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Monoclonal antibody-based therapies for Waldenstrom's macroglobulinemia

ABSTRACT: Highlights • anti-CD20 monoclonal antibodies have revolutionized treatment in WM.• Rituximab is the backbone of WM treatment in combination with chemotherapy and/or PIs.• Newer monoclonal antibodies, targeting CD20 or other surface antigens are emerging.• Small molecule based therapy, such as BTK or bcl-2 inhibitors are also gaining ground.• MoAbs-based combinations are an active, fixed duration, safe and cost effective option. Monoclonal antibodies have established an important role in the treatment armamentarium of hematological malignancies, including Waldenström's macroglobulinemia. Rituximab, an anti-CD20 monoclonal antibody, is established as standard therapy for this unique low grade lymphoma, due to its effectiveness and safety as monotherapy, in combination with chemotherapy or other targeted therapies in WM. Newer monoclonal antibodies, targeting CD20 or other surface antigens, have shown to be effective in patients with WM. In the current review we attempt to provide an overview of the mechanisms of action of monoclonal antibodies and discuss clinical evidence that support their use in WM and their therapeutic potential.

SUBMITTER: Fotiou D

PROVIDER: S-EPMC9098391 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Current and novel BTK inhibitors in Waldenstrom's macroglobulinemia.

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Waldenstrom's Macroglobulinemia patients: expression and aCGH data

Project description:Waldenström’s macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow and immunoglobulin M paraprotein production. Cytogenetic analysis is limited by the difficulty in obtaining tumor metaphases and the genetic basis of the disease remains poorly defined. We performed a comprehensive analysis in 42 WM patients by using high-resolution array-based comparative genomic hybridization with the Human Genome 244A microarray. Overall, 83% of samples have chromosomal abnormalities, with a median of three abnormalities per patient (range 0 to 27). The most common abnormality was 6q deletion (40%) and four non-overlapped minimal deleted regions (MDR) were identified. Gain of 6p was the second most common abnormality (17%) and its presence was always concomitant with 6q loss. An interstitial MDR was delineated at 13q14 including MIRN15A and MIRN16-1 in 10% of patients. Other recurrent deletions were 7q22, 8p, 11q22-q23, 11q23-q24 and 17p11-p13 (7% each). Copy gains were identified in chromosomes 18 (17%), 4 (12%), 3 (10%), 8q (10%) and Xq27.1-q28 (10%). To note, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3, two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the bone marrow microenvironment, highlight its biologic importance, and suggest a therapeutic role for inhibitors of NF-KB pathway activation in the treatment of Waldenström’s macroglobulinemia. Keywords: gene expression profiling; array comparative genomic hybridization

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Two-year outcomes of tirabrutinib monotherapy in Waldenstrom's macroglobulinemia.

Project description:The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment-naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO-4059-05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow-up of 24.8 months to update the efficacy and safety results and to report patient-reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease-related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health-related quality of life, assessed by cancer-specific questionnaires, was mostly maintained. Grade 3-4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment-related hypertriglyceridemia was also recognized. Nine patients experienced grade 1-2 bleeding events (33%), one patient experienced grade 2 treatment-related atrial fibrillation, and one patient experienced grade 1 treatment-related hypertension. Treatment-related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment-naïve and refractory/relapsed Waldenström's macroglobulinemia.

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