- Email: [email protected]
Adult Acute Lymphoblastic Leukemia: Treatment and Management Updates
ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2019) 150951
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Adult Acute Lymphoblastic Leukemia: Treatment and Management Updates Stephanie Gregory, FNP-C, BMTCNÒ * Augusta, Georgia, USA
A R T I C L E
I N F O
Article History: Available online xxx Key Words: novel therapies acute lymphoblastic leukemia blinatumumab CAR-T cell therapy bispecific antibodies inotuzumab ozogamicin cytokine release syndrome
A B S T R A C T
Objective: To present an overview of novel therapies for the treatment of adult acute lymphoblastic leukemia and to discuss nursing implications for these new therapies. Data Sources: Published manuscripts, Web sites, and pharmaceutical package inserts. Conclusion: Several promising therapies have emerged in the treatment of relapsed/refractory and minimal residual disease acute lymphoblastic leukemia. Implications for Nursing Practice: With the changing paradigm for hematologic malignancies, nurses must remain current in their knowledge regarding novel therapies, including their administration, toxicity profile, and management of adverse events. This article addresses the clinical benefits of novel agents and nursing implications for those agents. © 2019 Elsevier Inc. All rights reserved.
Introduction Multidrug chemotherapy regimens have been the mainstay for the treatment of acute lymphoblastic leukemia (ALL) and, although generally effective at achieving a high response rate, there are also, alternatively, high relapse rates indicating significant room for improvement.1,2 Prognosis for patients with relapsed/refractory (R/R) ALL is very poor. Traditionally, treatment for R/R ALL has relied on cytotoxic chemotherapies; however, results with these therapies have been underwhelming, only achieving complete remission (CR) rates in 30% to 40% of first salvage and 10% to 20% of second salvage regimens.3 Survival rates for patients with R/R disease are dismal, with less than 10% surviving to 5 years.2 Furthermore, studies have demonstrated that the presence of minimal residual disease (MRD) following induction therapy can be independently associated with inferior outcomes, including increased relapse rates and shorter survival.4 With the dawn of targeted therapies and personalized medicine there has been the development of many novel therapies to consider as inventive approaches to treating ALL. Although first-line therapies for ALL recommendations remain largely the same, these novel therapies have been effective and approved for use in the R/R ALL patient and for those with MRD. Clinical trials are currently evaluating these options in the first-line setting as well. This review will discuss novel therapies for patients with ALL to include monoclonal antibodies *Corresponding author: Stephanie Gregory, FNP-C, BMTCNÒ , CMR 415, Box 7835, APO, AE 09114. E-mail address: [email protected] https://doi.org/10.1016/j.soncn.2019.150951 0749-2081/© 2019 Elsevier Inc. All rights reserved.
such as inotuzumab ozogamicin (InO), bispecific antibodies like blinatumomab, and chimeric antigen receptor (CAR) T-cell therapy. Nursing implications for the management and care of patients receiving these treatments will be examined as well.
Bispecific Antibodies Bispecific antibodies are drug compounds that utilize two monoclonal antibody binding sites and engineer them into a single molecule.5,6 Blinatumomab is a bispecific T-cell engager (BiTE) and is the first drug developed in this class targeting CD19/CD3; it is also the first bispecific antibody approved by the US Food and Drug Administration (FDA) for the treatment of R/R and MRD ALL. Essentially, the molecule binds to the CD3 antigen receptor on the patient’s immune T cells and to the CD19 surface antigen of the cancer cells, bringing the two in close proximity and thus inducing more efficient extermination of the malignant cells.1 CD19 is a common B-cell surface marker expressed in more than 90% of ALL cases; hence, the exponential growth of clinical and pharmaceutical trials researching compounds with the ability to target this antigen over the past decade.7 Blinatumomab has demonstrated impressive results in clinical trials for patients with Philadelphia (Ph)-negative ALL. The TOWER trial, a phase 3 study comparing blinatumomab (n=271) with standard-ofcare chemotherapy (n=134) in patients with R/R Ph-negative ALL, demonstrated superior overall survival with a median 4.0 months in the standard-of-care group versus 7.7 months in the blinatumomab group (P = .01).8 Additionally, the rate of molecular remission in the blinatumomab cohort was significantly greater than that of the
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S. Gregory / Seminars in Oncology Nursing 00 (2019) 150951
standard-of-care cohort (76% v 48%, respectively).8 In patients with MRD, blinatumomab has proven effective at achieving MRD negativity, making it possible for patients to move forward with allogeneic stem cell transplant. In a study conducted by Topp et al,9 MRD negativity was successful in 80% of the study participants (n=20). In a subsequent study of patients with MRD, the BLAST trial (n=113), a complete response was noted in 78% of the cohort after the first cycle.10 The addition of tyrosine kinase inhibitors to regimens for patients with Ph-positive ALL has made a significant positive impact on outcomes. However, in the R/R setting, the overall survival prognosis is still poor.3 In light of this knowledge, further targeted therapies are being studied in hopes of improving outcomes for these patients. Blinatumomab alone demonstrated a low response rate of 36% in a phase 2 trial of 45 patients with Ph-positive ALL in the R/R setting. Some early case studies have been evaluating the compound in combination with second-generation or later tyrosine kinase inhibitors with some promising results.11 Nursing considerations Blinatumomab has a short half-life, requiring continuous intravenous infusion over several weeks that are usually administered for multiple cycles. This short half-life can be advantageous in that severe side effects can often be managed by simply stopping the infusion, resulting in reversal of symptoms within a few hours.5 The drawback is that these patients will require indwelling catheters to receive the continuous infusion, inviting the complications that are well known to be associated with central line accesses (including increased risk of infection and thrombosis). The most severe adverse events related to blinatumomab infusion include cytokine release syndrome (CRS) and neurotoxicity, which are discussed later in this article. To minimize these risks, the drug is usually given in a slowdose escalation format in the hospital, and the dose is gradually increased over several weeks.1 Neurologic symptoms are primarily dose-dependent and associated with higher doses of the drug, which are usually reversible with stopping infusion; the administration of dexamethasone has also been successful in treating neurotoxicity and is often used as prophylaxis.5 Chimeric Antigen Receptor (CAR) T-cell Therapy Perhaps one of the most revolutionary therapy options for both pediatric and adult patients to be developed in the past decade is chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a targeted immunotherapy in which the T lymphocytes are collected from the patient or a donor, through leukapheresis, and genetically engineered and expanded in the laboratory with customized receptors