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.