Sample CME Manuscript Submission: Response to the Article by Pham Et Al Entitled “review BRAF Inhibition and the Spectrum of Granulomatous Reactions”

To the Editor: We read with great interest the recently published literature review by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar regarding the spectrum of granulomatous reactions (GRs) associated with BRAF inhibitors. In agreement with the authors regarding the variability in GR diagnosis and relevant inconsistencies in reported cases, we would like to add the findings on 18 patients with GR related to BRAF inhibitors from the oncodermatology-specialized group of The European Academy of Dermatology and Venerology task force “Dermatology for Cancer Patients.”In our multicenter cohort, GRs were found slightly more often in men (61%), with a median age of 51 years at diagnosis (Tables I and II). Most often, GRs occurred with the combination of dabrafenib and trametinib (n = 9, 50%). GRs occurred on average 11 months after treatment introduction. In our cohort of patients, GRs mostly involved the skin (n = 13, 72%), as previously reported in the study by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google ScholarTable ICharacteristics of patients on BRAF inhibitors and granulomatous reaction developmentPatientsSiteSexAge at GR diagnosis, yPrimary cancerDrugPrevious ICITime to GR, moDiagnosis with histological confirmation onTreatment decisionSarcoidosis treatmentOutcome for sarcoidosisBest response to therapy (for cancer)Follow-up, moSkinMediastinalPulmonary1DüsseldorfM49MelanomaDabrafenib/trametinibNo26SkinContinuedCSRefractoryDP24YesYesNo2DüsseldorfM62MelanomaVemurafenib/cobimetinibPembrolizumab2SkinSwitchNonePRPR21YesYesNo3MadridM56NSCLCVemurafenibNo9SkinContinuedCS + MTXCRPR13YesYesYes4BarcelonaM62MelanomaDabrafenib/trametinibPembrolizumab3SkinContinuedNoneCRPR4YesYesNo5BarcelonaF79NLCHDabrafenibInterferon α8SkinStoppedCSPRPR6YesNoNo6ToulouseM49MelanomaVemurafenib then encorafenibNo52Bronchial+ lymph nodesStoppedCSCRCR60NoYesYes7ToulouseM71MelanomaDabrafenib/trametinibPembrolizumab6SkinStoppedNoneCRPR18YesNoNo8ToulouseF52MelanomaDabrafenib/trametinibNo5SkinStoppedNoneCRCR33YesNoNo9ToulouseF24HSVemurafenibNo24Lymph nodes + musclesContinuedCS + MTXPRCR28YesYesNo10ToulouseM36MelanomaVemurafenib then Dabrafenib/trametinibIpilimumab/nivolumab19BronchialContinuedCSPRCR32NoYesYes11ToulouseF54MelanomaDabrafenib/trametinibNo2Lymph nodesStoppedNoneSDCR65YesYesNo12ThessalonikiF61NSCLCCobimetinib/trametinibNo8Lymph nodesContinuedCSCRPR12YesYesNo13ParisM46MelanomaEncorafenib/binimetinibIpilimumab7SkinContinuedNoneRefractoryCR19YesNoYes14ParisF31MelanomaDabrafenib/trametinibPembrolizumab12BronchialStoppedNonePRCR20NoYesYes15ParisF76MelanomaVemurafenib/cobimetinibNo9NasalStoppedNoneCRPR31NoNoNo16ParisM32MelanomaDabrafenib/trametinibNivolumab6SkinContinuedNonePRCR5YesYesNo17ParisM25MelanomaDabrafenib/trametinibNo3Lymph nodesStoppedNoneCRCR1YesNoYes18ParisM51MelanomaDabrafenib/trametinibPembrolizumab9Lymph nodesContinuedNonePRCR1NoYesNoCR, Complete response; CS, corticosteroids; DP, disease progression; GR, granulomatous reaction; HS, histiocytic sarcoma; ICI, immune check point inhibitor; MTX, methotrexate; NLCH, non–langerhans cell histiocytosis; NSCLC, non–small cell lung cancer; PR, partial response; SD, stable disease. Open table in a new tab Table IIComparison between data reported in the study by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar and those in our seriesPatient characteristicsStudy by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google ScholarPresent seriesMean age (range), y53 (3-82)51 (24-79)Female (%)25/51 (49%)7/18 (39%)Vemurafenib (%)20/54 (37%)4/18 (22%)Dabrafenib (%)32/54 (59%)10/18 (56%)Indication for melanoma (%)45/51 (88%)14/18 (78%)Time to GR, mo10 (1-60)11 (2-52)Skin-limited GR (%)37/55 (67%)3/18 (17%)Skin + systemic GR (%)8/55 (15%)10/18 (55%)No skin involvement (%)10/55 (18%)5/18 (28%)BRAF inhibitor discontinuation (%)18/51 (35%)8/18 (44%)Systemic corticosteroids required (%)11/55 (20%)7/18 (39%)Response tumor: progression (%)14/32 (44%)1/18 (5%)Complete response (%)14/32 (44%)10/18 (56%)Partial response (%)4/32 (13%)7/18 (39%)GR, Granulomatous reaction. Open table in a new tab However, we observed manifestations exclusively on the skin in only 3 (17%) patients—lower than the 67% recently reported.