to identify and attack certain tumor-specific antigens.12 Similar to blinatumomab, CAR T cells currently target the CD19 B-cell marker because it is expressed in the majority of ALL cases but is not expressed on stem cells.12,13 It currently has indications for use in B-cell ALL, diffuse large B-cell lymphoma (DLBCL) but is being studied in other B-cell malignancies.14 When the CAR T cells are engaged, proliferation and activation of cytotoxic T cells occurs.3 There are studies ongoing looking at different costimulatory domains as well as those seeking to identify other tumor-specific antigens that may be targets for CAR T-cell therapy. Although CD19 is an excellent target because of its expression in the majority of ALL cases, it is also expressed on normal B cells throughout their development, and the use of immunotherapy targeting CD19 also risks damage to normal immune B cells, leading to aplasia.12 A more ideal target for future CAR T-cell therapy is one that targets a tumor-specific antigen that is unique to the tumor and not found on normal immune cells.12 Single-institution trials, including those conducted at Memorial Sloan Kettering Cancer Center, University of Pennsylvania, and the
National Cancer Institute show that, in patients with R/R ALL, CAR Tcell therapy has achieved superior results with 70% to 90% MRD-negative CR rates.15 17 Multicenter trials have also had encouraging results. A study by Maude et al15 demonstrated a 60% CR rate and median overall survival of 19.1 months. Tisagenlecleucel is currently the only CAR T-cell therapy approved for R/R ALL; however, other agents are being studied for effectiveness with this disease, including axicabtagene ciloleucel, a CAR T-cell therapy approved for R/R large B-cell lymphoma.18,19 Nursing considerations Nurses who administer targeted immunotherapies and monitor patients in the weeks following treatment should be familiar with the basic concepts behind the mechanism of action for CAR T-cell therapy and how they are prepared and administered. Currently, tisagenlecleucel is the only FDA-approved CAR T-cell therapy for the treatment of ALL and only in the R/R and MRD settings.3 T cells are collected via leukapheresis from the patient and, using gene modification, are manufactured in a lab to express the CAR on the surface of the T cell and then to proliferate into millions of CAR T cells; this process takes several weeks. Once manufactured, the cells are cryopreserved before returning to the treatment facility.14 Chemotherapy is administered before the CAR T-cell infusion for antileukemia effect, as well as to achieve lymphodepletion.12 Infusion should take place within 30 minutes of thawing and subsequent to premedications.14 Following CAR T-cell infusion, the cells can locate any cells expressing CD19 antigen and activate the T cell, resulting in proliferation and expansion of cytotoxic T cells and the ultimate killing of tumor cells.12 The T cells begin expanding within 7 to 10 days after CAR T-cell infusion and during this time are vulnerable to immunosuppressive effects. Therefore, corticosteroids, especially at high doses, are typically avoided (including those that may be used as premedication for blood products or other infusions).12 Additionally, although corticosteroids have been proven effective in the treatment of CRS, they are typically reserved for cases of refractory CRS in which there has been no response to tociluzimab.13 As with many therapies for ALL, CAR T-cell therapy is also known to induce cytopenias and increased risk of infection.20 Additionally, because of similar mechanisms of action, blinatumomab and CAR Tcell therapy share many unique similarities in their adverse effect profiles, including CRS and neurotoxicity, which are the most common severe toxicities and are reviewed in subsequent sections of this article. Fever is an expected side effect following infusion and typically occurs within the first 10 days.13 Fever should be treated according to your program’s standard protocols. Frequent assessments should be performed to identify any sequelae after CAR T-cell infusion and should include vital signs, review of systems, physical assessment, and neurological assessments.12 As mentioned previously, CAR T cells are not specific to CD-19 antigens found on the tumor cells and therefore can deplete the body’s normal B cells, as well lead to B-cell aplasia and hypogammaglobulinemia, which may require long-term management. Intravenous immunoglobulins may be administered to treat this in some patients.13 Tumor lysis syndrome is a less common side effect of CAR T-cell therapy but is possible because of the rapid cancer cell destruction, especially in patients with high tumor burden at the start of treatment. Tumor lysis syndrome should be managed according to established institutional protocols, including intravenous hydration, allopurinol prophylaxis, and monitoring of electrolytes and renal function.20 Because of the severe nature of the potential side effects of CAR T-cell therapy, it is only available to programs through Risk Evaluation and Mitigation Strategy programs established by the drug sponsor.20 Risk Evaluation and Mitigation Strategy requires authorized centers to observe specific guidelines to minimize the risks of treatment.20
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Inotuzumab Ozogamicin Inotuzumab ozogamicin (InO) is a monoclonal antibody that links a cytotoxic agent, calicheamicin, to an anti-CD22 antibody.21 The drug binds to DNA of the target cell causing DNA breakage and apoptosis of the cell.3 The findings reported by the INO-VATE clinical trial led to FDA approval of its use in the treatment of R/R B-cell ALL. The study compared (InO) with standard-of-care chemotherapy in the R/ R setting and demonstrated significantly improved results, with 81% of the InO cohort achieving CR.22 Additionally, the InO group achieved higher MRD-negativity rates, longer remission duration, and longer overall survival.22 InO has also demonstrated promising outcomes in combination with low-intensity chemotherapy regimens to minimize toxicity, and is currently being studied for use in elderly patients (median age, 68 years) newly diagnosed with B-cell ALL because this is a population notoriously difficult to treat with standard intensive chemotherapies.3,21 This drug has also been included in studies combined with tyrosine kinase inhibitors for Phpositive ALL and initial results have demonstrated successful rates of MRD negativity and CR in patients receiving InO compared with standard chemotherapy.3 The InO toxicity profile has been associated with an increased rate of veno-occlusive disease (VOD) and hepatotoxicity, especially in patients with prior allogeneic stem cell transplant. However, there have been fewer severe febrile neutropenia and thrombocytopenia events than those treated with standard chemotherapy.3 Nursing considerations InO is administered as an intravenous medication for 3 weekly doses per cycle.3 Premedication typically consist of antihistamine, antipyretic, and corticosteroid. Severe adverse events associated with this drug include myelosuppression leading to bleeding, as well as infection, pyrexia, elevated liver enzymes, and a boxed warning for veno-occlusive disease.23 Patients receiving InO should be monitored closely for any evidence of veno-occlusive disease, which may include rapid weight gain, hepatomegaly, abdominal pain, ascites, and elevated bilirubin.23 Any of these clinical manifestations should be reported immediately for medical management.
