Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy

Abstract

We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further.

Figure 1.

Representative patterns of BCR-ABL/ABL transcript values from individual patients from the 3 patient groups who did not satisfy criteria for MR. (A) Persistently negative; (B) fluctuating positive, low level; and (C) persistently positive, low level (but not satisfying criteria for molecular relapse). The upper broken horizontal line shows the 2.0% level (corresponding to cytogenetic relapse). The lower 2 broken horizontal lines show the 0.02% and 0.05% levels, respectively. UPN indicates unique patient number.

Figure 2.

Probability of relapse according to Q-PCR category. Patients in this study who met criteria for MR whose prior pattern of molecular monitoring could be assessed were considered in conjunction with patients in the same molecular remission category who did not relapse. It was possible thereby to derive projected risks of relapse for patients in each category. The respective risks in the 3 categories were significantly different (P = .009).

Figure 3.

Probability of disease progression after diagnosis of molecular relapse (n = 107). Progression was defined by finding evidence of cytogenetic or hematologic relapse in a patient who lacked such evidence when molecular relapse was diagnosed. Vertical lines represent patients in MR who had not progressed.