Advanced PET and MRI techniques for improved therapy response assessment in diffuse large B-cell lymphoma / follicular lymphoma grade 3B

Malignant lymphomas are a heterogeneous group of neoplasms with highly variable
biology and prognosis. Improved understanding of the tumor biology enables
selecting the most likely effective therapy, and will allow personalized
monitoring of treatment response in each patient and provide the opportunity to
switch from treatment strategy in case of a non-response. Early selection of
effective treatment strategy increases survival rate, and early stop of an
ineffective therapy will prevent unnecessary side-effects. Despite its
relatively high negative predictive value, early interim conventional (i.e.
single time-point) 18F-FDG PET lacks sufficient positive predictive value in
diffuse large B-cell lymphoma / follicular lymphoma grade 3B patients
undergoing R-CHOP chemotherapy. Consequently, biopsy confirmation of a positive
interim 18F-FDG PET scan is required before a change in therapy can be
justified. New non-invasive functional imaging techniques (obviating the need
for biopsies and so improving quality of life) are required to improve the
discrimination between residual tumor and inflammatory/necrotic changes, and to
detect failure of front-line R-CHOP at an early stage. In this project, the
value of dual time-point 18F-FDG PET, DWI, and 89Zr-rituximab PET for these
purposes will be investigated.

This project will first address the hypothesis that dual time-point 18F-FDG PET
and DWI improve the discrimination between residual active tumor and
inflammatory/necrotic changes after two cycles of R-CHOP in DLBCL / follicular
lymphoma grade 3B , and, secondly, aims to demonstrate the proof-of-concept
that interim 89Zr-rituximab PET after two cycles of R-CHOP can identify
patients in whom front-line R-CHOP is likely going to fail by detecting loss of
CD20 expression.

Patients eligible for enrollment in this multicenter, prospective, diagnostic
cohort study are adults aged *18 years with a newly diagnosed, histologically
proven, and previously untreated diffuse large B-cell lymphoma / follicular
lymphoma grade 3B, who are scheduled to undergo standard front-line R-CHOP-21
therapy. All patients will undergo dual time-point 18F-FDG PET and DWI both
before therapy and between 10 and 21 days after the second cycle of R-CHOP
chemotherapy. All patients with a site that is positive for residual tumor at
interim conventional (i.e. single time-point, 60 minutes after 18F-FDG
administration) 18F-FDG PET will also undergo subsequent interim 89Zr-rituximab
PET. Interim conventional 18F-FDG PET positive sites will be biopsied, if
safely accessible, and histologically examined for the presence of residual
tumor or inflammation, and degree of CD20 expression. In ten patients with a
negative interim conventional 18F-FDG PET scan but with a residual abnormality
on the corresponding low-dose CT-scan, a biopsy will be performed of the
residual abnormality on the CT scan to compare its histological characteristics
to that of interim conventional 18F-FDG PET positive sites. All patients will
routinely undergo an end-of-treatment 18F-FDG PET scan as part of standard
clinical care, and all patients will also be followed-up for two years for
relapsing disease. Therapy will not be changed on the basis of (interim) dual
time-point 18F-FDG PET, DWI, 89Zr-rituximab PET, and biopsy results.

-Patients will receive an infusion for the PET scans, and this may give some
discomfort/pain for a short time. -For the PET scans, radioactive tracers
(18F-FDG and 89Zr-rituximab) will be applied. Although this gives a certain
radiation dose, from previous research it is known that the health risks of the
total effective dose effecieve in adult patients with diffuse large B-cell
lymphoma / follicular lymphoma grade 3B are negligible / very low. Furthermore,
the radioactive tracers (18F-FDG and 89Zr-rituximab) have been used safely
without any side-effects so far. -Another possible disadvantage is that lying
still in the PET and MRI scanners and the duration of the scans can give some
discomfort. However, we will do everything we can to make it as comfortable as
possible for the patients. -A selection of the patients will get a biopsy; the
locale anaesthesia may give some discomfort/pain for a short time, but
otherwise the patient will not experience any pain during the remainder of the
procedure. Furthermore, serious complications will be avoided by aiming to
biopsy superficial residual abnormalities as much as possible; risky biopsies
that are anticipated to cause important complications will be avoided. There is
no personal benefit for participants in this study. This study may provide new
non-invasive diagnostic methods that allow for the early detection of treatment
response and drug resistance and this can lead to improved, individualized
treatment planning for patients with diffuse large B-cell lymphoma / follicular
lymphoma grade 3B in the future. We hope this will contribute to the overall
survival of patients and prevent unnecessary side-effects associated with
ineffective therapies. Society will benefit from these new diagnostic methods
because patients will then receive more cost-effective therapy.