Novel agents have revolutionized the treatment of cancer, resulting in many benefits for patients. These same agents, however, have been associated with new toxicity profiles compared with traditional chemotherapy. Most of these adverse events have been classified as mild or moderate, but unfortunately, severe and life-threatening complications also occur. This section will focus specifically on immunotherapy and subsequent gastrointestinal toxicity. The various approaches that will be discussed in this section include immune checkpoint inhibitors (ICIs), bispecific antibodies (BABs), chimeric antigen receptor (CAR) T cells, interleukin-2 (IL-2) and interferon-α (IFN-α), which attack cancer cells by activating the immune effector cells and disrupting immune tolerance. Immune therapies can be associated with durable responses; however, they are also associated with multiple toxicities as the activated immune system also attacks normal body cells along with the tumor tissue, resulting in several toxicities. The gastrointestinal system is significantly impacted, resulting in nausea, vomiting, anorexia, diarrhea, colitis, and hepatitis. There have been reports of acute pancreatitis due to ICIs, but clinical pancreatitis is rare and may be considered anecdotal at this time.
IMMUNE CHECKPOINT INHIBITORS
Currently, there are several ICIs that are approved by the US Food and Drug Administration (FDA). Ipilimumab, an anti-cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibody, was the first ICI approved to be used in metastatic melanoma. Nivolumab and pembrolizumab, which target programmed cell death protein-1 (PD-1) have been approved for use in melanoma, metastatic non–small-cell lung cancer (NSCLC), head and neck squamous cell cancer, urothelial carcinoma, gastric adenocarcinoma, and mismatch repair deficient solid tumors, as well as for classic Hodgkin’s lymphoma. Nivolumab is also approved for use in hepatocellular carcinoma and in patients with renal cell carcinoma. The combination of nivolumab and ipilimumab has been approved by the FDA for treatment of metastatic melanoma, renal cell carcinoma, and non-small cell lung cancer. Recently, programmed cell death protein-ligand 1 (PD-L1) antibodies have been approved, namely, atezolizumab (urothelial cancer, triple negative breast cancer and NSCLC) durvalumab (urothelial cancer) and avelumab (Merkel cell carcinoma and urothelial cancer) which also block the PD-1 pathway. This field is rapidly evolving, as new agents and combinations continue to be discovered and tested.
BISPECIFIC ENGAGER OF T-CELL ACTIVITY
Blinatumomab is a novel agent for the treatment of B-precursor acute lymphoblastic leukemia (ALL) that has demonstrated encouraging response rates in the setting of minimal residual disease (MRD)-positive (80% complete remission) and relapsed/refractory (R/R) patients. Blinatumomab is a monoclonal antibody which functions as a bispecific T cell engager, or BiTE, that is directed against CD19 on B cells and against CD3 on T cells. It is approved by the FDA for the treatment of R/R, Philadelphia (Ph)-negative and positive B-precursor ALL in adults and children. Due to the above success, the incorporation of blinatumomab in ALL patients in combination with chemotherapy, targeted therapies, or other immunotherapeutic approaches is currently being actively investigated.
CHIMERIC ANTIGEN RECEPTOR T CELLS
In this emerging treatment modality, T cells are isolated from a patient, genetically engineered to express a CAR, and reintroduced into the patient. CAR T cells have demonstrated efficacy primarily in the treatment of relapsed or refractory ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma. In August 2017, the FDA approved the first anti-CD19 CAR T cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed and/or refractory B-cell precursor ALL. In October 2017, the FDA approved axicabtagene ciloleucel for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
High-dose IL-2 was the first immunotherapy approved for treatment of metastatic melanoma based on durable responses observed, but recently its use has fallen out of favor due to significant toxicities. IL-2 is also approved for the treatment of renal cell carcinoma.
Patients with resected stage II or III melanoma are at high risk of recurrence. Adjuvant IFN-α has been used in the past to decrease the risk of recurrence of melanoma.
