Beta-blockers in the

Treatment of Infantile

Hemangiomas 5yrs experience

Josef Mališ V.Stará, S.Klovrzová, L.Nováková, M.Kynčl, A.Sukop,

B.Kocmichová, Š.Čapková, K.Bláhová

Dept. of Pediatric Hematology/Oncology

University Hospital Motol

Prague, Czech Rep.

Epidemiology

4-10% of infants < 1 year old

Up to 30% in prematured child* < 1.5kg birth weight

> 2.5 - 4 1

The most frequent infantile tumor

ISSVA Vascular Anomalies Classification (1996 – Enjolras O.)

Vascular Anomalies – « Angioma » = abusive term

Vascular Malformations Vascular Tumors

Slow flow Fast flow Complex

& combined

Infantile Hemangioma Others

Port-wine stains

Lymphatic Malformations = vesicules or cysts

Venous Malformations = blue and swelling

No regression – GLUT-1 (-) Possible regression

• RICH

• NICH • Tufted angioma

• Kaposiform Hemangioendothelioma

GLUT-1 (+) GLUT-1 (-)

Sturge-Weber Syndrome

• Kasabach-Merritt Phenom.

Main vascular tumor

Capillary Malformations = red

Infantile Hemangioma Types

55% 30%

15%

•bright red lesions •plaquelike or more rounded papules or nodules. •Uneven surface

•involve the deep dermis and subcutis •bluish to skin-colored nodules •Smooth in surface

•features of both superficial and deep hemangiomas •often with a red plaque overlying a bluish nodule

Deep « cavernous » Hemangioma

Combined Hemangioma

Superficial « strawberry » Hemangioma

All IH are hot to the touch

Infantile Hemangioma characteristics

By type By distribution By localisation

•Superficial

•Deep

•Combined

•Segmentary

•Localized

•Head

•Rest of body

Hemangioma Evolution Phases

W1 W4 M6 M12 M18 - 20 Y3 Birth

Nascent

(resting)

Proliferation & Plateau Involution

The most rapid IH growth is between 1&2 months** Reach 80% of their final size by 3 months*

80% have completed growth by 5 months of age*

80% : size X2

5% : size X3

5% : dramatical growth

IH size

Median age to ending involution***

Optimal time for starting treatment

Y7-Y9

Evolution Kinetics

Reach 80% of their final size by 3 months*

80% have completed growth by 5 months of age*

80% of final size =

3 months

100% of final size 6 months

Status of hemangioma at 5 months

80%

20%

Completed growth Stil l proliferating

Hemangioma Evolution Phases in pictures

W1 W4 M6 M12 M18 - 20 Y5 - 6 Birth

Nascent

(resting)

Growing & Plateau Involution

10W 3.5M 27M 3.5Y 5Y

12D 1.5M 3M 2.5Y

Disease Outcome

70 % - 100% in segmental IH

30 %

Residues

Residual Anomalies

Telangiectasias

Erythema

Atrophic scars

Anetoderma

Fibro-fatty residue

Hypopigmentation

Scars

Infantile Hemangioma localisation

Face (40%) – Neck (20%) = 60% of the cases

ie: eye – nose – lip – neck – « beard » - forehead - ears

Breast

Diaper area

Limbs - Hands

Infantile Hemangioma localisation

Eye Ears Nose

Lip Neck Beard Forehead

Limbs - Hands Breast Diaper area

Visceral hemangioma (liver)

IH compressing respiratory airways

Disease Complications

12%

88%

88% of cases = No treatment needed in early stage

Natural resolution

12% of cases = treatment needed in early stage

1. Life-threatening conditions

2. Functional risks

3. Permanent disfigurement

4. Painful ulcerated or bleeding IH

IH requiring treatments in brief

Vital Risks Functional Risks

Painful ulcerated or bleeding IH Permanent disfigurement

• Respiratory failure

• Heart failure

• Visual function failure • Maxillodental developpement • Nose necrosis • Ears closing – infection – deafness • Impact on the future breast

• Ulceration • Telangiectasias • Fibro-fatty lesions • Atrophic scars

Treatments – historical development

1. Treatment options

1. Steroids

2. Interferon

3. Vincristine

4. Lasers

5. Surgery

6. Alternatives

2. β-blockers : Propranolol

2008 : The story begins …

Leaute-Labreze C et al. N Engl J Med 2008;358:2649-2651

The story goes on …

Propranolol vs placebo

•Propranolol is a safe and effective medication for treating IHs

•Significant volume reduction and redness/elevation reduction sufficient to justify the use of propranolol as the first-line option for potentially disfiguring or complicated IHs.

•There was a significant improvement in IH redness and elevation based on investigator scores from clinical photographs at weeks

12 and 24 in the propranolol group compared with placebo. The

mean age at inclusion was 67 weeks in the Propranolol group

and 71 weeks in the placebo group.

Propranolol versus Corticosteroids

• Propranolol therapy was more clinically effective and more cost-effective than oral corticosteroids in treating IHs

• Propranolol resulted in fewer surgical interventions and demonstrated better tolerance, with minimal adverse effects, compared with oral corticosteroids

• Propranolol should be considered a first-line agent

Propranolol vs Prednisone : a retrospective comparative study

Prednisone

Propranolol

T = 0 1 month 2 months 6 months

The β-blockers

• Discovered in the 50’s.

• Propranolol: The first clinically useful β-blocker in angina pectoris

Discovered in the 50’s by Sir James W. BLACK against angina (1988 Nobel

Prize)

β1-β2 adrenergic receptors blocker

• How it works ?

