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Leukemia Service and Cellular Therapeutics Center
Memorial Sloan Kettering Cancer Center
New York, New York
Jae H. Park, MD, has disclosed that he has received consulting fees from Allogene, Amgen, AstraZeneca, Autolus, GlaxoSmithKline, Incyte, Kite, Novartis, and Takeda.
Several immunotherapies are now available for treating acute lymphoblastic leukemia (ALL), resulting in improved patient outcomes. However, these new therapies come with their own set of unique toxicities. Adverse events associated with different immunotherapies are in some ways distinct, but they all require a similar general approach. First, it is important to recognize and be aware of the potential toxicities associated with each agent—anticipation of potential adverse events is really the key to optimizing patient care and leads to the next step in the clinic, which is preparation. Preparation can take many forms, including the identification of patients with a high risk for developing adverse events. The final step for optimizing our patients’ care is taking appropriate actions to manage their toxicities.
T-cell–engaging therapies, such as the bispecific T-cell engager blinatumomab and CAR T-cell therapy tisagenlecleucel, result in immune system activation leading to unique toxicities that include cytokine-release syndrome (CRS) and neurotoxicity. CRS is caused by the release of inflammatory cytokines from T-cells and myeloid cells as the result of immune activation. Clinical symptoms of CRS range from fever, hypotension, tachycardia, and myalgia to respiratory insufficiency in severe cases that may require ICU-level care or supplemental oxygen support, including mechanical ventilation or intubation. It is important to be aware that the first manifestation of CRS is always fever, so if a patient starts to develop fever after receiving these T-cell–engaging therapies, you can anticipate a potential progression to severe CRS.
Management of CRS mainly consists of supportive measures. Fever is first treated with antipyretics such as acetaminophen or NSAIDs. If fever persists or if more systemic symptoms such as hypotension and respiratory problems develop, then supportive measures are provided for those symptoms. For hypotension, fluid bolus is usually the first measure. However, because patients with severe CRS often also present with capillary leak syndrome or congestion, I try to limit the amount of fluid they receive at one time and do not provide more than 2 liters of fluid bolus. If patients do not respond to 2 liters of normal saline, then I usually either move directly to vasopressors or additional measures.
For patients receiving blinatumomab, if CRS symptoms persist despite these supportive measures and patients’ hypotension or respiratory problems worsen, they often require a short-term dose interruption to determine if stopping the medication improves their symptoms within a few hours. Because the half-life of blinatumomab is very short, symptoms usually improve immediately after stopping the medication. However, if symptoms continue to persist despite the dose interruption, then a steroid—usually dexamethasone 10-20 mg—should be administered. These measures are almost always effective in reversing CRS for patients receiving blinatumomab. Once the symptoms resolve, blinatumomab can be restarted per the prescribing information. If restarting after an interruption of more than 4 hours, premedicate again with dexamethasone before starting the blinatumomab infusion.
For patients receiving tisagenlecleucel who present with persistent CRS symptoms, drug interruption is not an option because it is a single infusion, which makes management more challenging. Tocilizumab, an IL-6 receptor inhibitor, is approved for treating CRS associated with CAR T-cell therapy. For patients with severe CRS, which includes patients with hypotension requiring vasopressors or more than 6 liters of supplementary oxygen, tocilizumab is clearly indicated. However, I use tocilizumab in my practice before patients worsen to that degree. If a patient is not responding to a 1-liter fluid bolus but is otherwise stable, I may actually give tocilizumab to prevent progression to severe CRS, especially if the patient has a high disease burden indicating a higher risk of developing severe CRS. Patients who develop fever very early on, within 24-48 hours of infusion, are also at higher risk of progressing to severe CRS, so I may intervene earlier in those patients. Finally, I may also intervene early for some older patients who may not be able to tolerate severe CRS due to comorbidities. Anticipation and preparation are again key steps here: It is important to prepare tocilizumab and have it available before tisagenlecleucel is administered. If CRS is not managed in a timely manner, it can be severe and even fatal.
