Failure of Immunologic Purging in Mantle Cell Lymphoma Assessed by Polymerase Chain Reaction Detection of Minimal Residual Disease

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Abstract
To assess the clinical significance of minimal residual disease (MRD) detection by polymerase chain reaction (PCR) we analyzed samples from 26 patients with mantle cell lymphoma (MCL) who had undergone bone marrow transplantation (BMT) at the Dana-Farber Cancer Institute. The BCL-1/IgH translocation and clonally rearranged Ig heavy chain genes (IgH) provided molecular markers for detection and follow-up of MRD by polymerase chain reaction (PCR) amplification in 19 of the 26 (73%) MCL patients studied. IgH gene sequencing analysis showed somatic mutations in MCL that are characteristic of an antigen driven process suggesting that, in MCL, the final malignant transformation occurs in a mature B cell. Of the 19 patients with a PCR amplifiable marker, 17 underwent autologous, 1 an allogeneic, and 1 a syngeneic bone marrow transplantation (BMT). All patients had PCR-detectable MRD in the bone marrow (BM) at the time of BMT, irrespective of any history of histological BM involvement. In contrast to other B-cell malignancies, we found that immunological purging with complement-mediated lysis eradicated PCR-detectable MCL in only two patients. Moreover reinfusion of MRD was associated with a poor outcome. More than half of the patients undergoing autologous BMT had relapsed by the time of restaging at 2 years after autologous BMT. In four MCL patients in whom no residual lymphoma was reinfused, including the allogeneic and the syngeneic BMT, only one patient relapsed. Persistence of MRD detection after BMT was also associated with a high probability of relapse, although one patient did not have PCR-detectable MRD in peripheral blood or BM before relapse at nodal sites. We conclude that PCR amplification of disease-specific markers is a feasible and sensitive method to assess MRD and its clinical significance in patients with MCL. Moreover, PCR amplification provides a tool to evaluate modifications of purging and stem cell collection procedures that may be required for the management of this otherwise incurable disease.