In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. ...Toxic effects of grade 2 or higher included neutropenia in 22% of the patients.
Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion.
1
Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed.
Whole-genome sequencing has revealed a single activating somatic mutation in
MYD88
(resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of
CXCR4
in patients with Waldenström’s macroglobulinemia.
2
,
3
In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .
A dose-intense infusional chemotherapy program plus rituximab had a high degree of efficacy in patients with primary mediastinal B-cell lymphoma, which is genetically related to Hodgkin's lymphoma ...and predominantly affects young women.
Primary mediastinal B-cell lymphoma is a distinct pathogenetic subtype of diffuse large-B-cell lymphoma that arises in the thymus.
1
,
2
Although it comprises only 10% of cases of diffuse large-B-cell lymphoma, primary mediastinal B-cell lymphoma, which predominantly affects young women,
3
is aggressive and typically is manifested by a localized, bulky mediastinal mass, often with pleural and pericardial effusions. Less commonly, the disease involves extranodal sites, including the lung, kidneys, gastrointestinal organs, or brain.
4
,
5
This disease is clinically and biologically related to nodular sclerosing Hodgkin's lymphoma; the putative cell of origin for both conditions is a thymic B cell.
1
,
2
The . . .
Novel Approaches in Waldenström Macroglobulinemia Spinner, Michael A; Varma, Gaurav; Advani, Ranjana H
Hematology/oncology clinics of North America,
10/2018, Letnik:
32, Številka:
5
Journal Article
Recenzirano
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have paved the way for development of a plethora of novel therapeutic strategies. The success of ibrutinib in WM has ...shifted treatment paradigms away from conventional chemoimmunotherapy approaches. Recognition of high-risk genomic subgroups as well as mechanisms of acquired resistance to ibrutinib have led to targeting of additional pathways. In this article, the authors review ongoing and emerging trials of novel therapies in WM that target the B-cell receptor pathway beyond ibrutinib, toll-like receptor pathway, chemokine signaling, apoptotic pathway, chromatin remodeling, protein transport, the immune microenvironment, and CD19-directed immunotherapy.
Outcomes in mature T-cell lymphomas remain poor, with previous attempts at developing mAbs compromised by limited efficacy and significant immunocompromise. Anti-killer cell lectin-like receptor G1 ...mAbs may have greater selectivity and specificity for malignant T cells and avoid the toxicity concerns with previous agents. See related article by Assatova et al., p. 2514.
To date monoclonal antibodies have had limited success in improving outcomes for patients with T-cell lymphomas. Preclinical data suggests that anti-T-cell Receptor Vβ-segment monoclonal antibodies ...are a novel therapeutic strategy for patients with T-cell lymphomas that avoid several limitations of current therapies.
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma histology. Outcomes for patients with relapsed or refractory (R/R) disease remain suboptimal. Polatuzumab vedotin ...(polatuzumab) is a recently approved antibody drug conjugate that targets CD79b, with a tubulin toxin payload, that has demonstrated significant clinical activity and an acceptable toxicity profile when administered with both anti-CD20 monoclonal antibodies and chemotherapy in clinical trials.
In this article, we discuss the early-phase trials supporting the accelerated FDA approval of polatuzumab for patients with R/R DLBCL and review the status of and data from ongoing trials combining polatuzumab with other agents.
Polatuzumab is an important new tool for the management of patients with R/R DLBCL who are ineligible for or who relapse following standard second-line therapies. Combinations of polatuzumab with other agents may represent an opportunity to improve outcomes for this difficult to treat population. The recent publication of the POLARIX trial (NCT03274492) incorporating polatuzumab in the frontline treatment of DLBCL may impact the future role of this agent in the R/R setting.
Approach to High-Risk Multiple Myeloma Chen, Xiaoyi; Varma, Gaurav; Davies, Faith ...
Hematology/oncology clinics of North America,
04/2024, Letnik:
38, Številka:
2
Journal Article
Recenzirano
Improving the outcome of high-risk myeloma (HRMM) is a key therapeutic aim for the next decade. To achieve this aim, it is necessary to understand in detail the genetic drivers underlying this ...clinical behavior and to target its biology therapeutically. Advances have already been made, with a focus on consensus guidance and the application of novel immunotherapeutic approaches. Cases of HRMM are likely to have impaired prognosis even with novel strategies. However, if disease eradication and minimal disease states are achieved, then cure may be possible.
Patients with relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), ineligible for or relapsing after autologous stem‐cell transplant or chimeric antigen‐receptor T‐cell therapies have ...poor outcomes. Several novel agents, polatuzumab vedotin, tafasitamab, loncastuximab tesirine, and selinexor, have been approved and offer new opportunities for this difficult to treat population. Studies are evaluating combination of these agents with chemotherapy and other emerging therapies. Additionally, advances in our understanding of DLBCL biology, genetics, and immune microenvironment have allowed for the identification of new therapeutic targets like Ikaros and Aiolos, IRAK4, MALT1, and CD47 with several agents in ongoing clinical trials. In this chapter we review updated data supporting the use of the approved agents and discuss other emerging novel therapies for patients with R/R DLBCL.
