SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 585 BRIEF ARTICLES Cutaneous Toxicities of PI3K Inhibitors: A Series of Two Cases and Review of the Literature Simran A. Chadha, BS1, Jennifer L. Shastry, MD2, Joel C. Sunshine, MD2, Jennifer Choi, MD2*, Lauren Guggina, MD2* 1Northwestern University, Feinberg School of Medicine, Chicago, IL 2Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL *These authors contributed equally Phosphoinositide 3-kinase (PI3K) inhibitors are novel small molecule targeted inhibitors approved for the treatment of multiple hematologic malignancies, namely relapsed or refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and breast cancer.1,2 Isoform-specific PI3K inhibitors are a subclass of this broader category, consisting of agents targeting the p110- isoform (alpelisib and taselisib), the p110- isoform (idelalisib), and the p110- and p110- isoforms (duvelisib).3 The specificity of these molecular targets allows for higher dosage while limiting toxicity; however, cutaneous, endocrine, and gastrointestinal toxicities are common. We report two photo- accentuated duvelisib-induced skin eruptions, both requiring interruption of therapy and resolving with systemic steroids. Case 1 A 62-year-old man with a history of angioimmunoblastic T cell lymphoma (AITCL) presented with a pruritic skin eruption in the spring. The patient’s AITCL ABSTRACT Phosphoinositide 3-kinase (PI3K) inhibitors are a class of antineoplastic agents currently approved for the treatment of multiple hematologic malignancies and breast cancer. These medications have specific molecular targets to limit toxicity; however, cutaneous adverse effects are frequently reported and can require cessation of therapy. Morbilliform, eczematous, psoriasiform, and pityriasis rubra pilaris-like eruptions are most common, though exfoliative dermatitis and Stevens-Johnson syndrome/toxic epidermal necrolysis have also been reported. We highlight two cases of photo- accentuated skin reactions to duvelisib, a p110- and p110- isoform inhibitor. Both cases required oral corticosteroids and interruption of therapy for definitive management due to severity. While one patient was able to tolerate re-challenge with duvelisib and continue on therapy, both patients experienced recurrence of cutaneous eruptions with repeat exposure, establishing a notable temporal correlation. Thus, these cases contribute a novel presentation of adverse reactions to PI3K inhibitors to existing literature. INTRODUCTION CASE PRESENTATION SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 586 Figure 1. Case 1 clinical image of the initial eruption reveals photo-accentuated erythematous scaly plaques on the face and neck (a). Clinical image of the recurrent eruption demonstrates pink-orange scaly plaques on the face, neck, trunk, and extremities with sparing of the antecubital fossae (b). Biopsies of the left forearm (c) and the left upper arm (d) show a chronic spongiotic dermatitis with scattered necrotic keratinocytes and a dermal infiltrate composed of lymphocytes and eosinophils (H&E, 100x, 200x). had been previously treated with chemotherapy and autologous stem cell transplant, initially achieving complete remission. Recurrence of the AITCL prompted initiation of duvelisib three months prior to development of the skin eruption. On physical examination, the patient was noted to have erythematous, scaly thin plaques on the face, neck, dorsal hands and upper extremities with a psoriasiform appearance, accentuated in sun exposed areas. This photo-accentuated psoriasiform eruption improved after duvelisib was held for 1 month due to a transaminitis. One month after restarting the duvelisib, the patient presented with a new skin eruption. Physical examination revealed confluent, scaly, erythematous plaques on the face, scalp, and trunk (Figure 1a and 1b). There SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 587 Figure 2. Case 2 clinical images reveal erythematous papules coalescing into plaques on the neck, shoulders, and forearms with photo-accentuation (a, b). Biopsy of the left arm (c) demonstrates a spongiotic epidermis with vesiculation, significant papillary dermal edema, and a perivascular and interstitial dermal infiltrate (H&E, 100x). Higher power (d) reveals a