rapid-vivo-drug-response-prediction-using-leukemia-cell-grafts

Rapid <em>in vivo</em> Drug Response Prediction Using Leukemia Cell Grafts in Zebrafish Embryos

Zebrafish xenotransplantation is a pivotal technique for investigating human cancer pathogenesis and predicting individual drug responses. This document ...

Charité-Universitätsmedizin Berlin, Klinik für Pädiatrie m.S. Onkologie/Hämatologie

Second central nervous system (CNS) relapses represent about 7.3% of subsequent recurrences of childhood acute lymphoblastic leukemia (ALL). In most children these subsequent CNS relapses occur during the first 18 months after diagnosis of the first relapse (mean 1.42 +/- 0.73 years). We present a patient who suffered a second ALL relapse in the CNS more than seven years after diagnosis of his first relapse. The leukemic clone was completely stable over more than ten years as shown by minimal residual disease techniques. Possible reasons for the recurrence of the leukemic clone after this very long period of dormancy (e.g. role of the disease site, immune system dysfunction) are discussed.

Clonal stability of initial leukemia in a child with central nervous system relapse 7.4 years after bone marrow relapse of common acute lymphoblastic leukemic.

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.

Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.

This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).

Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.

In children with intermediate risk of relapse of acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. We hypothesized that the prognosis of patients with unsatisfactory reduction of minimal residual disease (MRD) can be improved by allogeneic hematopoietic stem-cell transplantation (HSCT).

Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group.

Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT).

Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials.

Real-time quantitative PCR (qPCR) using immunoglobulin/T-cell receptor gene rearrangements has been used as the gold standard for minimal residual disease (MRD) monitoring in acute lymphoblastic leukemia (ALL) for >20 years. Recently, new PCR-based technologies have emerged, such as droplet digital PCR (ddPCR), which could offer several methodologic advances for MRD monitoring. In the current work, qPCR and ddPCR were compared in an unbiased blinded prospective study (n = 88 measurements) and in a retrospective study with selected critical low positive samples (n = 65 measurements). The former included flow cytometry (Flow; n = 31 measurements) as a third MRD detection method. Published guidelines (qPCR) and the latest, revised evaluation criteria (ie, ddPCR, Flow) have been applied for data analysis. The prospective study shows that ddPCR outperforms qPCR with a significantly better quantitative limit of detection and sensitivity. The number of critical MRD estimates below quantitative limit was reduced by sixfold and by threefold in the retrospective and prospective cohorts, respectively. Furthermore, the concordance of quantitative values between ddPCR and Flow was higher than between ddPCR and qPCR, probably because ddPCR and Flow are absolute quantification methods independent of the diagnostic sample, unlike qPCR. In summary, our data highlight the advantages of ddPCR as a more precise and sensitive technology that may be used to refine response monitoring in ALL.

Article	Year
Clonal stability of initial leukemia in a child with central nervous system relapse 7.4 years after bone marrow relapse of common acute lymphoblastic leukemic. Haematologica\| PubMed ID: 15257960	2004
Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment. Leukemia\| PubMed ID: 21546902	2011
Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96. European journal of cancer (Oxford, England : 1990)\| PubMed ID: 23265714	2013
Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermed... Journal of clinical oncology : official journal of the American Society of Clinical Oncology\| PubMed ID: 23775972	2013
Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials. European journal of cancer (Oxford, England : 1990)\| PubMed ID: 34010787	2021
A New View on Minimal Residual Disease Quantification in Acute Lymphoblastic Leukemia using Droplet Digital PCR. The Journal of molecular diagnostics : JMD\| PubMed ID: 35691569	2022

Cornelia Eckert

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