Agents and Mechanism of Action
IMMUNE CHECKPOINT INHIBITORS
Checkpoint inhibitors work by the mechanism of “inhibition of inhibition” and thereafter stimulating the immune system by attenuating tolerance and can result in overwhelming inflammation, tissue damage, and autoimmunity. Checkpoint inhibitors work by inhibition of CTLA-4, PD-1 or PD-2; their ligands that normally limit immune reactions in order to avoid tissue damage, allow tolerance. Ipilimumab inhibits CTLA-4, an inhibitory receptor that is constitutively expressed on CD25(+) CD4(+) T-regulatory cells. CTLA-4 is upregulated on activated T cells and transmits an inhibitory signal to downregulate the immune response, thus acting as an immune checkpoint. As ipilimumab inhibits this signaling, it depletes T-regulatory cells and impairs their function in the blood or tumor microenvironment, thus maintaining T-effector cell activation, and increasing antitumor immunity. PD-1 is an immune checkpoint expressed on the surface of activated T cells. PD-L1 is selectively expressed on many tumors and on cells within the tumor microenvironment in response to inflammatory stimuli, such as interferon-γ. Signaling through the PD-1 pathway results in inhibition of cytokine production and apoptosis of PD-1+ tumor-infiltrating T cells. Along with the activation of the effector T lymphocytes, the ICI leads to the depletion of the regulatory T cells. Depletion of the regulatory T cells removes one of the most important antiinflammatory mechanisms of the immune system because these cells are responsible for the production of inhibitory cytokines, including, transforming growth factor-β, IL-10, and IL-35. By inhibition of this tolerance mechanism, ICIs stimulate cytotoxic T lymphocytes to kill tumor cells, and, as an off-target effect, also result in immune system activation and reactivity against the body’s own organs and tissues. They are known as immune related adverse events (irAEs) and are reported in about 85% of patients after treatment with ipilimumab and up to 70% of patients after blockade of the PD-1 axis. The frequency of severe, life-threatening or even fatal (grade ≥3) events is higher after ipilimumab (10%–40%) compared to nivolumab or pembrolizumab (<5%). , Combination of ICIs results in an increase in the incidence of severe toxicity. The various gastrointestinal (GI) manifestations of ICIs include nausea, vomiting, diarrhea, colitis, and hepatitis.
GI Manifestations With Immune Checkpoint Inhibitors
Gastrointestinal tract irAEs following anti-CTLA-4 inhibitors can range from mild diarrhea to severe colitis, or even death. The most common presentation is diarrhea (27%), followed by colitis. Severe enterocolitis unresponsive to immunosuppressive therapy that may even require a subtotal colectomy, as well as perforation or intractable diarrhea, has been reported in the early trials. These are now rare as the condition is recognized and treated aggressively. The median time of onset of ipilimumab-associated colitis is about 34 days. Some reports, however, note a correlation between adverse events and tumor regression, suggesting that toxicity may serve as evidence of immune activation.
The number of adverse events with anti-PD-1 therapies has been reported to be less than with anti-CTLA-4. Nivolumab treatment resulted in diarrhea and colitis in 17% of melanoma patients, with grade 3 toxicities in only 1.2% of patients. Pembrolizumab resulted in colitis in 2.8% of patients, and here a positive correlation was noted between the dosage and the adverse events. The median time of onset of irAE was longer for pembrolizumab (18 weeks) than for nivolumab (6 weeks).
Combination Anti-CTLA-4 and Anti-PD-1 Therapy.
