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Pediatric Cancer: Past, Present and Future Michael B. Harris, MD Co-Chief, Children’s Cancer Institute Joseph M. Sanzari Children’s Hospital Professor of Pediatrics Rutgers University-NJMS Conflicts Jazz Pharmaceutical’s speakers bureau Distribution of childhood cancer by type CureSearch data Frequency of cancer types among patients younger than 20 years Zhang J et al. N Engl J Med 2015;373:2336-2346. Distribution of childhood cancer by age Birth – 14 years 14 – 19 years Childhood and adolescent cancer incidence from birth to 19 years of age Rate per million children CA: A Cancer Journal for Clinicians (data compiled from SEER and the North American Association of Central Cancer Registries) Volume 64, Issue 2, pages 83-103, 31 JAN 2014 DOI: 10.3322/caac.21219 http://onlinelibrary.wiley.com/doi/10.3322/caac.21219/full#caac21219-fig-0002 Childhood and adolescent death rate Rate per million children CA: A Cancer Journal for Clinicians (data compiled from SEER and the North American Association of Central Cancer Registries) Volume 64, Issue 2, pages 83-103, 31 JAN 2014 DOI: 10.3322/caac.21219 http://onlinelibrary.wiley.com/doi/10.3322/caac.21219/full#caac21219-fig-0003 Survival over the last four decades Survival over the last four decades Time-line of progress THE JOURNEY FROM 1948 TO THE PRESENT Dr. Sidney Farber (September 30, 1903 – March 30, 1973) First report of remission in ALL Beginning of the chemotherapy era (June 3, 1948) Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-Aminopteroyl-Glutamic Acid (Aminopterin) Sidney Farber, M.D.†, Louis K. Diamond, M.D.‡, Robert D. Mercer, M.D.§, Robert F. Sylvester, Jr., M.D.¶, and James A. Wolff, M.D.∥ N Engl J Med 1948; 238:787-793 (June 3, 1948) Timeline of progress in childhood cancer • 1947 – First-ever remission of pediatric leukemia • 1955 – U.S government establishes network of researchers to pursue childhood cancer cures (Children’s Cancer Study Group) At the time only 10% of children with cancer are cured • 1958 – Combining chemotherapy drugs (6MP + methotrexate) found to prolong leukemia survival • 1967 – Treating the CNS (IT MTX + RT) helps achieve first cures for ALL ASCO Cancerprogress.net Timeline of progress in childhood cancer • 1969 – Formation of the National Wilms Tumor Study Group Increase in cure rate with addition of actinomycin D + vincristine to surgery and RT and elimination of RT to low risk group 1 • 1971 – Knudson’s two hit hypothesis • 1972 – New research network, Intergroup Rhabdomyosarcoma Study Group, seeks cures for soft tissue sarcomas in children • 1975 – Successful use of adjuvant therapy in osteosarcoma ASCO Cancerprogress.net Timeline of progress in childhood cancer • 1986 – Scientists discover gene mutations of RB1 and TP53 (retinoblastoma and Li-Fraumeni syndrome) linked to increased risk of childhood and adult cancers • 1987 – Chemotherapy before surgery helps children with bone cancer avoid amputation • Late 1980s – Improved combination chemotherapy regimens boost pediatric leukemia cure rates Cure rates for pediatric acute lymphoblastic leukemia climb above 80 percent with the introduction of combination chemotherapy regimens ASCO Cancerprogress.net Timeline of progress in childhood cancer • 1991 – Genetic discovery (expression of MYCN) helps guide treatment decisions for neuroblastoma • 1993 – Major study, Children’s Cancer Survivor Study, tracks long-term health of childhood cancer survivors • 1998 – MOPP can be replaced by ABVD to reduce side-effects for children with Hodgkin lymphoma • 1999 – Intensive chemotherapy, with radiation and stem cell transplant, improves neuroblastoma survival ASCO Cancerprogress.net Timeline of progress in childhood cancer • 2001 – NCI consolidates clinical research for childhood cancers = Children’s Oncology Group POG, CCG, IRSG and NWTS join to form COG • 2003 – Adding two drugs (ifosfamide and etoposide) to standard chemotherapy improves