Antigen receptor rearrangements in the lymphoid malignancies

Provan, Drew (1996) Antigen receptor rearrangements in the lymphoid malignancies. University of Southampton, Doctoral Thesis.

Abstract

Various methods for detection of minimal residual disease (MRD) were evaluated in acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and multiple myeloma.

Southern blotting was found to be labour intensive, slow, added little additional information to that provided by PCR amplification, and should be replaced in MRD studies by a PCR-based approach. PCR allowed rapid determination of residual disease in all neoplasms studied and, combined with sequencing of amplified PCR products and constructing patient specific oligonucleotides for probing post-treatment samples, was reliable and specific.

From the evaluation of patients with ALL, patients up to two years from diagnosis were found to harbour residual tumour in the absence of florid clinical or morphological relapse. In CLL, patients undergoing autologous and allogeneic bone marrow transplantation were assessed using amplification of IgH. After PCR amplification, patient specific probes were constructed using junctional region nucleotides. All patients with CLL undergoing autologous BMT had PCR detectable disease before immunological marrow purging. After purging, disease was detectable in half and autologous marrows. Although PCR detectable disease was present early after transplant in most patients receiving a PCR positive marrow, only those patients in whom persistent or re-emerging PCR positivity was detected demonstrated over clinical relapse. Similar findings were obtained for the allogeneic BMT group; only patients who were found to be persistently positive following transplant had other evidence of disease relapse.

Within the myeloma group studied, IgH PCR amplification demonstrated the presence of residual myeloma cells in purged autologous marrow despite the apparent absence of contaminating cells using immunophenotypic analysis.

This study confirms the finding of other groups that persistence of disease in ALL may be seen for up to two years following diagnosis. The project also clearly shows that high dose therapy with bone marrow transplantation may be curative in low grade lymphoid malignancies such as CLL.

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