Pathology Results of Tissue Biopsy during Idelalisib-Associated Diarrhea/Colitis
Authors: Yeung Cecilia C.S. , Hockenbery David M. , Westerhoff Maria , Coutre Steven , Sedlak Ruth H. , Dubowy Ronald L. , Marcondes A. Mario , Munugalavadla Veerendra , Taylor Kerry , Bosch Francesc 
Published: October 2019

Abstract
Introduction: Idelalisib (IDELA) is a targeted PI3Kd inhibitor approved for the treatment of patients (pts) with relapsed CLL/FL. The established toxicity profile of IDELA includes diarrhea/colitis with a grade ≥3 incidence of ~15%. Here, we present the histopathological-as well as immune profiling and viral testing-results of gastrointestinal tissue specimens from pts who received diagnostic biopsies for abdominal pain or diarrhea during treatment with IDELA.
Methods: Intestinal biopsy specimens obtained from 31 pts during treatment with IDELA across 10 trials (monotherapy n = 3 or in combination with: rituximab n = 9; ofatumumab n = 14; and bendamustine/rituximab n = 5) were reviewed separately by 2 independent pathologists with expertise in the area of gastrointestinal and transplant pathology. If more than 1 biopsy time point per pt was available (n = 3), all time points would be evaluated and, if discordant, would be reported separately. Evaluation included hematoxylin and eosin stain; and immunohistochemistry (IHC) for CD3, CD8, FOXP3, CD79a, CMV, and adenovirus (as adequate tissue allowed). Additionally, droplet digital PCR (ddPCR) was performed for cytomegalovirus (CMV), adenovirus, and human herpesvirus 6 (HHV-6). Colon/small bowel tissues from 18 normal individuals who underwent biopsy during routine screening colonoscopy and had normal pathology results were included as controls.
Results: Baseline characteristics of pts included CLL n = 24 (77.4%) and iNHL n = 7 (22.6%), age range 50 to 82 years with median 65.6 years, male n = 19 (61.3%). IDELA median dose = 150 mg BID. Diarrhea/colitis (Grade 1-3) was reported in 24 cases (75%) including 1 case of hemorrhagic colitis. One patient each had concurrent laboratory-confirmed Mycobacterium avium-intracellulare and norovirus and 2 patients were excluded from histomorphological analysis, 1 due to celiac disease and 1 due to total loss of glands secondary to CMV. Four distinct morphological patterns were identified: 1) predominantly normal, 2) apoptotic, 3) inflammatory/ischemic, and 4) mixed apoptotic/inflammatory/ischemic. CMV IHC was performed in all 31 cases; 2 showed strong/moderate positivity, and 2 were weakly positive. Adenovirus IHC was performed on 29 specimens, and 1 was weakly positive. ddPCR performed on 27 formalin-fixed paraffin-embedded tissues identified 6 positive CMV cases (including all 4 IHC+ cases), 0 adenovirus cases, and 1 HHV-6-positive case. Among the CMV cases, the most common pattern was mixed, seen in 4 of 6 cases, whereas the most common morphologic feature was apoptosis, seen in 5 of 6 cases. A summary of findings is shown in Table 1.
Conclusion: In this subset of pts who underwent intestinal biopsy during IDELA clinical trials, most biopsies (87%) were performed in the context of ongoing diarrhea/colitis and the majority of tissue samples (90%) revealed some component of inflammation. Immune profiling by IHC showed increased Tregs in patterns associated with glandular destruction. Immunohistochemistry and ddPCR for virus in conjunction with microbiology studies revealed that in 28% of these cases, a pathogen was identified. This dataset suggests that in a significant number of cases, idelalisib-associated diarrhea/colitis may be due to an infectious etiology secondary to immune dysfunction that results in either an inflammatory/ischemic or a mixed histologic pattern; however, the majority of these cases have no identifiable infectious etiology. Based on these findings, we recommend that a workup of pts with idelalisib-associated diarrhea/colitis should include a complete evaluation for infectious causes including intestinal biopsy when a pathogen is elusive with standard testing.

Disclosures
Yeung: Gilead Sciences: Research Funding. Hockenbery:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Consultancy, Research Funding. Dubowy:Gilead Sciences: Employment, Equity Ownership. Marcondes:Gilead Sciences: Employment, Equity Ownership. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Bosch:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Research Funding.