Transplantation for CML: lifelong PCR monitoring?

Comment on Kaeda et al, page 4171

In this issue of Blood, Kaeda and colleagues present a molecular analysis of 243 patients with Ph⁺ CML who underwent conventional allogeneic transplantation (∼ one half with T-cell depletion) over a 20-year interval for whom detailed post-transplantation BCR-ABL PCR data were available.

Chronic myelogenous leukemia (CML) management continues to evolve rapidly. Allogeneic transplantation had been considered the optimum management for the newly diagnosed CML patient for whom transplantation was feasible, as determined by age, donor availability, and lack of comorbid conditions. Imatinib has now relegated transplantation to second-line therapy, although some consider transplantation as third- or even fourth-line therapy. However, a recurring cautionary note is echoed that imatinib does not offer a known curative option and that we are delaying proven curative therapy to later in the disease course, possibly negatively influencing the excellent transplantation outcomes.FIG1 

Recognizing that polymerase chain reaction (PCR) sensitivity has increased over the past decade, the findings are rather eye opening, especially in light of our desire to attribute “cured” status to allograft recipients. Specifically, of the patients studied by Kaeda and colleagues, 53% relapsed as determined by molecular criteria alone or by progression to abnormal cytogenetic or hematologic states. In addition, in the remaining 47%, the majority had multiple episodes when low positive BCR-ABL PCR results were observed after transplantation, from which the probability of future relapse could be defined (see figure). Thus, in the entire cohort, only approximately 15% were classified as persistently negative, defined as always PCR negative (6.6%; 16 patients) for BCR-ABL or with a single, detectable low-level positive result (8.2%; 20 patients). Patients were found with relapse or with BCR-ABL PCR signals whether or not T-cell depletion was used, thus raising the question, to these authors, whether some or potentially even all patients after allogeneic transplantation continue to harbor small quantities of residual leukemic cells.

Concomitant with this publication, at the IBMTR/ASBMT 2006 meetings, one of the authors, Dr John Goldman, presented long-term follow-up of 8738 CML patients who had undergone transplantation between 1978 and 1998 and were evaluated for long-term survival.¹  Nearly 3000 patients were identified as living 5 years or longer, and of those long-term survivors, approximately 10% experienced late relapse of their CML, even as late as 15 years after the transplantation. These data in combination with the data presented by Kaeda et al clearly indicate a critical need for ongoing serial monitoring of all CML patients who have undergone and will undergo allogeneic transplantation. The importance of this monitoring is highlighted by the desire to identify CML patients early, prior to hematologic relapse, so that they can be assessed for treatment options, such as donor leukocyte infusions, imatinib, or perhaps other second-generation kinase inhibitors.²  Thus, we laud these authors for their detailed analysis and await validation of these remarkable long-term data from other centers or other cooperative groups, and with recognition that at least one group has reported lower PCR BCR-ABL positivity and subsequent relapse rates in similar CML cohorts, although with less lengthy follow-up and in the absence of T-cell depletion.³  ▪