Indolent Mantle Cell Lymphoma: A Distinct Subgroup Characterized by Leukemic Phase Disease without Lymphadenopathy.

Mantle cell lymphoma (MCL), defined by the pathognomic CCND1/IGH translocation, commonly presents with lymphadenopathy and has an aggressive clinical course with poor survival. However, a minority of patients with MCL present with lymphocytosis without substantial adenopathy. The clinical and pathologic features of this group of patients are not currently well understood.

Patients with monoclonal B-cell lymphocytosis, positive CCND1/IGH translocation status by FISH analysis and absence of lymphadenopathy were identified in our institutional B-cell lymphoproliferative disorder database. A comprehensive review of clinical, laboratory, and histopathologic features was conducted. Results of ancillary immunophenotypic, molecular genetic, and cytogenetic studies were reviewed. Univariate survival analysis was performed using the method of Kaplan and Meier.

We identified a total of 35 patients meeting the selection criteria (10 female and 25 male; median age 66 yrs, range 41-86). The median absolute lymphocyte count at presentation was 8.7 × 10⁹/L (range 2.7-180). Eleven patients subsequently developed adenopathy (MCL-LN) while 24 patients had persistent lymphocytosis without adenopathy (MCL-PB). There were no significant differences in age, gender, absolute leukocyte count, percent bone marrow involvement by lymphoma, or immunophenotypic features of the neoplastic B-cells between these 2 subgroups at initial evaluation. All 11 MCL-LN (100%) and 14 of the 24 MCL-PB patients (58%) had splenomegaly at presentation. Morphologic and immunophenotypic features in peripheral blood (n=35), bone marrow (n=34), lymph node (n=7), spleen (n=7) and other involved tissues (n=4) were typical of MCL in 34 patients. One patient had an unusual disease recurrence resembling hairy cell leukemia, but was retained in the analysis given the persistence of the CCND1/IGH abnormality and molecular evidence of clonal identity with previous specimens. All patients with MCL-LN and 12/24 (50%) of patients with MCL-PB received therapy including R-CHOP, cladribine, or rituximab. The remaining 12 MCL-PB patients (50%) were managed expectantly. Patients with MCL-PB (median survival of 156 months from diagnosis) had a significantly better survival than patients with MCL-LN (13 months) regardless of splenic involvement (P=0.0002) (Figure 1).

Among patients with MCL presenting in leukemic phase without adenopathy, we have identified 2 subgroups with distinct clinical outcomes. Patients who do not develop subsequent lymph node involvement (MCL-PB) have a generally more favorable clinical outcome. These findings imply fundamental differences in the pathobiology and molecular oncogenesis between these subgroups, suggesting the presence of distinct MCL entities.

Figure 1

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Survival from Diagnosis

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Survival from Diagnosis

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Zent:Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Genentech: Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphenon E International: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Gnentch: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospire: Research Funding; Polyphenon Pharma: Research Funding; Sanofi-Aventis: Research Funding; Biogenc-Ides: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding.