Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse

We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipul ated (n = 44) or partially T-cell-depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML), Chimerism was ass essed by polymerase chain reaction (VNTR [variable number of tandem repeats ]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fract ions, whereas MRD was investigated in whole blood by reverse transcriptase- PCR (RT-PCR) of both p210(BCR-ABL) and p190(BCR-ABL) hybrid transcripts. Of 55 patients, 14 (including 6 T-cell-depleted patients) had cytogenetic rel apse at 5-80 months and progressed to hematologic relapse, while 41 patient s remained in prolonged cytogenetic remission 12-107 months post-BMT. Befor e leukemia recurrence, patients in the relapse group showed a consistent ev olution pattern sequentially featured by persistent p210(BCR-ABL) positivit y increasing mixed chimerism (NIC) in myeloid cells, p190(BCR-ABL) positivi ty and, finally, cytogenetic relapse, Myeloid MC preceded cytogenetic relap se by 2-12 months, whereas p190(BCR/ABL) was detected 1-6 months prior to c ytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negat ive for p190(BCR-ABL); 10 patients tested positive for p210(BCR-ABL) at var iable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210(BCR-ABL) negative and dis-played full DC or transie nt MC due to the persistence of recipient T cells. Two patients in the rela pse group were successfully reinduced into molecular remission with donor l ymphocyte infusion. Sequential molecular analysis after such treatment show ed the inverse pattern to that observed prior to relapse, ie, progressive d isappearance of p190(BCR-ABL) transcripts, conversion of myeloid chimerism to donor type, and, finally, p210(BCR-ABL) negativity. We conclude that lin eage-specific chimerism and p190(BCR-ABL) messenger RNA (mRNA) analyses con tribute a better characterization of CML evolution after BMT and enable ear ly identification of patients at the highest risk of relapse. (Blood. 2000; 95:2659-2665) (C) 2000 by The American Society of Hematology.