High Risk Therapy Made Easy: Supporting High Risk Patients Through Complex Therapy

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

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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.

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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

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.

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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

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

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.

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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

Adverse Events from Blinatumomab

Most common AEs: central and peripheral neurotoxicity and cytokine release syndrome (CRS)

All neurotoxicity is reversible

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

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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

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

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.

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Exciting News!

Blincyto approved September 2016 for pediatric ALL patients.

Photo taken from http://www.blincyto.com/blincyto-blinatumomab/mechanism-of-action/

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

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)

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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.

Case Study - Brian

•Transplant 7/31 with umbilical cord •Died 9/12 from infectious complications from transplant.

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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

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

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

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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

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 GMCSF/IL-2) ● Each course has 2 weeks of oral retinoic acid following admission

Dinutuximab Supportive Care

● Complex admission ● Systematic approach for the supportive care ● Pain team, Nursing, Providers, OT/PT ● Many reactions can occur including: − allergic reactions, hypotension, pain, fevers etc. ● Supportive medication Includes: − 1:1 nursing, frequent VS, pain medications, fluids, scheduled anti histamines, Tylenol and at times celebrex, nebulizer treatments in some cases, neurontin that begins prior to admission, albumin and lasix

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DINUTUXIMAB

● Most common side effect is Neuropathic pain − Abdominal cramps, extremity or back pain − PCA/Narcan drip, Direct comfort measures include: lidoderm patches, hot or warm pack, massage

Dinutuximab Supportive care

ANBL0032 INTERVENTION CHEAT SHEET

● Prior to Infusion each day: Hemoglobin > 8 Albumin > 3.0 Platelets >20,000 Ensure emergency med sheet is in room Ensure algorithm for hypotension and anaphylaxis are in room and readily available

● Pain: Usually neuropathic, Most commonly present in abdomen and extremities Start PCA 20 – 30 minutes prior to start of antibody – continuous rate plus boluses Tylenol q 6 hours Gabapentin TID Monitor on continuous pulse oximeter May decrease/shut off PCA when CH14.18 is completed per Pain Team. If stop CH14:18 for prolonged time please let Pain Team know.

Dinutuximab Supportive care

● Itching: Administer bendaryl q 6 hrs, Claritin and zantac may also be ordered. Notify provider if additional meds needed. Atarax may be used instead or with benadryl

● Cough: Begin scheduled albuterol nebulizer treatments possibly Budesonide May need atrovent or fluid retention correction Bronchospasm: Need racemic epinepherine

● Fever > 38.5: Administer Tylenol q 4 – 6 hours Draw blood cultures from all lumens – x1 every 24 hours if febrile Start IV antibiotics per provider order (may be for 48 hours) May start Celebrex scheduled if renal function is normal

● Fluid/Electrolyte Imbalance: Strict I & O q 4 hours and prn BID weights If albumin < 3.0, give albumin followed by lasix Auscultate lung sounds If receiving GT/JT feeds, consider decreasing IV fluids If patients is fluid overloaded, discuss with provider Monitor urine for heme and specific gravity

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Dinutuximab Supportive care worksheet

● Allergic Reaction: Have emergency meds and equipment ready at the bedside For Dinutuximab, if mild reaction (localized hives, rigors) decrease rate by 50% and page Provider, refer to page 54 in protocol If grade 3-4 reaction STOP BOTH IL-2 and CH14:18, and page Provider. See page 54 in protocol. Coughing may signal bronchospasm May need to support with benadryl q 4 – 6 hours, atarax, O2, epinephrine, albuterol, budesonide, atrovent, racemic epinepherine, IV fluids, etc…

● AVOID STEROIDS unless approved by provider

● Hypotension: Hold Dinutuximab and IL-2, Page Provider NS bolus If pain well managed, consider decreasing narcotic infusion Algorithm

Other infusion concern

Renal compromise − Can have decreased renal perfusion • Give lasix prn, or fluid bolus • If urine has heme will need BUN, Creatinine checked Neuropathy − PT to follow inpatient − Follow pupillary response Thrombocytopenia/Anemia − Follow counts twice weekly while inpatient

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Preventing infection and related complications in HR patients • Infection is a major cause of morbidity and mortality in cancer patients • ONS and APHON have EBP clinical guidelines for “Prevention of Infection” • Children’s Minnesota formed multidisciplinary team to develop a guideline for anti-microbial prophylaxis in HR patients • Prophylaxis Anti-microbial Guideline developed from variety of guidelines (COG 2016; Lehrnbecher et al., 2017; NCCN, 2017; Science et al., 2014; Tacke et al., 2014; Tomblyn et al., 2009; Wolf et al., 2017)

Learning lesson… Daniel R: 17yo with relapsed VHR ALL • Diagnosed with VHR B-lineage ALL December 2017 − Induction MRD 3.6%; Consolidation MRD 0.011; 1 month later MRD negative − Started on study, AALL1131: due to + MRD at end of Induction; treated per AALL0232 − EOT April 2016 • Relapsed Nov 2017 − Started TACL 2012-002 with Marqibo (on study) − Day 5: Prophy meds started: bactrim, levofloxacin, micafungin − Day 5: Febrile and grew Beta hemolytic streptococci (pansensitive) from blood cultures within 24 hours • Would have upfront prophy made a difference?

Prophylaxis Anti-Microbial Guideline

1. Pneumocystis jiroveci (PJP) • Indication: conventional chemotherapy; oral chemo known to increase risks for PJP (temsirolimus, everolimus, ..nibs) • First line: Bactrim • Alternative: Pentamidine* (Neb or IV) • Nursing consideration: * can cause QTc prolongation

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Prophylaxis Anti-Microbial Guideline (cont.)

2. Antibacterial • Indication: AML patients; Relapsed ALL; AYA leukemia patients • First Line: Levofloxacin • Alternative: Ciprofloxacin* WITH Amoxicillin/clavulanate or Cefepime q 12 hr dosing (if inpatient) • Nursing consideration: * can cause QTc prolongation

Prophylaxis Anti-Microbial Guideline (cont.)

3. Antifungal • Indication: AML patients; Relapsed ALL; AYA leukemia patients; history of fungal sepsis • First line: Voriconazole*^ • Alternative: Micafungin/Posaconazole*^ • Nursing Considerations: * can cause QTc prolongation ^ caution CYP450 drug interaction

Prophylaxis Anti-Microbial Guideline (cont.)

4. Alpha Hemolytic Strep • Indication: hospitalized and relapsed ALL during Induction or receiving HD cytarabine (HD >1000mg/m²/day or 66mg/kg/day • First line: Vancomycin • Nursing considerations: Weekly VRE evaluation; treatment vs prophy dosing

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Prophylaxis Anti-Microbial Guideline (cont.)

5. Antiviral • Indication: Previous HSV episode or AYA with prolonged neutropenia • First line: Valacyclovir • Alternative: Acyclovir • Nursing consideration: swab first experience with mucositis for HSV

Nursing considerations

• Risk of prolonged QT intervals − Risk increases: • with using >2 drugs with potential of prolonged QT interval (multiple medications have this potential) • History of: heart disease, bradycardia, anthracycline use, renal or liver dysfunction • Decrease levels of calcium, potassium, and/or magnesium − Repeat EKG after 5 doses of new drug − If stable and <500 continue to monitor pt and electolytes − If QT ≥500 consult Electrophysiologist

Nursing Considerations

Azole and VinCRIStine interactions • caution CYP450 drug interaction-chrome P450 3A4 can lead to excessive vinca alkaloid exposure and severe neurotoxicity. • Most common adverse effects included: GI toxicity, peripheral neuropathy, hyponatremia and SIADH, and autonomic neuropathy (Moriyama et al., 2012) • Guidelines we adapted: − Avoid use of azole 1 day before, day of VCR administration, and 1 day post (adopted from Voriconazole Guidelines- St Jude (unpublished), 2017)

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Follow-up since initiating our guidelines

• No CLABSI has occurred in hospitalized patients who followed guideline appropriately since initiation in May 2018 • No significant azole/VCR adverse effects observed • No significant risk for QTc observed • No concerns with VRE with us of Vancomycin

Future plans: • Monitor appropriate use of guidelines • Monitor SE or resistance related to use of prophy guidelines

Questions?

References Children’s Oncology Group (2016). Supportive Care Guidelines. Accessed from www.chidrensoncologygroup.org Lehrnbecher, T., Robinson, P., Fisher, B., Alexander, S., Ammann, RA., Beauchemin, M., . . . Sung, L. (2017). Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 Update. Journal of Clinical Oncology. Doi: 10.1200/JCO.2016.71.7017 JCO F&N Guidelines for Pediatric Patients (MASCC) Maude, S. L., Barrett, D., Teachey, D. T., & Grupp, S. A. (2014). Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer journal (Sudbury, Mass.), 20(2), 119. Moriyama, B., Henning, S.A., Leung, J., Falade-Nwulia, O., Jarosinski, P., Penzak, S.R., & Walsh, T.J. (2012). Adverse interactions between antifungals azoles and vincristine: Review and analysis of cases. Mycoses. Doi: 10.1111/j.1439-0507.2011.02158.x NCCN Guidelines: Prevention and Treatment of Cancer-Related Infections. V.1.2018; Accessed 3.2018 Reinwald M, Boch, T., Hofmann, WK., & Buchheidt, D. (2015). Risk of infectious complications in hemato- oncological patients treated with kinase inhibitors. Biomarker Insights, 10(S3) 55-68. Science, M., Robinson, PD, MacDonald, T., Rassekh, SR, Dupuis, LL, & Sung, LL. (2014). Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients. C17 Council. Pediatric Blood & Cancer, 61, p.393-400. Doi: 10.1002/pbc.24847 Tacke, et al. (2014). Primary prophylaxis of invasive fungal infections: 2014 Update of Infectious Disease. Annals of Hematology. Tomblyn M., Chiller, T., Einsele, H., Gress, R., Sepkowitz, K., Storek, J., . . . Boeckh, MA. (2009). Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: A global perspective. American Society for Blood and Marrow Transplantation. 15(10):1143-1238. Voriconazole Therapeutic Drug Monitoring Guidelines for Pediatrics, St. Jude Children’s Research Hospital, Haidar, C. et al. Unpublished. Feb 2015. Wolf, J., Tang, L., Flynn, PM., Pui, CH., Gaur, AH., Sun, Y., . . . Jeha, S. (2017). Levofloxacin Prophylaxis during induction therapy for pediatric acute lymphoblasic leukemia. Clinical Infectious Disease. Doi/10.1093/cid/cix644/4157396 © 2018 45

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