Neurotoxicity is another common toxicity associated with both blinatumomab and tisagenlecleucel, usually presenting within 7-10 days of starting therapy. Neurotoxicity is more common and severe with tisagenlecleucel than blinatumomab and is often, but not always, preceded by CRS. Neurotoxicity can develop independently of CRS without fever or after resolution of CRS, so it is important to continue monitoring patients following CRS. Although not impossible, it is rare to develop neurotoxicity 2 weeks after therapy initiation, so monitoring in the first 2 weeks is critical. Patients with high-disease burden and early or severe symptoms are at a higher risk of developing neurotoxicity, so it is important to monitor those patients even more closely.
For blinatumomab, the same management strategies used for CRS, including dose interruptions and use of steroids, apply to neurotoxicity management. For tisagenlecleucel, neurotoxicity management is distinct from CRS management because tocilizumab does not work for neurotoxicity resolution. If CRS and neurotoxicity present together, it is reasonable to use tocilizumab to manage CRS. For isolated neurotoxicity without CRS, dexamethasone 10‑20 mg is given instead of tocilizumab. The timing of intervention differs based on risk factors, but intervention is usually required for grade 2 or borderline grade 3 neurotoxicity with encephalopathy symptoms, such as confusion, forgetfulness, and aphasia. If a patient is experiencing seizures or more severe symptoms, steroid intervention needs to start immediately. Duration of steroid treatment also differs based on the duration and severity of neurotoxicity. In my experience, if you wait too long and intervene with steroid treatment when a patient is already experiencing grade 3/4 neurotoxicity, prolonged duration of steroid treatment is necessary. However, if you intervene before a patient presents with grade 3 symptoms, it often leads to shorter duration and less cumulative dose of steroids. It is also important to consult with a neurologist before starting treatment using these T-cell–engaging therapies and comanage the toxicities that may occur.
Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome
For the antibody–drug conjugate inotuzumab ozogamicin, the main toxicity is veno‑occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS). VOD is likely caused by calicheamicin, the chemotherapy agent conjugated to the CD22 monoclonal antibody. Patients who have received a prior allogeneic bone marrow transplant are at a higher risk of developing VOD with inotuzumab ozogamicin, so we must determine if inotuzumab ozogamicin is the right choice for them. If inotuzumab ozogamicin is deemed to be the best therapy option, we need to be aware of the heightened risk of hepatoxicity. Inotuzumab ozogamicin is conventionally used as a bridge to transplant, so once a response is achieved, we try to proceed directly to transplant. To minimize the risk of VOD, inotuzumab ozogamicin is typically administered for no more than 2 full cycles prior to transplant. Double-alkylating agents should also be avoided to reduce the risk of VOD. Increasing the time from the last exposure of inotuzumab ozogamicin to conditioning chemotherapy is also helpful, although that is not always feasible.
VOD toxicity can be reduced by administering ursodiol as prophylaxis in patients who will receive inotuzumab ozogamicin. An ultrasound prior to treatment can help determine if there are preexisting liver diseases and if the patient may be at increased risk of developing hepatotoxicity. All patients should be monitored by measuring liver enzymes and bilirubin once they begin treatment with inotuzumab ozogamicin. In our practice, we measure liver enzymes and bilirubin at least weekly while patients are receiving active therapy. We also monitor weight changes as a sign of any fluid retention and assess for abdominal bloating and any ascites. If there is any concern, we obtain another ultrasound. Defibrotide is the only medication that is currently approved to treat VOD, and it is only indicated for VOD with renal or pulmonary dysfunction following a transplant. However, if a patient develops VOD clinically significant enough to warrant defibrotide treatment, it is often too late to reverse the toxicity. That is why it is very important to reduce the risk of VOD as much as possible for patients receiving inotuzumab ozogamicin.
What challenges do you encounter when managing toxicities in patients treated with immunotherapies for ALL? I encourage you to answer the polling question and share your thoughts in the discussion box below.
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