perivascular and interstitial infiltrate composed of lymphocytes and eosinophils (H&E, 200x). were pink-orange scaly plaques on the bilateral palms with sharp demarcation at the wrists, well-demarcated pink plaques on the extremities, and areas of spared skin in flexural areas clinically resembling pityriasis interrupted due to the eruption; his skin improved with oral and topical steroids, and then worsened with subsequent re- challenge of duvelisib. Multiple punch biopsies were performed throughout the evolution of the patient’s rash. Histopathology demonstrated parakeratosis, SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 588 Table 1. Previously Reported Cutaneous Toxicities of PI3K Inhibitors Age/ Sex Malignancy PI3K inhibitor Time to reaction Morphology Histopathology Reaction type Treatment of cutaneous eruption PI3K therapy outcome Successful re- challenge (if interrupted)? Associated adverse events Case 1 (our case) 62 M AITCL Duvelisib 3 months Photo-accentuated psoriasisform pink-orange scaly plaques on the face, neck, forearms, which generalized with areas of sparing Parakeratosis, acanthosis, and spongiosis of epidermis, lymphocytic infiltrate with neutrophils and eosinophils in the upper dermis Photo- accentuated PRP-like Systemic corticosteroids, topical corticosteroids Interrupted No Transaminitis Case 2 (our case) 55 F PTCL Duvelisib 1 month Photo-accentuated erythematous papules coalescing into plaques on the face, neck, arms Perivascular and interstitial dermatitis with eosinophils Photo- accentuated morbilliform eruption Systemic corticosteroids, topical corticosteroids, oral antihistamines Interrupted Yes Transaminitis, neutropenia, fatigue Gabriel et al. 65 M CLL Idelalisib 3 months Exfoliative rash with diffuse scaling of torso, extremities, tongue, glans penis, and desquamation of soles Not performed Exfoliative dermatitis Not specified Not specified N/A Transaminitis, normocytic anemia Hammami et al. 56 M FL Idelalisib 4 months Skin eruption, unspecified Subacute spongiotic dermatitis, superficial dermal lymphohistiocytic infiltrate with eosinophils Eczematous Systemic corticosteroids Discontinued N/A Colitis Huilaja et al. 61 M CLL Idelalisib 1 months Macular erythematous eruption with desquamation on upper arms/trunk, peeling on palms Hyperkeratosis and focal parakeratosis, acanthotic thickening, focal spongiosis, perivascular lymphohistiocytic infiltrate with some eosinophils Not specified Oral corticosteroids, topical corticosteroids Discontinued N/A Transaminitis Machan et al. 82 F FL Idelalisib 11 months Erythematosquamous papules and plaques on back/buttocks with pustules of scalp/forehead T-cell infiltration with psoriasiform epidermal hyperplasia, subcorneal pustule, and mild perivascular lymphocytic infiltrate Psoriasiform Topical corticosteroids Interrupted Yes None Dewan et al. 59 M CLL P110-delta inhibitor 17 months Photodistributed erythematous papules and large plaques on arms/legs, which spread to face, scalp, trunk, soles Psoriasiform epidermal hyperplasia, mild spongiosis, parakeratosis, intraepidermal/intracorneal neutrophils Psoriasiform Oral acitretin, topical corticosteroids, photoprotection Interrupted Yes Not specified 57 M CLL P110- delta/gamma inhibitor 15 days Guttate papules and erythematous plaques with overlying micaceous scale on knees and intertriginous areas, nail pitting, palmoplantar pustules Psoriasiform dermatitis with inflamed parakeratosis Psoriasiform Topical corticosteroids, topical tacrolimus, topical retinoid Interrupted Yes Not specified 81 M SLL/CLL P110-delta inhibitor 5 months Thin erythematous papules coalescing into plaques with overlying micaceous scale on trunk/extremities Spongiotic and suprabasilar acantholysis with superficial dermal lymphocytic infiltrate Psoriasiform Topical corticosteroids Discontinued N/A Not specified 72 M MZL P110-delta inhibitor 3 months Thin erythematous plaques on gluteal cleft, inguinal folds; large plaques with overlying micaceous scale on neck, chest, extremities, scalp Not performed Psoriasiform Topical corticosteroids Discontinued (for colitis adverse effect) N/A Colitis Dewan et al. 40s F Anaplastic oligoden- droglioma Dual pan- class I PI3K inhibitor 4 days Pruritic photodistributed orange-pink erythroderma with islands of