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.
Presenter : Patrick A. Brown
Patrick A. Brown and Bijal Shah
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.
Joseph C. Alvarnas and Patrick A. Brown
Patrick A. Brown and Joseph C. Alvarnas
Victoria T. Brown, Dana Drzayich Antol, Patrick N. Racsa, Melea A. Ward and Jarushka Naidoo
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.
Ndiya Ogba, Nicole M. Arwood, Nancy L. Bartlett, Mara Bloom, Patrick Brown, Christine Brown, Elizabeth Lihua Budde, Robert Carlson, Stephanie Farnia, Terry J. Fry, Morgan Garber, Rebecca A. Gardner, Lauren Gurschick, Patricia Kropf, Jeff J. Reitan, Craig Sauter, Bijal Shah, Elizabeth J. Shpall and Steven T. Rosen
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.
Joseph C. Alvarnas, Patrick A. Brown, Patricia Aoun, Karen Kuhn Ballen, Stefan K. Barta, Uma Borate, Michael W. Boyer, Patrick W. Burke, Ryan Cassaday, Januario E. Castro, Peter F. Coccia, Steven E. Coutre, Lloyd E. Damon, Daniel J. DeAngelo, Dan Douer, Olga Frankfurt, John P. Greer, Robert A. Johnson, Hagop M. Kantarjian, Rebecca B. Klisovic, Gary Kupfer, Mark Litzow, Arthur Liu, Arati V. Rao, Bijal Shah, Geoffrey L. Uy, Eunice S. Wang, Andrew D. Zelenetz, Kristina Gregory and Courtney Smith
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.
Joseph C. Alvarnas, Patrick A. Brown, Patricia Aoun, Karen Kuhn Ballen, Naresh Bellam, William Blum, Michael W. Boyer, Hetty E. Carraway, Peter F. Coccia, Steven E. Coutre, Jennifer Cultrera, Lloyd E. Damon, Daniel J. DeAngelo, Dan Douer, Haydar Frangoul, Olga Frankfurt, Salil Goorha, Michael M. Millenson, Susan O'Brien, Stephen H. Petersdorf, Arati V. Rao, Stephanie Terezakis, Geoffrey Uy, Meir Wetzler, Andrew D. Zelenetz, Maoko Naganuma and Kristina M. Gregory
The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.
Patrick A. Brown, Bijal Shah, Amir Fathi, Matthew Wieduwilt, Anjali Advani, Patricia Aoun, Stefan K. Barta, Michael W. Boyer, Teresa Bryan, Patrick W. Burke, Ryan Cassaday, Peter F. Coccia, Steven E. Coutre, Lloyd E. Damon, Daniel J. DeAngelo, Olga Frankfurt, John P. Greer, Hagop M. Kantarjian, Rebecca B. Klisovic, Gary Kupfer, Mark Litzow, Arthur Liu, Ryan Mattison, Jae Park, Jeffrey Rubnitz, Ayman Saad, Geoffrey L. Uy, Eunice S. Wang, Kristina M. Gregory and Ndiya Ogba
The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.
Featured Updates to the NCCN Guidelines
Patrick A. Brown, Matthew Wieduwilt, Aaron Logan, Daniel J. DeAngelo, Eunice S. Wang, Amir Fathi, Ryan D. Cassaday, Mark Litzow, Anjali Advani, Patricia Aoun, Bhavana Bhatnagar, Michael W. Boyer, Teresa Bryan, Patrick W. Burke, Peter F. Coccia, Steven E. Coutre, Nitin Jain, Suzanne Kirby, Arthur Liu, Stephanie Massaro, Ryan J. Mattison, Olalekan Oluwole, Nikolaos Papadantonakis, Jae Park, Jeffrey E. Rubnitz, Geoffrey L. Uy, Kristina M. Gregory, Ndiya Ogba and Bijal Shah
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.