Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantation for B-cell lymphoma

Abstract

Although molecular biologic techniques can now detect minimal numbers of residual cancer cells in patients in complete clinical remission, the clinical significance of minimal residual disease has never been conclusively established. If the detection of minimal residual disease predicts which patients will relapse, then therapy could be altered based upon the detection of these cells. The t(14;18) can be detected by polymerase chain reaction (PCR) amplification in 50% of patients with B-cell non-Hodgkin's lymphoma and allows detection of one lymphoma cell in up to 1 million normal cells. To determine the clinical significance of the detection of minimal residual lymphoma cells in the bone marrow (BM) PCR amplification was used to detect the presence of residual lymphoma cells after autologous BM transplantation (ABMT) in serial BM samples from 134 patients with B-cell lymphoma in whom a bcl- 2 translocation could be detected. PCR analysis was performed on a total of 542 BM samples obtained while these patients were in complete remission. Disease-free survival was markedly increased in patients with no PCR-detectable lymphoma cells in the marrow compared with those in whom residual lymphoma cells were detected (P < .00001), and the presence of detectable lymphoma cells was associated with a 48-fold increase in the risk of relapse. Of the 77 patients (57%) with no PCR- detectable lymphoma cells in their most recent BM sample, none have relapsed. In contrast, all 33 patients (25%) who have relapsed had PCR- detectable lymphoma cells detected in their BM before clinical relapse occurred. In 19 patients (14%), residual lymphoma cells in the BM were detected early following transplantation and subsequently were no longer detectable, although these patients received no further therapy. In these patients, residual lymphoma cells may already have been irreversibly damaged by the high-dose therapy or an endogenous immune mechanism may be capable of eliminating residual lymphoma cells in some patients. Therefore, although the detection of minimal residual disease by PCR following ABMT in patients with lymphoma identifies those patients at high risk of relapse, the presence of residual minimal disease early after transplantation may not be associated with poor prognosis in a small subset of patients. Confirmatory studies will be required to determine more definitively the role of minimal disease detection to identify which patients require additional therapy.

The relative role of peripheral blood and bone marrow for monitoring molecular evidence of disease in follicular lymphoma by quantitative real‐time polymerase chain reaction

“…In the majority of follicular lymphoma (FL) cases, the detection of t(14;18) by polymerase chain reaction (PCR) is a characteristic marker that presents a suitable target for molecular monitoring (Gribben et al, 1993;Apostolidis et al, 2000). A significant factor in effective molecular monitoring, may be the choice of the most appropriate tissue.…”

Clinical and molecular remission after allogeneic blood cell transplantation in a patient with mantle‐cell lymphoma

“…In our experience, HDS chemotherapy with PBPC support induced a molecular remission in only one of eight MCL patients (Corradini et al, 1995a). Even though the relationship between PCR-negativity and cure is still under investigation, some data from leukaemia and follicular lymphoma studies suggest that PCR-negativity is correlated with a longer disease-free survival (Gribben et al, 1993;Lo Coco et al, 1992), and may therefore be considered an aim for high-dose chemotherapy.…”

Oligonucleotide clonospecific probes directed against the junctional sequence of t(14;18): a new tool for the assessment of minimal residual disease in follicular lymphomas

“…If, as stated by Gribben et al (1993Gribben et al ( , 1994, the absence of residual lymphoma cells in either bone marrow (BM) or peripheral blood (PB) is associated with increased disease-free survival, and if the detection of minimal residual disease is associated with an increase in the risk of relapse, then the detection of these residual cells should change the clinical management of these patients. A prospective study, however, is required to determine the value of eliminating minimal residual disease.…”

“…Several studies have demonstrated that PCR is a sensitive method for detecting residual lymphoma cells in peripheral blood (PB) or bone marrow (BM), but the clinical significance of detection of these cells has not been conclusively established (Stelter-Stevenson et al, 1988;Price et al, 1991a;Gribben et al, 1991b;Lambrechts et al, 1992). However, in one study reported by Gribben et al (1993Gribben et al ( , 1994 it was clearly demonstrated that, after high-dose myeloablative therapy and autologous BM transplantation (ABMT), the absence of amplifiable sequences in the purged bone marrow, as well as in BM and blood samples obtained after transplantation, correlated with a markedly increased disease-free survival. # 1996 Blackwell Science Ltd, British Journal of Haematology 94: [676][677][678][679][680][681][682][683][684] The presence of the t(14;18)(q32;q21) translocation in the majority of cases of follicular lymphoma (Yunis et al, 1982;Weiss et al, 1987;Lee et al, 1987) offers an opportunity for molecular monitoring of subclinical disease.…”