The frequency of colitis reported in the literature ranges from 8% to 27%, but the incidence of diarrhea is around 54% in patients treated with anti-CTLA-4 and anti-PD-1 combination therapy. In a meta-analysis of patients treated with ICIs, the relative risk (RR) of all-grade diarrhea and colitis was 1.64 (95% confidence interval [CI], 1.19 to 2.26; P = .002) and 10.35 (95% CI, 5.78 to 18.53; P < .001), the RR of high-grade diarrhea and colitis was reported to be 4.46 (95% CI, 1.46 to 13.57; P = .008) and 15.81 (95% CI, 6.34 to 39.42; P < .001), respectively. RR of upper-GI symptoms (e.g., vomiting) was not significant. Frequency of intestinal perforation has been described at approximately 1%. Compared with lower GI toxicities, the incidence of upper GI toxicities, namely, dysphagia, nausea/vomiting, and epigastric pain, is much less common.
Hepatitis Associated With Immune Checkpoint Inhibitors
Hepatitis is a less frequent complication of ICI therapy. It is characterized by elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), with or without increased bilirubin. The median onset of transaminase elevation is approximately 6 to 14 weeks after starting ICIs. Hepatitis is generally picked up on routine laboratory evaluation, but some patients may also present with fever or abdominal discomfort. Any-grade hepatic toxicities with ipilimumab 3 mg/kg monotherapy is less than 4% and this increases to up to 15% when ipilimumab is dosed at 10 mg/kg. , The incidence of hepatitis is about 5% in patients treated with anti-PD-1 inhibitors only, but this increases to about 25% to 30% grade 3-15% in patients on combination ipilimumab and nivolumab.
Pancreatitis Associated With Immune Checkpoint Inhibitors
Reports of acute pancreatitis with ICIs are rare, whereas asymptomatic elevation of lipase and amylase are more common. Of note is the rare complication of autoimmune endocrine dysfunction of the pancreas with acute onset of type 1 diabetes.
Celiac Disease Associated With Immune Checkpoint Inhibitors
Rare irAE such as celiac disease have also been observed with ICI treatment presenting with nausea, vomiting, diarrhea or abdominal pain. Histological features include intraepithelial lymphocytosis, lymphoplasmacytic inflammation of the lamina propria, villous atrophy and crypt hyperplasia on small bowel biopsy. A gluten-free diet is a reasonable strategy for these patients (either alone or in combination with immunosuppression).
Mechanism of Immune Checkpoint Inhibitor–Mediated GI and Hepatic Manifestations
Biomarkers Predictive of GI irAE.
A study with 162 advanced melanoma patients with pretreatment blood samples for biomarkers showed higher baseline levels of immune-related genes (CD3E, IL2RG, CD4, CD37, IL-32, and RAC-2), cell-cycle associated genes (SPATAN1, BANF1, BAT1, PCGF1, FP36L2, and WDR1) and genes involved in vesicle trafficking (PICALM, SNAP23, and VAMP3) in patients who developed GI irAEs compared to those who did not. Biomarkers were also studied 3 weeks after treatment with ICIs; CD177, a unique neutrophil surface marker that plays an essential role in neutrophil activation and also mediates migration, was noted to be elevated. Carcino-embryonic antigen-related cell adhesion molecule (CEACAM), an adherence mediator important in neutrophil migration, was also found to be significantly increased in the GI irAE group. Another inflammatory cytokine, IL-17, has also been proposed as a predictor of irAEs, and has been correlated with the development of grade 3 GI toxicities.
Role of the Gut Microbiome.
The gut microbiome has been implicated in the response to ICI therapy. This holds significant promise as fecal transplants in addition to ICI therapy may play a role in enhancing therapy. Fecal abundance of Bacteroides fragilis negatively correlated with tumor size following CTLA-4 blockade. Interestingly, as the B. fragilis polysaccharide capsule is known to induce IL-12–dependent TH1 immune responses, these immunogenic bacteria show potential to act as “anticancer probiotics.”