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar The most representative skin lesions included erythema nodosum, isomorphic skin reactions, granulomatous nodules, and macrocheilitis.Systemic manifestations included lymph node enlargement (n = 12, 66%) and pulmonary infiltrates (n = 6, 33%). Five (28%) patients had systemic manifestations with no skin involvement, similar to the results reported by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google ScholarPham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar reported that 20% of patients with GRs required systemic corticosteroids; in our study, 7 (39%) patients with GRs required systemic corticosteroids, possibly a direct consequence of the higher rate of systemic manifestations of GRs. A favorable outcome was observed in 89% of our patients; however, 2 patients were refractory to systemic corticosteroids and required second-line therapy with methotrexate.BRAF inhibitor was discontinued in 1 patient (5%) with GR involving the skin only (similar to 5% reported in the study by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar).GRs that are induced by BRAF inhibitors are an uncommon adverse event. Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar recently described the largest series of BRAF inhibitor–related GRs based on data from the literature. In contrast to the findings of Pham et al,1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar the patients in our study were recruited through clinical consultation by a homogeneous group of European experts in oncodermatology and a higher rate of systemic involvement was found in our cohort, requiring management with systemic immunosuppressive therapies. Interestingly, 50% of our patients had been pretreated with immune checkpoint inhibitors—a finding not reported by Pham et al,1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar when this exposure is also known to be associated with the development of GRs.2Apalla Z. Nikolaou V. Fattore D. et al.European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force ‘Dermatology for cancer patients’ position statement.J Eur Acad Dermatol Venereol. 2022; 36: 332-350Crossref PubMed Scopus (7) Google Scholar,3Kumar A.B. Bryce A. Vishnu P. Markovic S. McEvoy M. Associations of cutaneous immune-related adverse effects of immunotherapy with treatment response in patients with metastatic melanoma.SKIN. 2021; 5: 108-117Crossref Google ScholarFinally, after a median follow-up time of 20 months, only 5% of our patients showed tumor progression. This could support the hypothesis that GR represents a positive prognosis marker, like immune checkpoint inhibitor–induced vitiligo, associated with a favorable tumor response in melanoma.4Rzepecki A.K. Cheng H. McLellan B.N. Cutaneous toxicity as a predictive biomarker for clinical outcome in patients receiving anticancer therapy.J Am Acad Dermatol. 2018; 79: 545-555Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarIn conclusion, we report 18 additional patients treated with BRAF inhibitors who developed GRs. Our results support the data extracted from a recent study by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar GRs are not necessarily associated with a worse overall prognosis and do not usually require BRAF inhibitor therapy discontinuation. Although skin GRs represent the most frequent diagnosis and may indeed occur exclusively, they should prompt an extensive examination for the detection of systemic involvement, as observed in most of our patients. To the Editor: We read with great interest the recently published literature review by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar regarding the spectrum of granulomatous reactions (GRs) associated with BRAF inhibitors. In agreement with the authors regarding the variability in GR diagnosis and relevant inconsistencies in reported cases, we would like to add the findings on 18 patients with GR related to BRAF inhibitors from the oncodermatology-specialized group of The European Academy of Dermatology and Venerology task force “Dermatology for Cancer Patients.” In our multicenter cohort, GRs were found slightly more often in men (61%), with a median age of 51 years at diagnosis (Tables I and II). Most often, GRs occurred with the combination of dabrafenib and trametinib (n = 9, 50%). GRs occurred on average 11 months after treatment introduction. In our cohort of patients, GRs mostly involved the skin (n = 13, 72%), as previously reported in the study by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar CR, Complete response; CS, corticosteroids; DP, disease progression; GR, granulomatous reaction; HS, histiocytic sarcoma; ICI, immune check point inhibitor; MTX, methotrexate; NLCH, non–langerhans cell histiocytosis; NSCLC, non–small cell lung cancer; PR, partial response; SD, stable disease. GR, Granulomatous reaction. However, we observed manifestations exclusively on the skin in only 3 (17%) patients—lower than the 67% recently reported.