Download Pediatric Cancer: Past, Present and Future

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!!
Thank You