Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600-mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Widespread Hypertrophic Lichen Planus following Programmed Cell Death Ligand 1 Blockade

Hypertrophic lichen planus (HLP) may not have the typical histological findings of lichen planus and often mimics squamous cell carcinoma (SCC). Distinguishing between the two can pose a diagnostic challenge. Here, we present a case of eruptive HLP mimicking SCC in the context of programmed cell death ligand 1 (PD-L1) immune checkpoint inhibition. A 73-year-old woman recently treated with durvalumab, an anti-PD-L1 antibody, presented to our clinic with diffuse hyperkeratotic papules and plaques previously thought to be eruptive SCC. The lesions did not respond to topical fluorouracil and continued to appear despite discontinuation of immunotherapy. Further histological analysis revealed intraepidermal epithelial proliferation with lichenoid inflammation. Subsequent treatment with topical corticosteroids significantly improved the size and number of lesions. The diagnosis of HLP was made based on histological features and response to topical steroids in the context of recent immunotherapy. This case reveals HLP as a potential adverse effect of PD-L1 inhibition and highlights the need for additional diagnostic assessment in patients presenting with eruptive hyperkeratotic lesions, especially on the lower extremities.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Mixed Germ Cell Testicular Cancer with Left Ventricular Metastasis Presenting with Embolic Stroke and Small Bowel Tumor Seeding

Testicular germ cell tumors (GCTs) metastasize in a very predictable fashion involving the retroperitoneal nodes first followed by hematogenous spread to distant organs like lungs, liver, and brain. Metastasis to heart is an extremely rare entity for GCT and fewer than 20 cases have been reported in the literature so far. We have summarized here a unique case of nonseminomatous germ cell tumor (NSGCT) with intracardiac metastasis resulting in systemic macroembolization to liver, spleen, brain, bowel and musculoskeletal tissues. This led to multiple adverse sequelae including ischemic stroke and bowel perforation

A Phase II, Open-Label Study of Bortezomib (Velcade®), Cladribine, and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas

Abstract Background: Mantle cell lymphoma (MCL) is characterized by initial sensitivity to both chemotherapy and radiation but also by an invariable relapse and eventual resistance to treatment. Bortezomib (Velcade) is a proteasome inhibitor and is approved as a single agent for relapsed MCL and in combination therapy as part of initial therapy (Goy et al, JCO 2005; Robak et al, NEJM 2015). Cladribine is a purine nucleoside analog effective in indolent and mantle cell lymphomas (Inwards et al, 2008; Rummel et al, 1999), with 52% durable CR rate reported in MCL in combination with rituximab, and it shows CR rates of up to 20% in relapsed and up to 32% in untreated indolent lymphomas (Kay et al, 1992; Fridrik et al, 1998). The median age at diagnosis for these lymphomas is approximately 65 years which precludes many patients from receiving combination therapies which have significant toxicities, representing an unmet need for novel combinations with high efficacy, good tolerability and non-overlapping toxicities. We investigated a combination of bortezomib, cladribine and rituximab(VCR) in both front line and relapsed/refractory (R/R) settings with a primary objective to determine 2-year progression free survival(PFS) in patients with MCL, marginal zone, lymphoplasmacytic, small lymphocytic, and relapsed follicular lymphomas (NCT00980395). Methods: Adult patients with histologically confirmed mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic lymphoma (both frontline and relapsed), or follicular lymphoma (relapsed/refractory), platelet counts ≥100,000, absolute neutrophil count >1000, creatinine clearance >20 ml/min who met treatment criteria were eligible. Prior treatment with bortezomib and/or rituximab was acceptable. Patients with grade 2 or greater peripheral neuropathy, myocardial infarction in the last 6 months or other active cardiac ailments were excluded. Rituximab 375 mg/m2 IV day 1, Cladribine 4 mg/m2 IV over 2 hours days 1-5, Bortezomib 1.3 mg/m2 IV days 1 and 4 were administered every 28 days, which constituted a cycle, for a maximum of 6 cycles. Results: Twenty-four patients were enrolled with planned follow-up of two years from end of treatment. Eleven patients had mantle cell lymphoma (MCL) and rest was indolent lymphomas; 42% received the treatment as frontline. All patients received at least one cycle. Median age was 65 years, 75% were male, 96% were Caucasians, 54% of patients had bulky disease (>5cm), and 75% of patients had bone marrow involvement. Fifty eight percent of patients had grade 3 or greater adverse events and 67% of patients did not receive all 6 cycles, with median number of cycles being 5. Most common grade 3/4 adverse events were leukopenia (33%), thrombocytopenia (25%), fatigue (21%) and anemia (4%). There were no deaths due to adverse events. Overall response rate was 92% and another 4% had stable disease. The overall CR rate was 33%, and duration of response for those in CR was 41.5 months. After a two year minimum follow-up, median progression free survival (PFS) was 42 months and median time to progression was 33 months. The overall 2 year PFS was 63%. The 2 year PFS in patients with no prior therapy and prior therapy were 78%, and 54% respectively. In patients with no prior therapy, median OS was not reached. Conclusion: This study shows VCR is an effective regimen in indolent and mantle cell lymphomas. This combination has better response rates that better than both single agent bortezomib and cladribine (Kay et al, 1992; Fridrik et al, 1998; Goy et al, JCO 2005). In combination, VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) was reported to have a complete response rate of 53 % and a median PFS of 24.7 months (Robak et al, NEJM 2015), and rituximab-cladribine-vorinostat had similar response rates (100%) but a CR rate of 69%(Spurgeon et al, ASH annual Meeting 2012). Rituximab-Cladribine combination is reported to have a response rate of 87% and a median PFS of 37.5 months (Spurgeon et al; Leuk Lymphoma 2011) which is slightly lower than our study. This regimen is associated with significant cytopenias leading to majority of patients not receiving all of the 6 planned cycles but has significant activity in mantle cell and indolent lymphomas. Figure 1 Figure 1. Disclosures Anwer: Seattle Genetics: Other: Advisory Board Participant; Incyte: Speakers Bureau. Persky:Gilead: Speakers Bureau; Merck: Research Funding; Spectrum: Research Funding. Puvvada:Spectrum: Other: Institutional Research Funding; Gilead: Speakers Bureau; Takeda: Other: Institutional Research Funding; Pharmacyclics: Other: Advisory Board participant; Seattle Genetics: Other: Advisory Board participant, Institutional Research Funding; Abbvie: Other: Advisory board participant