Nintedanib Treatment in Unicentric Castleman Disease

Unicentric Castleman Disease (UCD) is a rare non-malignant localised disease involving one or more lymph nodes, associating germinal centre atrophy, mantle zone thickening and intense vascular proliferation penetrating the germinal centres. Patients usually seek medical attention because of a localised, sometimes compressive, lymph node or the development of life-threatening autoimmune complications (paraneoplastic pemphigus or PNP or myasthenia gravis or MG). The best treatment option is complete surgical excision, but it has been recently demonstrated that up to half of the patients cannot undergo surgery. In these patients, an efficient medical approach needs be defined, as no current medical treatment has demonstrated to lower morbidity and mortality. The cause of UCD is currently unknown and current data favour a scenario of stromal impairment leading to the loss of lymph node architecture rather than one of a primary hematopoietic disease. UCD lesions are often associated with synchronous follicular dendritic cell (FDC) proliferation and can sometimes evolve towards a true FDC sarcoma (FDCS), indicating a possible role for FDC, a germinal centre stromal cell component, in UCD pathogenesis. A recurrent somatic activating mutation in PDGFRB (p.N666S) has been recently described in the CD45 negative (non-hematopoietic) compartment of up to 17% UCD specimens. Moreover, activation of the VEGFR pathway is thought to play a role in the development of the disease, especially in the increased vascularity characteristic of the UCD lesion.

Nintedanib is a commercially available tyrosine-kinase inhibitor targeting PDGF, VEGF and FGF receptors. The drug has obtained European Market Authorization in 2015 for the treatment of Non-Small Cell Lung Cancer and Idiopathic Pulmonary Fibrosis with a satisfactory safety profile. The hypothesis is that nintedanib could benefit patients with unresectable or partially resectable UCD.


Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ (equal to or greater than) 18 years
2. Written informed consent
3. Biopsy-proven diagnosis of hyaline-vascular Unicentric Castleman disease
4. Unresectable or partially resectable UCD lesion or surgery refusal
5. Available oral route
6. Affiliated to National French social security system (registered or being a beneficiary of such a scheme)
7. Women of childbearing potential should be advised and agree to avoid becoming pregnant while receiving treatment and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of treatment; pregnancy testing must be conducted prior to treatment and during treatment as appropriate; breast-feeding should be discontinued during treatment
8. In male patients, with WOCBP partner(s), willingness to use adequate contraceptive measures to prevent his partner from becoming pregnant during the study, prior to administration of the first dose of study treatment until 3 months after the last dose of study treatment

Exclusion Criteria:

1. Synchronous Follicular Dendritic Cell sarcoma
2. Known hypersensitivity to nintedanib, soy or peanut or to any of the excipients of the experimental drug, or known hypersensitivity to the auxiliary drugs listed or to any of their excipients.
3. For women of childbearing age: negative serum or urine pregnancy test at inclusion and confirmed each month during the study, up to 3 months after the last dose.
4. Inability to obtain informed consent
5. Patients under legal protection
6. Liver transaminases (AST and/or ALT) \&gt;3N
7. End-stage liver disease (Child B or C cirrhosis)
8. End-stage renal failure (CrCl\&lt;30 mL/min)
9. Severe hemorrhagic or thromboembolic events in the past 6 months
10. Uncontrolled systemic illness such as chronic heart failure, unstable angina, hypertension; history of myocardial infarction or stroke or aneurysm
11. Major injuries in the 10 days prior to start of the study, or Recent surgery with inadequate wound healing, or Abdominal surgery in the past 4 weeks.
12. Severe pulmonary hypertension
13. Bleeding risk, any of the following:

    1. Known genetic predisposition to bleeding.
    2. Patients who require

1. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin) 2. High dose antiplatelet therapy corresponding to a combination of two anti-platelet aggregation treatment (aspirin + an Inhibitor of P2Y12 receptor) 14. Contraindication to the experimental drug or auxiliary drugs listed 15. Patients under guardianship or curatorship and protected adults or unable to consent 16. Enrollment in another interventional study (ongoing at the time of inclusion)