Propranolol Dose Escalation in Lymphedema in Patients

Lymphatic malformations (LMs) arise from abnormal development of lymphatic vasculature.
Primary lymphedema is considered a form of LM. Recently, results in the investigators'
laboratory demonstrated that propranolol, a pan beta-adrenergic receptor (βAR) antagonist,
had cytotoxic and anti-proliferative effects against cells isolated from LM tissues.
Preliminary results from treating symptomatic LM patients with propranolol at a dose range
from 0.7-1mg/kg/day demonstrated a 70% positive response rate, with patients reporting
improvement in their symptoms.

Propranolol has been used for different indications for many years. Propranolol is accepted
for use in infants with hemangiomas and supraventricular tachycardia. Hemangeol was approved
by the FDA for use in infants with hemangiomas. However, βAR antagonists are not without
potential adverse effects, including hypotension, bradycardia, hypoglycemia, bronchospasms,
and sleep disturbances. FDA-approved dose range for treating hemangiomas in infants (>5
weeks old, >2kg) ranged from 1-3mg/kg/day in divided doses. Propranolol doses of up to
4mg/kg/day has been used for pediatric supraventricular tachycardia. Therefore, the
investigator's experience with propranolol use in LM patients have been at the low end of
most accepted clinical indications. The investigators propose to escalate propranolol
dosages up to 3mg/kg/day in this study, well below the dose ranges currently used in
clinical settings.

This dose range of 0.7-1mg/kg/day was chosen for LM patients as it was the low end of dose
range for infants treated with propranolol for problematic hemangiomas, a related vascular
anomaly. At this dose, no significant hemodynamic adverse effects were noted in LM patients.
However, when patients stopped propranolol or their dose fell below 0.7mg/kg/day, they
suffered rebound worsening of their symptoms. Moreover, inflammatory events such as
infections temporarily overcame the effects of 0.7-1mg/kg/day of propranolol. Thus, it is
unknown whether maximum propranolol efficacy was achieved at the current dose range. The
investigators propose to examine whether optimized propranolol usage for treatment of LM
patients has been achieved. The primary endpoint for this study is to ascertain whether LM
patients can tolerate higher doses of propranolol, as measured by known propranolol adverse
effects and patient-reported symptoms. A secondary endpoint will address whether
patient-reported LM symptoms and quality of life are improved with higher doses of
propranolol; objective findings such as LM size on physical examination and imaging studies
will be analyzed as well. In addition, LM tissue biopsies will acquired from patients before
and after propranolol treatment for further analyses of disease progression.

Inclusion Criteria:

- Primary lymphedema

- Measurable disease

- Adequate functional status: Karnofsky >50% (>age 16), Lanky >50 (
- No prior therapy within 4 weeks of enrollment

- Adequate bone marrow, renal function, cardiac, and pulmonary function, negative
pregnancy test (for women).

Exclusion Criteria:

- Secondary lymphedema

- Patients already receiving other investigational drugs

- Patients with known contraindications to receiving propranolol

- Other medical comorbidities including but not limited to: pheochromocytoma,
bradycardia, bronchospasm/reactive airway disease, decompensated heart failure, heart
block, ongoing active infections.