Ibrutinib response in cutaneous transformed lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma (LPL) accounts for approximately 2% of hematologic malignancies [1,2] and classically involves the bone marrow and peripheral blood, with less common involvement of the lymph nodes and spleen. LPL is often associated with a monoclonal paraprotein, usually IgM, which when symptomatic is referred to as theclinicalsyndromeWaldenströmmacroglobulinemia(WM).Disease manifestations may be due to the paraprotein or less commonly, secondary to tissue infiltration by lymphoma cells that consist of mature B-lymphocytes, plasmacytoid lymphocytes, and plasma cells. Cutaneous involvement is uncommon in LPL, most often related to the IgM and can range from dermatoses to crystal-storing histiocytosis cutaneous amyloidosis lymphoma cells is extremely rare, and when this occur, the neoplastic cells growth patterns interstitial, and dermal of cases of the differentiation


Lymphoplasmacytic lymphoma (LPL) accounts for approximately 2%
of hematologic malignancies [1,2] and classically involves the bone marrow and peripheral blood, with less common involvement of the lymph nodes and spleen. LPL is often associated with a monoclonal paraprotein, usually IgM, which when symptomatic is referred to as the clinical syndrome Waldenström macroglobulinemia (WM). Disease manifestations may be due to the paraprotein or less commonly, secondary to tissue infiltration by lymphoma cells that consist of mature B-lymphocytes, plasmacytoid lymphocytes, and plasma cells.
Cutaneous involvement is uncommon in LPL, most often related to the IgM paraprotein and can range from bullous dermatoses to crystalstoring histiocytosis to cutaneous amyloidosis [2]. Dermal infiltration by lymphoma cells is extremely rare, and when this does occur, the neoplastic cells show varying growth patterns including interstitial, nodular, and diffuse dermal infiltrates. Over 90% of cases of LPL harbor the myeloid differentiation primary response 88 gene (MYD88) p.L265P mutation [1][2][3]. LPL is generally indolent with a median survival of 5-10 years; however, the uncommon transformation to diffuse large B-cell lymphoma (DLCBL) portends a poor prognosis with a median survival of 2 years [1,2,4]. Furthermore, infiltration of the skin by transformed LPL is more common than in nontransformed disease with a recent review finding cutaneous involvement in 12% of histologically transformed cases [5].
We present a 78-year-old male with a history of WM diagnosed in 2014 when a bone marrow biopsy showed LPL (Figure 2A The lesions remained flat for 7.5 months following therapy initiation ( Figure 1D). At most recent follow-up, the patient has sustained disease control at 18 months from initiation of ibrutinib therapy.
In nearly all LPL cases, the MYD88 p.L265P mutation is present.
Wildtype MYD88 is activated by toll-like receptors and interleukin-1 pathways and subsequently activates downstream NF-kB signaling [6,7]. The p.L265P mutation causes the mutant MYD88 to form a constitutively active complex with BTK, with subsequent downstream hyperactivation of the NF-kB pathway and lymphomagenesis [6,7].
In recent years, small-molecule inhibitors have become increasingly common in the treatment of hematopoietic neoplasms. Ibrutinib, a BTK inhibitor, is one such compound that has been approved for use in While ibrutinib is a common therapy for LPL and also shows some efficacy in certain subtypes of DLBCL, we know of only two papers addressing the use of ibrutinib in transformed LPL. The first is of a 63-year-old female originally presenting with LPL within the bone marrow who later developed CNS disease and a submandibular lymph node, the latter of which demonstrated DLBCL by histology [11]. Interestingly, molecular testing showed the presence of MYD88 p.L265P mutation in the original bone marrow specimen; however, it was lacking in the lymph node [11]. Clonality analysis testing revealed the bone marrow and the lymph node to be the same B-cell clone. The authors suggested there was loss of the mutation with high-grade transformation of the LPL [11]. Nonetheless, ibrutinib therapy was initiated.
Unfortunately, while the patient showed a promising initial response, she relapsed 5 months later and subsequently passed away [11]. Given the absence of the MYD88 mutation in the transformed sample, it is difficult to ascribe this initial response to effectiveness of that therapy in all stages of LPL as opposed to representing a case of the known phenomena of ibrutinib response in non-GC DLBCL and the possibility that the LPL and DLBCL in that sample arose from the same ancestral clone through activation of different pathways [11]. The second paper consists of a study assessing ibrutinib monotherapy in patients with relapsed or refractory DLBCL. Of the 20 patients included, two were originally diagnosed with LPL [12]. The overall response rate was 35% with an overall survival of 22.4 months. Interestingly, the response was not found to depend on the original lymphoma subtype [12]. However, one patient discontinued therapy early and one patient passed away while on therapy; the specific details on the two LPL patients including the presence or absence of the MYD88 L265P mutation were not given.
In conclusion, we report the first known case of a patient with molecularly confirmed high-grade transformation of a previously diagnosed lymphoplasmacytic lymphoma who showed marked rapid and sustained control of his disease with initiation of targeted therapy.
Historically, high-intensity chemotherapy has been the most common high-grade transformation who are not considered to be ideal candidates for more intensive therapy due to age, frailty, or the presence of significant comorbidities or who have failed standard approaches.