The understanding of acute lymphoblastic leukemia ALL in childhood and adolescence has largely changed due to extensive genetic research in recent years: ALL is now considered to be a very heterogeneous disease group. The leukemia cells present themselves with quite differently activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate methods of assessing therapy response "minimal residual disease [MRD] tests" has provided new insights into very different mechanisms of action, including factors influenced by host factors; this has had practical clinical consequences for the use of more individualized therapy. However, the own and international study data show that the therapy toxicity of the contemporary chemotherapy concepts has become unacceptably high, in particular with respect to those intensified therapies used for the treatment of patients at high risk of ALL relapse.

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Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Blood , 06 Feb , 14 : DOI: Review Free to read. A 3-year-old boy presented with a leukocyte count of 5. He was enrolled in the St. After 19 days of remission induction therapy with 1 high dose of methotrexate, 14 days of prednisone, 2 doses of vincristine and daunorubicin, and 6 doses of Escherichia coli -derived asparaginase, flow cytometry examination of his bone marrow revealed the presence of minimal residual disease MRD amounting to 3 leukemic cells per 10 mononucleated cells 0.

Because of the near-haploid ALL karyotype and negative day 46 MRD, he was assigned to receive intensive chemotherapy for 3 years.

MRD remained undetectable throughout treatment. He has remained in continuous complete remission for A 9-year-old boy presented with a 3-month history of progressive pallor and upper respiratory tract infection. He had no hepatosplenomegaly or mediastinal mass. An abnormal blood count with hemoglobin 3. He was enrolled on the Total Therapy XV study and began remission induction therapy with high-dose methotrexate followed by prednisone once per day, vincristine once per week, daunorubicin once per week, and E coli —derived asparaginase 3 times per week.

On day19 of treatment, Three additional doses of asparaginase were given, and the remaining remission induction therapy consisted of cyclophosphamide, mercaptopurine, and cytarabine.

After consolidation treatment with 4 courses of high-dose methotrexate plus mercaptopurine as well as 1 course of re-intensification therapy with dexamethasone, etoposide, high-dose cytarabine, and asparaginase, MRD decreased to 0.

The first report of minimal ie, not morphologically evident residual disease MRD in leukemia was published nearly 4 decades ago. Thus, a fundamental concept in the modern evaluation and management of acute leukemia was introduced: bone marrow in complete remission may contain leukemic cells detectable by methods that are more sensitive and objective than morphologic examination.

The initial microscopic methods were subsequently replaced by flow cytometry, and the number and quality of antibodies available for leukemia immunophenotyping progressively increased. By amplifying these unique molecular signatures using patient-specific polymerase chain reaction PCR primers or, as shown more recently, by subjecting PCR-amplified DNA fragments of these genes to deep-sequencing analysis, MRD at levels of 1 in or more cells can be detected. Other patients harbor MRD at levels that can range from 0.

Pediatric oncologists treating children and adolescents with ALL have pioneered the use of MRD to monitor response to treatment, and all major pediatric oncology centers and cooperative groups worldwide now systematically use MRD levels to guide treatment decisions Table 1. Genetic abnormalities of leukemic lymphoblasts have prognostic significance and have been used to inform treatment decisions. Our Total Therapy Studies XV and XVI relied on MRD measurements for final risk assignment, an approach that may over-ride or lessen the prognostic impact of specific genetic abnormalities of leukemic cells.

If so, it should be possible to use this information to adjust treatment intensity and avoid over- or undertreatment. This strategy resulted in a 5-year event-free survival of In our study, there were too few hypodiploid patients with positive MRD at the end of remission induction to conclusively determine whether allogeneic HSCT can improve their outcome. Children and adolescents with ALL who do not achieve morphologic remission after the initial 4-week course of chemotherapy induction failure have been regarded as having chemotherapy-resistant disease and should be considered as candidates for allogeneic HSCT.

However, an international collaborative study showed that the prognostic impact of induction failure after conventional remission induction therapy was not uniform among different subtypes of ALL.

Case 2 had T-ALL, with residual disease by flow cytometry of Because of poor early response to initial chemotherapy, he received allogeneic HSCT after achieving MRD-negative status with further chemotherapy. With the increasing optimization of standard therapy and the availability of new agents for ALL, an ever more refined risk algorithm that combines presenting biologic and genetic features with MRD measurements is needed to develop optimal postremission treatment strategies.