sparing and overlying fine desquamative scale, palmoplantar keratoderma Pityriasiform changes with alternating ortho and parakeratosis, spongiotic dermatitis, and numerous eosinophils PRP-like Systemic corticosteroids, oral acitretin, topical steroids, oral antihistamines Not specified N/A Essential tremor 60s M CLL Idelalisib 5 months Diffuse orange-red erythroderma with islands of sparing, nonscarring alopecia, palmoplantar keratoderma Pityriasiform changes with alternating ortho and parakeratosis, spongiotic dermatitis, and numerous eosinophils PRP-like Systemic corticosteroids, oral acitretin, topical corticosteroids, topical retinoids Discontinued N/A Leukopenia, anemia, thrombocyto penia, suppurative adenitis 60s M SLL Idelalisib 6 weeks Diffuse orange-red patches with follicular prominence and islands of sparing over trunk/extremities Subacute spongiotic dermatitis with pityriasiform scale and superficial perivascular lymphocytic infiltrate PRP-ilke Systemic corticosteroids, topical corticosteroids Discontinued N/A Peripheral eosinophilia, transaminitis Abbreviations: pityriasis rubra pilaris (PRP), angioimmunoblastic T cell lymphoma (AITCL), peripheral T cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL). SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 589 acanthosis, and spongiosis of the epidermis and a lymphocytic infiltrate with occasional neutrophils and eosinophils in the upper dermis. Occasional necrotic keratinocytes were seen (Figure 1c and 1d). Repeat imaging demonstrated no evidence of lymphoma; his AITCL was considered to be in remission on duvelisib. Given worsening of the rash after multiple re-challenges, the patient was diagnosed with a photo- accentuated, duvelisib-induced PRP-like skin eruption. Case 2 A 55-year-old woman with a history of primary refractory CD30-positive peripheral T cell lymphoma (PTCL) presented with a pruritic eruption on the face, neck, and upper extremities in the summer. The PTCL was previously treated with chemotherapy; however, duvelisib was initiated after repeat imaging and lymph node biopsy revealed progressive disease. One month after introducing duvelisib, the patient developed concurrent skin rash and transaminitis. Within five days, the rash progressed in severity and duvelisib was held. Physical examination revealed photo-accentuated erythematous papules coalescing into plaques on the face, chest, dorsal arms (Figure 2a and 2b). A punch biopsy of her left forearm was performed, and histopathologic analysis demonstrated a perivascular and interstitial dermatitis with eosinophils (Figure 2c and 2d). The patient was treated with topical triamcinolone, antihistamines, and an oral prednisone taper. Within three weeks, the rash significantly improved and duvelisib was resumed at a lower dose. After resumption of duvelisib, the patient had persistent pruritus and xerosis, managed with oral antihistamines and topical emollients. Her rash recurred three and a half months later, albeit with markedly decreased severity, and rapidly resolved with topical triamcinolone. She remains stable on duvelisib with complete tumor response. Given temporal association with duvelisib initiation and recurrence with re- challenge, the patient was diagnosed with duvelisib-induced photo-accentuated morbilliform skin eruption. PI3K inhibitors block the PI3K/AKT/mTOR pathway, a signaling cascade that regulates cell proliferation, growth, motility, and survival through extracellular signaling. Isoform-specific PI3K inhibitors are a sub- class that take advantage of this pathway’s impact on oncogenesis.3 Cutaneous adverse events are commonly observed, occurring in 17-45% of patients, varying per isoform target.4-6 Though the majority of eruptions are mild, skin toxicities are the second most common grade 3 and 4 toxicity, per Common Terminology Criteria for Adverse Events (CTCAE) grading, for alpelisib and duvelisib.6 Cutaneous eruptions related to PI3K inhibitors present variably and can develop days to months after drug initiation (Table 1). A diffuse maculopapular rash with or without pruritus and xerosis is the most frequently reported skin manifestation; however phase I and II trials did not characterize cutaneous reactions with specific descriptors.3 Case reports have delineated various clinical