1. Improving the treatment of children with cancer through registry-driven research Childhood Cancer Registries: a “good” model Franco Locatelli, MD, PhD Department of Pediatric Hematology-Oncology, IRCCS, Bambino Gesù Children’s Hospital, Roma University of Pavia, Italy franco.locatelli@opbg.net

2. Childhood Cancer is a rare disease…

3. Childhood cancers are significantly different from adult cancers

4. Causes of Death Children PEDIATRIC ONCOLOGY

5. Five ‑ year relative survival rates for selected primary cancers according to year of diagnosis (1975–2006) among patients younger than 20 years Pui, C.-H. et al. Nat. Rev. Clin. Oncol. 2011;28;8:540-549

6. Today, in 2016, a 20-year old young adult in 800 is a subject cured by a cancer suffered in childhood

7. Important Steps in the History of Childhood Cancer Research PEDIATRIC ONCOLOGY  Multi-institution Cooperation  Leukemia Chemotherapy refinements  Conduction of Clinical Trials  Treatment of Solid Tumors  Multi-Disciplinary Team Care  Use of information deriving from registries  Stratification of patients in risk groups

8. The main purposes of childhood cancer registries are: To monitor incidence, prevalence and survival trends of cancer over time in different geographical areas and social classes. To assess, by providing comparative data, the quality and results of the diagnosis and treatment of cancer. To investigate the differences in incidence, survival and access to treatments. To evaluate the long-term outcome, through monitoring of late sequels of cancer treatment. To support research into the causes of cancer.

9. Tumor Registries: Worldwide distribution 526 Registries

10. Tumor Registries: distribution and coverage in Europe Eva Steliarova-Foucher et al. Lancet 2004 © European Union / ENCR, 2014 · JRC 90053 225 Registries / 40 Countries Automated Childhood Cancer Info.System (ACCIS)

11. To monitor incidence, prevalence and survival trends of cancer over the course of time in different geographical areas and social classes.

12. AIEOP: integrated framework Mod. 1.01 Registry 52.406 pts 55 AIEOP Centers Unique Patient Number TCSE Registry 9.734 pts 11.633 TCSEs Protocol’s Follow-up Clinical Data Warehouse AIEOP protocols ALL AML SELH ID SM DBARTB NBL 1525 3012544 2467 140 23659 11.591 SmartLab Biologic data base network Anagraph ic Diagnosi s Follow- up Pts IS 957 Total pts: 19.820 Off-Therapy Registry

13. AIRTUM Registries (2003-2008, 0-19 years) 269 new cases/year/million in Italy, about 800 cases (15-19 years) 164 new cases/year/million in Italy, about 1.500 cases (0-14 years) 360.000 new cases/year in Italy (all ages)

14. AIRTUM Registries (2003-2008, 0-19 years) Age-standardized rates (x 10 6 ) by malignant cancer type and gender. 0-14 yrs 15-19 yrs

15. Kaatsch P et al, Eur J Cancer 42,1961–1971, 2006. Smith MA et al, J Clin Oncol 28:2625-2634, 2010 I tumori in Italia – Rapporto AIRTUM 2008 – Tumori infantili Epidemiol Prev, 32 (2) suppl 2; 1-111, 2008. Europe, 0-14 yrs USA, 0-19 yrs Italy, 0-14 yrs Tumor Registries (1978-2006, 0-19 years) Age-standardized rates (x 10 6 ) in Europe, Italy and USA for malignant cancer in children and adolescents.

16. To assess, by providing comparative data, the quality and results of the diagnosis and treatment of cancer. To investigate the differences in incidence, survival and access to treatments.

17. There are still survival disparities between Countries and European regions

18. AIEOP Mod.1.01 Registry Cases treated with AIEOP protocols by age Resident in Italy, period 2008-2010 AIEOP protocols (0-14 yrs: 72%, 15-19 yrs: 63%) AIEOP Centers Non AIEOP Centers (AIOM 192, SIE 224, ecc) 0% 20% 40% 60% 80% 100% <15 15-1920-39 92 % 65 % 15 % 25 % 1 % Age (Years)

19. AIEOP Mod.1.01 Registry Survival by protocol 11144 cases (0-14 yrs: 10558, 15-19 yrs: 586) period 1989-1998 0-14 yrs 15-19 yrs Overall AIEOP Non AIEOP protocols p = 0.000 AIEOP Non AIEOP protocols p = 0.000 AIEOP Non AIEOP protocols p = 0.003

20. Outcome of adolescents with cancer is inferior to that of children for many cancers

22. Secondary Malignant Neoplasms: The snake in the bathtub

23. Risk of subsequent malignant neoplasms by radiation dose for breast cancer.

24. Why we need innovative therapies for Pediatric Tumors? Dose-intense multimodality Multiagent approaches Improved outcome for childhood cancers Unsolved Issues How to treat children with refractory and relapsed malignancies? How to manage toxicities related to intense chemo/radiation therapy? Target Therapies Because the optimisation of present treatments has reached its limits

26. CAR T Lymphocytes Targeting CD19 as a valid clinical option for ALL relapsed patients

27. 93% CR rate for relapsed/refractory ALL after CAR T cells CTL019 59 r/r Pediatric ALL patients – 55 in CR at 1 mo (93%) median f/u 12 mo – 6 went to subsequent transplant, 1 to DLI – 6 mo RFS: 76% – 12 mo RFS: 55% – 18 patients in remission beyond 1 year, 13 without further therapy – 20 relapses, 7 CD19+ and 13 CD19- CNS – 98% of pts have CTL019 detectable in CSF – 0 CNS relapses – 4 pts CNS2 on D-1, all CNS1 at D28 >200 patients with CLL, ALL, NHL, MM have received CTL019

28. CAR T CELL THERAPY TRIALS FOR LEUKEMIA AND/OR LYMPHOMA: WORLD DISTRIBUTION anti-CD19 CAR T cells anti-CD20 CAR T cells anti-CD7 CAR-pNK cells anti-CD30 CAR T cells anti-CD19 CAR T cells (21) h anti-CD19 CAR T cells (1) anti-CD22 CAR T cells (3) anti-CD30 CAR T cells (2) anti-CD19 CAR T cells Novartis Novartis (2/3) Novartis Novartis (1/2) Novartis 1 (in 14 centers) JUNO Therapeutics 2 (in 15 centers) Kite Pharma 3 (in 20 centers)

29. Take-home messages Treatment of childhood cancers represents one of the greatest success of modern medicine. Registry-driven studies have significantly contributed to the achievement of this result. Continuous refinements of therapies and risk-stratification can further optimize long-term outcome. However, cancer survivors are subjects to be followed for years after treatment discontinuation. EU efforts should be concentrated to the elimination of outcome disparities, also through the support of the activities of cancer registries in childhood. EU must invest on innovative, targeted therapies, developed not only by industry, but also by academic institutions.