3
Table 1 Risk factors for cytokine release syndrome. Increased age Presence of comorbidities High disease burden Higher doses of CAR T cells administered Type of CAR T cell administered (costimulatory domain CD28 > 4-1BB) Higher doses of blinatumomab Concurrent development of infectious illness Conditioning chemotherapy containing fludarabine Data from Brudno and Kochenderfer,13 Frey,24 and Riegler et al.25
adverse events. The general consensus is that early identification of CRS manifestation and early intervention is the best approach to preventing severe and life-threatening ramifications.25 The nurse is often the first to identify concerning issues that arise in the patients and, therefore, must be knowledgeable on what signs and symptoms to report so that early intervention can occur. Treatment for CRS currently consists primarily of supportive care measures, close monitoring of fluid status, corticosteroids, and tocilizumab, which is the only FDA approved drug for the treatment of CRS to date.25 Tocilizumab is a monoclonal antibody that inhibits binding of IL-6 to its receptor, thereby minimizing the immune activation overexpressed in CRS. The use of tocilizumab should be implemented early in patients with grade 3 or 4 CRS. It is critical that all alternative sources of symptoms (such as infection, sepsis, tumor lysis syndrome) are ruled out and that CRS diagnosis is certain before administering tocilizumab because there is some concern that the drug may inhibit the antitumor effect of CAR T cells, given that IL-6 has both pro-inflammatory as well as anti-inflammatory effects.25 An additional dose of tocilizumab may be administered if no improvement is seen within 24 hours, in addition to corticosteroids. There is currently no standardized approach to the treatment of CRS; however, a few treatment algorithms have been published with variations on treatment with corticosteroids, tocilizumab, and supportive care measures.13,29 Management strategies to consider are reviewed in Table 2.5,12,20,30
Cytokine Release Syndrome
Neurotoxicity
Cytokine release syndrome (CRS) is a condition in which the highlevel immune activation from the administered compound triggers a systemic inflammatory response.24 CRS has been associated with immunotherapies, including monoclonal antibodies and bispecific antibodies (such as blinatumomab and CAR-T-cell therapy).25 The exaggerated immune response leads to release of cytokines and elevations in inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa), interferon-ᵞ (IFNᵞ), interleukin-2, and many more.20 Several factors have been identified as increasing the risk for developing CRS. These are described in Table 1. CRS symptoms can often appear similar to an infection. Fever is the trademark sign of CRS and can be very high (105°F); the presence of fever is a diagnostic requirement for CRS. Patients may also experience flu-like symptoms (myalgias, fatigue, chills), tachycardia, hypotension, and in severe cases multiorgan dysfunction (pulmonary edema, cardiac dysfunction, renal impairment, coagulopathy, hepatic failure), and death.25 The condition can range from very mild to very severe and life-threatening. There have been many attempts to develop grading scales for a standardized approach to the management of this condition.17,26 28 The different scales use variations on criteria based on patient response to fluids, vasopressors, the need for oxygen supplementation, and the presence of organ dysfunction to define the levels of severity.17,26 28 Following a consistent grading approach for specific diseases and conditions can help with a more streamlined approach to treatment and management of serious
Blinatumomab and CAR T-cell therapy have both been associated with neurotoxicity and there is currently no clear understanding as to the cause of these symptoms.5,13 With blinatumomab there is an association of increased neurotoxicity with higher doses and, because of the short half-life of the drug, neurotoxicity symptoms are usually reversible with the discontinuation of the continuous infusion, which are also responsive to dexamethasone. The use of dexamethasone as prophylaxis and the step-wise manner in which the dose of the drug is increased over several weeks in patients receiving blinatumomab has decreased the development of neurological symptoms.5 CAR T-cell neurotoxicity can present in a number of ways: delirium, hallucinations, encephalopathy, tremors, ataxia, dysphasias, language disturbance, seizures, somnolence, and many more.13,20 In some cases, neurological toxicities have led to the need for intubation and ventilation to support the patient until resolution of adverse effects.13 Symptoms can coincide with CRS or can occur independently without signs of CRS. Patients with neurological symptoms following CAR T-cell infusion should undergo comprehensive neurological evaluation, including imaging scans and lumbar puncture as appropriate.13 Treatment typically includes the use of corticosteroids as front-line therapy in the case of isolated neurotoxicity because tocilizumab does not cross the blood brain barrier.25 Any evidence of neurologic impediment recognized by the nurse should be reported immediately for early intervention.