survival for children with early-stage Ewing sarcoma • 2005 – Research sheds light on long-term health problems of childhood cancer survivors Childhood Cancer Survivor Study: childhood cancer survivors have a five time greater chance to experience moderate to severe health problems compared to their siblings ASCO Cancerprogress.net Timeline of progress in childhood cancer • 2005 – Nelarabine approved by FDA for childhood refractory/recurrent T-cell acute lymphoblastic leukemia or lymphoma • 2007 – Children with intermediate risk neuroblastoma benefit from less aggressive treatment • 2009 – Immunotherapy for children with neuroblastoma proven to be effective • 2009 – Targeted therapy (imatinib) improves survival for children with PH+ ALL Timeline of progress in childhood cancer • 2010 – Review finds major success against childhood cancers An estimated 38,000 childhood cancer deaths have been averted in the United States between 1975 and 2006. Cancer death rates declined by more than 50 percent in this period. Attributed to improved drugs, treatment strategies and past investments and collaboration in clinical trials. During the same period childhood cancer incidence increased significantly with acute lymphoblastic leukemia (ALL) rising most quickly (0.6%/year). ASCO Cancerprogress.net Timeline of progress in childhood cancer • 2010 – Late effects of childhood cancer substantially reduce life expectancy A modeling study based on data from the Childhood Cancer Survivor Study shows that life expectancy for survivors of childhood cancer is about 10 years shorter, on average, than in the general population. This effect is due to an increased risk of heart and lung problems and second cancers later in life. The findings increase the urgency of long-term health screenings for childhood cancer survivors, who now number over 388,000 in the U.S. ASCO Cancerprogress.net Challenges for the future • Significant mortality for Advanced stage neuroblastoma High risk leukemia (ALL and AML) Brain tumors such as high grade gliomas, diffuse intrinsic pontine glioma (DIPG) Recurrent disease • Progress is stagnant in a number of tumors especially in rhabdomyosarcoma, other softtissue sarcomas, bone tumors and very poor for metastatic disease at Dx in these cancer types • Reducing late-effects in cancer survivors New approaches to improve survival with a decrease in late-effects • Post-genomic era Genome and exome wide association studies (GWAS, EWAS) Determining susceptibility to cancers Diagnosis and prognosis Precision (personalized) therapy Immunotherapy – CAR-T cells, BiTEantibodies, checkpoint inhibitors, vaccines Viral vectors (oncolytic, genetic manipulation) Limiting therapy in good responders and patients with excellent prognosis Genetic analysis (pre and post-genome) and ALL • International collaboration has led to impressive findings leading to increased survival in ALL • Minimal residual disease (MRD) best prognostic indicator in B and T cell ALL • “Simple” cytogenetics Hyperdiploid (>53 chromosomes, DNA index ≥1.16) = good prognosis); Hypodiploid (<44 chromosomes) = Poor prognosis Trisomy 4, 10 = good prognosis ETV6-RUNX1 = good prognosis Ph+ ALL = Poor prognosis t(4;11) (q21;23) = Poor prognosis MLL (11q23) = Poor prognosis Adapted from Pui et al, JCO 2015;2938 Genetic analysis (pre and post-genome) and ALL (continued) • Next generation sequencing New subtypes of ALL PH+ like, CRLF2, IKZF1 Could this be treated with a tyrosine kinase inhibitor (ex. dasatanib) to improve prognosis? Intracytoplasmic amplification of chr 21 (iAMP21) Poor prognosis GWAS has shown inherited genetic basis for ALL in some patients with 7 loci discovered (with more to come) Drug toxicity TMPT (Thiopurine methyltransferase) mutation: decreases methylation of 6-MP and TG increasing toxicity Methotrexate (decreased excretion); l-asparaginase (increased hypersensitivity) Adapted from Pui et al, JCO 2015;2938 Estimated frequency of specific genotypes of