For these patients, we recommend allogeneic HSCT. Because MRD levels before transplantation are directly associated with risk of relapse posttransplant, 38 additional treatment directed at reducing levels of MRD before transplant should be considered. Numerous studies have demonstrated the strong association between MRD levels and treatment outcome in childhood ALL, 5 , 6 supporting the concept that MRD during the initial phases of chemotherapy provides a reliable measurement of the drug sensitivity of leukemic lymphoblasts.

This realization has profoundly refined risk-directed therapy, with MRD being applied in virtually all major protocols for pediatric ALL to guide treatment decisions. Table 1 summarizes some of the risk classification guidelines used in current pediatric ALL trials in the United States and Europe.

It is evident that there is no consensus on the precise time points at which MRD should be measured and on the levels used for treatment decisions. The algorithms are typically built on the experience of previous correlative studies by each study group, with the timing for MRD studies adapted to the treatment design and schedule in each individual protocol. The predictive value of MRD depends on the preceding and subsequent treatment and must be determined in the context of each treatment regimen.

There are, however, some general principles that can be extrapolated from the published data and that are exemplified by the cases discussed here.

The best treatment option for these patients at this point in time is allogeneic HSCT, particularly if levels of MRD can be reduced to undetectable status before transplant.

Emergent immunotherapeutics might facilitate MRD reduction in these patients and could also be curative without further treatment. To this end, MRD-guided therapy can improve the outcome of some high-risk groups of patients, such as older adolescents 41 and those with hypodiploidy, 22 or Ph-like ALL.

The use of MRD in ALL relies on highly sophisticated methods and a detailed understanding of its clinical significance, evolving over 4 decades of basic, translational, and clinical research. Conceivably, newer methods that can detect MRD at lower levels than the standard threshold of 0.

The risk features and MRD time points to be used must be selected with caution. Thus, in a recent analysis of the AIEOP-BFM study, an increased relapse rate was observed for patients with B-ALL regarded as standard risk defined primarily by leukocyte count and age who had received reduced-intensity delayed intensification because of negative MRD on days 33 and Thus, MRD monitoring can contribute to the development of novel immunotherapeutic approaches by serving as an eligibility or response criterion.

Contribution: D. Conflict-of-interest disclosure: The authors declare no competing financial interests. Read article at publisher's site DOI : Cancer Cell Int , , 14 Nov Short NJ , Ravandi F. Haematologica , 8 , 04 Jul Blood Adv , 3 13 , 01 Jul Free to read. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Leukemia , 31 8 , 22 May Cited by 4 articles PMID: Cited by: 0 articles PMID: Leukemia , 6 Suppl , 01 Jan Cited by 15 articles PMID: Pediatr Hematol Oncol , 20 2 , 01 Mar Cited by 2 articles PMID: Cancer Genet Cytogenet , 1 , 01 Jan Cited by 11 articles PMID: Coronavirus: Find the latest articles and preprints.

Europe PMC requires Javascript to function effectively. Recent Activity. Recent history Saved searches. Search articles by 'Dario Campana'. Campana D 1 ,.

Search articles by 'Ching-Hon Pui'. Pui CH 2. Affiliations 1 author 1. Departments of Oncology and Pathology, St. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Free full text. Prepublished online Feb 6. PMID: Dario Campana 1 and Ching-Hon Pui 2, 3.

Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Dec 4; Accepted Feb 1. This article has been cited by other articles in PMC.

Go to:. Case 1 A 3-year-old boy presented with a leukocyte count of 5. Case 2 A 9-year-old boy presented with a 3-month history of progressive pallor and upper respiratory tract infection.

Table 1. Open in a separate window. Immunological monitoring of residual disease in treated thymic acute lymphoblastic leukaemia. Leuk Res. Campana D, Pui CH. Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia.

Campana D.


Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia.

Baruchel, Y. Bertrand, A. Biondi, M. Campbell, A. Colombini, V. Conter, L. Dalla Pozza, S.


Table 1 European study groups participating in the development of recommendation for MRD assessment

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Blood , 06 Feb , 14 : DOI: Review Free to read. A 3-year-old boy presented with a leukocyte count of 5.

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Valentino Conter, Claus R. Blood ; 16 : — PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. Medscape, LLC designates this educational activity for a maximum of 1. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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