presentations, including, but not limited to, eczematous, psoriasiform, and PRP-like eruptions, as well as exfoliative dermatitis and Stevens- Johnson syndrome/toxic epidermal necrolysis.3,5,7-12 Histopathology for specific eruptions largely resembles the clinical correlate, and non-specific eruptions commonly reveal perivascular and dermal infiltration by eosinophils and lymphocytes, DISCUSSION SKIN November 2020 Volume 4 Issue 6 Copyright 2020 The National Society for Cutaneous Medicine 590 with or without epidermal spongiosis.5 This report of two cases of PI3K inhibitor-induced rash adds photo-accentuated eruptions to the clinical presentations previously reported in the literature. The pathophysiology of these toxicities is attributed to the effects of PI3K inhibition on subsets of lymphocytes, including T- regulatory cells and differentiation of Th1 and Th2 lymphocytes. Disruption in immune regulation and self-tolerance thus results in toxicities of an autoimmune nature.1 Of note, PI3K inhibitors are effective photosensitizing agents and demonstrated potential utility in photodynamic therapy for cancer, thereby suggesting a possible mechanism underlying the photo-accentuated cutaneous toxicity noted in this case series.13 According to CTCAE guidelines, eruptions should be stratified by severity corresponding to body surface area involvement. Lower grade toxicities can be managed with high potency topical corticosteroids and antihistamines, whereas severe and persistent toxicities require systemic corticosteroids and possible interruption of PI3K inhibitor therapy. Notably, if therapy is interrupted, re- challenge at a lower dosage can be trialed. Close monitoring is paramount, as one in four patients experience recurrence of cutaneous toxicity with resumption of therapy, as reflected in this case series.5 While PI3K inhibitors are currently approved for a narrow range of malignancies, ongoing clinical trials present promising data for future utility in treatment of multiple solid tumors. Thus, the cutaneous toxicities of PI3K inhibitors merit recognition as the use of these agents expands.12 Conflict of Interest Disclosures: None Funding: None Corresponding Author: Lauren Guggina, MD Northwestern University Feinberg School of Medicine 676 North Saint Clair Chicago, IL 60611 Email: lguggina@nm.org References: 1. Greenwell IB, Ip A, Cohen JB. PI3K Inhibitors: Understanding Toxicity Mechanisms and Management. Oncology (Williston Park). 2017;31(11):821-828. 2. Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. 3. Nunnery SE, Mayer IA. Management of toxicity to isoform alpha-specific PI3K inhibitors. Ann Oncol. 2019;30 Suppl 10:x21-x26. 4. Flinn IW, Patel M, Oki Y, et al. Duvelisib, an oral dual PI3K-delta, gamma inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. Am J Hematol. 2018;93(11):1311-1317. 5. Ransohoff JD, Kwong BY. Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. Clin Lymphoma Myeloma Leuk. 2017;17(12):834-851. 6. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898. 7. Gabriel JG, Kapila A, Gonzalez-Estrada A. A Severe Case of Cutaneous Adverse Drug Reaction Secondary to a Novice Drug: Idelalisib. J Investig Med High Impact Case Rep. 2017;5(2):2324709617711463. 8. Hammami MB, Al-Taee A, Meeks M, et al. Idelalisib- induced colitis and skin eruption mimicking graft- versus-host disease. Clin J Gastroenterol. 2017;10(2):142-146. 9. Huilaja L, Lindgren O, Soronen M, Siitonen T, Tasanen K. A slowly developed severe cutaneous adverse reaction to idelalisib. J Eur Acad Dermatol Venereol. 2018;32(5):e192-e193. 10. Machan S, Plaza C, Perez-Gonzalez Y, Rodriguez- Pinilla M, Requena L, Cordoba R. Management of psoriasis-like rash associated with idelalisib monotherapy in a patient with refractory follicular lymphoma: a case report. J Med Case Rep. 2020;14(1):35. 11. Dewan AK, Sowerby L, Jadeja S, et al. Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition. Clin Exp Dermatol. 2018;43(8):890-894. 12. Dewan AK, Gupta S, Bach DQ, et al. Psoriasiform eruptions secondary to phosphoinositide 3-kinase inhibition. JAAD Case Rep. 2019;5(5):401-405. 13. Hayashida Y, Ikeda Y, Sawada K, et al. Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor. Int J Cancer. 2016;139(3):700-711. mailto:lguggina@nm.org mailto:lguggina@nm.org