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Immunotherapies have dramatically increased response rates in the relapsed/refractory setting of acute lymphoblastic leukemia. These emerging therapeutic options include blinatumomab, a bispecific T-cell engager construct; inotuzumab, an antibody–drug conjugate; and CAR T cells. Despite significantly improved rates of response, however, CAR T-cell therapy is the only approach associated with durable survival in a significant proportion of patients. Immunotherapies come with characteristic toxicity profiles. Inotuzumab is associated with hepatotoxicity, and blinatumomab and CAR T cells are associated with both cytokine release syndrome and neurotoxicity. Furthermore, immunotherapy is not always successful. Several mechanisms of failure exist, including failure to manufacture the CAR product, failure to engraft or lack of persistence of CAR T cells, endogenous T cell or CAR T-cell exhaustion, and antigen escape.

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of diseases with different morphologic, cytogenetic, and molecular subgroups, some of which have significant therapeutic implications. It typically presents with an aggressive clinical course, and among adults, responds poorly to standard chemotherapy, and carries a high risk for relapse. Despite the significant progress made in inducing remission, frequent relapses remain a challenge. Novel drugs, such as potent later-generation tyrosine kinase inhibitors, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies, are being investigated in patients with ALL. This summary describes therapies currently approved for the treatment of patients with ALL, identifies emerging targeted immunotherapies for patients with ALL, and discusses adverse events and mechanisms of resistance.

Background: Anti-PD1/PD-L1 therapy is standard-of-care for patients with a variety of advanced malignancies. Although clinical trials report a lower incidence of grade 3-4 toxicities than observed with cytotoxic agents, it is imperative that clinicians identify and manage the unique toxicities of these agents. We aimed to identify real-world incidence of immune-related toxicities and management for patients treated with anti-PD1/PD-L1 agents prior to publication of clinical practice guidelines. Methods: Patients enrolled in a Humana Medicare Advantage plan who initiated any anti-PD1/PD-L1 therapy September 1, 2014–February 28, 2018 were identified. NCCN Guidelines for immune-related toxicity were used to determine appropriate pharmacy and medical codes from administrative claims data for toxicity identification and management. ICD-10 codes were examined for patients requiring hospital or ED visits, and HCPCS and NDC codes were used for patients requiring toxicity treatment (eg, corticosteroids, anti-TNFα). Results: 6,005 patients were identified; 39.1% were female, median (IQR) age was 72 years (67–77). The majority (64.7%) had thoracic cancers; 16.3% genitourinary cancers; and 12.8% skin cancers. The median number of anti-PD1/PD-L1 doses received was 4 (2–8). Overall, 62.5% (n=3,751) of patients experienced >1 toxicity with half (n=1,913) requiring an inpatient stay or ED visit, and the other half (n=1,838) receiving outpatient toxicity medication. A similar proportion of patients developed >1 toxicity, regardless of age: <75 years, 62.4% (n=2,416); and 62.5% (n=1,335) >75 years. Systemic corticosteroids were used by 61.3% (n=2,300) of patients that experienced toxicity. The most frequently observed toxicity in this dataset by organ system was cardiovascular (18.5%, n=1,108), which was comprised largely of arrhythmias (13.7%; n=823), and endocrine toxicities (15.8%; n=950), mostly type 2 diabetes (11.9%; n=714). Conclusion: Real-world data from a large Medicare Advantage plan indicate that half of patients receiving anti-PD1/anti-PD-L1 may experience a toxicity resulting in an inpatient stay or ED visit with no difference by age. While attribution of toxicity may be challenging using claims data, the spectrum of immune-related toxicities in the real world may differ from those reported in clinical trials. Future research should evaluate incidence and management of toxicities post-guideline release and monitor changes in site of care for management.

Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.

Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.