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S. Gregory / Seminars in Oncology Nursing 00 (2019) 150951 Table 2 Management strategies for CAR T-cell therapy. Infusion Premedicate per institution protocols, avoid corticosteroids Thaw product per protocols and administer within 30 minutes of thawing Supportive care Perform thorough physical examination, vital signs, intake and output, weight, and neurologic assessments per institution protocols Provide supportive care for mild CRS symptoms: fever, myalgia, headache, anorexia, nausea or vomiting Fever is usually the presenting symptom of CRS but should have infection work-up performed and managed per program protocols to potentially include hospital admission Monitor for respiratory symptoms including measuring oxygen saturation. Provide oxygen support for hypoxia, obtain imaging as ordered. Mechanical ventilation may be required in severe cases Consider tocilizumab +/- corticosteroids for higher-grade CRS per institution protocols Transfer to ICU as needed for progressing or severe toxicity For neurologic changes, consider neurology consultation, diagnostic testing (MRI, CT, lumbar puncture, EEG). Allopurinol and hydration for the management of tumor lysis syndrome and frequent monitoring and replacement of electrolytes Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CT, computed tomography; ICU, intensive care unit; MRI, magnetic resonance imaging; EEG, electroencephalogram. Data from Viardot et al,5 Callahan et al,12 Brudno and Kochenderfer,13 Anderson and Latchford,20 and Smith and Venella.30
Conclusion and Future Considerations Targeted therapies have brought about more effective and personalized treatment methods than traditional standard chemotherapies, with improved outcomes in the R/R and MRD setting. Given the dramatic improvements seen using these novel therapies in the salvage setting, it seems likely that the next step will be to include antibody-targeted therapies with lower-intensity chemotherapies in the frontline setting as well. Currently there are several ongoing studies investigating combinations of these therapies.3 Research continues in the development of alternative antibody-drug conjugates, as well as other CAR T-cell therapies. Additionally, because CD-19 is expressed on both tumor cells and normal B cells, the search continues for an optimal antigen target that is more tumor-specific to minimize damage to normal immune cells. As targeted therapies continue to take the oncology field by storm, nurses are faced with the challenge of maintaining competency related to how these therapies are administered and which potential drug reactions, side effects, and other complications may be expected. Providing excellent care to patients undergoing oncology treatment means staying current in the evolving therapies for specific diseases, maintaining competencies, and being knowledgeable and confident in the management of potential adverse reactions for any therapy the nurse is responsible for administering. Nurses play a pivotal role in educating patients and their families on what to expect when receiving these novel treatments and in identifying any clinical presentation that warrants concern in these patients, such as symptoms of CRS and neurological toxicity. Additionally, because the CAR T-cell field is still new, further development of universal grading scales and treatment algorithms are needed for the management of related toxicities. References 1. Liu D, Zhao J, Song Y, Luo X, Yang T. Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia. J Hematol Oncol. 2019;12:1–13.
€ kbuget N, Dombret H, Ribera JM, et al. International reference analysis of out2. Go comes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101:1524–1533. 3. Paul S, Rausch C, Nasnas P, Kantarjian H, Jabbour E. Treatment of relapsed/ refractory acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2019;17: 166–175. 4. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3: e170580. 5. Viardot A, Bargou R. Bispecific antibodies in haematological malignancies. Cancer Treat Rev. 2018;65:87–95. 6. Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:1–7. 7. Naddafi F, Davami F. Anti-CD19 monoclonal antibodies: a new approach to lymphoma therapy. Int J Mol Cell Med. 2015;4:143–151. € kbuget N, et al. Blinatumomab versus chemotherapy for 8. Kantarjian H, Stein A, Go advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–847. € kbuget N, Zugmaier G, et al. Long-term follow-up of hematologic 9. Topp MS, Go relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185–5187. € kbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual 10. Go disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–1531. 11. Assi S, Kantarjian H, Short NJ, et al. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk. 2017;17:897–901. 12. Callahan C, Banewicz D, Ely B. CAR T-cell therapy: pediatric patients with relapsed and refractory acute lymphoblastic leukemia. Clin J Oncol Nurs. 2017;21:22–28. 13. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321–3330. 14. Lamprecht M, Dansereau C. CAR T-cell therapy: update on the state of the science. Clin J Oncol Nurs. 2019;23:6–12. 15. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–1517. 16. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 1928z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:1–23. 17. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose escalation trial. Lancet. 2015;385:517–528. 18. Kymriah. Package insert. East Hanover, NJ: Novartis; 2017. 19. Wierda WG, Bishop MR, Oluwole OO, et al. Updated phase 1 results of ZUMA 3: KTE-C19, an anti-CD19 chimeric antigen receptor T cell therapy, in adult patients with relapsed/refractory acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):897. 20. Anderson K, Latchford T. Associated toxicities: assessment and management related to CAR T-cell therapy. Clin J Oncol Nurs. 2019;23:13–19. 21. Yilmaz M, Kantarjian H, Ravandi-Kashani F, Short NJ, Jabbour E. Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Current treatments and future perspectives. Clin Adv Hematol Oncol. 2018;16:216–223. 22. Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375: 740–753. 23. Besponsa. Package insert. New York, NY: Pfizer; 2018. 24. Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol. 2017;30:336–340. 25. Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323–335. 26. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–638. 27. Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018;11:1–12. 28. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). V5.0. 2018. Bethesda, MD; National Institutes of Health. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. (Accessed May 6, 2019). 29. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T cell therapy assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62. 30. Smith L, Venella K. Cytokine release syndrome: inpatient care for side effects of CAR T-cell therapy. Clin J Oncol Nurs. 2017;21:29–34.
