/m2, three times per week, plus s.c. rIL-2 at (14.4-18.0) x 10(6) IU/m2 on days 1 and 2, followed by 4.8 x 10(6) IU m-2 day-1 5 days/week for 6 consecutive weeks. These treatment regimens were well tolerated in the outpatient setting; no toxic death occurred, and none of the patients developed life-threatening toxicity due to a capillary leak syndrome. Upon s.c. combination therapy, dyspnea at rest occurred in 6% of patients and grade III and IV hypotension occurred in 7% and 4%, respectively; plasma protein was significantly decreased (mean nadir +/- standard deviation, 67 +/- 5 g/l). In addition, s.c. therapy led to a significant increase in serum creatinine (mean peak +/- standard deviation, 115.1 +/- 21.4 mumol/l) and urea nitrogen (mean peak +/- standard deviation, 6.5 +/- 2.5 mmol/l); electrolyte disturbances and direct nephrotoxicity never caused major clinical symptoms. This was in marked contrast to a multitude of dose-limiting and life-threatening adverse reactions reported upon i.v. rIL-2 therapy. We conclude that palliative low to intermediate-dose s.c. rIL-2/rIFN alpha combination therapy, in contrast to i.v. treatment, can be administered in the ambulatory setting with good practicability and excellent safety. This outpatient regimen is as effective against metastatic renal cell cancer as the most aggressive i.v. rIL-2 protocol reported.