8/21/2018 High Risk Therapy Made Easy: Supporting high risk patients through complex therapy Lori Ranney, MSN, APRN, CPNP, CPHON Mylynda Livingston, MSN, APRN, AC PC-PNP, CPON Teresa Herriage, DNP, APRN, CPNP, CPHON Children’s Minnesota Disclaimers and Confidentiality Protections Children’s Minnesota makes no representations or warranties about the accuracy, reliability, or completeness of the content. Content is provided “as is” and is for informational use only. It is not a substitute for professional medical advice, diagnosis, or treatment. Children’s disclaims all warranties, express or implied, statutory or otherwise, including without limitation the implied warranties of merchantability, non-infringement of third parties’ rights, and fitness for a particular purpose. This content was developed for use in Children’s patient care environment and may not be suitable for use in other patient care environments. Children’s does not endorse, certify, or assess third parties’ competency. You hold all responsibility for your use or nonuse of the content. Children’s shall not be liable for claims, losses, or damages arising from or related to any use or misuse of the content. This content and its related discussions are privileged and confidential under Minnesota’s peer review statute (Minn. Stat. § 145.61 et. seq.). Do not disclose unless appropriately authorized. Notwithstanding the foregoing, content may be subject to copyright or trademark law; use of such information requires Children’s permission. This content may include patient protected health information. You agree to comply with all applicable state and federal laws protecting patient privacy and security including the Minnesota Health Records Act and the Health Insurance Portability and Accountability Act and its implementing regulations as amended from time to time. Please ask if you have any questions about these disclaimers and/or confidentiality protections. © 2018 2 Speaker Disclosure Statement o Lori Ranney has no industry relationships to disclose. o Mylynda Livingston has no industry relationships to disclose. o Teresa Herriage has no industry relationships to disclose. © 2018 3 1 8/21/2018 Objectives: • Learner will be able to identify strategies to support patients undergoing immunotherapy drugs; blinatumomab and dinutuximab • Learner will be able to identify high risk (HR) patients that would benefit from upfront infection prophylaxis based on risk factors © 2018 4 New Therapies for ALL Blinatumomab (BLINCYTO) received FDA approval for children with relapsed or refractory ALL in 2016. BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. © 2018 5 © 2018 6 2 8/21/2018 Lessons Learned from Early Blinatumomab Studies Evidence of clinical activity and benefit Very short half-life: 2 hours − Required continuous exposure for clinical benefit Results in T cell Activation: − T cell proliferation − Lysis of tumor cells − Cytokine release Development of AALL1331: Blinatumomab with UKALLR3 backbone © 2018 7 Blinatumomab administration Blinatumomab is a 28 day continuous IV infusion. IV bag will be changed every 96 hours •Hospitalization: Hospitalization is STRONGLY recommended during the first 9 days of the first blinatumomab cycle and the first 2 days of subsequent blinatumomab cycles in case of a cytokine reaction (from package insert for Blincyto) Premedication: Dexamethasone − Day 1: 6-12 hours prior to initiation of infusion − Day 1: 30 minutes prior to infusion Blinatumomab infusion should not be interrupted for LP procedures © 2018 8 Administration – continued Avoid Interruptions − Any interruption >1 hour should be recorded Any interruptions >4 hours requires readmission to hospital to resume − A new bag of Blinatumomab should be prepared when resuming after >4 hour interruption − Additional dexamethasone pre-medication For interruptions due to line issues the infusion should be switched to the other lumen to re-start as fast as possible. © 2018 9 3 8/21/2018 Administration Pearls Avoid flushing the dedicated Blinatumomab line − Can result in a bolus dose of Blinatumomab − Bolus dose less concerning on AALL1331 compared to early phase trials (reduced tumor burden) Avoid flushing with IV Blinatumomab bag changes Some flushing is unavoidable! − End of 28 day infusion − Unblocking CVL occlusions − Hospital policies © 2018 10 Adverse Events from Blinatumomab Most common AEs: central and peripheral neurotoxicity and cytokine release syndrome (CRS) All neurotoxicity is reversible © 2018 11 Cytokine Release Syndrome Constellation of inflammatory symptoms Results from cytokine elevations Associated with T cell proliferation CRS ranges from mild to severe to life threatening Mild: flu-like symptoms, fever, myalgia Severe: vascular leak, hypotension, pulmonary edema, coagulopathy Life threatening: can lead to multi-system organ failure Cytokine elevations can be measured Degree of elevation does not always correlate to clinical severity © 2018 12 4 8/21/2018 Management of CRS Reported with first cycle of Blini, typically within first 12- 72 hours Most Significantly elevated Cytokines: IL10, IL6, IFNy Is it possible to target the Cytokines themselves? Anti IL6 (tocilizumab) – resolution of CRS Reversal and clinical improvement seen within 24 hours Maude, Journal of Cancer, 2014; Barrett, Current Opinions in Pediatrics, 2014 © 2018 13 Case Study - Noah • Diagnosed 12/30/08 at age 3 with pre B ALL • Completed therapy on 4/22/12 • Routine off therapy long-term follow-up visit reveals relapse in peripheral blood on 4/22/16 • Flow on relapse marrow shows + CD 10, CD19, CD22, CD34, CD 52, CD 79a, TdT • Enrolled on relapse study COG AALL1331 • End of Block I marrow shows MRD 10.2% • Determination by COG of Intermediate Risk and randomized to receive arm of study with Blinatumomab © 2018 14 Noah (cont.) • Cycle 1 of Blinatumomab started on 6/7/16 • Did well with only mild neurological side effects as well as fever for 24 hours after drug started – all resolved within 36 hours • End of Cycle 1 (Block II) MRD (after 28 days of Blinatumomab) is negative! • Proceeds per study Cycle 2 (28 more days of Blinatumomab) • No signs of CRS or neurological toxicity • Proceeds to 6/6 umbilical cord blood transplant at U of MN Sept 2016. • Doing well now 24 months post transplant. © 2018 15 5 8/21/2018 Exciting News! Blincyto approved September 2016 for pediatric ALL patients. Photo taken from http://www.blincyto.com/blincyto-blinatumomab/mechanism-of-action/ © 2018 16 The Future of Blinatumomab •Use in off study pediatric patients •Bridging therapy for MRD positive patients to prep for transplant •Single agent versus in combination with other chemotherapy backbones © 2018 17 Case Study - Bryan •Presented at age 9 on 9/23/15 with WBC 600,000 and diagnosed with PH + ALL. •Received 4 drug Induction per COG AALL1131 with addition of dasatinib. •CHG with IKAROS •Day 29 marrow MRD 0.01. Fish + for BCR/ABL at 0.2%. •Follow up marrow after 2 cycles of Consolidation is negative (MRD and FISH) © 2018 18 6 8/21/2018 Bryan (cont.) •CNS (3b) and Bone Marrow relapse 3/13/17. •Received TACL Carfilzomib study (Carfilzomib, dex, dauno, PEG, Vinc. •Marrow shows 25% blasts, 75% BCR/ABL positivity by FISH, and 61% positivity for IKAROS •Salvage therapy consisted of cytoxan/etoposide (5 days) and nilotinib (30 days). •Marrow with 4.6% blasts, 5% BCR-ABL postivity by FISH. © 2018 19 Case Study - Brian •Transplant 7/31 with umbilical cord •Died 9/12 from infectious complications from transplant. © 2018 20 © 2018 21 7 8/21/2018 Neuroblastoma ● Small round blue cell tumor ● Arises from neural crest cells (nerve tissue) ● Arises from adrenal gland or paraspinal sympathetic nerves. ● Most common extra cranial tumor of childhood ● More than half have high risk disease ● Cause is unknown ● ALK gene described in 2008 © 2018 22 Incidence of Neuroblastoma ● Males more than females ● 8% of all childhood cancer ● 15% of childhood cancer deaths ● 40% - under 1 year ● Most diagnosed under 5 years of age (~90%) ● Familial ● Most cause is unknown © 2018 23 Treatment High Risk ● Standard of Care (~18 months) ● NMTRC012 − 6 cycles of induction chemotherapy − Surgical resection after 4 or 5 cycles − Molecular Guided Therapy at start of cycle 3 ● Autologous HSCT − Busulfan/Melphalan • Less toxicity then CEM ● Radiation therapy (standard or proton beam) − Primary site, plus boost to remaining MIBG + sites ● MRD therapy − Dinutuximab − 3F8 ● Maintenance − 2 years DFMO © 2018 24 8 8/21/2018 MRD therapy Dinutuximab with IL-2/GMCSF Most have problems with refractory microscopic residual disease ANBL0032 started in October 2001 Stopped randomization with median follow-up of 2.1 yrs after randomization, event free survival was significantly higher for patients randomized to immunotherapy, with 2- yr estimates of 66%+5% vs 46%+5% Post radiation and within 200 days post BMT Immunotherapy targets a tumor associated antigen, GD2. Highly expressed on NBL cells. Some expression on normal cells 6 courses (courses 1, 3 uses GM-CSF for ADCC and 2, 4 uses IL-2) Each course has 2 weeks of oral retinoic acid following admission © 2018 25 Dinutuximab with IL-2/GMCSF ● Most have problems with refractory microscopic residual disease ● ANBL0032 started in October 2001 ● Post radiation and within 200 days post BMT ● Immunotherapy targets a tumor associated antigen, GD2. ● 6 courses (alternate