Semiquantitative analysis of residual disease in patients treated for adult T‐cell leukaemia/lymphoma (ATLL)

Abstract

Summary. Many adult T-cell leukaemia/lymphoma (ATLL)patients who respond to induction treatment, then relapse. Knowing the clonality pattern of residual tumourous clones during treatment could help understand disease evolution and aid therapeutic decisions. We developed a sensitive and semi-quantitative molecular analysis of these clones in ATLL patients. DNA samples from PBMCs derived from eight ATLL patients were studied over time by quadruplicate linker mediated PCR (LMPCR) amplification of HTLV-1 integration sites. Patients were treated with combination chemotherapy, zidovudine-interferon-alpha and/or by peripheral stem cell transplantation or allogeneic bone marrow transplantation. Persistence of tumourous clones at a high frequency (>1/ 300 PBMCs) was frequently observed, even in complete responders, and was invariably correlated with relapse and/ or poor outcome. Fluctuation in the frequency of some tumourous clones was observed with evidence for clonal change under treatment in one patient, indicating that treatment of ATLL can result in the selection of resistant clones. Finally, allogeneic bone marrow transplantation (BMT) using an HTLV-1 infected sibling as donor was found to be associated with long-lasting disappearance of tumourous clones and a possible cure of the disease. Longterm persistent clonal expansion of circulating HTLV-1 bearing T cells which derived from the donor bone marrow was evidenced in this patient. In conclusion, variable success in treatment of ATLL is probably due to the clonal heterogeneity which results in the selection of resistant clones. Semi-quantitative assessment of residual disease (RD) through LMPCR may predict treatment failure. Accordingly, additional therapy may be tailored to the clonality pattern observed after first-line therapy.

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

“…Other investigators have demonstrated that persistence of tumor clones in ATLL patients invariably correlated with disease relapse. 73 These data indicate that AZT and IFN-␣ is a suppressive rather than a curative regimen; patients in clinical remission should remain on this therapy long term. Recently, a number of ATLL patients have been reported to be in continuous remission after allogeneic stem cell transplantation.…”

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo

“…As detailed above, suppressing the anti-HTLV-1 cellular immune response contributes to the development of ATLL, whereas restoring it might have a curative effect in animal models, 98 as in humans. 56 How could somatic mutations help an infected cell escape CTL response? The generation of Tax escape mutants is the first explanation that comes to mind.…”

“…This persistence was invariably correlated with relapse and/or poor outcome. 56 A fluctuating frequency of some tumor clones was observed, with evidence for clonal change under treatment in one patient, indicating that treatment of ATLL can result in the selection of resistant clones. Finally, allogeneic bone marrow transplantation (BMT) using an HTLV-1-infected sibling as donor was found to be associated with the long-lasting disappearance of tumor clones and a possible cure of the disease.…”

High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis

“…LMPCR and run-o were performed as already described (Cavrois et al, 1995;1996a,b, 1998Leclercq et al, 1998Leclercq et al, , 1999. Brie¯y, DNA was digested with NlaIII in 16NlaIII bu er for 3 h at 378C.…”