The Complex Nature of Neuroblastoma in Infancy

Ro Bagatell, MD

POGO Multi-Disciplinary Symposium on Childhood Cancer

November 10, 2017

Case 1

• Infant girl born at term to 30 year old G3P23 mother after unremarkable pregnancy

• Baby with significant distress in the delivery room, large rock hard neck mass causing tracheal deviation/obstruction

Case 1

• Tissue diagnosis obtained: neuroblastoma

• Metastatic workup negative, histology favorable, MYCN non-amplified, no Segmental Chromosomal Aberrations, DNA Index >1

• Treated with moderate intensity chemotherapy x 4 cycles

• Rapid response

• Residual mass debulked - <50% volume remained

Case 2

• Infant boy born at term via NSVD to 27 year old G1P01 mother after an unremarkable pregnancy, labor and delivery

• Prenatal ultrasound had shown a mass that appeared to arise from the left kidney

Case 2

• Clinically well baby

• Discharged home following full imaging and laboratory evaluation

• Never required surgery or medical therapy

• Now completely well

Case 3

• 30 day old girl born at term following unremarkable pregnancy, labor, delivery

• Went home with mom, no problems in first 2 weeks of life but parents subsequently noticed abdominal fullness

• Ultrasound – hepatomegaly + right adrenal mass

• Referred to local hospital – CT confirmed same

• Transferred for further work up and treatment

Case 3

• On exam HR 110, RR 78

• Emaciated, cranky, pale infant

• No distress but abdomen tense, distended with prominent veins at surface, massive hepatomegaly; abdominal girth 49 cm

• Tissue obtained for histology, biology from limited liver biopsy

• CVL placed, marrows done (<10% tumor)

Case 3

• Required increased vent support post-op, +electrolyte abnormalities

• Started on etoposide/carboplatin

• Increasing abdominal distension, increased vent support, decreased urine output, coagulopathy

• Emergent XRT initiated

• Unstable the following day, extensive resuscitation efforts unsuccessful, pt expired

Neuroblastoma in Infants

• All of these patients had neuroblastoma diagnosed within the first months of life

• Median age of dx of NBL is ~2 years, but it is by far the most common malignancy in neonates

• ~25% of cases of cancer in neonates are NBL

London, JCO, 2005

n-=3666

Distribution of Tumors in Infants

A Heterogeneous Disease

Embryology of Neuroblastoma

Matthay et al, 2016

Clinical Presentation

• >70% adrenal, but may occur anywhere along the sympathetic chain

• Symptoms in neuroblastoma are like real estate . . .. .location, location, location

• Urinary catecholamines elevated in >80%

• Hypertension not very common

• Skin lesions– not common but helpful

Metastatic Disease

Marrow

Anterior Posterior

MIBG Avid Bony Disease

Risk Stratification

• Key prognostic factors:• Age

• Shown to be a continuous variable but practical considerations require a cut-off for designation of favorable vs unfavorable

• Convention is 18 months (547 days)

• Stage• Out: INSS (surgical staging system)

• In: INRG (imaging based staging system)

INRG Staging

Cohn et al, JCO, 2009

Key concept: Stage is likely a proxy for biological factors that we have not yet identified

Histology

• Guiding principle of oncology: Where there is an issue, you need to get tissue • Almost always true

• Histology is a prognostic factor in NBL

• INPC: degree of differentiation, mitosis-karyorrhexis index, stromal content, age

• Hold this thought: MS infants are a special case

Biologic Features and Risk Stratification

MYCN amplification

Particularly important in patients with localized disease, infants with metastatic disease

Brodeur et al, 2016

Tumor Biologic Features and Risk Stratification

Segmental Chromosomal Aberrations

Schleiermacher et al, BJC 2012

DNA Index

George et al, JCO 2005

MS <3 mo no bx no bx no bx no bxHM or tumor symptoms (bx when stable)

IRResponse-based

therapy on ANBL1232

MS <3 mo not amp absent DI>1 favorableNo HM, no tumor symptoms

LRMS score-based

therapy on ANBL1232

MS <3 mo not amp present any anyNo HM, no tumor symptoms

IRResponse-based

therapy on ANBL1232

MS <3 mo not amp any DI=1 anyNo HM, no tumor symptoms

IRResponse-based

therapy on ANBL1232

MS <3 mo not amp any any unfavorableNo HM, no tumor symptoms

IRResponse-based

therapy on ANBL1232

MS <3 mo AMP any any any HR

MS 3-<12 mo no bx no bx no bx no bxTumor symptoms (bx when stable)

IRResponse-based

therapy on ANBL1232

MS 3-<12 mo not amp absent DI>1 favorable LRMS score-based

therapy on ANBL1232

MS 3-<12 mo not amp present any any IRResponse-based

therapy on ANBL1232

MS 3-<12 mo not amp any DI=1 any IRResponse-based

therapy on ANBL1232

MS 3-<12 mo not amp any any unfavorable IRResponse-based

therapy on ANBL1232

MS 3-<12 mo AMP any any any HR

MS 12-<18 mo not amp absent DI>1 favorable ***** IRMS score-based

therapy on ANBL1232

MS 12-<18 mo not amp present any any HR

MS 12-<18 mo not amp any DI=1 any HR

MS 12-<18 mo not amp any any unfavorable HR

MS 12-<18 mo AMP any any any HR ANBL1531

*****Note: Stage MS patients from 12-<18 mo require ALL favorable biology to be IR; if any biology information is absent the default is to treat as HR

