Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience

Abstract

Summary The population‐based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)‐driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10−3 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre‐HCT MRD results, 22 were MRD‐positive, one with MRD ≥10−3. After a median follow‐up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5–47·7) for MRD‐positive versus 5·1% (95% CI: 1·3–19·2), P = 0·02) for MRD‐negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6–51·0, P = 0·012). Non‐relapse mortality did not differ between the two groups, resulting in disease‐free survival of 85·6% (95% CI: 75·4–97·2) and 67·4% (95% CI: 50·2–90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre‐HCT MRD‐positive patients.

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

“…MRD was analyzed by RQ‐PCR according to the EuroMRD guidelines or by multicolor flow cytometry as described in the NOPHO ALL2008 guidelines . MRD results were categorized as either negative or positive < 10 −4 ; positive ≥ 10 −4 but <10 −3 ; positive ≥ 10 −3 ; or positive but below a quantitative range of 10 −3 …”

Declining mortality rates in children admitted to ICU following HCT

“…However, in a recent Nordic study with more patients included, CMV mismatch was associated with higher TRM underlining the significance of CMV infection for general outcome following HCT, also in children. 23 Acute GvHD grade 2-4 was not significantly associated with mortality. Schrecter et al have previously shown a lower mortality correlated with aGvHD after a second HCT possibly as children with aGvHD most often have neutrocyte take and thus be more resistant to, that is, bacterial infections.…”

CAR T cells vs allogeneic HSCT for poor-risk ALL

“…5 NOPHO recently retrospectively examined HSCT outcomes in CR1 and reported a 5-year DFS of 79.1%. 25 Persistent MRD was the indication for HSCT in only 35% of this cohort, and 17% received a transplant without a protocol indication. The population studied differed from the COG AALL0232 population referenced above in several potentially relevant features; however, these and other promising results in CR1 led many to consider HSCT for persistent MRD, for example, the current prospective examination on the European trial AEIOP-BFM-ALL 2009.…”

“…Although HSCT is often considered for patients with anticipated poor survival with chemotherapy alone, relevant to this population, detectable MRD at the time of HSCT has been consistently associated with an increased risk of relapse, as is MRD post-HSCT. 23,25,27,40,41 Further intensification of chemotherapy to decrease or eliminate MRD and HSCT itself are not without significant risk of morbidity and mortality. 3,22,28,42 Therefore, the possibility of durable remission without consolidative HSCT is one aim of an ongoing trial developed by the COG and Novartis.…”