10/7/2014. I have no conflicts of interest I will discuss drugs used for non-fda approved causes

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1 Stuart H. Gold The University of North Carolina at Chapel Hill October 3, 2014 I have no conflicts of interest I will discuss drugs used for non-fda approved causes 1

2 Pediatric oncology cooperative groups Common childhood cancer types Childhood ALL as a paradigm Importance of role of cytogenetics in ALL ALL advances Targeted/novel therapies Late effects What the present and future may hold yo WM Dx ALL precursor B, WBC 9k, induced with 3 drugs, progressive disease and CNS involvement, died without ever leaving the hospital with intractable seizures year old WM- Dx ALL precursor B chromosomes revealed t(9;22), Philadelphia chromosome, unclear of significance, treated with a 4 drug induction, early relapse, unable to get back into remission, and died 6 months after diagnosis 2

3 yo WM, WBC 35k, precursor B ALL, cytogenetics revealed t(4;11), bone marrow monthly for 2 years, no return of cytogenetic abnormality 2% of all cancers occur in kids 10% of all childhood deaths Leading cause of death from disease Genetic lessons - heritable cancers Cooperative group trials lessons Good cure rates 0-15 yo 9000 cases/yr yo 3700 cases/yr yo 1500 cases/yr ~2500 children and adolescents die yearly of cancer each year 3

4 Adult cancer 1.5 million per year Prostate 219k cases per year Lung 214k cases per year Breast 180k cases per year AL - 23% (ALL:AML 4:1) CNS - 21% Neuroblastoma - 7% Lymphoma - 6% Wilms Tumor - 6% Hodgkins - 5% Rhabdomyosarcoma - 3% Retinoblastoma - 3% Osteogenic Sarcoma - 2.5% Ewing s Sarcoma - 2% Children s Oncology Group A success story 4

5 1955 First NCI sponsored cooperative group Acute Leukemia Chemotherapy Cooperative Study Group A 9 institutions First protocol: 6MP vrs Azaserine for ALL N=125 Protocol was 9 pages Study lasted one year Name change Children s Cancer Study Group A patients First phase I/II trials Surgical and Radiation Therapy Committees Biology and Translational Research Nursing, late effects, supportive care committees. Pathology ref ctr >15,000 COG specimens provided to investigators >130 investigators received COG specimens 93 COG publications 5

6 the merger CCG + POG + NWTS + IRSG = Children s Oncology Group COG 8300 Members 222 Institutions Representing - US, Canada, Puerto Rico, Australia, Switzerland, Netherlands, New Zealand, Israel <15 yo - >90% oncology pts on CCG/POG trials <25% oncology pts enrolled Survival 10 yr post diagnosis 82% ~5000 patients enrolled per year on COG trials ~45,000 cancer survivors in active follow-up 6

7 Phase I trials - 11 Phase II trials - 20 Phase III trials - 30 Pilot studies - 4 Stem cell transplant - 7 Biopathology and translational 17 Cancer control/supportive care - 9 Open to accrual 44 Closed to accrual but in f/u 40 Phase I 1* Phase II 8* Phase III 19* Biology 8 Other 5* Three more studies to open soon 21 investigational drug studies James Bradley - 12 years Gwen Konsler 10 years 7

8 All these studies PRC IRB Consents Annual Renewals Amendments Adverse events reporting Auditing HIPAA Finances CIRB 4 data deadlines per year data score 99.3% Year Pt # 125 ~4500 Time 1 yr to complete >5 yrs Design 2 arm study 5 arm #pages Consent 36 page 3 yr EFS 0% >90% 1 classification trial 5 trials for new dx 6 trials for recurrent disease 2 biology trials 8

9 Estimated Survival Percentage 10/7/2014 Influence of Site of Treatment and Use of Research Protocol* Treatment of Patient: 4-Year Disease Free Survival... in a pediatric cancer center on protocol 58 %... outside pediatric cancer center on protocol 40 %... outside pediatric cancer center off protocol 19 % *Murphy SB: Med Pediat Oncol 24:279, 1995 Behrman RE, Kliegman RM, Jenson HB (Eds.) Nelson's Textbook of Pediatrics. 17th Ed (in press) 100 Years of Accrual No. Patients Years From Study Entry Tubergen DG, Bleyer A: The Leukemias Acute Lymphocytic Leukemia T and B cell 9

10 Most common childhood malignancy (25% of all pediatric cancers); 2500/yr in US Peak 2-5yr in industrialized countries More common in whites than AA, M>F (esp T cell) Fever, purpura, fatigue Organomegaly, adenopathy Arthralgias, bone pain, arthritis Head ache, cranial nerve palsy Prolonged viral illness Skin rash Bleeding Physical exam: testes, cranial nerves, papilledema, lymphadenopathy, organomegally Labs: cbc/diff;coags; chemistries, type and cross; cxr Blood smear review 10