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Adult Acute Lymphoblastic Leukemia: Treatment and Management Updates Stephanie Gregory, FNP-C, BMTCNÒ * Augusta, Georgia, USA
A R T I C L E
I N F O
Article History: Available online xxx Key Words: novel therapies acute lymphoblastic leukemia blinatumumab CAR-T cell therapy bispecific antibodies inotuzumab ozogamicin cytokine release syndrome
A B S T R A C T
Objective: To present an overview of novel therapies for the treatment of adult acute lymphoblastic leukemia and to discuss nursing implications for these new therapies. Data Sources: Published manuscripts, Web sites, and pharmaceutical package inserts. Conclusion: Several promising therapies have emerged in the treatment of relapsed/refractory and minimal residual disease acute lymphoblastic leukemia. Implications for Nursing Practice: With the changing paradigm for hematologic malignancies, nurses must remain current in their knowledge regarding novel therapies, including their administration, toxicity profile, and management of adverse events. This article addresses the clinical benefits of novel agents and nursing implications for those agents. © 2019 Elsevier Inc. All rights reserved.
Introduction Multidrug chemotherapy regimens have been the mainstay for the treatment of acute lymphoblastic leukemia (ALL) and, although generally effective at achieving a high response rate, there are also, alternatively, high relapse rates indicating significant room for improvement.1,2 Prognosis for patients with relapsed/refractory (R/R) ALL is very poor. Traditionally, treatment for R/R ALL has relied on cytotoxic chemotherapies; however, results with these therapies have been underwhelming, only achieving complete remission (CR) rates in 30% to 40% of first salvage and 10% to 20% of second salvage regimens.3 Survival rates for patients with R/R disease are dismal, with less than 10% surviving to 5 years.2 Furthermore, studies have demonstrated that the presence of minimal residual disease (MRD) following induction therapy can be independently associated with inferior outcomes, including increased relapse rates and shorter survival.4 With the dawn of targeted therapies and personalized medicine there has been the development of many novel therapies to consider as inventive approaches to treating ALL. Although first-line therapies for ALL recommendations remain largely the same, these novel therapies have been effective and approved for use in the R/R ALL patient and for those with MRD. Clinical trials are currently evaluating these options in the first-line setting as well. This review will discuss novel therapies for patients with ALL to include monoclonal antibodies *Corresponding author: Stephanie Gregory, FNP-C, BMTCNÒ , CMR 415, Box 7835, APO, AE 09114. E-mail address: [email protected] https://doi.org/10.1016/j.soncn.2019.150951 0749-2081/© 2019 Elsevier Inc. All rights reserved.
such as inotuzumab ozogamicin (InO), bispecific antibodies like blinatumomab, and chimeric antigen receptor (CAR) T-cell therapy. Nursing implications for the management and care of patients receiving these treatments will be examined as well.
Bispecific Antibodies Bispecific antibodies are drug compounds that utilize two monoclonal antibody binding sites and engineer them into a single molecule.5,6 Blinatumomab is a bispecific T-cell engager (BiTE) and is the first drug developed in this class targeting CD19/CD3; it is also the first bispecific antibody approved by the US Food and Drug Administration (FDA) for the treatment of R/R and MRD ALL. Essentially, the molecule binds to the CD3 antigen receptor on the patient’s immune T cells and to the CD19 surface antigen of the cancer cells, bringing the two in close proximity and thus inducing more efficient extermination of the malignant cells.1 CD19 is a common B-cell surface marker expressed in more than 90% of ALL cases; hence, the exponential growth of clinical and pharmaceutical trials researching compounds with the ability to target this antigen over the past decade.7 Blinatumomab has demonstrated impressive results in clinical trials for patients with Philadelphia (Ph)-negative ALL. The TOWER trial, a phase 3 study comparing blinatumomab (n=271) with standard-ofcare chemotherapy (n=134) in patients with R/R Ph-negative ALL, demonstrated superior overall survival with a median 4.0 months in the standard-of-care group versus 7.7 months in the blinatumomab group (P = .01).8 Additionally, the rate of molecular remission in the blinatumomab cohort was significantly greater than that of the
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S. Gregory / Seminars in Oncology Nursing 00 (2019) 150951
standard-of-care cohort (76% v 48%, respectively).8 In patients with MRD, blinatumomab has proven effective at achieving MRD negativity, making it possible for patients to move forward with allogeneic stem cell transplant. In a study conducted by Topp et al,9 MRD negativity was successful in 80% of the study participants (n=20). In a subsequent study of patients with MRD, the BLAST trial (n=113), a complete response was noted in 78% of the cohort after the first cycle.10 The addition of tyrosine kinase inhibitors to regimens for patients with Ph-positive ALL has made a significant positive impact on outcomes. However, in the R/R setting, the overall survival prognosis is still poor.3 In light of this knowledge, further targeted therapies are being studied in hopes of improving outcomes for these patients. Blinatumomab alone demonstrated a low response rate of 36% in a phase 2 trial of 45 patients with Ph-positive ALL in the R/R setting. Some early case studies have been evaluating the compound in combination with second-generation or later tyrosine kinase inhibitors with some promising results.11 Nursing considerations Blinatumomab has a short half-life, requiring continuous intravenous infusion over several weeks that are usually administered for multiple cycles. This short half-life can be advantageous in that severe side effects can often be managed by simply stopping the infusion, resulting in reversal of symptoms within a few hours.5 The drawback is that these patients will require indwelling catheters to receive the continuous infusion, inviting the complications that are well known to be associated with central line accesses (including increased risk of infection and thrombosis). The most severe adverse events related to blinatumomab infusion include cytokine release syndrome (CRS) and neurotoxicity, which are discussed later in this article. To minimize these risks, the drug is usually given in a slowdose escalation format in the hospital, and the dose is gradually increased over several weeks.1 Neurologic symptoms are primarily dose-dependent and associated with higher doses of the drug, which are usually reversible with stopping infusion; the administration of dexamethasone has also been successful in treating neurotoxicity and is often used as prophylaxis.5 Chimeric Antigen Receptor (CAR) T-cell Therapy Perhaps one of the most revolutionary therapy options for both pediatric and adult patients to be developed in the past decade is chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a targeted immunotherapy in which the T lymphocytes are collected from the patient or a donor, through leukapheresis, and genetically engineered and expanded in the laboratory with customized receptors to identify and attack certain tumor-specific antigens.12 Similar to blinatumomab, CAR T cells currently target the CD19 B-cell marker because it is expressed in the majority of ALL cases but is not expressed on stem cells.12,13 It currently has indications for use in B-cell ALL, diffuse large B-cell lymphoma (DLBCL) but is being studied in other B-cell malignancies.14 When the CAR T cells are engaged, proliferation and activation of cytotoxic T cells occurs.3 There are studies ongoing looking at different costimulatory domains as well as those seeking to identify other tumor-specific antigens that may be targets for CAR T-cell therapy. Although CD19 is an excellent target because of its expression in the majority of ALL cases, it is also expressed on normal B cells throughout their development, and the use of immunotherapy targeting CD19 also risks damage to normal immune B cells, leading to aplasia.12 A more ideal target for future CAR T-cell therapy is one that targets a tumor-specific antigen that is unique to the tumor and not found on normal immune cells.12 Single-institution trials, including those conducted at Memorial Sloan Kettering Cancer Center, University of Pennsylvania, and the
National Cancer Institute show that, in patients with R/R ALL, CAR Tcell therapy has achieved superior results with 70% to 90% MRD-negative CR rates.15 17 Multicenter trials have also had encouraging results. A study by Maude et al15 demonstrated a 60% CR rate and median overall survival of 19.1 months. Tisagenlecleucel is currently the only CAR T-cell therapy approved for R/R ALL; however, other agents are being studied for effectiveness with this disease, including axicabtagene ciloleucel, a CAR T-cell therapy approved for R/R large B-cell lymphoma.18,19 Nursing considerations Nurses who administer targeted immunotherapies and monitor patients in the weeks following treatment should be familiar with the basic concepts behind the mechanism of action for CAR T-cell therapy and how they are prepared and administered. Currently, tisagenlecleucel is the only FDA-approved CAR T-cell therapy for the treatment of ALL and only in the R/R and MRD settings.3 T cells are collected via leukapheresis from the patient and, using gene modification, are manufactured in a lab to express the CAR on the surface of the T cell and then to proliferate into millions of CAR T cells; this process takes several weeks. Once manufactured, the cells are cryopreserved before returning to the treatment facility.14 Chemotherapy is administered before the CAR T-cell infusion for antileukemia effect, as well as to achieve lymphodepletion.12 Infusion should take place within 30 minutes of thawing and subsequent to premedications.14 Following CAR T-cell infusion, the cells can locate any cells expressing CD19 antigen and activate the T cell, resulting in proliferation and expansion of cytotoxic T cells and the ultimate killing of tumor cells.12 The T cells begin expanding within 7 to 10 days after CAR T-cell infusion and during this time are vulnerable to immunosuppressive effects. Therefore, corticosteroids, especially at high doses, are typically avoided (including those that may be used as premedication for blood products or other infusions).12 Additionally, although corticosteroids have been proven effective in the treatment of CRS, they are typically reserved for cases of refractory CRS in which there has been no response to tociluzimab.13 As with many therapies for ALL, CAR T-cell therapy is also known to induce cytopenias and increased risk of infection.20 Additionally, because of similar mechanisms of action, blinatumomab and CAR Tcell therapy share many unique similarities in their adverse effect profiles, including CRS and neurotoxicity, which are the most common severe toxicities and are reviewed in subsequent sections of this article. Fever is an expected side effect following infusion and typically occurs within the first 10 days.13 Fever should be treated according to your program’s standard protocols. Frequent assessments should be performed to identify any sequelae after CAR T-cell infusion and should include vital signs, review of systems, physical assessment, and neurological assessments.12 As mentioned previously, CAR T cells are not specific to CD-19 antigens found on the tumor cells and therefore can deplete the body’s normal B cells, as well lead to B-cell aplasia and hypogammaglobulinemia, which may require long-term management. Intravenous immunoglobulins may be administered to treat this in some patients.13 Tumor lysis syndrome is a less common side effect of CAR T-cell therapy but is possible because of the rapid cancer cell destruction, especially in patients with high tumor burden at the start of treatment. Tumor lysis syndrome should be managed according to established institutional protocols, including intravenous hydration, allopurinol prophylaxis, and monitoring of electrolytes and renal function.20 Because of the severe nature of the potential side effects of CAR T-cell therapy, it is only available to programs through Risk Evaluation and Mitigation Strategy programs established by the drug sponsor.20 Risk Evaluation and Mitigation Strategy requires authorized centers to observe specific guidelines to minimize the risks of treatment.20
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Inotuzumab Ozogamicin Inotuzumab ozogamicin (InO) is a monoclonal antibody that links a cytotoxic agent, calicheamicin, to an anti-CD22 antibody.21 The drug binds to DNA of the target cell causing DNA breakage and apoptosis of the cell.3 The findings reported by the INO-VATE clinical trial led to FDA approval of its use in the treatment of R/R B-cell ALL. The study compared (InO) with standard-of-care chemotherapy in the R/ R setting and demonstrated significantly improved results, with 81% of the InO cohort achieving CR.22 Additionally, the InO group achieved higher MRD-negativity rates, longer remission duration, and longer overall survival.22 InO has also demonstrated promising outcomes in combination with low-intensity chemotherapy regimens to minimize toxicity, and is currently being studied for use in elderly patients (median age, 68 years) newly diagnosed with B-cell ALL because this is a population notoriously difficult to treat with standard intensive chemotherapies.3,21 This drug has also been included in studies combined with tyrosine kinase inhibitors for Phpositive ALL and initial results have demonstrated successful rates of MRD negativity and CR in patients receiving InO compared with standard chemotherapy.3 The InO toxicity profile has been associated with an increased rate of veno-occlusive disease (VOD) and hepatotoxicity, especially in patients with prior allogeneic stem cell transplant. However, there have been fewer severe febrile neutropenia and thrombocytopenia events than those treated with standard chemotherapy.3 Nursing considerations InO is administered as an intravenous medication for 3 weekly doses per cycle.3 Premedication typically consist of antihistamine, antipyretic, and corticosteroid. Severe adverse events associated with this drug include myelosuppression leading to bleeding, as well as infection, pyrexia, elevated liver enzymes, and a boxed warning for veno-occlusive disease.23 Patients receiving InO should be monitored closely for any evidence of veno-occlusive disease, which may include rapid weight gain, hepatomegaly, abdominal pain, ascites, and elevated bilirubin.23 Any of these clinical manifestations should be reported immediately for medical management.
3
Table 1 Risk factors for cytokine release syndrome. Increased age Presence of comorbidities High disease burden Higher doses of CAR T cells administered Type of CAR T cell administered (costimulatory domain CD28 > 4-1BB) Higher doses of blinatumomab Concurrent development of infectious illness Conditioning chemotherapy containing fludarabine Data from Brudno and Kochenderfer,13 Frey,24 and Riegler et al.25
adverse events. The general consensus is that early identification of CRS manifestation and early intervention is the best approach to preventing severe and life-threatening ramifications.25 The nurse is often the first to identify concerning issues that arise in the patients and, therefore, must be knowledgeable on what signs and symptoms to report so that early intervention can occur. Treatment for CRS currently consists primarily of supportive care measures, close monitoring of fluid status, corticosteroids, and tocilizumab, which is the only FDA approved drug for the treatment of CRS to date.25 Tocilizumab is a monoclonal antibody that inhibits binding of IL-6 to its receptor, thereby minimizing the immune activation overexpressed in CRS. The use of tocilizumab should be implemented early in patients with grade 3 or 4 CRS. It is critical that all alternative sources of symptoms (such as infection, sepsis, tumor lysis syndrome) are ruled out and that CRS diagnosis is certain before administering tocilizumab because there is some concern that the drug may inhibit the antitumor effect of CAR T cells, given that IL-6 has both pro-inflammatory as well as anti-inflammatory effects.25 An additional dose of tocilizumab may be administered if no improvement is seen within 24 hours, in addition to corticosteroids. There is currently no standardized approach to the treatment of CRS; however, a few treatment algorithms have been published with variations on treatment with corticosteroids, tocilizumab, and supportive care measures.13,29 Management strategies to consider are reviewed in Table 2.5,12,20,30
Cytokine Release Syndrome
Neurotoxicity
Cytokine release syndrome (CRS) is a condition in which the highlevel immune activation from the administered compound triggers a systemic inflammatory response.24 CRS has been associated with immunotherapies, including monoclonal antibodies and bispecific antibodies (such as blinatumomab and CAR-T-cell therapy).25 The exaggerated immune response leads to release of cytokines and elevations in inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa), interferon-ᵞ (IFNᵞ), interleukin-2, and many more.20 Several factors have been identified as increasing the risk for developing CRS. These are described in Table 1. CRS symptoms can often appear similar to an infection. Fever is the trademark sign of CRS and can be very high (105°F); the presence of fever is a diagnostic requirement for CRS. Patients may also experience flu-like symptoms (myalgias, fatigue, chills), tachycardia, hypotension, and in severe cases multiorgan dysfunction (pulmonary edema, cardiac dysfunction, renal impairment, coagulopathy, hepatic failure), and death.25 The condition can range from very mild to very severe and life-threatening. There have been many attempts to develop grading scales for a standardized approach to the management of this condition.17,26 28 The different scales use variations on criteria based on patient response to fluids, vasopressors, the need for oxygen supplementation, and the presence of organ dysfunction to define the levels of severity.17,26 28 Following a consistent grading approach for specific diseases and conditions can help with a more streamlined approach to treatment and management of serious
Blinatumomab and CAR T-cell therapy have both been associated with neurotoxicity and there is currently no clear understanding as to the cause of these symptoms.5,13 With blinatumomab there is an association of increased neurotoxicity with higher doses and, because of the short half-life of the drug, neurotoxicity symptoms are usually reversible with the discontinuation of the continuous infusion, which are also responsive to dexamethasone. The use of dexamethasone as prophylaxis and the step-wise manner in which the dose of the drug is increased over several weeks in patients receiving blinatumomab has decreased the development of neurological symptoms.5 CAR T-cell neurotoxicity can present in a number of ways: delirium, hallucinations, encephalopathy, tremors, ataxia, dysphasias, language disturbance, seizures, somnolence, and many more.13,20 In some cases, neurological toxicities have led to the need for intubation and ventilation to support the patient until resolution of adverse effects.13 Symptoms can coincide with CRS or can occur independently without signs of CRS. Patients with neurological symptoms following CAR T-cell infusion should undergo comprehensive neurological evaluation, including imaging scans and lumbar puncture as appropriate.13 Treatment typically includes the use of corticosteroids as front-line therapy in the case of isolated neurotoxicity because tocilizumab does not cross the blood brain barrier.25 Any evidence of neurologic impediment recognized by the nurse should be reported immediately for early intervention.