Risk Assignment 2.0INRGSS AGE MYCN SCA DI INPC Misc. Risk/Rx Notes:

INRG

StageAge

MYCN

StatusSCA DI INPC Risk

MS 3-<12 mo not amp absent DI>1 favorable Low

MS 3-<12 mo not amp present any any Intermediate

MS 3-<12 mo not amp any DI=1 any Intermediate

MS 3-<12 mo not amp any any unfavorable Intermediate

MS 3-<12 mo AMP any any any High

Risk Assignment in Infants without

Symptomatic Hepatomegaly

Irwin and Hogarty, in preparation

INRG

StageAge

MYCN

StatusSCA DI INPC Risk

MS 12-<18 mo not amp absent DI>1 favorable Intermediate*

MS 12-<18 mo not amp present any any High

MS 12-<18 mo not amp any DI=1 any High

MS 12-<18 mo not amp any any unfavorable High

MS 12-<18 mo AMP any any any High

Risk Assignment in Infants without

Symptomatic Hepatomegaly

*All testing must be done and favorable; if not done treat as HR

Current High-Risk TherapyTopo/Cy-1

Topo/Cy-2

Harvest

Cisplat/VP

Surgery

VAdriaC

Cisplat/VP

Induction

TC

CEM

Tandem Auto Transplant

Local XRT Radiation

Dinutuximab + cytokines and isotretinoin

Immunotherapy

14-16 months of therapy

•Acute toxicities• Vomiting, poor feeding,

malnutrition• Electrolyte abnormalities• Cytopenias requiring transfusions• Infections• Central lines, risk of thrombosis• Pain • Growth delay• Developmental issues

•Late effects• Hearing loss• Chronic kidney disease• Impaired growth• Delayed/impaired puberty,

infertility• Hypothyroidism• Pulmonary fibrosis• Dental issues• Cardiac insufficiency• Diabetes/metabolic syndrome• Second malignancies

High Risk Therapy and Infants

Resect/Biopsy All Just In Case?

• Resection or biopsy NOT indicated in specific settings

• Small, localized tumors in infants will usually take care of themselves • Newborn screening changed incidence but not survival

• Expectant observation study (ANBL00P2)• 84 patients observed; only 16 went on to resection

• 11 NBL (9 Stage 1); 5 NOT NBL

• 81% of observed patients were spared resection

• 3 year EFS 98%, OS 100%

Nuchtern, Ann Surg, 2012

What About Infants withMetastatic Disease?

• ANBL0531 study for patients with intermediate risk neuroblastoma • 46 patients with MS NBL

• 28 <3 months of age

• 5 deaths due to complications of hepatomegaly

• Disproportionately high death rate in patients <3 months of age

Treat First, Biopsy Later?

Symptom Score 2 indicates need to treat

Just Do It

• Current clinical practice: treat early and often

• Convincing presentation +/- urine catecholamines = sufficient evidence of NBL in a young infant with hepatomegaly

• Carboplatin and Etoposide are very effective

• Can be given via PIV

• Difficult to• Not biopsy• Not put in semi-permanent line• Not stage the patient

• Imperative to prevent an intervention-related demise

Treat First, Biopsy Later

• In most cases, patients stabilize within 1 day and begin to improve clinically within the next 2-3 days

• May only need one or two cycles of therapy to be safe to biopsy

Why Do Some NBLs Regress

with Minimal or No Therapy?

Brodeur and Bagatell, 2014

• PHOX2B, ALK aberrations associated with hereditary predisposition, multifocal disease

• ALK mutation status and prognosis• Correlates with inferior outcome in pts with intermediate

risk but not low risk disease

• Difficult to interpret role as prognostic marker in high risk disease

• Role of ALK inhibitor unclear in patients who do well with limited or no therapy

Targeted Therapy for NBL in Infants?

Targeted Therapy for NBL in Infants?

• Infants >12 months old at diagnosis with high risk NBL + ALKaberrations: eligible for ANBL1531 Arm E

Arm E

Topo/Cy-2

Surgery

Harvest

Cisplat/VP

VAdriaC

Cisplat/VP

Post-Consolidation Therapy:Dinutuximab + cytokines and isotretinoin PLUS CRIZOTINIB

for 12 extra months

Local XRT

TC

CEM

Cri

zoti

nib

Cri

zoti

nib

Cri

zoti

nib

• Neuroblastoma is the most common malignancy in neonates

• Presentation can vary dramatically• Some patients will experience spontaneous regression

• Unfavorable biology associated with poorer outcome

• Treatment is based on risk of recurrence• Incorporates age, stage, histology, biology

• Full evaluation is important when safe, but first do no harm

• Much to be learned about neuroblastoma in infants

Summary

• Julie Park

• Sue Cohn

• Meredith Irwin

• Mike Hogarty

• Steve DuBois

• Emily Greengard

• Meaghan Granger

• Greg Yanik

• Brian Weiss

• Arlene Naranjo

• Anneliese Rosdil

• Catherine Shannon

Thanks