**4.3 Treatment-related colitis/diarrhea**

Gastrointestinal AEs are another most common treatment-related AEs during ICI therapy. Physicians should carefully distinguish colitis from diarrhea; and when colitis symptoms emerge, hospitalization and discontinuation of ICIs should be considered. In cases of mild symptoms, administration of corticosteroids or antidiarrheals could be applied [168], and additional infliximab may be needed [169].

#### **4.4 Treatment-related cardiovascular disease**

The incidences of treatment-related cardiovascular diseases are frequently underestimated, as reported by Jain et al. [170]. They identified 16,574 patients who received ICIs from a total of 2,687,301 patients and 1:1 matched to 2875 patients who received

*Immune Checkpoint Inhibitors in Hodgkin Lymphoma and Non-Hodgkin Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.107435*

chemotherapy or 4611 patients who received targeted agents. They observed the onsets of treatment-related cardiovascular diseases included stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). In addition, anti-CTLA-4 therapy was more commonly related to treatment-related cardiovascular diseases. Moreover, another retrospective analysis indicated that inhibition of PD-1/ PD-L1 was significantly associated with the risk of myocarditis, and males may have an increased risk of certain cardiovascular AEs [171]. In another meta-analysis including 2576 trials/studies and 20,244 patients, combined therapy of PD-1 blockade and chemotherapy may increase the risk of myocardial disease of all grades; although there was no significant increase in the risk of other cardiovascular diseases [172].

#### **4.5 Other autoimmune diseases**

As PD-1 blockade non-specifically activates the immune system, the induction of autoimmune-like diseases is the major concern of the toxicity incurred. Examples of symptoms during the treatment of HL include autoimmune type I diabetes [173–176], autoimmune encephalitis [177–179], autoimmune hepatitis [36], autoimmune nephritis [36, 38], and autoimmune hemolytic anemia [180, 181]. In cases of autoimmune diseases, the use of immunosuppressive treatment or delay of ICI therapy should be seriously considered.

#### **4.6 Association between toxicity and efficacy**

Although treatment-related AEs severely affect the treatment outcomes of ICIs, the onset of AEs that are immune-related may be directly associated with the efficacy of ICIs. In a study of 106 patients who underwent PD-1 blockade monotherapy, Rogado et al. [182] observed that patients with immune-related AEs have a higher ORR of 82.5% (vs 16.6%) and longer PFS of 10 months (vs 3 months), as compared with those without immune-related AEs. Although the detailed underlying mechanisms remain to be elucidated, concerns about the effect of corticosteroids and other immunosuppressants administration on ICI efficacy have been raised. However, some studies suggested that the use of corticosteroids and other immunosuppressants may not impair the anti-tumor activities of ICIs [183, 184].

### **5. Conclusions**

ICIs therapies have demonstrated remarkable efficacy in several subtypes of HL and NHL, and some ICIs (e.g., pembrolizumab) have been approved to use in HL and PMBCL. Especially, anti-PD-1/PD-L1 antibodies in a combination with other therapies have acquired promising results, and AEs are common in these treatments. Thus, we need to do more clinical trials and real-world studies to further explore the effectiveness and safety of ICIs treatment in lymphoma.
