Rituximab, lenalidomide, and ibrutinib in relapsed/refractory primary cutaneous diffuse large B‐cell lymphoma, leg type

Abstract

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is an exceedingly rare extra-nodal variant of diffuse large B-cell lymphoma (DLBCL) with an aggressive natural history that often manifests as red cutaneous tumour lesions on the lower extremities. This aggressive lymphoma subtype carries a poor prognosis with a 5-year overall survival of ~50%.1 Like other subtypes of DLBCL, initial therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemoimmunotherapy is the current standard of care for this unique DLBCL subtype. However, many patients with PCDLBCL-LT are elderly; therefore, advanced age and comorbidities can be preclusive to aggressive, multiagent chemotherapy. Additionally, with the chemoresistant nature of PCDLBCL-LT and the relatively poor prognosis, many patients experience disease relapse and thus, novel treatment paradigms are needed for salvage therapy. The myeloid differentiation factor 88 (MYD88) protein activates nuclear transcription factor κB (NF-κB) and promotes lymphoma cell survival. This mutation has been associated with older age and poor overall survival in DLBCL.2 While only present in ~16% of DLBCL cases, MYD88 L265P mutation is present in the majority of PCDLBCL-LT cases.3 Malignancies in which MYD88 L265P mutation is present, such as Waldenström macroglobulinaemia, have demonstrated high response rates with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. In the setting of MYD88 mutation-positive PCDLBCL-LT, ibrutinib has demonstrated responses as a single-agent; however, evidence has been limited to case reports.4, 5 Recently, the combination of ibrutinib plus rituximab and lenalidomide has demonstrated efficacy in the treatment of DLBCL in a phase Ib study.6 In the present study, we report two cases in which the combination of rituximab, lenalidomide, and ibrutinib produced deep and durable responses. A 78-year-old man was referred to our institution with left lower extremity (LLE) cutaneous nodules. Positron emission tomography/computed tomography (PET/CT; Fig 1) demonstrated several hypermetabolic cutaneous nodules in the left leg with the largest measuring 2·2 × 1·3 cm and maximum standardised uptake value (SUVmax) of 11·6. Punch biopsy of a nodule showed large lymphoid cells, upon immunohistochemical staining, to be positive for CD20, BCL2, MUM1, and negative for CD10, CD5, CD30, BCL6 (only few weakly positive cells), with a Ki-67 of 60%, consistent with PCDLBCL-LT, non-germinal centre B-cell (non-GCB) subtype (Fig 2). Fluorescence in situ hybridisation (FISH) was negative for MYC proto-oncogene, MYC, BCL2, and BCL6 rearrangements. The patient was treated with three cycles of R-CHOP and achieved a complete response (CR) on interim PET/CT scan. He was then treated with an additional three cycles of mini-R-CHOP, dose reduced due to neutropenic fever. At 4 months after finishing chemotherapy, he presented with new nodules in his left lower leg. Repeat PET/CT showed new cutaneous and subcutaneous nodules in the left leg with largest measuring 1·4 × 0·8 cm (SUVmax 15·6). Biopsy was consistent with known history of PCDLBCL-LT, but now with Ki-67 of 95%. FISH was again negative for MYC, BCL2, and BCL6 rearrangements. Further molecular testing by quantitative polymerase chain reaction (qPCR) revealed a MYD88 L265P mutation. The patient was not considered a candidate for high-dose chemotherapy with autologous stem cell transplantation due to his advanced age; therefore, palliative options were then sought for salvage therapy. He received radiation to the LLE nodule, 30 Gy (15 fractions). A follow-up, post-radiation PET/CT showed improved subcutaneous LLE lesions; however, there was also new interval development of an fluorodeoxyglucose (FDG)-avid lesion measuring 3 × 4 cm (SUVmax 19) in the left inguinal area. Upon disease progression, he was initiated on ibrutinib 560 mg per os (po) daily, lenalidomide 25 mg po daily days 1-21 every 28 days, and rituximab 375 mg/m2 intravenously (IV) every 28 days. After four cycles of therapy, an interim PET/CT scan demonstrated a CR with no hypermetabolic uptake to indicate active, recurrent, or metastatic disease. Lenalidomide was decreased to 20 mg with cycle five due to Grade 3 diarrhoea, Grade 2 fatigue and Grade 3 neutropenia. Ibrutinib was decreased to 420 mg daily with cycle six due to Grade 3 neutropenia, weight loss and anorexia. While his diarrhoea and neutropenia improved with dose reductions of lenalidomide and ibrutinib, his functional status was still in decline, therefore lenalidomide was discontinued after six cycles. The patient completed six cycles of the triplet combination and then continued ibrutinib 420 mg po daily as maintenance. This adjustment in therapy led to a significant improvement in his performance status and he tolerated ibrutinib maintenance without any serious adverse events. At 9 months after starting therapy at his most recent oncology follow-up, he had a PET/CT that demonstrated a continued CR. A 61-year-old man with PCDLBCL-LT was referred to our institution after relocating to the area. He initially presented to an outside facility with a 6-month history of progressive LLE rash. Skin punch biopsy was morphologically consistent with PCDLBCL-LT with background chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), for which he received six cycles of R-CHOP with marked improvement in skin rash after therapy initiation. This