The gut microbiota plays an important role in maintaining mucosal tolerance by promoting T-regulatory cell expansion or by stimulating anti-inflammatory cytokines. The intestinal microbial composition was sampled in a prospective study from 34 melanoma patients prior to CTLA-4 blockade. Although the patients all shared a similar proportion of Firmicutes , the Bacteroidaceae family was underrepresented in patients who later developed immune-mediated colitis. Bacteroidetes exert anti-inflammatory effects through various pathways. The combination of (1) polyamine transport system and (2) the biosynthesis of vitamins riboflavin (B2), pantothenate (B5), and thiamine (B1) resulted in 70% sensitivity and 83% specificity for predicting patients at risk of developing colitis. Thus, the microbiome may play a role in developing immune-related colitis. Further supporting this hypothesis is the observation that intestinal reconstitution of germ-free mice with the combination of B. fragilis and Burkholderia cepacia reduced histopathological signs of colitis.
Diarrhea and Colitis
Anti-CTLA-4: Colitis seen after anti-CTLA-4 inhibitors is characterized by the presence of neutrophilic inflammation with increased intraepithelial lymphocytes, crypt epithelial cell apoptosis, and few or no features of chronicity.
Anti-PD-1: Two patterns of colitis are seen following the use of anti-PD-1: active colitis (active inflammation, neutrophilic crypt micro-abscesses, increased crypt epithelial cell apoptosis, and presence of crypt atrophy/dropout) or lymphocytic colitis (increased intraepithelial lymphocytes in surface epithelium, surface epithelial injury, and expansion of the lamina propria). Similar histological changes can also be observed outside of the colon in the duodenum, stomach, and/or small bowel. Features of inflammatory bowel disease (IBD)-type chronicity are seen in patients with recurrent anti-PD-1 colitis, which may develop many months after stopping anti-PD-1 therapy.
Patchy chronic duodenitis or chronic gastritis with rare granulomas can be seen. These findings suggest the possibility of immune mechanisms which are directed towards region-specific epitopes.
Liver biopsies of patients on ICIs, reveal a pan-lobular active hepatitis with a predominant CD8-positive inflammatory infiltrate, and hence, the pathological presentation mimics autoimmune hepatitis, and suggests underlying injury to hepatocytes. The cytotoxic T cell infiltrate can also result in injury to the bile ducts, manifesting as mild portal mononuclear infiltrate around the proliferated bile ductules.
BISPECIFIC ENGAGER OF T CELL ACTIVITY/BLINATUMOMAB
Blinatumomab is a bispecific antibody that belongs to a class of agents, which work as engagers of T cell activity via binding to CD19 and CD3. The drug is approved for relapsed or refractory B-precursor ALL. It is administered as a 4-week continuous infusion. Blinatumomab infusion is associated with cytokine release syndrome (CRS), which is a potentially life-threatening systemic inflammatory reaction observed after infusion of agents targeting different immune effectors and also with hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). The frequency of grade 3 or higher CRS ranged from 2% to 6% in clinical trials in adult patients with relapsed/refractory ALL, and was 6% in a trial conducted in children. Fortunately, CRS is fatal in a very small number of patients. The syndrome manifests with symptoms of fever, chills, hypotension, and tachycardia during or immediately after drug administration.
GI, Hepatic, and Pancreatic Manifestations of Blinatumomab
Blinatumomab can present with a broad spectrum of constitutional and organ-related disorders, and numerous blood test abnormalities. Patients present with nausea, vomiting, diarrhea, and hepatotoxicity (grade ≥3 increased ALT and AST in 9%–16% cases). ,
Cases of pancreatitis have been reported during blinatumomab treatment; this has been observed mostly during clinical trials. It is important for physicians to be alert, and monitor amylase and lipase if clinically indicated.
HLH/MAS has also been observed in patients receiving blinatumomab infusion.
Mechanism of Blinatumomab-Mediated GI and Hepatic Toxicities
The two blinatumomab-mediated mechanisms for hepatotoxicity are CRS and HLH/MAS.
