Measurement of Minimal Residual Disease (MRD) after Consolidation Therapy as a Means of Early Detection of Relapse in Adult Acute Lymphoblastic Leukemia (ALL).

Outcome for patients with adult ALL after relapse is poor, even if a second remission is achieved by salvage therapy and is consolidated by an allogeneic stem cell transplantation. There is considerable evidence from studies in childhood ALL and other hematologic malignancies that administration of salvage therapy in early molecular relapse may improve prognosis. We therefore investigated the value of continuous MRD-monitoring in prospectively monitored standard risk patients of the German Multicenter ALL-studies 06/99 and 07/03 during and after maintenance treatment beyond the first year of therapy. MRD was assessed by quantitative realtime PCR using clone-specific primers for the leukemia-specific Ig/TCR gene rearrangements. MRD high risk-patients (those with MRD > 10⁻⁴ at two successive time points after induction during the first year of therapy) are candidates for early therapy escalation according to the study protocol and were thus excluded from this analysis. Of the 108 remaining patients (77 male, 31 female), 30 (28%) became MRD-positive again after a median follow-up of 18 months after the end of consolidation treatment. Of these, 17 (57%) already relapsed. When only considering patients with MRD measurable within the quantitative range of the PCR 16/19 (84%) already relapsed. Of the MRD-negative patients only 5 of 78 (6%) have relapsed after a median follow up of 23 month after end of initial therapy. After conversion to MRD positivity, the median time to relapse was 9.5 months, with a median time to relapse of only 2.5 months once the patients’ MRD was within the quantitative range of the PCR assay. Taken together, these data indicate that, if done at regular intervals, MRD-monitoring allows for accurate and timely identification of patients in need for treatment escalation in the vast majority of cases and may help to avoid overtreatment for those patients who are cured by conventional chemotherapy alone.