MUSCLE study - Mitochondrial dysfUnction: a key player in doxorubicin-induced Skeletal and Cardiac muscLE damage?

Patients with diffuse large B-cell lymphoma (DLBCL) are often treated with
R-CHOP chemotherapy with the intent to cure the disease, but this treatment can
also lead to serious toxicities, which may last for many years. R-CHOP contains
doxorubicin, which has detrimental effects on skeletal and cardiac muscles.
Loss of skeletal muscle mass is associated with treatment modifications (i.e.,
dose delay/reduction/discontinuation), increased levels of fatigue, decreased
quality of life (QoL) and shorter survival. Cardiomyopathy might lead to
chronic heart failure in the long-term, which negatively affects prognosis as
well. Preclinical studies investigating underlying mechanisms of these
detrimental effects suggest that mitochondrial dysfunction plays a key role.
However, human data is lacking due to the need of invasive repeated muscle
biopsies. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) is an
innovative, non-invasive technique, which enables repeated measures of skeletal
and cardiac muscle mitochondrial energy metabolism.

To demonstrate the ability of using non-invasive 31P-MRS to monitor changes of
in vivo markers of mitochondrial function in skeletal and cardiac muscles
(i.e., skeletal muscle PCr recovery rate constant and cardiac PCr/ATP ratio) in
DLBCL patients during treatment with R-CHOP. Furthermore, we will assess the
feasibility of undergoing the study measurements for patients with DLBCL during
intensive R-CHOP treatment and explore the association between changes in in
vivo measured mitochondrial function in skeletal and cardiac muscle tissue and
changes in muscle mass, physical fitness, muscle strength, physical activity
levels measured by Fitbit, chemotherapy completion rate and patient-reported
outcomes, including physical activity, fatigue and quality of life.

Cohort study

Included patients will visit the UMC Utrecht 3 times (i.e., before, halfway
during and after completion of chemotherapy treatment). During these visits,
participants will undergo 31P-MRS imaging of the calf muscles and of the heart
at 7 Tesla. During the calf muscle scan, patients will be asked to perform a
mild exercise challenge (i.e., dynamic plantar flexions). 7T 31P-MRS is a safe
and reliable technique for subjects without contra-indications for undergoing
MRI. Possible side-effects are limited to short-term vertigo and nausea. In
addition, anthropometrics will be measured and small tests to evaluate muscle
strength and physical performance will be performed. Participants will be asked
to complete questionnaires regarding physical activity, quality of life and
fatigue. Finally, patients will be asked to wear a Fitbit, provided by the
study team, to objectively assess their levels of physical activity.
Subjects will not experience direct benefits by participating in this study. By
the end of the study, we will demonstrate the ability to non-invasively monitor
skeletal and cardiac muscle mitochondrial damage using 31P-MRS, which is a
pre-requisite to assess the efficacy of (non-)pharmacological interventions.