CRS is characterized by an increase in inflammatory cytokine release after the activation and cytotoxic damage of monocytes, macrophages, and different lymphocyte populations. This is associated with extensively high levels of IL-6, which plays a central role in the pathophysiology of these toxicities. Other effects that could be mediated by the release of cytokines include nausea/vomiting and increased AST/ALT levels. The increase in cytokine levels coincides with the early peak in the adverse events’ incidence and the development of severe peripheral B lymphocytopenia within days of blinatumomab initiation.
HLH is a rare condition characterized by inappropriate immune activation and cytokine release that typically presents with fever and splenomegaly in association with hyperferritinemia, coagulopathy, hypertriglyceridemia, and cytopenias.
ADOPTIVE CELLULAR THERAPY (CAR T CELL AND T CELL RECEPTOR GENE THERAPIES)
Cellular immunotherapy consists of autologous or allogenic T cells which have been genetically engineered to express CARs or T cell receptors (TCRs) to redirect cytotoxicity specifically towards cancer cells. These therapies are currently emerging as a promising modality for a broad range of cancers. In August 2017, the FDA approved the first anti-CD19 CAR T cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed and/or refractory B-cell precursor ALL. Currently, novel targets such as CD20, NY-ESO-1, and B-cell maturation antigens, are being explored with CAR-based and TCR-redirected cell therapies in preclinical studies and early phase clinical trials, in hematological and non-hematological malignancies. The release of the multitude of chemokines and cytokines results in CRS with diverse manifestations including different organ systems, such as cardiovascular, respiratory, integumentary, GI, hepatic, renal, hematological, and nervous system, and manifests as high fever, hypotension, hypoxia, and/or multiorgan toxicity. There is a high risk of development of CRS in patients with bulky disease.
GI and Hepatic Manifestations With CAR T-Cell Therapy
The GI and hepatic manifestations of CRS include nausea, vomiting, diarrhea (GI), and increased AST, ALT, or bilirubin levels (hepatic), which are reversible with CRS resolution. In a phase I clinical trial of axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma by Neelapu et al., the incidence of any grade nausea was 58%, any grade anorexia and grade 3 or higher anorexia was 50% and 2%, respectively; any grade diarrhea and grade 3 or higher diarrhea was 43% and 4%, respectively; and any grade vomiting and grade 3 or higher vomiting was 34% and 1%, respectively. Phase I results of the ZUMA-1 study showed that 1/7 patients (14%) developed grade 3 or higher ascites and one in seven patients (14%) developed grade 3 AST elevation. There are studies which have shown that high serum levels of IL-6, soluble gp 130, IFN-γ, IL-15, IL-8, and/or IL-10, either 1 day before or 1 day after CAR T cell infusion, are associated with the subsequent development of CRS, but prospective validation is required for the above tests. The onset of symptoms of CRS toxicity is usually seen within the first week after treatment with CAR T cells and typically peaks within 1 to 2 weeks of cell administration.
Mechanism of CAR T Cell–Mediated GI and Hepatic Toxicities
The three mechanisms responsible for GI and hepatic toxicity with cellular immunotherapy (CAR T cells, TCR-gene therapies) are CRS (most common acute toxicity of CAR T cells), off-target effects, and HLH/MAS.
CRS: The most common toxicity associated with the use of cellular immunotherapy is mediated by the activation of T cells or engagement of their T cell receptors or CARs with antigens which are expressed by the tumor cells. Thus, the activated T cells release cytokines and chemokines, namely IL-2, soluble IL-2Rα, IFN-γ, IL-6, soluble IL-6R, and GM-CSF, and result in hypotension and capillary leak syndrome.
Off-target effects: CAR T cells can also potentially damage normal tissues by targeting a tumor-associated antigen that is also expressed on those tissues. Examples of this mechanism of action have been reported in the literature. In one study, 3 patients with metastatic renal cell carcinoma who were treated with CAR T cells targeting carboxy-anhydrase-IX experienced grade 3 to 4 increases in ALT, AST, or total bilirubin. Liver biopsies of these affected patients demonstrated cholangitis with T cell infiltration surrounding the bile ducts. Surprisingly, bile duct epithelial cells were found to express carboxy-anhydrase-IX.
