P048 - MAPK AND AKT/MTOR INHIBITION IMPROVES CHILDHOOD RASOPATHY-ASSOCIATED CARDIOMYOPATHY

Thursday, October 27, 2022

4:45 PM – 4:55 PM EDT

Location: Room 201

Presenter(s)

Gregor Andelfinger

Pediatric Cardiologist
Hôpital Sainte Justine
CHU Sainte Justine, Université de Montréal
Montréal, Quebec, Canada

First Author(s)

Gregor Andelfinger

Pediatric Cardiologist
Hôpital Sainte Justine
CHU Sainte Justine, Université de Montréal
Montréal, Quebec, Canada
MZ

Martin Zenker

Magdeburg, Sachsen-Anhalt, Germany

Author(s)

MZ

Martin Zenker

Magdeburg, Sachsen-Anhalt, Germany
GN

Gabrielle Norrish

London, England, United Kingdom
MR

Mark Russell

Paediatric Cardiologist
Ann Arbor, Michigan, United States
JM

Jonathan Meisner

Ann Arbor, Michigan, United States
DP

David Peng

Ann Arbor, Michigan, United States
TP

Terence Prendiville

Crumlin, Limerick, Ireland
JK

Jake Kleinmahon

New Orleans, Louisiana, United States
PK

Paul F. Kantor

Chief, Division of Cardiology
University of Southern California, Children's Hospital Los Angeles
Los Angeles, California, United States
DG

Danielle Gottlieb Sen

Baltimore, Maryland, United States
Derek Human

Pediatric Cardiologist
BC Children's Hospital
University of British Columbia
Vancouver, British Columbia, Canada
PE

Peter Ewert

Munich, Bayern, Germany
MK

Marcus Krueger

Munich, Bayern, Germany
DR

Daniela Reber

Munich, Bayern, Germany
BD

Birgit Donner

Basel, Basel-Stadt, Switzerland
CH

Christopher Hart

Bonn, Nordrhein-Westfalen, Germany
IO

Irena Odri-Komazec

Innsbruck, Vorarlberg, Austria
SR

Stefan Rupp

Giessen, Hessen, Germany
AH

Andreas Hahn

Giessen, Hessen, Germany
AH

Anja Hanser

Tübingen, Baden-Wurttemberg, Germany
MH

Michael Hofbeck

Tübingen, Baden-Wurttemberg, Germany
JD

Jos Draaisma

Nijmegen, Gelderland, Netherlands
FU

Floris Udink ten Cate

Nijmegen, Gelderland, Netherlands
AM

Alessandro Mussa

Torino, Lombardia, Italy
GF

Giovanni Ferrero

Torino, Lombardia, Italy
LV

Laurence Vaujois

Québec City, Quebec, Canada
MR

Marie-Josée Raboisson

Montréal, Quebec, Canada
MD

Marie-Ange Delrue

Montréal, Quebec, Canada
CM

Christopher Marquis

Montréal, Quebec, Canada
YT

Yves Théorêt

Montréal, Quebec, Canada
JK

Juan Kaski

London, England, United Kingdom

Senior Author(s)

BG

Bruce Gelb

New York, New York, United States
CW

Cordula Wolf

Munich, Bayern, Germany

Author(s)

CW

Cordula Wolf

Munich, Bayern, Germany

Background: No causal therapies exist for severe pediatric-onset cardiomyopathy associated with germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM). In order to evaluate the benefit of small molecule inhibitors of target of rapamycin (mTORi) or MAPK kinase (MEKi) in RAS-CM patients, we have sought to compile cases of compassionate use of these agents.

METHODS AND RESULTS: Case series collecting pre-defined variables on safety and clinical outcome on 25 children with progressive RAS-CM receiving off-label or compassionate use mTORi or MEKi after exhaustion of standard therapies in 17 European and North-American centers.
Over a follow-up period of 296 patient-months (median, 5.5 months; range, 1.5-50), transplant-free survival in critically ill patients < 6 months of age treated with mTORi and/or MEKi was 75% compared to 39% in natural history controls (p=0.031). Freedom from surgical intervention was 52% (11 of 21 patients in whom surgical outflow tract resection was indicated), and improvement in clinical functional status and decrease in NT-proBNP z-score by at least 20% from baseline occurred in 85% and 70.6% of patients, respectively (median [range] change in Ross classification -1.3 [-2 – 0] and in NT-proBNP z-score -1.8 [-3.7 - +0.4], p< 0.001, before treatment versus last treatment timepoint). No life-threatening adverse events related to mTORi or MEKi were observed.
Skin and mucous membranes were the most common organs affected by side effects, requiring cessation or reduction of therapy in 16% of patients.

Conclusion: Selected RASopathy patients may benefit from novel mechanism-informed therapeutics targeting the RAS/MAPK pathway. Clinical trials are needed to substantiate the findings reported in this case series.