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar The most representative skin lesions included erythema nodosum, isomorphic skin reactions, granulomatous nodules, and macrocheilitis. Systemic manifestations included lymph node enlargement (n = 12, 66%) and pulmonary infiltrates (n = 6, 33%). Five (28%) patients had systemic manifestations with no skin involvement, similar to the results reported by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar reported that 20% of patients with GRs required systemic corticosteroids; in our study, 7 (39%) patients with GRs required systemic corticosteroids, possibly a direct consequence of the higher rate of systemic manifestations of GRs. A favorable outcome was observed in 89% of our patients; however, 2 patients were refractory to systemic corticosteroids and required second-line therapy with methotrexate. BRAF inhibitor was discontinued in 1 patient (5%) with GR involving the skin only (similar to 5% reported in the study by Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar). GRs that are induced by BRAF inhibitors are an uncommon adverse event. Pham et al1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar recently described the largest series of BRAF inhibitor–related GRs based on data from the literature. In contrast to the findings of Pham et al,1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar the patients in our study were recruited through clinical consultation by a homogeneous group of European experts in oncodermatology and a higher rate of systemic involvement was found in our cohort, requiring management with systemic immunosuppressive therapies. Interestingly, 50% of our patients had been pretreated with immune checkpoint inhibitors—a finding not reported by Pham et al,1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar when this exposure is also known to be associated with the development of GRs.2Apalla Z. Nikolaou V. Fattore D. et al.European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force ‘Dermatology for cancer patients’ position statement.J Eur Acad Dermatol Venereol. 2022; 36: 332-350Crossref PubMed Scopus (7) Google Scholar,3Kumar A.B. Bryce A. Vishnu P. Markovic S. McEvoy M. Associations of cutaneous immune-related adverse effects of immunotherapy with treatment response in patients with metastatic melanoma.SKIN. 2021; 5: 108-117Crossref Google Scholar Finally, after a median follow-up time of 20 months, only 5% of our patients showed tumor progression. This could support the hypothesis that GR represents a positive prognosis marker, like immune checkpoint inhibitor–induced vitiligo, associated with a favorable tumor response in melanoma.4Rzepecki A.K. Cheng H. McLellan B.N. Cutaneous toxicity as a predictive biomarker for clinical outcome in patients receiving anticancer therapy.J Am Acad Dermatol. 2018; 79: 545-555Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In conclusion, we report 18 additional patients treated with BRAF inhibitors who developed GRs. Our results support the data extracted from a recent study by Pham et al.1Pham J.P. Star P. Phan K. Loh Y. Joshua A.M. Smith A. Review BRAF inhibition and the spectrum of granulomatous reactions.J Am Acad Dermatol. 2021; (S0190-9622(21)02688-8)Abstract Full Text Full Text PDF PubMed Google Scholar GRs are not necessarily associated with a worse overall prognosis and do not usually require BRAF inhibitor therapy discontinuation. Although skin GRs represent the most frequent diagnosis and may indeed occur exclusively, they should prompt an extensive examination for the detection of systemic involvement, as observed in most of our patients. Dr Comont has received honoraria and/or research or educational support from AbbVie, AstraZeneca, Bristol Myers Squibb (Celgene), Novartis, and Takeda. Dr Freites-Martinez is a consultant for ISDIN, L´Oreal, Galderma, and Shook, Hardy & Bacon LLP and represents Sanofi Aventis US LLC. Drs Marcaillou, Dion, Baroudjian, Ezrine, Carrera, Anderle, Apalla, Pages, Lebbe, Meyer, and Sibaud have no conflicts of interest to declare.