Ibrutinib Can Induce Complete Remissions and Sustained Responses in Refractory Cutaneous or Leg-Type Diffuse Large B-Cell Lymphoma
Authors: Bloehdorn Johannes , Weissinger Stephanie Ellen , Sindrilaru Anca , Schoensteiner Stefan , Peters Thorsten , Moeller Peter , Marienfeld Ralf , Viardot Andreas 
Published: October 2019

Abstract
Background: Primary cutaneous diffuse large B-cell lymphoma, leg-type (LT-DLBCL) is an extremely aggressive DLBCL subtype typically occurring at lower extremities and with very poor prognosis due to early relapses and refractory (R/R) disease. Previous studies have shown increased BCR dependence in DLBCL being observed in association with the mutation status of BCR associated genes and MYD88.
Aim: Primary goal was to assess the clinical course in patients with primary cutaneous DLBCL and to elucidate the potential of alternative treatments with regard to molecular characteristics.
Methods: We identified 16 patients with cutaneous DLBCL treated at our center of which 8 patients had typical localization and were histologically confirmed as LT-DLBCL. The other 8 patients showed cutaneous DLBCL at other anatomic sites (DLBCL-OS) and were classified as DLBCL/DLBCL NOS. Three R/R patients received ibrutinib as off-label individual treatment attempt (420 mg daily). We extended the clinical and molecular analysis for the ibrutinib exposed DLBCL by 1 R/R oropharyngeal DLBCL. Specimen from R/R ibrutinib exposed and 3 other patients were analyzed for CD79B, MYD88, CARD11 and BTK mutations by targeted resequencing analysis. PD-1/PD-L1 expression was assessed in 2 cases with relapse after ibrutinib. Treatment was initiated after signed informed consent.
Results: The median age at diagnosis was 51 years in DLBCL-OS and 80 years in LT-DLBCL (total range 37-91). Patients received a median of 2 (0-7) treatments and response to last chemotherapy was different for DLBCL-OS (6 complete remissions (CR), 2 R/R) and LT-DLBCL (2CR, 5R/R). One LT-DLBCL patient showed stable disease (SD) without treatment. LT-DLBCL patients showed a significantly shorter median overall survival (OS) (21,5 months vs. not reached, p=0.009). After ibrutinib treatment we observed 1 ongoing CR for 10 months till date for a DLBCL-OS with CD79B p.Y197S and MYD88 L273P mutation and 1 CR for 6 months in a LT-DLBCL being WT for all sequenced genes. However, this patient relapsed with a highly proliferative disease and died shortly after. The 3rd patient with LT-DLBCL had an isolated MYD88 L265P mutation and showed a PR for 1 month. Samples from patients with indolent clinical course showed a MYD88 p.S251N and BTK p.P385S mutation (LT-DLBCL with SD) or were WT for all sequenced genes (2 patients with DLBCL-OS and ongoing CR). The patient with R/R oropharyngeal DLBCL had a MYD88 L265P and CD79B c.587A mutation, 4 prior treatment regimen and fulminant progression during the last 2 treatments. Initial response to ibrutinib was rapid with a drop of LDH levels from 2200 U/L to 620 U/L within 7 days and consecutive decrease to 323 U/L. However, this patient relapsed after 30 days of treatment.
Immunomodulatory effects of ibrutinib and potential synergistic treatment with checkpoint inhibitors have previously been suggested. We specifically investigated PD-1/PD-L1 expression in tissues obtained from the two patients progressing after ibrutinib treatment. Remarkably, we observed increased expression for PD-1 (moderate) and PD-L1 (strong) in non-tumor bystander cells. Treatment with nivolumab was initiated in 1 patient with early clinical benefit. However, the patient refused the continuation of this treatment.
Conclusion: Patients with LT-DLBCL are older and show a poor clinical course compared to cutaneous DLBCL at other anatomic sites. MYD88 L265P mutations were observed only in chemo-refractory cases with extranodal DLBCL. Ibrutinib can induce complete remissions and sustained responses in chemo-refractory extranodal DLBCL but relapses may be more aggressive and disseminated. Mutational patterns and ibrutinib response were in line with previous hypothetical models for sensitivity to BCR inhibition. Combining ibrutinib and checkpoint inhibitors may be considered in future trials for LT-DLBCL patients.

Disclosures
Weissinger: Bristol-Myers Squibb: Research Funding. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.