11 Tumor Lysis Leukocytosis Superior vena cava syndrome Fever, Infection and neutropenia Bone marrow aspirate Peripheral blasts Flow cytometry Cytogenetics/FISH Each cell is counted and identified by specific cell surface markers Rapid test, blood or bone marrow Flow markers are patient specific Useful on future marrows to pick up minimal residual disease - MRD Helpful in defining a recurrence 11

12 May take a while but some translocations assure a correct dx {Kathleen Rao} APML t(15;17) CML t(9;22) Burkitt s Lymphoma t(8;14) Solid tumors can mimic leukemia Numerical changes Most are diploid or hyper dip (>50 chrom);hyperdipoid is good; hypodiploid is bad Trisomy 4, 10 favorable prognosis Structural changes TEL-AML: t(12;21)(p12;q22) - good prognosis t(9;22) Philadelphia chromosome - bad t(4;11),mll gene rearrangement bad Age 1-10 yo best White count <50k best Immunophenotype B cell best Ploidy hypodiploid bad, hyperdiploid good Cytogenetics Rapidity of response to treatment Minimal residual disease 12

13 Group wbc (/mm 3 ) age(yr) standard <50, Standard/low<50, high >50,000 >10 (>13) infant <1 (<6mo) T-cell Additional risk features: Minimal residual disease cytogenetics LR EFS 5 yr >95% 15% of the popn Avg 90-95% 36% HR 88-90% 25% VH <80% 24% Morphology 2-3% Routine flow cytometry - ~1% Flow cytometry MRD 0.01% PCR 0.001% Currently use 0.01% at day 28 as positive 13

14 4 year EFS <0.01% 88% % >0.1 51% Induction, consolidation, interim maintenance, delayed intensification, maintenance Induction remission rates 95%+ Total treatment over 2 years for girls, 3 years for boys Intensive therapy for first ~8 months, weekly visits 14

15 Delayed intensification, important Cranial Irradiation almost elliminated Rapidity of bone marrow response Dexamethasone improved outcome But not without toxicity Cytogenetics Minimal residual disease Prognostic features may change with therapy advances Getting away from lots of bone marrows Risk stratifies Good cytogenetics Trisomy 4,10, t(12;21) iamp21 new and bad Intrachromosomal amplification of at least 4 copies of RUNX1 on a single chromo Detected by FISH ~2% preb ALL Tend to be: older, lower WBC, 3x risk of recurrence 15

16 Prior high risk trial 70% vrs 88% EFS Prior standard risk trial 81% vrs 94% EFS For both MRD positive or neg If iamp21 positive on new avg risk trial Off protocol and to new HR protocol to VHR arm (<80% survival) Dexamethasone is better Dex lower albumin, higher glu, more F/N, more infections, no diff in induction deaths Dex in induction predicts higher osteonecrosis >/= 10yo Over 10 yo use pred, under dex Discontinuous dex in DI High dose methotrexate better than escalating dose methotrexate for the high risk patient HD MTX no diff in toxicity No diff in neuro, sz, mucositis Decrease in BM and CNS recurrences Much higher cost and hospitalizations 16

17 Capizzi n=1217 HD MTX n=1209 BM relapse 5.5% 3.4% CNS 2.6% 1.8% DFS 82% vrs 75% VHR >13 or CNS3 or iamp21 or MLL-R or hypodip MRD>0.01% d 29 or Induction failures Trying new drug combinations Cyclophosphamid/Etoposide vrs Clofarabine/Cyclophosphamide/Etoposide Clofarabine arm too toxic See if can avoid anthracycline and alkylators.. Reducing therapy and potential of long term side effect by adding moderate dose methotrexate Two imbedded QOL studies 17

18 Targeted Therapies Monoclonals Newer agents Eg Tyrosine Kinase Inhibitors Refining chemotherapy Refining bone marrow transplant Improved supportive care Gene therapy Recognition and prevention and more and more research Breakpoint on chr9 c-abl Breakpoint on chr 22 BCR Two new hybrid genes bcr/abl on 22 is the major actor Protein product p210 augmented tyrosine kinase activity and autophosphorylates, translocated into the cytoplasm 18

19 First target therapy against tyrosine kinases Specifically blocks the activity of the bcr/abl protein Revolutionalized CML therapy and now Ph+ ALL Cytogenetics looks the same Different breakpoint Protein product p190 Historically poor prognosis Chemotherapy 20-30% cure Allo BMT 60% Chemo + Imatinib 88% 3 yr EFS Expert Rev Hematol Dec;3(6): doi: /ehm Philadelphia chromosome-positive acute lymphoblastic leukemia in children: new and emerging treatment options. Schultz KR, Prestidge T, Camitta B. Source Division of Pedatric Hematology, Oncology, Blood and Marrow Transplantation, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada. kschultz@interchange.ubc.ca 19