material was reviewed at our institution, confirming a large cell infiltrate that was immunohistochemically positive for CD20, BCL2, FOXP1, immunoglobulin M (IgM), MYC (90%), with limited MUM1 positivity (<30%). There was also a smaller lymphoid component positive for CD20, BCL2, CD5, IgM, and CD23. Biopsy was reported negative for a variety of special stains, including CD30, CD10, cyclin D1, programmed cell death 1 (PD1) and programmed death-ligand 1 (PD-L1). Additional molecular testing with qPCR also revealed a MYD88 L265P mutation; FISH was negative for BCL2 and BCL6 rearrangements but showed MYC/IGH fusion in 86% of nuclei. This was consistent with the known history of PCDLBCL-LT, non-GCB subtype, with background CLL that was a distinct clone. Large-cell Richter transformation was considered in the differential histologically, but the clinical and ancillary study findings supported a separate primary large-cell lymphoma unrelated to the CLL clone. Clonal studies, including Ig gene rearrangement studies, were unable to be performed on the original materials. Several weeks after completing chemotherapy he began to develop a recurrent LLE rash. A PET/CT demonstrated new hypermetabolic subcutaneous and cutaneous nodular thickening at the medial left lower leg compatible with active lymphoma. Punch biopsy of a LLE lesion showed large lymphoid cells, similar to the previous biopsy material. The patient developed non-ischaemic cardiomyopathy with reduced left ventricular ejection fraction of 40–45% secondary to R-CHOP and therefore was not considered a candidate for haematopoietic stem cell transplant. He initiated second-line therapy with ibrutinib 560 mg po daily, lenalidomide 20 mg po daily days 1–21 every 28 days, and rituximab 375 mg/m2 IV every 28 days. Of note, lenalidomide has a labelled warning for an increased risk of cardiovascular events in the treatment of CLL (Celgene Corporation7) After two cycles of treatment, an interim PET/CT scan demonstrated a CR. Lenalidomide was reduced to 15 mg with cycle three and then further reduced to 10 mg with cycle five due to rash, which improved with dose reduction. He has otherwise tolerated treatment without any serious adverse events. Rituximab was discontinued after six cycles; ibrutinib and lenalidomide were continued. PET/CT 13 months after starting therapy shows continued CR, and the patient remains in remission clinically at 20 months. An MYD88 L265P mutation present in PCDLBCL-LT can trigger the activation of NF-κB through two divergent pathways, one of which involves BTK.8 Therefore, BTK can play a critical role in the pathogenesis and cell survival of lymphomas harbouring a MYD88 L265P mutation, making BTK inhibition an attractive therapeutic target. The BTK inhibitor ibrutinib disrupts chronic B-cell receptor signalling, thereby leading to decreased NF-κB activity. The immunomodulatory drug lenalidomide downregulates interferon regulatory factor 4 downstream of the B-cell receptor and MYD88 signalling, leading to increased interferon beta secretion and decreased NF-κB activity.9 Lenalidomide has demonstrated single-agent activity in patients with relapsed/refractory PCDLBCL-LT with an overall response rate (ORR) of ~26%.10 Although ibrutinib is active in relapsed/refractory DLBCL, response rates are relatively low when used as monotherapy with an ORR of 37% in activated B-cell type (ABC) and 5% in GCB and CR rates of 16% and 0% in ABC and GCB subtypes respectively.11 Preclinical studies have suggested increased synergistic activity when ibrutinib and lenalidomide are combined.9 This is more prominent in non-GCB subtypes of DLBCL, as these molecular subtypes are more dependent on the B-cell receptor signalling pathway for cell survival. More recently, the MYD88 L265P mutation has been shown to be one of the defining features of the MCD genetic subtype, which encompasses extra-nodal DLBCL subtypes such as PCDLBCL-LT.12 Lenalidomide combined with rituximab may help to overcome rituximab resistance in DLBCL and has demonstrated an ORR and CR in 33% and 22% of patients respectively.13 In a phase Ib study, the combination of rituximab, lenalidomide, and ibrutinib demonstrated a 44% ORR (28% CR rate) in patients with relapsed/refractory DLBLC.6 Patients with non-GCB subtype DLBCL had higher ORR (65%) and CR rates (41%) compared to the composite cohort in the trial. This combination was found to be safe and efficacious and is currently being evaluated in a larger phase II trial. To our knowledge, this is the first case series of PCDLBCL-LT treated with a combination of rituximab, lenalidomide, and ibrutinib. We chose this triplet regimen based on the presence of the MYD88 L265P mutation in PCDLBCL-LT, the short duration of response with chemoimmunotherapy, and the favourable response rates observed in previous studies relative to that observed with lenalidomide/rituximab or ibrutinib monotherapy in relapsed/refractory DLBCL. In conclusion, the combination of rituximab, lenalidomide, and ibrutinib led to clinically meaningful responses in two patients with relapsed/refractory PCDLBCL-LT and could potentially represent a novel therapeutic approach for patients with this rare aggressive subtype of DLBCL harbouring MYD88 mutation. Donald C. Moore and Steven I. Park wrote the manuscript. Elton T. Smith provided the pathology images. Amy C. Soni, Elton T. Smith, Jonathan Levine, Bei Hu, Tamara K. Moyo, Ryan Jacobs, Nilanjan Ghosh, and Steven I. Park critically revised the manuscript.

Topics & Concepts