HR BP (2h after administration)

Cardiac contractility cardiac excitability

Renin Angiotensin II = Arterial Pressure

Broncho-constriction

Propranolol Mechanism of Action (3 paths)

W1 W4 M6 M12 M18 - 20 Birth

Nascent & Proliferation

Plateau Involution

Léauté-Labrèze C, Taïeb A. [Efficacy of beta-blockers in infantile capillary haemangiomas: the physiopathological significance and therapeutic consequences]. Ann Dermatol Venereol. 2008 Dec;135(12):860-2. Epub 2008 Nov 20. Review. French. PubMed PMID: 19084699

Hypoxic

stress

HIF

CD133 VEGF

bFGF Mesenchymal

Stem Cells

VEGF

bFGF

CD133 stem cells Immature endothelial cells Pericyte Adipocyte Mast cell

Β-blocker Apoptosis

Vasoconstriction Y3 Y7-Y9

Side effects due to Propranolol in hemangioma patients

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

Sleep d

isturb

ance

Hypote

nsion

Som

nolence

Cool or m

ottled e

xtre

miti

es

Pulmonar

y sym

ptom

s

Bradyc

ardia

Hypogl

ycem

ia

Diarrh

ea

Gastro

inte

stin

al dise

ase

Propranolol Efficacy - Conclusion

• Propranolol was initiated at a mean age of 6.6 months

• Mean treatment duration of 6.4 months

• Response rate for patients with IHs treated with propranolol was 98% (range 82%–100%)

• IH rebound growth in 17% of patients.

• Adverse events reported in 31% (changes in sleep = 11% - acrocyanosis = 5%)

Propranolol for IHs showed a high rate of efficacy and a low rate of serious adverse events

Randomized study design 2011-2012

• Adaptive Design: Phase II/III Trial

• Double-Blind Randomized Controlled Trial in Parallel Groups

• Infants with proliferating infantile hemangiomas requiring systemic therapy and located anywhere on the body except

on the diaper area, with largest diameter of at least 1.5 cm • Age at initiation = 1 to 5 months (proliferating phase only)

• Placebo versus 4 propranolol Regimens,

• Administration twice daily (Dose escalation in 2 weeks – D7 – D14)

• No corticosteroid comparator arm ( Not FDA/EMA approved in IH)

Study design

1 mg/kg/day

Placebo

3 mg/kg/day

Placebo

Placebo

3 months 6 months

1 mg/kg/day

3 mg/kg/day

Doses and durations discussed with

European and US Health Agencies

Randomization 24 months

Main efficacy endpoint

Follow-up

Patients

102

98

101

55

Regular patients’ pictures

100

• In conclusion, this trial shows that oral propranolol at a dose of 3 mg per kilogram per day for 6 months is effective in the treatment of infantile hemangioma.

N Engl J Med 2015; 372:735-746 February 19, 2015

Our experience • Since 2009 - 2014 – 231 children were treated

Head + face 121 52 %

Thorax 33 14 %

Liver (only 6 4 %

Liver + skin. 4 2 %

Extremities 31 13 %

Multipl. lesion (more than 10) 25 11 %

Neck + mediastinum 6 2 %

Mucosal (mouth) 5 2%

• Treatment duration: med. 10,7 měs. (4 mths; 2,5 yrs) ≤6mths age – 4,7 mths

≥6mths to 1 y age - 8,1 mths

Response very good in 98% , in 3% the surgery needed for removal of residual lesions

• In 5% regrowths after completion of propranolol, preferably in deep IH

Management of infants with IHs • (2 )- 4 days hospitalization

• Initial investigation: history of the child – search for risk factors blood pressure (BP), heart rate (HR) electrocardiogram, ECHO glycemia, basal biochemistry

• Dose escalation: 0,5..1..2 (3) mg/kg/d in 2 (3) doses

• Propranolol administration close to feeding

• BP and HR 1 hr after drug administratin

• HR monitoring after target dose achieving during sleeping

IH treatment in our Hospital

Conclusions:

• Superficial IH – „most gratefull“ for treatment,

responding well, rapidly and almost without any

ressiduals

• Mixed and deep (particularly) have tendency for

regrowth after treatment completion

• The best effects of BBs th can be achieved when the

treatment is started during first 4(5) mths of life

• Whenever the features of spontaneous involution

of IH appear, the chance for succesful treatment

(without any residues) decreases.

Hemangioma Evolution Phases

W1 W4 M6 M12 M18 - 20 Y3 Birth

Nascent

(resting)

Proliferation & Plateau Involution

The most rapid IH growth is between 1&2 months** Reach 80% of their final size by 3 months*

80% have completed growth by 5 months of age*

80% : size X2

5% : size X3

5% : dramatical growth

IH size

Median age to ending involution***

Optimal time for starting treatment

Y7-Y9

Side effects:

• Slow dose escalation in preterm or lowbirth weight babies (hypoglycemia)

• Sleep disturbancies

• Colder extremities

• Only once allergic reaction to BBs in sirup

Who? Where? When?

Who?

• Oncologist/dermatologist + other specialists: radiologist, cardiologist, neonatologist, surgeon, etc.

Where?

• Institutions where all these specialists and facilities are available

When?

• ASAP – as soon as possible – during the rapid growth phase

Thank you! • Josef Mališ

• Dept. Of Pediatric Hematology/Oncology University Hospital Motol, Prague, Czech Rep.

• josef.malis@fnmotol.cz