20 Bad disease, esp under 6 mo with MLL-R FLT3 kinase - highly expressed/activated in MLL-R ALL Lestaurtinib (CEP-701) selectively kills MLL-R cells (both in vivo and in vitro) No advantage to BMT over chemo -New vincristine strategies -Bortezomib proteosome inhibitor -Blinatumomab monoclonal antibody, bi-specific T-cell engager (BiTEs) targets CD19 -MLN8237 selective aurora kinase inhibitor -INCB inhibits JAK family of kinases -Temsirolimus m-tor inhibitor For example: AML Lymphoma Neuroblastoma 20

21 Gemtuzumab ozogamicin anti CD33 linked to cholicheamicin Bortezomib proteosome inhibitor Sarafenib multitargeted tyrosine kinase inhibitor Burkitt s Lymphoma Rituximab anti-cd20 Combined with our standard chemotherapy backbone in high risk mature B cell lymphoma patients Anti-GD2 monoclonal antibodies Uniformly expressed in neuroblastoma Normal: neurons, peripheral nerve fibers, skin melanocytes Targeted immunotherapy Passive immunotherapy antibody dependent cellular toxicity 21

22 Given with IL-2 and GM-CSF Pain, vascular leak, hypersensitivity 2 year EFS 66% vrs 46% (p=0.01) Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363: , 2010 Norepinephrine analogue Meta-iodobenzylguanidine Concentrated in the sympathetic nervous system I-123 used radiographically I-131 used therapeutically 2 cycles chemo stem cell harvest 2 cycles of chemo surgery 1 cycle of chemo MIBG therapy with SCR Autologous bone marrow transplant radiation therapy immunotherapy (5 cycles chimeric antibody, GMCSF, IL2, isotretinoin) 22

23 Long term side effects and issues. United States 270,000 childhood cancer survivors 1/640 (20-39 yo) is a cancer survivor Dependent on age of child Dependent on type of tumor and location Dependent on treatment Chemotherapy Irradiation therapy Surgery 23

24 Growth/development - radiation, IT Cognitive - radiation, intrathecals Endocrine - radiation Infertility - alkylators Secondary malignancies - VP16, Alkylators Cardiac (anthracyclines) Hepatotoxicity - 6MP, 6TG, MTX Pulmonary bleo Bone AVN - steroids Emotional Transitioning back to primary care giver Transitioning to adult oncologist 24

25 yo WM Dx ALL precursor B, WBC 9k, induced with 3 drugs, progressive disease and CNS involvement, died without ever leaving the hospital with intractable seizures 2013 >95% children ALL achieve a remission Induction Deaths ~0.005% year old WM- Dx ALL precursor B chromosomes revealed t(9;22), unclear of significance, treated with a 4 drug induction, early relapse, unable to get back into remission, and died 6 months after diagnosis May yo, 1 week history of cough, fever, bruising and rt knee pain. Found to have pancytopenia and hepatosplenomegaly. WBC 3, hgb 8, plt 8 precursor B ALL Standard Risk until cytogenetics returned Ph+ 25

26 Treated on Ph+ clinical trial with intensive chemotherapy + dasatinib Treated from 5/09 3/12 Off therapy BM, cytogenetics and FISH nl PCR 27/100,000 + Treated with continuous dasatinib PCR 11/100,00 + March yo WM, WBC 35k, precursor B ALL, cytogenetics revealed t(4;11), bone marrow monthly for 2 years, no return of cytogenetic abnormality treated as HR 2013 married with children, Heme/onc nurse November month old, fever, cytopenias, septic hip, WBC 6.3, hgb 5.5, plt 9 Started treatment on standard risk Cytogenetics t(9;11)(p22;q23) Moved to very high risk protocl Doing well 26

27 Around since about ~35-40 new oncology pt per year 149 new children with cancer 2012 Adding a new physician (total 11) Added 1 new nurse practitioner (total 7) Two managers of our data, need more Ten Physicians 5 General Ped Heme/Onc clinical Phase 1/2 1 Hemophilia/thrombosis/clinical and bench research 2 BMT 1 Sickle cell 1 combo general heme/onc & bench research Cellular therapies Six nurse practitioners One sickle cell One bmt One inpt genl heme/onc Four outpt genl heme/onc 27

28 Pediatric Oncology Brain Tumor Survivors clinic Pediatric Hematology Sickle cell Hemophilia Thrombosis Vascular Malformations Pediatric BMT/cellular Therapies/ID Main office Page operator Hospital School teachers Recreational therapists Psychologists Art therapist Nurses clinic and the ward Pediatric Surgeons Radiation Oncology 28

29 Pediatric Radiologists Cytogenetics folks Special hematology Pathology And all of our Pediatric consultants True team effort, multidisciplinary approach 29