Molecular basis for therapeutic decisions in chronic myeloid leukemia patients after allogeneic bone marrow...

Recent progress in the development of diagnostic techniques has greatly facilitated the monitoring of minimal residual disease (MRD) in patients with chronic myeloid leukemia (CML) after allogeneic bone marrow transplantation (BMT), the only curative treatment for this disease. The presence of the P210(bcr-abl) rearrangement in CML cells has allowed highly sensitive detection of MRD by polymerase chain reaction (PCR). However, complete eradication of the leukemic clone may not be a necessary prerequisite for long-term remission or cure. This observation limits the value of qualitative PCR analysis for prediction of progressive disease and highlights the need to monitor the proliferative activity of the malignant clone in order to permit timely detection of impending relapse and, thus, early therapy. This article discusses the applicability of several molecular methods to the monitoring of treatment efficacy and early assessment of clonal expansion in patients with CML after BMT. It also presents guidelines for clinical use of PCR analyses and the most effective approaches to treat relapsed patients.

The authors have been working in this field, both experimentally and at a clinical level, contributing original papers to peer-reviewed journals. The material examined in this review includes articles published in journals covered by MedLine and reviews from journals with a high impact factor.

In view of the very limited value of qualitative PCR in detecting CML patients destined to relapse after BMT, several investigators have developed molecular assays that enable the kinetics of MRD to be monitored over time (e.g. quantitative PCR for P210(bcr-abl), PCR analysis of whole blood/lineage-specific chimerism and qualitative PCR for P190(bcr-abl)). These molecular strategies closely trace the kinetics of leukemic regrowth. Disease evolution in relapsed patients is consistently characterized by the sequential detection of increasing P210(bcr-abl) transcript levels, increasing myeloid mixed chimerism and finally, P190(bcr-abl) positivity preceding cytogenetic relapse. A 10-fold or greater increase in the expression of P210(bcr-abl) confirmed by a minimum of three independent quantitative PCR analyses and/or a progressive increase in the percentage of host myeloid cells in three consecutive chimerism analyses and/or P190(bcr-abl) mRNA detection must be regarded as an indication of incipient disease progression and should provide a rationale for initiation of treatment. There are various approaches to the management of the patient who relapses. The first step, if possible, is to reduce or terminate immune suppression. If the patient is not receiving this therapy, he or she can be treated with hydroxyurea or interferon or can be offered a second transplant. However, infusion to the patient of lymphoid cells (DLI) collected from the original donor has the capacity to restore complete remission in 70-80% of cases. Currently, several strategies are being used to minimize the severity of graft-versus-host disease after DLI (optimization of transfused lymphocyte doses, modification of the transfused lymphocyte subsets, administration of lymphocytes in escalating doses or lymphocyte transfection with a suicide gene), to reduce the incidence of marrow aplasia (stem cell support) and to increase the rate of complete responses (cytokines associated with DLI, leukemia-reactive cytotoxic lymphocytes, tyrosine kinase inhibitors or pre-emptive DLI).