Radiosensibilisierung durch BRAF Inhibitoren.

HINTERGRUND: In der letzten Zeit wurden in der Literatur vermehrt erhöhte Hauttoxizitäten während einer Kombinationstherapie mit BRAF Inhibitoren und Radiotherapie beschrieben. MATERIAL UND METHODIK: Wir berichten über sieben Melanompatienten in einem nicht resezierbaren Stadium III oder IV, die eine kombinierte Behandlung aus Bestrahlung und BRAF-Inhibitor erhielten. ERGEBNISSE: Bei allen Patienten konnte durch die Kombinationstherapie ein gutes lokales Ansprechen erreicht werden. Nur bei zwei Patienten wurde eine schwere Radiodermatitis (CTCAE Grad 3 bzw. 4) beobachtet. Bei diesen Patienten, die beide Vemurafenib erhielten, trat die Radiodermatitis nach ein bzw. zwei Wochen auf und resultierte in einer Unterbrechung der BRAF-Inhibitor Behandlung.. Die kumulative Dosis bis zum Zeitpunkt der Strahlendermatitis betrug 10 Gy bzw. 35 Gy. Bei allen anderen Vemurafenibpatienten konnten nur milde Reaktionen im Sinne einer Radiodermatitis CTCAE Grad 2, beim Dabrafenibpatienten CTCAE Grade 1 diagnostiziert werden. Bei einem Patienten wurde eine Recalldermatitis nach 14 Tagen einer beendeten Strahlentherapie mit einer kumulativen Dosis von 30 Gy diagnostiziert. SCHLUSSFOLGERUNGEN: Schwere Toxizitätsreaktionen der Haut unter einer BRAF-Inhibitionen treten nicht häufig auf und sind meistens gut therapierbar. Deshalb sollte die Kombinationstherapie bei aggressiv wachsenden Melanomen eine Therapieoption bleiben. Obwohl ein erhöhtes Risiko der Hauttoxizität unter einer Kombinationstherapie von Radiatio und BRAF-Inhibitoren besteht, wird diese von den meisten Patienten gut toleriert. Sequenzielle Therapie anstelle von gleichzeitiger Behandlung scheint die Toxizitätreaktionen nicht zu verhindern.

Radiosensitization by BRAF inhibitors.

BACKGROUND: Increased skin toxicity during combination therapy with a BRAF inhibitor and radiation therapy has recently been reported. MATERIAL AND METHODS: We present seven melanoma patients with non-resectable stage III or IV disease and concomitant treatment with a BRAF inhibitor and radiation therapy. RESULTS: In all patients, combination therapy yielded a good local response. Only two patients, both on vemurafenib, showed severe radiation dermatitis (CTCAE grade 3/4) after one and two weeks, respectively, resulting in interruption of BRAF inhibitor treatment. The respective cumulative radiation dose was 10 Gy and 35 Gy. The remaining vemurafenib patients displayed only mild radiation dermatitis CTCAE grade 2; the only dabrafenib patient CTCAE grade 1. In one patient, recall dermatitis was diagnosed 14 days after completion of radiation therapy with a cumulative dose of 30 Gy. CONCLUSIONS: Severe skin toxicity caused by BRAF inhibitor-induced radiosensitization is not common and usually amenable to treatment. Thus, combination treatment should remain a therapeutic option, especially in melanoma patients characterized by aggressive tumor growth. Although there is an increased risk of skin toxicity during combination therapy, it is usually well tolerated by most patients. Sequential - instead of simultaneous - treatment does not seem to prevent such toxicity reactions.

Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions.

BACKGROUND: Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody introducing immune responses in melanoma patients. Treatment experiences from named-patient programs support the evaluation of the efficacy and tolerability of new medicines under usual circumstances of health care practice. Here, the largest ever reported cohort treated with ipilimumab 3 mg/kg alone is described. METHODS: This report retrospectively analyzes data of 198 patients who were followed up in 15 hospital centers in Germany between April 2010 and March 2013. Patients had received prior therapy for unresectable stage III or IV melanoma before receiving ipilimumab (4 doses of 3 mg/kg every 21 d). Routine staging and tumor response evaluation procedures were applied. RESULTS: Of the patients, 119 received the planned 4-course therapy schedule; in further 79 patients, the number of doses was reduced mainly because of toxicity or fast progression. In all, 196 patients were eligible for evaluation of the efficacy of ipilimumab under routine care conditions. Median overall survival (OS) was 6.8 months [95% confidence interval, 5.6-10.3] from the start of therapy. OS differed significantly among patients who received 4 doses (n=119) and those receiving <4 doses (n=79) (14.2 vs. 2.0 mo; P<0.0001). The overall response rate (ORR) of 11% was in the same range as reported from previous clinical trials; and stable disease (SD) was observed in 11% resulting in a disease control rate (ORR+SD) of 22%. In 23 of the 79 patients with reduced dosing, dose omission was most probably caused by toxicity, whereas 56 patients had progressive disease before receiving all 4 treatment cycles. Immune-related adverse events (irAE) were reported in 30% of all treated patients, the occurrence of irAE correlated significantly with the probability of response to therapy and prolonged OS. CONCLUSION: In this named-patient program including heavily pretreated patients, the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings from the confirmatory clinical trial.

Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

Manifestation of palmoplantar pustulosis during or after infliximab therapy for plaque-type psoriasis: report on five cases.

Infliximab is a monoclonal antibody directed against TNF-alpha. It has been approved for use in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis and plaque-type psoriasis. In case reports, positive effects on pustular variants of psoriasis have also been reported. However, paradoxically, manifestation of pustular psoriasis and plaque-type psoriasis has been reported in patients treated with TNF antagonists including infliximab for other indications. Here, we report on 5 patients with chronic plaque-type psoriasis who developed palmoplantar pustulosis during or after discontinuation of infliximab therapy. In two of the five cases, manifestation of palmoplantar pustulosis was not accompanied by worsening of plaque-type psoriasis. Possibly, site-specific factors or a differential contribution of immunological processes modulated by TNF inhibitors to palmoplantar pustulosis and plaque-type psoriasis may have played a role.