HLH/MAS: There have also been reports of fulminant HLH/MAS with CAR T-cell therapy. HLH/MAS is marked by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan failure. A diagnosis of CAR T cell–related HLH/MAS can be made if a patient has a peak ferritin >10,000 ng/mL during the CRS phase (typically observed within the first 5 days after cell infusion) and has developed any two of the following: grade 3 or higher organ toxicities involving the liver, kidney, or lung, or hemophagocytosis in the bone marrow or other organs. HLH/MAS belongs to a spectrum of systemic hyperinflammatory disorders, and thus it is not surprising that these syndromes can occur with cellular therapies. Fulminant refractory HLH/MAS is observed in 1% of patients treated with CAR T-cell therapy.
Interleukin-2 (IL-2) is a cytokine, or biologic response modifier, produced by activated natural killer (NK) cells which promotes clonal T cell expansion during an immune response. It also helps develop and mature T regulatory cells, promotes NK cell activity, and mediates immune tolerance by activation-induced cell death. It mainly binds to IL-2 receptors of either high-affinity containing α(CD25)-, β(CD122)- and γ(CD132)-chains or low-affinity receptors that contain only α- and β-chains. IL-2 induces proliferation and differentiation of both CD4+ and CD8+ cells to effector cells or memory cells. IL-2 elicits a combination of immune responses, including both activation of innate immune effectors including NK cells and macrophages, and specific immune responses mediated by T effector and memory cells for long-term control of tumor recurrence. Subsequent release of various cytokines, including other interleukins, interferons, and colony stimulating factors, is also believed to be important in induction of tumor regression.
GI and Hepatic Manifestations of High-Dose IL-2
Nausea and vomiting are very common adverse events related to IL-2. These symptoms are likely related to the emetogenic potential of IL-2 and the use of nonsteroidal anti-inflammatory drugs as premedication. Anorexia is also very common during IL-2 therapy and may be secondary to systemic inflammation. When IL-2 is associated with diarrhea, it is usually secretory in nature. Hepatic enzyme and function abnormalities are commonly noticed during IL-2 treatment. This can range from asymptomatic laboratory elevations to symptomatic signs of hepatitis. This tends to accumulate in severity as cumulative dose increases. In the PROCLAIM registry, fewer than 5% of patients had hepatitis that required intervention (i.e., holding IL-2). Patients can present with several laboratory abnormalities including low albumin, mild coagulopathy, hyperbilirubinemia, and hepatic enzyme elevation. Clinically, IL-2–related hepatitis can present with jaundice, right upper quadrant abdominal pain, anorexia, nausea, vomiting, and mild abdominal tenderness.
Mechanism of IL-2 Mediated GI and Hepatic Toxicities
In general, toxicities of IL-2 are directly related to the systemic effects of IL-2 and also subsequent cytokines released by T cell activation.
IFN-α induces the transcription of several genes via the JAK-STAT pathway and other signaling pathways. The antitumor mechanism of IFN-α is the cumulative result of cytostatic, anti-angiogenic, and immune-modulatory activities. The immune-modulatory effects of IFN-α include induction of cytokines, upregulation of major histocompatibility antigen expression, enhancement of phagocytic activity of NK cells and macrophages, and augmentation of T cell cytotoxicity against tumor cells.
GI and Hepatic Manifestations With IFN-α
IFN-α2b is the most widely recognized adjuvant IFN-α therapy for patients with resected melanoma who are at high risk for relapse. However, the regimen is associated with significant toxicity. IFN-α is associated with all-grade nausea (66%), vomiting (66%), anorexia (69%), and transaminitis (63%). Grade 3/4 adverse events observed are nausea (9%), vomiting (6%), and transaminitis (14%–29%). Hepatotoxicity occurs soon after initiation of treatment but can occur anytime during treatment. Other causes of elevated liver function tests, such as alcohol, hepatitis B, and hepatitis C, should be considered in this group of patients. Hepatotoxicity, generally manifested as transaminitis, is a common but serious adverse event; as an example, two patients died of liver failure in the E1684 trial.
