Cutaneous Toxicities of PI3K Inhibitors: A Series of Two Cases and Review of the Literature

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. 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). The specificity of these molecular targets allows for higher dosage while limiting toxicity; however, cutaneous, endocrine, and gastrointestinal toxicities are common. We report two photoaccentuated duvelisib-induced skin eruptions, both requiring interruption of therapy and resolving with systemic steroids.

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 photoaccentuated duvelisib-induced skin eruptions, both requiring interruption of therapy and resolving with systemic steroids. 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 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 rechallenge of duvelisib. Multiple punch biopsies were performed throughout the evolution of the patient's rash. Histopathology demonstrated parakeratosis, Copyright 2020 The National Society for Cutaneous Medicine 588  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 photoaccentuated, 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 rechallenge, 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 subclass 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][5][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][8][9][10][11][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
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 Tregulatory 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, rechallenge 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