Comment on Brüggemann et al, page 1116

Most adults with ALL achieve a CR but then relapse from clinically inapparent MRD. The ability to predict who will relapse while still in a minimal disease state has important clinical implications.

In this issue of Blood, Brüggemann and colleagues have identified the prognostic importance of monitoring minimal residual disease (MRD) in adult patients with standard-risk acute lymphoblastic leukemia (ALL) through a systematic study of real-time immune (IGH or TCR) gene quantitative polymerase chain reaction (PCR). This is an important study because adult ALL has long been a frustrating disease for hematologists. Despite the dramatic improvement in treatment results for children with ALL, the story for adults is very different and without evidence of marked improvement in the past 2 or 3 decades. Modern regimens can induce CR in 70% to 90% of adult patients; however, most of these patients will ultimately relapse and succumb to their disease.1  There have been well-established prognostic features in adult ALL dating back to 1988 when both the MSKCC and BFM groups published the first multivariate analyses.2,3  Subsequently, multiple studies have confirmed the findings that the pretreatment variables of older age, higher white blood cell (WBC) count, and the presence of the Philadelphia chromosome are all associated with a worse prognosis. In addition, these studies consistently found that time to complete response was also a strong predictor of long-term disease-free survival. Indeed, this last feature—the fact that early response correlates with “cure”—may represent in part the clinical precursor of the important study presented by Brüggemann and colleagues. Though it is not known with certainty why early response correlates with improved outcome, the hypothesis is that such patients have more sensitive disease than slower remitters and that if this is carried to the next logical step such patients should also have lower disease burdens (MRD) when in remission than those patients who respond more slowly to treatment.

It has been recognized since the late 1990s that monitoring of MRD in children with ALL has prognostic significance and can help guide important clinical decisions. Unfortunately, up to now the story has been less clear in adult patients. The study by Brüggemann and colleagues clearly defines the use of studying MRD in adult patients with ALL. Focusing on a well-defined group of patients with standard-risk disease (there is much less urgency to study high-risk patients as their relapse frequency is already known to be very high) the authors, using pretreatment specimens, attempted to determine the clone-specific rearrangements in the IGH or TCR gene. Once these genes were sequenced, patient (allele)-specific oligonucleotides were designed for each MRD target to be used in future patient-specific real-time quantitative (RQ)-PCR. A preliminary pilot phase (subsequently confirmed in the main cohort) identified that using early time points (day 11 and day 24) and a late time point (week +16) allowed stratification of these patients into 3 groups. Patients who are MRD negative at day 11 (and 24) have an excellent prognosis with a 3-year risk of relapse of 0%. Conversely, patients who are MRD positive at 16 weeks have a 94% risk of relapse at 3 years. Clearly, the first group (early MRD negative) should remain on the prescribed chemotherapy program and not consider allogeneic transplantation in first remission. The latter group should go on to allogeneic transplantation while still in remission and not wait for clinical relapse. Unfortunately, there are some limits to the applicability of these results. The first is the labor intensity required to make patient-specific probes, certainly something that at this time is restricted to research laboratories at major medical centers. The second is that the 2 predictive groups (early MRD-negative patients and late MRD-positive patients) constitute only one third of standard-risk patients. The “middle group,” which is composed of the other two thirds of patients, has a 47% risk of relapse at 3 years, and for this group MRD determination offers no benefit. Clearly, determination of MRD is an important prognostic tool in adult ALL; however, we are still far from the point of being able to tell in advance for every patient with ALL who will do well with current therapy and who is destined to relapse. ▪

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