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Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia.

ABSTRACT: Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells. This tumor almost always displays the capability of secreting large amounts of monoclonal immunoglobulins (Ig) of the M class (Waldenström Macroglobulinemia, WM). The clinical manifestations of WM/LPL may range from an asymptomatic condition to a lymphoma-type disease or may be dominated by IgM paraprotein-related symptoms. Despite the substantial progresses achieved over the last years in the therapy of LPL/WM, this lymphoma is still almost invariably incurable and exhibits a propensity towards development of refractoriness to therapy. Patients who have progressive disease are often of difficult clinical management and novel effective treatments are eagerly awaited. In this review, we will describe the essential clinical and pathobiological features of LPL/WM. We will also analyze some key aspects about the current knowledge on the mechanisms of drug resistance in this disease, by concisely focusing on conventional drugs, monoclonal antibodies and novel agents, chiefly Bruton's Tyrosine Kinase (BTK) inhibitors. The implications of molecular lesions as predictors of response or as a warning for the development of therapy resistance will be highlighted.

SUBMITTER: Piazza F

PROVIDER: S-EPMC8787211 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab.

Project description:CD52 is expressed on malignant cells in lymphoplasmacytic lymphoma (LPL), including IgM-secreting Waldenström macroglobulinemia (WM). We examined the activity of alemtuzumab in 28 symptomatic LPL (27 IgM and 1 IgA) patients. The median prior number of therapies for these patients was 2 (range, 0-5) and 43% had refractory disease. Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing, and also received hydrocortisone, acyclovir, and Bactrim or equivalent prophylaxis. Patients had a complete response (n = 1), a partial response (n = 9), or a MR (n = 11) for an overall and major response rate of 75% and 36%, respectively. Median serum Ig decreased from 3510 to 1460 mg/dL (P < .001 at best response). With a median follow-up of 64 months, the median time to progression was 14.5 months. Hematologic and infectious complications, including CMV reactivation, were more common in previously treated patients and were indirectly associated with 3 deaths. Long-term follow-up revealed late-onset autoimmune thrombocytopenia (AITP) in 4 patients at a median of 13.6 months after therapy, which contributed to 1 death. Alemtuzumab is an active therapy in patients with LPL, but short- and long-term toxicities need to be carefully weighed against other available treatment options. Late AITP is a newly recognized complication of alemtuzumab in this patient population. This study is registered at www.clinicaltrials.gov as NCT00142181.

| S-EPMC3138682 | biostudies-literature

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| S-EPMC7139754 | biostudies-literature

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| S-EPMC8556471 | biostudies-literature

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| S-EPMC7299735 | biostudies-literature

Lymphoplasmacytic lymphoma infiltrating both lacrimal glands in a patient with Waldenstrom's macroglobulinemia.

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| S-EPMC6992929 | biostudies-literature

Acquired mutations associated with ibrutinib resistance in Waldenstrom macroglobulinemia.

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| S-EPMC7484977 | biostudies-literature

68Ga-Pentixafor PET/CT for Imaging of Chemokine Receptor 4 Expression in Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma: Comparison to 18F-FDG PET/CT.

Project description:18F-FDG PET/CT has some limitations in the evaluation of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL), an indolent B-cell lymphoma that primarily involves the bone marrow. Because there is a high level of chemokine receptor 4 expression in the B cells of WM/LPL patients, we performed a prospective cohort study to evaluate the performance of 68Ga-pentixafor, which targets chemokine receptor 4 in WM/LPL, and to compare it with the performance of 18F-FDG. Methods: Seventeen patients with WM/LPL were recruited. All patients underwent both 68Ga-pentixafor PET/CT and 18F-FDG PET/CT. A positive PET/CT result was defined as the presence of focal lesions with positive PET results or diffuse bone marrow patterns (uptake > liver). The rates of positive results for PET/CT scans of bone marrow, lymph nodes, and other extramedullary involvement were statistically compared. Results: 68Ga-pentixafor PET/CT had a higher rate of positive results than 18F-FDG PET/CT (100% vs. 58.8%; P = 0.023) in the recruited WM/LPL patients. The sensitivities of 68Ga-pentixafor PET/CT and 18F-FDG PET/CT for detecting bone marrow involvement were 94.1% and 58.8%, respectively (P = 0.077). In terms of detecting lymph node involvement, 68Ga-pentixafor PET/CT had a significantly higher rate of positive results than 18F-FDG PET/CT (76.5% vs. 11.8%; P = 0.003). In addition, 68Ga-pentixafor detected more paramedullary and central nervous system involvement than 18F-FDG. Conclusion: 68Ga-pentixafor might be a promising imaging agent for the assessment of WM/LPL.

| S-EPMC6894383 | biostudies-literature

Waldenstrom macroglobulinemia treatment algorithm 2018.

Project description:Waldenström macroglobulinemia is often an indolent disorder, and many patients are candidates for observation with careful monitoring. For symptomatic patients, one must distinguish between those patients whose symptoms are related to immunologic manifestations associated with the IgM monoclonal protein and those that have symptoms related to progressive marrow and nodal infiltration with lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, the driver for therapy in the majority of patients is progressive anemia, secondary to bone marrow replacement by lymphoplasmacytic lymphoma. Recent introduction of MYD88 mutational analysis has been very useful for diagnostic purposes but is unclear what effect it might have on the prognosis or response rate to therapy. An algorithm is provided on the management of asymptomatic individuals and the sequence used for chemotherapeutic intervention of symptomatic patients.

| S-EPMC5928091 | biostudies-literature

Thalidomide and rituximab in Waldenstrom macroglobulinemia.

Project description:Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, <or= 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www.clinicaltrials.gov as #NCT00142116.

| S-EPMC2597120 | biostudies-literature

Management of Waldenstrom macroglobulinemia in 2020.

Project description:The management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient's symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and ?2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient's clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.

| S-EPMC7727571 | biostudies-literature

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