childhood acute lymphoblastic leukemia (ALL) among patients treated in the St Jude Total Therapy Study XV.13 Genetic abnormalities among (A) all but black patients and (B) black patients Ching-Hon Pui et al. JCO 2015;33:2938-2948 ©2015 by American Society of Clinical Oncology Germline mutations and cancer predisposition in pediatric cancer • SJCRH study • 1120 patients studied • 8.5% of patients had a germline mutation that predisposed them to cancer General population 1.1% had germline mutation Autistic population 0.6% had germline mutation • Family history of cancer in 40% of patients Zhang J et al. NEJM 2015; 373:24 Distribution of Germline Mutations in Different Gene Categories and Cancer Subtypes Zhang J et al. N Engl J Med 2015;373:2336-2346 Is the future here? BRENTUXIMAB VEDOTIN CONJUGATED ANTIBODY HODGKIN DISEASE Conjugated antibody with chemotherapeutic agent Brentuximab Monomethyl auristatin E Clin Med Insights Oncol (2012) v.6 Is the future here? IMMUNOTHERAPY: A BITE, A CART AND A CHECKPOINT Bispecific engaging antibody Blinatumomab is a CD19/CD3 bispecific T-cell engaging (BiTE) antibody that binds to CD3+ T-cells and colocalizes them with CD19+ B-cells, thereby activating the T-cells and inducing perforinmediated death of the targeted Bcells Discovery Medicine; April 21, 2016 (online) CAR T-Cells By modifying T cells to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens, researchers can prime the cells to recognize and kill tumor cells that would otherwise escape immune detection. The process involves extracting a patient’s T cells, transfecting them with a gene for a CAR, then reinfusing the transfected cells back into the patient Improving CAR T-cells Probability of event free survival and survival after CAR T-Cell infusion and overall survival at 6 months Overall Survival at 6 Months. Maude et al; NEJM 2014; 371:1507 Checkpoint inhibition CTLA-4 CTLA-4 acts to downregulate Tcells. CTLA-4 is a negative regulator of immunity. Antibody blockade of CTLA-4 results in antitumor immunity. Michael A. Postow et al. JCO doi:10.1200/JCO.2014.59.4358 ©2015 by American Society of Clinical Oncology Checkpoint inhibition PD-1 PD-1 when engaged by its ligand (PDL1/PD-L2) inhibits kinase signaling that lead to T-cell activation. Inhibiting PD-1 leads to increased activation of T-cell antitumor activity. PD-1 is also expressed on many other immunologic cells including Bcells and natural killer cells. Michael A. Postow et al. JCO doi:10.1200/JCO.2014.59.4358 ©2015 by American Society of Clinical Oncology Takeaway messages from the past and present for the future (I) • Post Genomic era has arrived and will inform physicians how patients should be treated Prognostic prediction Molecular targeted therapy Evaluation for potential drug toxicity Personal and familial susceptibility to cancer • Immunotherapy will be a valuable component in treating cancer with conjugated antibodies, BiTE, CAR T-cells and checkpoint inhibitors Takeaway messages from the past and present for the future (II) • It is imperative to decrease late-effects of therapy Presently there are over 388,000 survivors of childhood cancer of whom 2/3 have some late-effect and 1/3 have serious late-effects that effect their quality-of-life Reduce treatment for good “actors” Precision medicine that limits collateral damage Genomic analysis that predicts toxicity of medications Preventive measures to treat potential late-effects Takeaway messages from the past and present for the future (III) • New paradigms are needed for future research Should we use progression free survival rather than decrease in tumor size as an end point in evaluating a therapeutic agents efficacy Are randomized clinical trials best method to determine a regimens efficacy Use of adult data to hasten drug development in children Hasten FDA approval for promising new therapies • The future is exciting and cancer will be defeated!! 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