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S. Gregory / Seminars in Oncology Nursing 00 (2019) 150951 Table 2 Management strategies for CAR T-cell therapy. Infusion Premedicate per institution protocols, avoid corticosteroids Thaw product per protocols and administer within 30 minutes of thawing Supportive care Perform thorough physical examination, vital signs, intake and output, weight, and neurologic assessments per institution protocols Provide supportive care for mild CRS symptoms: fever, myalgia, headache, anorexia, nausea or vomiting Fever is usually the presenting symptom of CRS but should have infection work-up performed and managed per program protocols to potentially include hospital admission Monitor for respiratory symptoms including measuring oxygen saturation. Provide oxygen support for hypoxia, obtain imaging as ordered. Mechanical ventilation may be required in severe cases Consider tocilizumab +/- corticosteroids for higher-grade CRS per institution protocols Transfer to ICU as needed for progressing or severe toxicity For neurologic changes, consider neurology consultation, diagnostic testing (MRI, CT, lumbar puncture, EEG). Allopurinol and hydration for the management of tumor lysis syndrome and frequent monitoring and replacement of electrolytes Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CT, computed tomography; ICU, intensive care unit; MRI, magnetic resonance imaging; EEG, electroencephalogram. Data from Viardot et al,5 Callahan et al,12 Brudno and Kochenderfer,13 Anderson and Latchford,20 and Smith and Venella.30
Conclusion and Future Considerations Targeted therapies have brought about more effective and personalized treatment methods than traditional standard chemotherapies, with improved outcomes in the R/R and MRD setting. Given the dramatic improvements seen using these novel therapies in the salvage setting, it seems likely that the next step will be to include antibody-targeted therapies with lower-intensity chemotherapies in the frontline setting as well. Currently there are several ongoing studies investigating combinations of these therapies.3 Research continues in the development of alternative antibody-drug conjugates, as well as other CAR T-cell therapies. Additionally, because CD-19 is expressed on both tumor cells and normal B cells, the search continues for an optimal antigen target that is more tumor-specific to minimize damage to normal immune cells. As targeted therapies continue to take the oncology field by storm, nurses are faced with the challenge of maintaining competency related to how these therapies are administered and which potential drug reactions, side effects, and other complications may be expected. Providing excellent care to patients undergoing oncology treatment means staying current in the evolving therapies for specific diseases, maintaining competencies, and being knowledgeable and confident in the management of potential adverse reactions for any therapy the nurse is responsible for administering. Nurses play a pivotal role in educating patients and their families on what to expect when receiving these novel treatments and in identifying any clinical presentation that warrants concern in these patients, such as symptoms of CRS and neurological toxicity. Additionally, because the CAR T-cell field is still new, further development of universal grading scales and treatment algorithms are needed for the management of related toxicities. References 1. Liu D, Zhao J, Song Y, Luo X, Yang T. Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia. J Hematol Oncol. 2019;12:1–13.
€ kbuget N, Dombret H, Ribera JM, et al. International reference analysis of out2. Go comes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101:1524–1533. 3. Paul S, Rausch C, Nasnas P, Kantarjian H, Jabbour E. Treatment of relapsed/ refractory acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2019;17: 166–175. 4. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3: e170580. 5. Viardot A, Bargou R. Bispecific antibodies in haematological malignancies. Cancer Treat Rev. 2018;65:87–95. 6. Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:1–7. 7. Naddafi F, Davami F. Anti-CD19 monoclonal antibodies: a new approach to lymphoma therapy. Int J Mol Cell Med. 2015;4:143–151. € kbuget N, et al. Blinatumomab versus chemotherapy for 8. Kantarjian H, Stein A, Go advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–847. € kbuget N, Zugmaier G, et al. Long-term follow-up of hematologic 9. Topp MS, Go relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185–5187. € kbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual 10. Go disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–1531. 11. Assi S, Kantarjian H, Short NJ, et al. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk. 2017;17:897–901. 12. Callahan C, Banewicz D, Ely B. CAR T-cell therapy: pediatric patients with relapsed and refractory acute lymphoblastic leukemia. Clin J Oncol Nurs. 2017;21:22–28. 13. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321–3330. 14. Lamprecht M, Dansereau C. CAR T-cell therapy: update on the state of the science. Clin J Oncol Nurs. 2019;23:6–12. 15. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–1517. 16. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 1928z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:1–23. 17. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose escalation trial. Lancet. 2015;385:517–528. 18. Kymriah. Package insert. East Hanover, NJ: Novartis; 2017. 19. Wierda WG, Bishop MR, Oluwole OO, et al. Updated phase 1 results of ZUMA 3: KTE-C19, an anti-CD19 chimeric antigen receptor T cell therapy, in adult patients with relapsed/refractory acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):897. 20. Anderson K, Latchford T. Associated toxicities: assessment and management related to CAR T-cell therapy. Clin J Oncol Nurs. 2019;23:13–19. 21. Yilmaz M, Kantarjian H, Ravandi-Kashani F, Short NJ, Jabbour E. Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Current treatments and future perspectives. Clin Adv Hematol Oncol. 2018;16:216–223. 22. Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375: 740–753. 23. Besponsa. Package insert. New York, NY: Pfizer; 2018. 24. Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol. 2017;30:336–340. 25. Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323–335. 26. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–638. 27. Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018;11:1–12. 28. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). V5.0. 2018. Bethesda, MD; National Institutes of Health. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. (Accessed May 6, 2019). 29. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T cell therapy assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62. 30. Smith L, Venella K. Cytokine release syndrome: inpatient care for side effects of CAR T-cell therapy. Clin J Oncol Nurs. 2017;21:29–34.