Abstract
"Double-hit" and "double-expressor" lymphomas represent distinct but overlapping subsets of aggressive B-cell non-Hodgkin lymphoma. The high rates of bone marrow involvement by these lymphomas pose a major therapeutic challenge due to the chemotherapy-resistant nature of the bone marrow microenvironment and the limited utility of rituximab-based salvage regimens in patients with relapsed/refractory disease. Preclinical studies utilizing high-dose cyclophosphamide in combination with the anti-CD52 monoclonal antibody alemtuzumab have recently shown promise in the treatment of intramedullary disease, and a Phase I human trial is now underway. In support of such efforts, here we perform CD52 target validation on a series of double-hit (n = 40) and double-expressor (n = 58) lymphomas using immunohistochemistry. CD52 expression levels varied considerably across samples, however positive staining was observed in 75% of both double-hit and double-expressor lymphomas. Similarly, high levels of CD52 expression were seen in patients whose disease was associated with high-risk clinical features, including primary refractory status (73%), higher IPI score (76%), and bone marrow involvement (74%). CD52 expression was not significantly correlated with diagnostically relevant pathologic features such as morphology, cytogenetic findings or other immunophenotypic features, but was notably present in all cases lacking CD20 expression (n = 6). We propose that CD52 expression status be evaluated on a case-by-case basis to guide eligibility for clinical trial enrollment.
Highlights
Treatment regimens incorporating the anti-CD20 monoclonal antibody rituximab have been the cornerstone of therapy for aggressive B-cell lymphomas for nearly two decades [17]
Despite the improvement in survival compared with chemotherapy alone, one third of patients with aggressive B-cell lymphomas are not cured by standard rituximab-based therapies [18]
The high frequency of primary refractory disease in patients with DHL is further complicated by the disappointing results of rituximab-based salvage strategies [5, 22]
Summary
While the prognosis of DHL is worse than that of DEL, both show inferior overall and progression-free survival compared to non-double-expressor DLBCL, even after accounting for the presence of other high-risk features [3, 4] These recently defined lymphoma categories represent major therapeutic challenges, in large part due to the high failure rates of initial and traditional salvage chemotherapy regimens in patients with relapsed/refractory disease. Given the primary role of macrophages in antibody-mediated antitumor activity in this context, novel treatment approaches that improve the efficacy of therapeutic antibodies through enhanced effector cell responses are considered highly desirable To this end, work by Pallasch et al has shown that the therapeutic antibody-refractory nature of the BM microenvironment can be temporarily abrogated through the synergistic effects of high-dose cyclophosphamide (CTX), which induces the release of stress-associated cytokines by leukemic cells, leading to macrophage recruitment and phagocytosis [7]. CD52 expression status was not correlated with diagnostically relevant pathologic features, necessitating its evaluation on a case-by-case basis for all patients being considered for clinical trial enrollment
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