Mechanism of IFN-α Mediated GI and Hepatic Toxicities
Nausea and Vomiting.
Increased activity of IFN-α, IL-1 and other proinflammatory cytokines are implicated in the pathophysiology of nausea and vomiting. These cytokines act on the monoamine transmitters, especially serotonin. The enterochromaffin cells in the GI mucosa become activated in response to the cytokines to increase the production of 5-HT3.
Cytokines such as IFN-α, IL-1, and TNF-α are implicated in anorexia through their impact systemically as well as within the central nervous system.
Hypertriglyceridemia over 1000 mg/dL is associated with acute pancreatitis, and has been anecdotally reported in patients treated with IFN-α. IFN-α decreases the clearance of lipoproteins rich in triglycerides and hence induces hepatic lipogenesis, resulting in hypertriglyceridemia.
IFN-α acts on the CYP450 enzyme system and suppresses the activation of certain isoenzymes. This plays an important role in the potential for drug interactions as 90% of drug metabolism occurs through the CYP 450 system.
Pharmacologic Approaches for Management and Treatment
IMMUNE CHECKPOINT INHIBITORS
Approach to a Patient With Diarrhea and/or Colitis
The most common clinical presentation of immune-related GI toxicities vary from very frequent loose stools to colitis symptoms (mucus in the stools, abdominal pain, fever, rectal bleeding). The symptom onset is in the range of 5 to 10 weeks after initiation of ICIs, but it can occur even months after discontinuation of ICIs.
The distinction between ICI-associated diarrhea and colitis is a subtle yet important one. Clinicians should be vigilant as to the presence of abdominal pain, rectal bleeding, mucus in the stool, or fever, as these findings may signal colitis, a potentially life-threatening complication of ICIs. Furthermore, cases of intestinal perforation have been described and thus urgent assessment and management is recommended in suspicious cases. , ICI-associated colitis can be distributed uniformly or can be localized to certain areas, more commonly the proximal colon. , Diarrhea and/or colitis has been observed months after discontinuation of immunotherapy and can mimic IBD, and thus careful history taking is important in establishing this diagnosis.
Differential Diagnosis of Colitis.
Active colitis with an apoptotic pattern on biopsy should include other causes of colitis with prominent apoptosis, such as:
Infections (cytomegalovirus [CMV])
Acute graft versus host disease (GVHD)
Medications: There are many medications associated with colitis, most of which are immunosuppressants. Patients receiving ICIs are unlikely to be receiving these immunosuppressive medications; however, this bears mention, as some chemotherapeutic agents fall within this category. Colitis secondary to mycophenolate mofetil (MMF) may be apoptosis-predominant and show apoptotic microabscesses. 5-Fluorouracil (5-FU) and anti-TNF antibody have also been reported to substantially cause crypt apoptosis. Methotrexate (MTX) and capecitabine can cause crypt apoptosis, dilated damaged crypts, and architectural distortion. The PI3 kinase inhibitor, idelalisib, can cause acute inflammation, increased intraepithelial lymphocytes, and prominent apoptosis.
Idiopathic inflammatory disease: Chronic idiopathic inflammatory bowel disease has been classified into Crohn’s disease (CD) and ulcerative colitis (UC). The histological features of CD include granulomas, focal crypt distortion, and ileal involvement. On the other hand, biopsies of patients with UC show type II NK cells that produce significant quantities of IL-13. Also observed in UC are diffuse chronic inflammation, diffuse crypt atrophy, mucin depletion, and absence of ileal inflammation.
