The safety, tolerability, and toxicity management of therapies for DLBCL are part and parcel with efficacy in considering selection among treatment regimens. In the treatment of DLBCL, there are potential toxicities during any line of therapy, and these have to be balanced against the efficacy. These considerations, along with supportive care, are important components of patient counseling.

For traditional second-line therapy for a relapsing patient who is transplant eligible, we typically use rituximab, ifosfamide, carboplatin, and etoposide phosphate (R-ICE); rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP); or rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP). These are intensive chemotherapy regimens that, on one level, serve to identify patients who can tolerate such therapy, and they may offer potent cytoreduction, with the quality of remission being the biggest predictor of success with subsequent high-dose chemotherapy and autologous stem cell transplantation. The toxicities reported are predominantly cytopenias, which require white blood cell growth factor support to all patients. In addition, platinum-based regimens can cause kidney dysfunction, so we monitor for that. Further, nausea and vomiting can also occur, for which we administer antiemetics, and neuropathy also often occurs.

Rituximab plus gemcitabine and oxaliplatin (R-GemOx) is a lower-intensity regimen that might be used in a patient with DLBCL who is not planning to go to transplant; it has a favorable safety profile with less severe cytopenias. However, oxaliplatin is associated with a cold-sensitive peripheral neuropathy, which can be bothersome to patients.

Then we have novel therapies that we use in later lines of therapy for individuals with DLBCL. Three chimeric antigen receptor (CAR) T-cell therapies are approved by the US Food and Drug Administration in the third-line setting: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Axicabtagene ciloleucel uses a CD28 co-stimulation domain in the CAR, leading to a more rapid and earlier peak expansion of CAR T cells. This can result in a higher rate and severity of cytokine release syndrome and neurologic toxicity, both of which are class effects of CAR T cells. In contrast, the other 2 agents use the 4-1BB co-stimulation domain, which leads to a more gradual expansion and a longer area under the curve, which translates into lower rates and degrees of cytokine release syndrome and neurologic toxicity. Thus, we need to take the toxicity profile into consideration when selecting a treatment since it may be difficult to manage these toxicities when severe, especially in older patients.

Other agents in this space also have unique toxicity profiles. With tafasitamab plus lenalidomide, you can see infusion reactions from the monoclonal antibody, but most of the toxicity comes from lenalidomide (eg, cytopenias, rash, and diarrhea), which often results in lenalidomide dose reductions. Lenalidomide also increases the risk of thrombosis, so thromboprophylaxis should be given to all patients, usually with a low-dose aspirin.

With the bendamustine, rituximab, and polatuzumab vedotin regimen, toxicities include neuropathy and cytopenias. Myelotoxicity is due to the bendamustine, so we must pay attention to cytopenias and the risk of opportunistic infections. I recommend pneumocystis and antiviral prophylaxis for all of my patients who are receiving bendamustine. Fatigue and nausea may also occur.

Loncastuximab tesirine is an anti-CD19 antibody-drug conjugate that has a unique toxicity profile in that it can produce liver function test elevations (gamma-glutamyltransferase), peripheral edema, or a capillary leak–like syndrome that appears to be dose dependent and potentially cumulative. Patients require dexamethasone for 3 days, beginning the day before the administration of loncastuximab tesirine.

Finally, patients taking selinexor most commonly experience systemic constitutional toxicities (eg, asthenia, malaise, fatigue, nausea, vomiting, anorexia, and weight loss), in addition to some cytopenias. Such individuals may require dose reductions for constitutional symptoms that are impairing their quality of life.