Summary
Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a unique rare subtype of Hodgkin lymphoma (HL) which differs clinically, pathologically and biologically from classic HL, warranting ...a nuanced approach to treatment. CD20 expression by malignant lymphocyte‐predominant cells, a tendency for late relapses, and the risk of transformation to aggressive large B‐cell lymphoma are characteristic features with important implications for treatment and follow‐up. Recognition of histopathological variant patterns is also critical, with important implications for prognosis and treatment. The optimal management for NLPHL is unclear and opinions differ as to whether treatment paradigms should be similar to, or differ from, those for classic HL. Therapy differs for early versus advanced stage disease and for frontline versus relapsed or refractory disease. Potential treatment strategies include radiotherapy, combined modality therapy, chemotherapy, rituximab and watchful waiting. Given the excellent overall survival of NLPHL, treatment choices should be geared towards reducing long‐term toxicity and optimizing survivorship. In this review, we provide an overview of the current literature and discuss modern principles in the management of NLPHL.
Introduction Treatment options for relapsed/refractory multiple myeloma (RRMM) are limited and associated with a poor median overall survival (OS) of 12.4 months (m) (Mateos et al. Leukemia 2022). ...The MajesTEC-1 trial demonstrated promising clinical activity of teclistamab (Tec), a BCMAxCD3 bispecific antibody, with an overall response rate (ORR) of 63%, complete response rate (CR) of 39.4%, median progression-free survival (PFS) of 11.3 m, and OS of 18.3 m. Here we present the results of a multicenter, retrospective study examining real-world patient characteristics and outcomes in patients with RRMM receiving Tec outside of a clinical trial, including those who would have been ineligible for the registrational study. Methods An IRB-approved retrospective study of patients with RRMM treated with Tec at 4 academic centers was performed. Patient demographics, prior treatments, clinical outcomes and toxicities with special attention to cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infection were extracted from the electronic patient record. Response rate was compared using Fisher's exact test. Median PFS and OS were estimated by Kaplan-Meier and compared using the log-rank test. Trial eligibility was evaluated using the MajesTEC-1 eligibility criteria. Results A total of 45 patients, who received at least 1 dose of Tec, were evaluated. Of these 39% were derived from under-represented minorities (25% Black, 14% Hispanic). Patient characteristics and comparison to the MajesTEC-1 population are summarized, Table 1. High-risk cytogenetic features were present in 42.2% of patients, and 46.7% had extra-medullary disease (EMD). All patients were triple class exposed and 80% were penta-class exposed. Most patients (84.4%) would have been ineligible for MajesTEC-1 due to cytopenias (44.4%), prior BCMA-directed therapy (42.2%), inadequate washout (42.2%), and poor performance status (PS) (26.7%). Therapy was delivered according to protocol with no increased rate of infections or bleeding, even in the group of patients with low blood counts and poor PS. CRS/ICANS events of any grade were observed in 55% and 13% of patients, respectively, during step-up dosing. Most CRS/ICANS events were mild-moderate in severity (CRS 42.2% grade 1, 11.1% grade 2; ICANS 4.4% grade 1, 0% grade 2) and were managed conservatively with antipyretics, tocilizumab (37.8%), and steroids (13.3%). Grade 4 CRS and ICANS were only seen in 1 patient; a separate individual experienced grade 5 ICANS after the third step up dose. The overall response rate (ORR) was 48.9% (95% CI 33.7-64.2) with 22.2% (95% CI 11.2-37.1) achieving at least a very-good partial response (VGPR). On univariate analysis prior anti-BCMA exposure was associated with an adverse ORR (23% vs 61%; p=0.02). Ineligibility for enrollment in MajesTEC-1, the presence of high-risk cytogenetics or EMD were not associated with ORR or depth of response. Updated follow up time, median PFS and OS will be presented at the meeting to allow time for data to mature. The presence of high-risk cytogenetics was associated with worse PFS (median NR vs 2.1 m, HR 2.32; p=0.041). Receipt of prior BCMA therapy and MajesTEC-1 ineligibility were not associated with PFS or OS. At the time of data cut-off, 19 (42.2%) patients remained on Tec; reasons for discontinuation included disease progression, infections, and CRS/ICANS in 19 (42.2%), 4 (8.8%), and 3 (6.7%) patients, respectively. Conclusion Overall, Tec demonstrated significant clinical activity even in a group of heavily pre-treated real-world patients comprising high-risk and extramedullary disease populations. The overall toxicity profile was similar to prior reports demonstrating that side effects can be readily managed using simple approaches with only limited patients needing more intensive interventions. These results also suggest Tec may be used in patients previously excluded from clinical trials because of adverse clinical characteristics with high ORR being seen and an absence of increased toxicity. In the BCMA-naive population ORR were similar to MajesTEC-1, but were lower in the previously BCMA-exposed population. High-risk cytogenetics and EMD remain adverse prognostic features with Tec despite similar ORR.
PDF
