Successful Treatment of Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type With Single-Agent Venetoclax

Abstract

Primary cutaneous large B cell lymphoma, leg type (PCDLBCL-LT) is recognized as a specific disease entity within the WHO classification of lymphomas, accounting for 20% of all primary cutaneous B cell lymphomas. PCDLBCL-LT typically presents in the elderly, (median age of presentation 76 years, has a female/male ratio of 7:2, predominantly involves the lower leg and is often associated with poor clinical outcome. Most primary cutaneous large B cell lymphoma, leg type (PCDLBCL-LT) exhibit an activated B-cell like diffuse large B-cell lymphoma (ABC DLBCL) phenotype, both immunohistochemically and on gene expression profiling. Gene expression profiling is associated with constitutive NF-kB pathway activation and upregulation of apoptosis inhibiting genes. Mutations of MYD88, are reported in up to 69% of cases of PBDLBCL-LT. Small case series of patients with MYD88 mutated PCDLBCL-LT have demonstrated responses of short duration to inhibition of BCR signaling via BTK inhibition. High level BCL2 expression provides rationale for investigation of BCL2 inhibition in this disease. We report a case of MYD88 wild-type chemotherapy-refractory PCDLBCL-LT treated successfully with single agent venetoclax. A 77 year old gentleman was diagnosed with PCDLBCL-LT, of the left lower leg in 2006, with isolated cutaneous involvement. Immunohistochemistry showed co-expression of CD20, CD79A PAX5, BCL2, BCL6, IRF4 and CD10, with a Ki67 fraction of 90%. Following development of chemotherapy refractory disease, we obtained venetoclax through the UK Abbvie compassionate access scheme. Venetoclax was commenced at 400mg OD and escalated at weekly intervals to 800mg and 1200mg. 1200mg was not tolerated due to persistent grade 2 diarrhoea and grade 2 fatigue; 800mg was adopted as a maintenance dose. Clinical response was observed after 24 hours. Biopsy following 2 weeks on treatment showed a complete histological and immunohistochemical response. 18 FDG-PET/CT scan at 2 months showed a complete metabolic response. Treatment with venetoclax was stopped one month after demonstration of metabolic remission. However, within four weeks of stopping venetoclax, disease recurred, confined to the left lower leg. Venetoclax was recommenced at a dose of 400/800 mg on alternate days. Eighteen months later his disease remains in complete remission. Whole exome tumor DNA sequencing was performed at relapse. Somatic mutations were identified by paired analysis of tumor and germline DNA. Neither MYD88 mutations nor mutations in BCL2 or any other BCL2 family member identified. No amplification of the BCL2 gene was detected. Potential genetic "drivers" of this malignancy included previously described ARID1A and NOTCH2 mutations, as well as biallelic deletion of RB1 and CDKN2A and monoallelic loss of TP53. Only very low levels of circulating free DNA (0.068 ng/ml plasma) were detected pre and during treatment, comparable to levels in healthy individuals. We demonstrate that single agent venetoclax may induce a complete response without significant toxicities in...

Identifying and addressing unmet clinical needs in primary cutaneous B‐cell lymphoma: A consensus‐based paper from an ad‐hoc international panel

“…Recently, other novel targeted therapies have been explored by identifying the mutational landscape and specific altered pathways involved in onset and progression of PCDLBCL‐LT 78,79 such as the Bruton tyrosine‐kinase inhibitors(ibrutinib), 79 BCL2 inhibitors or immune check‐point inhibitors. However, only single case reports are available reporting the clinical activity of these new agents in heavily pretreated patients 80–82 …”

“…However, only single case reports are available reporting the clinical activity of these new agents in heavily pretreated patients. [80][81][82] Finally…”

Spontaneous Regression of Primary Cutaneous Diffuse Large B-Cell Lymphoma on Sequential FDG PET

“…It typically presents in elderly women, and is often associated with poor clinical outcome. [1][2][3] Patients typically present with rapidly developing red-to-plum-colored nodules on one or both legs. Extracutaneous spread typically occurs to regional lymph nodes and bone marrow with the central nervous system being the most common location of visceral involvement.…”

Limitations of Monitoring Disease Progression Using Circulating Tumor DNA in Lymphoma: An Example From Primary Cutaneous DLBCL Leg-type

“…He commenced venetoclax in January 2017. A rapid and complete metabolic response was obtained, 7 before he relapsed in January 2019 (Figure 1 ). The patient then received 3 weeks of ibrutinib but experienced further rapid clinical progression.…”

“…No BCL2 mutations nor new mutations involved in regulation of apoptosis were detected, and levels of BCL2 expression were maintained on immunohistochemistry despite treatment with venetoclax for 2 years (Figure 1 C). Following relapse on venetoclax, 7 to enhance detection of residual disease, we analyzed sequential ctDNA samples. Serial plasma samples were analyzed by ddPCR over a 3-year period for the ARID1A p.R1461* and NOTCH2 p.R2400* nonsense variants, present in all biopsy samples, which are likely truncal mutations (Figure 2 ); 1 plasma sample was additionally assessed by CAPP-Seq during treatment on venetoclax (Figure 2 B).…”