Diagnostic Workup for Grades 2, 3, and 4 Colitis.
When a patient presents with acute diarrhea, it is important to rule out infectious and inflammatory causes of diarrhea, and hence, should obtain the workup detailed below:
Complete blood count (CBC) and comprehensive metabolic panel (CMP), thyroid stimulating hormone (TSH), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
Stool culture to evaluate for bacterial infectious etiology
Clostridium difficile testing to evaluate for C. difficile colitis
CMV DNA polymerase chain reaction (PCR) to evaluate for CMV colitis
Stool ova and parasites to evaluate for parasitic infections
Inflammatory markers (fecal leukocytes/lactoferrin, fecal calprotectin) and fecal occult blood test (FOBT) to evaluate for inflammatory etiology
Screening laboratory work (HIV, viral hepatitis testing, and blood QuantiFERON for TB) in the event that patients will need to be given infliximab (infliximab can cause reactivation of viral hepatitis and TB, and can increase the risk of opportunistic infections in patients with HIV)
Computed tomography (CT) scan of the abdomen and pelvis to evaluate for extent of colitis and concomitant inflammation and/or infection
GI endoscopy with biopsy (colonoscopy): The presence of ulcerations in the colon predicts a corticosteroid-refractory disease, and thus these patients may require early infliximab. For grade 2 or higher diarrhea, once infectious etiology has been ruled out, systemic immunosuppression should be initiated promptly. Colitis can be associated with a normal mucosa; however, colonoscopy may be helpful as it may identify certain inflammatory features, such as CMV infection on immunohistochemical staining.
Colitis secondary to anti-CTLA-4 can manifest in two ways: diffuse colitis characterized by mesenteric vessel engorgement and segmental colitis with moderate wall thickening and pericolonic fat stranding (seen on CT). The most accurate means of evaluating the extent and the severity of the colitis is via colonoscopy because recent data has shown that the presence of ulceration on endoscopy predicts for steroid-refractory disease. Colonoscopic examination is recommended for persistent grade 2 or higher diarrhea because of the risks associated with endoscopic procedures. Endoscopic examination often shows inflammatory changes in a continuous pattern throughout the gastrointestinal tract, such as exudates, granularity, loss of vascularity, and ulcerations. Although colonoscopy is considered the gold standard exploratory technique, rectosigmoidoscopy also appears to be a feasible option. Whereas on one hand, colonoscopy requires an efficient bowel preparation and general sedation in the vast majority of patients, a rectosigmoidoscopy can be performed without sedation with a simple enema preparation and can lead to a rapid diagnosis. Even in the absence of morphological abnormalities, biopsies should be taken to evaluate for colitis.
Patients not responding to immunosuppressive agents may need repeat endoscopy. This is particularly important in patients with grades 3 and 4 toxicity. Repeating endoscopy for disease monitoring should be offered when it is clinically indicated or when the plan is to resume therapy.
Restarting Checkpoint Inhibitors
Grades 2 or 3: If patients improve from their irAE after adequate treatment, they can be rechallenged with anti-PD-1 therapy as only a small proportion of patients with ICI-related colitis experience recurrences with anti-PD-1 resumption alone.
Grade 4 diarrhea/colitis: ICI therapy should be permanently discontinued.
Approach to a Patient With Nausea/Vomiting/Epigastric Pain
The approach to these patients is similar to that of patients with colitis. Initial treatment is corticosteroids followed by TNF-α blockers for refractory cases. Notably, the evidence for this approach is based on case studies.
When patients present with diarrhea/colitis and previous immunotherapy exposure is considered a possible etiology, the patient should be referred to a gastroenterologist experienced with immunotherapy-related colitis and an endoscopy with biopsy should be performed. In some cases, colitis can progress to chronic IBD long term. These patients should continue to follow up with a gastroenterologist long-term.
Table 19.1 describes the management of ICI-mediated grade 2 to 4 diarrhea based on the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group and the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines.