9/21/2016 Objectives • Review newest therapies in pediatric oncology • Discuss the use of Blinatumomab in pediatric Update in Pediatric Oncology patients • Review Car T‐Cell immunotherapy in pediatric Katie Bruce, PharmD, BCPPS patients Pharmacy Clinical Specialist • Discuss the latest therapy approved for use in Pediatric Oncology and BMT The Children’s Hospital at TriStar neuroblastoma Centennial Disclosure • I have no financial conflicts to disclose Pediatric Leukemia Pediatric Leukemia Classification • Acute lymphoblastic leukemia (ALL) is the most • Over 85% of childhood ALL is B‐cell ALL common cancer in children ▫ Most commonly precursor‐B cell ALL ▫ Accounts for ~30% of all cancers 2% mature B‐cell ALL ▫ 3000 new cases in US each year ▫ 15% T‐cell ALL (Birth –21 years old) Investigating use of nelarabine and/or high dose methotrexate ~ 80% are ALL and ~20% are AML ▫ Incidence of 3.4 cases per 100,000 • Risk Criteria ▫ Most common between 2 and 5 years old ▫ Initial WBC count ▫ Boys > girls ▫ Age • Higher incidence in Caucasians and Hispanics vs. African ▫ Cytogenetics American Children ▫ Immunologic subtype www.curesearch.org www.curesearch.org 1 9/21/2016 Risk Stratification Outcomes • ~85% overall 5‐year event‐free survival ▫ 90 –95 % in low‐ or standard‐risk pre‐B ALL with good response to induction chemotherapy ▫ 75 –85 % in high‐risk with good early response ▫ <75% in very high‐risk (Ph+, hypodiploid, CNS3) or slow response to chemo • T‐cell ALL survival lower at 70 –75 % • Infant ALL ▫ Poor prognosis with 10‐30% event‐free survival www.cancer.gov www.childrensoncologygroup.com Relapsed/Recurrent ALL Relapsed/Recurrent B‐ALL • 20 ‐ 25% relapse or fail initial treatment • Backbone Chemotherapy for relapse B‐ALL ▫ Bone marrow, CNS, testes, lymph nodes Block 1Block 2Block 3 ▫ Aggressive re‐induction, consolidation, ± SCT PRED 40 mg/m2/day, ETOP Days 1‐5 HD ARAC Days 1, 2, 8, ▫ 5 ‐ 60% survival Days 1‐29 CPM Days 1‐5 9 VCR 1.5 mg/m2, Days HDMTX Day 22 with L‐ASP Days 2, 9 1, 7, 15, 21 leucovorin IT MTX or ITT Days 1, • 60‐75% of recurrences occur within first year after PEG 2500 IU/m2 , 22 Days 2, 9, 16, 23 completion of therapy DOXO 60 mg/m2 , on • Rates decrease years 2 ‐ 4 and are rare after 5 years Day 1 post‐treatment IT ARAC Day 1 IT MTX Days 15, 29 (or ITT if CNS positive) www.cancer.gov www.childrensoncologygroup.org Blinatumomab (Blincyto®) Blinatumomab (Blincyto®) • AALL1121‐ Phase I/II trial • Novel agent for B‐linegage malignancies ▫ Early data shows efficacy in relapse patients • Fusion protein ▫ Bispecific T‐cell engager (BiTE®) antibody, dual • AALL1331‐ Phase III trial, currently enrolling patients specificity for CD19 and CD3 ▫ Risk stratification after Block 1 • Through CD3 binding, it recruits and engages T‐cells for lysis of CD19 positive B‐cells ▫ Randomized to Block 2 or blinatumomab • Accelerated approval from FDA for Also may receive salvage blinatumomab if relapsed/refractory B‐cell ALL relapse/refractory on standard therapy ▫ Phase II trial showed CR in 43% of patients after 2 ▫ Dose of blinatumomab 15 µg/m²/24 hours x 4 weeks cycles (Topp et al. Lancet Oncol. 2015a) then one week off www.childrensoncologygroup.org Benjamin JE, Stein AS. Ther Adv Hematol.2016 2 9/21/2016 Blinatumomab (Blincyto®) Blinatumomab (Blincyto®) • Adverse reactions • Continuous infusion over 4 weeks ▫ Cytokine release syndrome (CRS) ▫ Half life‐ 2 hours Chills, fever, flushing, bronchospasm, hypotension Give dexamethasone prior to starting infusion ▫ Reduces adverse reactions because concentrations at ▫ Neurologic steady state Headache, tremor, dizziness, confusion, memory impairment, • Observe in hospital for the first 9 days aphasia, seizures • Stop infusion and give steroids. Should be reversible Bag change every 48 hours ▫ Coagulopathy Prolong activated PTT, fibrinogen decreased, INR increased ▫ Hepatic abnormalities ALT and AST increased, bilirubin increase, GGT increase Benjamin JE, Stein AS. TherAdv Hematol.2016 Benjamin JE, Stein AS. TherAdv Hematol.2016 Chimeric antigen receptor (CAR) T‐cell CAR T‐Cell Therapy: The Process therapy • T‐cells collected from patient • T‐cells re‐engineered in labratory • Adoptive cell therapy (ACT) to produce chimeric antigen • Pediatrics trials in B‐Cell ALL pediatric patients at NCI receptor (CARs) on their surface (CTL019) and CHOP • Expand the CAR T‐cells in the lab • Using CTL019, an antigen that targets CD19 until there are millions ▫ • Patient given chemotherapy CD19 is a B‐cell surface protein preparatory regimen ▫ Universal expression in B‐cell ALL (cyclophosphamide‐based) before infusion • CAR T‐cells infused into patient • Hopefully, CAR T‐cells guard against recurrence https://www.lls.org/treatment/types‐of‐treatment/immunotherapy/chimeric‐antigen‐receptor‐car‐t‐cell‐therapy Maude SL, et al. Blood. 2015 CAR T‐cell Adverse Reactions CAR T‐Cell Therapy • Preliminary results • CRS‐ most common and potentially severe ▫ Potenially correlation to presence of CRS and response to ▫ 90 % CR in 30 adult and pediatric patients (CHOP CAR T‐cells Phase I)¹ ▫ Severity might correlate to tumor burden Probability of persistence of CAR T‐cells at 6 months • Inflammatory response related to exponential T‐cell being 68% proliferation and increased cytokines ▫ ▫ 88% CR in 16 adult patients with relapsed B‐cell ALL at Marked increases in IL‐2, IL‐6, IL‐10 and interferon ▫ Wide range of severity, from flu‐like symptoms to multi‐ Memorial Sloan‐Kettering² organ failure Persistent of CAR T‐cells of 1‐3 months • Tocilizumab‐ IL‐6 inhibitor ▫ 70 % CR in 20 children and adults at NCI³ ▫ Used to treat CRS ▫ Other IL‐6 inhibitors might be effective Average persistence is 68 days • Steroids‐ controversial‐ maybe useful for 2‐4 day burst 1.Maude SL, Frey N, Shaw PA, et al. N Engl J Med. 2014. 2.Davila ML, Riviere I, Wang X, et al. Sci Transl Med. 2014 3.Lee DW, Kochenderfer JN, Stetler‐Stevenson M, et al. Lancet. 2015. Maude SL, et al. Blood. 2015 3 9/21/2016 Incidence and Epidemiology • Solid tumor that originates from primordial neural crest cells that normally give rise to adrenal medulla and sympathetic ganglia Neuroblastoma • Most common extracranial solid tumor in children, accounting for 8 –10 % of childhood malignancies ▫ Accounts for 15% of childhood mortality • 800 cases annually in the US ▫ Median age of diagnosis is 19 months and ~90% diagnosed by age 5 ▫ Occurs more often in males than females (1.2:1) www.cancer.gov Pathogenesis Pathophysiology • Exact cause is unknown • Originates in adrenal medulla or paraspinal site in ▫ Most common cytogenetic abnormalities are deletions sympathetic nervous system or rearrangements of the short arm of chromosome 1 Can present along a spectrum of differentiation from benign ganglioneuroma to ganglioneuroblastoma, or or chromosome 17 malignant neuroblastoma • N‐MYC is an oncogene on chromosome 2 • “Small blue round cell” neoplasm ~25% of patients with neuroblastoma have N‐MYC Differentiate from Ewings, NHL, PNET, amplification rhabdomyosarcoma Associated with advanced stage disease and poor prognosis • 65% are abdominal and 20% are thoracic Maris, J. N Eng J Med. 2010 Maris, J. N Eng J Med. 2010 Signs and symptoms Diagnosis and Staging • Thoracic/pelvic tumor • Orbital tumor • Urine catecholamines (VMA and HVA) are elevated in 85 – 90% of ▫ Abdominal fullness/discomfort ▫ Opsoclonus –myoclonus patients ▫ Bowel or bladder symptoms (Dancing eye syndrome) ▫ Normal VMA < 8 μg/mL and HVA < 17 μg/mL ▫ Hypertension (renal ▫ Proptosis or periorbital ▫ VMA:HVA ratio also important vasculature) ecchymoses Higher the ratio, the better the prognosis ▫ Cord compression (emergency) • Bone lesions • Lab Studies: CBC, liver and kidney function, coags, ferritin, LDH, ▫ Respiratory compromise ▫ Focal pain, limp, refusal to walk neuron specific enolase, and urine catecholamines • Skin nodules (Infants) ▫ Horner’s Syndrome • Diagnostic Imaging: CT of chest, abdomen, pelvis; MRI of head and ▫ Secretory diarrhea secondary to • Nonspecific spine (if indicated), MIBG scan (bone/soft tissue scan), ECHO, GFR increased vasoactive intestinal ▫ Fever, weight loss, generalized peptide pain • Tissue studies: Bilateral bone marrow biopsies and aspirates and tissue from mass large enough for histopathology, N‐MYC Maris, J. N Eng J Med. 2010 amplification, cytogenetics www.childrensonocologygroup.org 4 9/21/2016 INSS Staging High Risk Neuroblastoma Long term survival is about 34 - 40% with High Risk Group • INSS Stage 4 > 18 months of age • INSS Stage 4 with N‐MYC, regardless of age • INSS Stage 4 between 12 –18 months of age with unfavorable histology and or diploid DNA content • INSS Stage 3 with N‐MYC amplification, regardless of age • INSS Stage 3 with unfavorable histology, greater than 18 months of age • INSS Stage 2 with N‐MYC amplification, regardless of age • INSS Stage 4S with N‐MYC amplification At time of diagnosis, 78% of children and 43% of infants have www.childrensonocologygroup.org stage 3 or 4 disease www.cancer.org Treatment of High Risk Neuroblastoma Prognosis • 5 year survival for infants is 83%, children age 1 ‐ 4 • Patients receive 6 cycles of Induction chemotherapy on ANBL0532 years is 55%, and children 5 years and older is 40% ▫ Cycle 1: Cyclophosphamide/Topotecan • Two year survival in stage 3 or 4 is 10 ‐ 30% ▫ Cycle 2: Cyclophosphamide/Topotecan ▫ Cycle 3: Cisplatin/Etoposide ▫ Cycle 4: Vincristine/Doxorubicin/Cyclophosphamide ▫ Cycle 5: Cisplatin/Etoposide ‐‐‐‐ SURGERY‐‐‐‐ ▫ Cycle 6: Vincristine/Doxorubicin/Cyclophosphamide • Autologous stem cell transplant ▫ Two transplants Thiotepa and Cyclophosphamide Carboplatin, Etoposide, Melphalan www.cancer.gov • Radiation www.childrensoncologygroup.org Dinutuximab Citation Study Design and Treatment Regimen Results Conclusion Dinutuximab (Unituxan®) A.L. Yu, Design: Drug Control Inclusion of 2010 Randomized, Phase 3 Study Number Number immunotherapy to (%) (%) (n=113) (n=113) isotretinoin therapy • Anti‐GD2 monoclonal antibody Treatment: resulted in significantly 2‐Yr 66±5 46±5 Addition of ch14.18 with GM‐CSF and Event‐ superior event‐free and • COG studies ANBL0032 and ANBL0931 interleukin‐2 to isotretinoin therapy free overall survival.