Discussion
We described a case of an IgA lambda, MYD88L265 mutation+ lymphoplasmacytic lymphoma with lytic bone lesions that was successfully treated with rituximab, cyclophosphamide and dexamethasone resulting in a complete response. There is scarce literature on optimal treatment for patients with WM/LPL and lytic bone disease. A multitude of novel agents are approved for the treatment of WM/LPL such as BTK inhibitors, proteasome inhibitors and monoclonal antibodies and many more next-generation therapies in these drug classes are under development in addition to BCL2- inhibitors like venetoclax and phosphatidylinositol 3 kinase inhibitors such as idelalisib and umbralisib [22]. However, the efficacy of these agents in WM/LPL patients with lytic bone disease is unknown. The efficacy of agents such as proteasome inhibitors, immunomodulatory drugs, and alkylating agents on bone remodeling in MM is well established [23]. In lymphoid malignancies like chronic lymphocytic leukemia (CLL), only BTK inhibitors like ibrutinib have shown promising therapeutic response in patients with osteolytic lesions [24-26]. There is evidence that the BTK inhibitor ibrutinib can suppress bone resorption by inhibition of both osteoclast differentiation and function, predominantly by downregulation of expression of Nuclear Factor Of Activated T Cells 1 (NFATc1), the key transcription factor for osteoclastogenesis, and disruption of the formation of the actin ring in mature osteoclasts [27]. In one case of an elderly woman with relapsed CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma) with widespread lytic disease and pathological fractures, treatment with ibrutinib monotherapy (420 mg q.d.) with monthly denosumab (120 mg s.c.) for only 9 months resulted in remineralization of her skeletal lesions and partial disease response. The combination of a BTK Inhibitors with a bone-resorptive agent provided significant clinical benefit with remarkable improvement in patient mobilization after about 12 months of treatment with sclerosis of skeletal lesions as noted on serial CT and MRI scans [28].
The modulation of bone remodeling by anti-myeloma agents such as immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies provide insight into their potential efficacy and mechanism of action in patients with WM/LPL [29]. Via interactions with the bone marrow microenvironment, malignant plasma cells are able to orchestrate the production of osteoclast-activating factors (i.e. RANKL) and osteoblast-inhibitory factors which leads to asynchronous bone turnover, net bone loss and osteolytic lesions. Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib inhibit NF-κB (nuclear factor kappa-B) mediated osteoclast maturation and ultimately, bone resorption via the RANKL and OPG (osteoprotegerin) pathway [30]. Terpos et al demonstrated that bortezomib also increased bone formation markers like bone-specific alkaline phosphatase (ALP) and osteocalcin levels with only four cycles of treatment in 34 relapsed MM patients [21]. Furthermore, bortezomib has shown inhibition of osteoclastogenesis in combination with the immunomodulatory drug lenalidomide in vitro. [31]. Both of these agents have also shown the ability to reduce tumor burden in MM patients through their inhibitory effect on osteoclast-derived growth and survival factors and blocking of RANKL secretion from bone marrow stromal cells [31, 32]. Lenalidomide inhibits osteoclastogenesis as evidencde by decreased serum biochemical markers of bone turnover [32]. Pomalidomide, another immunomodulatory drug, has shown potent osteoclast inhibitory activity in vitro with its downregulating effect on transcription factor PU.1 and significant blunting of RANKL upregulation, thus normalizing the RANKL-OPG ratio [33]. Daratumumab, an anti-CD38 monoclonal antibody inhibits bone remodeling by blocking the interaction of CD38 expressing monocytes and osteoclast-progenitor cells thus inhibiting bone resorption activity in bone marrow cells of MM patients [34, 35]. In a study of 51 MM patients, high dose chemotherapy with melphalan followed by autologous stem cell transplant (ASCT) resulted in a significant reduction of sRANKL/OPG ratio, with a concomitant decrease in markers of bone resorption starting the second month post-ASCT[36]. Further investigation is needed on whether these active anti-MM agents have similar effects on bone turnover in patients with non-Hodgkin lymphomas such as WM/LPL with lytic bone lesions.
Although chemoimmunotherapy combinations are current standard treatment regimens and are highly active with high response rates, they can cause immunosuppression and cytopenias which may not be well tolerated by elderly, frail patients. With a median age of diagnosis of WM/LPL being 70 years, consideration must be given to patient frailty and ability to tolerate such a treatment. However, cyclophosphamide is well tolerated in elderly patients when used as a combination regimen with rituximab and dexamethasone (DRC). This was demonstrated in a study conducted by Dimopolous et al in a large multicenter trial of 72 patients with WM, whose median age was 69 years and among which 63% patients were older than 65 years old. Based on analysis of this study, therapy with DRC was well tolerated and only about 10% of patients experienced grade 3 or 4 neutropenia, and 10% of patients developed neutropenic fever requiring hospitalization and intravenous antibiotics. No patients developed grade 3 or 4 thrombocytopenia. Therefore, DRC is a safe and well-tolerated regimen, even in elderly frail patients [37]. The DRC regimen was also used successfully in a 64-year-old patient who was diagnosed with WM and had mixed lytic and sclerotic lesions on skeletal radiographs and CT scans. The patient tolerated 6 cycles of DRC treatment with no significant toxicity or signs of lymphoma progression after a follow up of 32 months. The majority of the patient’s bone lesions also disappeared with treatment except for one persistent bone lesion which was treated with 8Gy of radiation therapy [38]. Based on the available data, including our case report, DRC is an efficacious regimen for patients with WM and lytic bone lesions.
Interestingly, our patient was on denosumab every 6 months for osteoporosis, but there are no consensus guidelines on the use of antiresorptive agents for patients with WM/LPL and lytic bone lesions. Most of the literature and evidence comes from the treatment of MM as previously described [21]. The risk of high bone turnover and premature osteoporosis in lymphoma patients due to treatment with high dose corticosteroids can be counteracted by the prophylactic use of antiresorptive agents. In patients with lymphoma receiving chemotherapy, treatment with the second-generation bisphosphonate pamidronate every 3 months for 1 year reduced both bone loss and the risk of new vertebral fractures [39]. A prospective randomized phase III trial investigated the benefit of using zoledronic acid (ZA) in 74 newly diagnosed lymphoma patients undergoing chemotherapy and with a baseline bone mineral density (BMD) of ≥ −2.0. A dose of 4mg IV ZA was given at trial enrollment and at 6 months along with oral calcium (1200 mg) and vitamin D (400 or 800 IU). Fifty-three patients were evaluable for response: 24 received ZA and had stable BMD during the observation period, whereas 29 patients in the control group had decreased BMD (P<0.05 at lumbar spine and bilateral femoral neck) [40]. Further investigation into use of antiresorptive agents for patients with WM/LPL and lytic bone lesions is warranted.