): Many cancer patients in clinical complete remission (CR) harbor occult malignancy in the form of minimal residual disease (MRD). The regrowth of this malignant population can result in clinical relapse. Detecting MRD affords an opportunity to identify patients at risk for relapse. Potentially curative, but toxic and costly therapy can then be directed towards these patients at a time when their disease may be most amenable to further treatment, while sparing those who are truly cured from unnecessary therapy. Virtually all lymphomas are characterized by an immunoglobulin or T cell receptor rearrangement unique to an individual's tumor. The sequences of greatest diversity comprising complementarity region-III (CDR-III) or the V-beta counterpart provide excellent targets for clone specific MRD probes. This sequence can be exploited to detect MRD in a highly specific and sensitive method termed clonotypic polymerase chain reaction (PCR.) This proposal aims to investigate the utility of clonotypic PCR in predicting clinical outcome. The applicants have developed a novel competitive PCR assay based on the hypothesis that a threshold effect exists below which residual disease may be controlled and remain clinically dormant. This hypothesis predicts that a quantitative assessment of MRD is more prognostic than a qualitative one. This competitive clonotypic assay will be tested in the setting of a non-transplant chemotherapy intense protocol with curative intent for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. It will also be used to investigate the incidence and significance of tumor contamination in the leukapheresis products collected for peripheral blood stem cell transplantation (PBSCT) in the setting of relapsed and refractory low and intermediate grade lymphoma. Finally, quantitative clonotypic PCR will be used to determine if a reservoir of clinically occult disease exists in the peripheral blood or bone marrow of patients with limited stage intermediate grade lymphoma. The translational nature of this project reflects the candidate's long term goal of interfacing between the laboratory and the clinic. The institutional environment is uniquely suited because of its research facilities, seminars and widely renowned experts. In addition, the extensive patient population facilitates the execution of a large number of clinical protocols in a timely manner.
| Noy, A; Verma, R; Glenn, M et al. (2001) Clonotypic polymerase chain reaction confirms minimal residual disease in CLL nodular PR: results from a sequential treatment CLL protocol. Blood 97:1929-36 |
