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Leukemia and lymphoma diagnostics

Translating knowledge about leukemias and lymphomas into new diagnostics and improved therapies.

Teamleader: Dr. V.H.J. (Vincent) van der Velden

Background

Acute leukemias are malignancies of immature hematopoietic cells. Depending on the involved cell type, two main categories of acute leukemia can be distinguished: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Further subdivision can be made, dependent on immunophenotype and genetic aberrations. Such subdivision is necessary because the different subgroups have different clinical outcomes and consequently require different therapeutic approaches.

ALL is most prominent in childhood and, using current chemotherapeutic regimens, has a 5-year event free survival up to 85%. For this group of patients it will especially be important to recognize those patients with a high risk of relapse, who may benefit from treatment intensification, and those with a low-risk of relapse, who may benefit from treatment reduction. In contrast, AML is most frequent in adults (especially those >60 years of age) and although chemotherapy induces clinical remission in the vast majority of patients, most of them ultimately relapse, resulting in a 5-year survival of ~40%. It is therefore clear that new therapeutic modalities are required for this type of leukemia.

We and others have recently shown that detection of low numbers of leukemic cells during and after treatment, so called detection of minimal residual disease (MRD), is of prognostic value in acute leukemia. In our laboratory, flowcytometric immunophenotyping, PCR analysis of chromosome aberrations, and PCR analysis of immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements are used for MRD detection in several patient groups to investigate the kinetics of tumor cell disappearance and thereby define the in vivo treatment effectiveness and their risk of relapse. In addition, MRD information is used to determine the efficacy of new therapies, including antibody-mediated chemotherapy, and to provide insight into the immunobiology of acute leukemia (e.g. Ig/TCR gene rearrangement patterns in leukemia subtypes).


Aims of our translational research

The main aim of our translational research is to improve our understanding on the immunobiology of hematological malignancies and to evaluate their response to treatment in order to improve diagnostics and to optimize treatment protocols.

Our specific aims are:

  1. To obtain insight in the immunobiological characteristics of childhood acute leukemia. This includes a.o.:
    a. Analysis of extramedullary acute leukemia for identifying markers that may predict extramedullary localization and that may be used as new therapeutic targets;
    b. Analysis of acute leukemia at the myeloid-lymphoid interface for understanding which molecules play a role in lineage specification and commitment.
  2. To analyze Minimal Residual disease:
    a. Development and standardization of sensitive techniques to measure MRD in acute leukemia patients; this concerns both cellular and molecular methods;
    b. Recognition of MRD-based subgroups of patients that may benefit from treatment intensification or treatment reduction. 
  3. To innovate diagnostics of hematological malignancies, by applying state-of-the-art technologies and exploring new possibilities for flow cytometric diagnostics;
  4. To identify parameters which affect the efficacy of antibody-based chemotherapy in acute leukemia.

Selection of scientific achievements during the last few years

  1. Immunobiology of acute leukemia
    - Detailed analysis of Ig/TCR rearrangement patterns in several subgroups of acute lymphoblastic leukemia patients has provided insight in the development of leukemias and has given important information for the selection of Ig/TCR targets for minimal residual disease detection (Jansen MW, et al. Leukemia. 2007 21(4):633-41; Szczepanski et al. Blood. 2004 May 15;103(10):3798-804).
    - Unique expression of chemokines and homing receptors may be involved in extramedullary localization of acute leukemia (Annels NE, et al. Blood. 2004; 103(7):2806-8).
  2. Minimal residual disease
    - All critical steps in molecular MRD diagnostics have been standardized at the international level and international guidelines for RQ-PCR data interpretation have been developed (van der Velden et al. Leukemia. 2008;22(3):641-4; van der Velden et al. Leukemia. 2007;21(4):604-11).
    - Within the international Interfant-99 study, the immunobiology of infant acute lymphoblastic leukemia has been analyzed in detail and the prognostic significance of minimal residual disease detection has been determined.
    - In collaboration with Germany, Austria, and Italy, the applicability of MRD diagnostics in childhood ALL has been demonstrated (Flohr et al. Leukemia. 2008;22(4):771-82).
  3. Innovative diagnostics
    - In collaboration with the VUmc, the diagnostic significance of flowcytometric immunophenotyping in patients with myelodysplastic syndrome has been analyzed. Flow cytometry in MDS identified aberrancies in the myelomonocytic lineage not otherwise determined by cytomorphology. In addition, flow cytometry identified patients at risk for transfusion dependency and/or progressive disease independent of known risk groups, which might have impact on treatment decisions and the prognostic scoring system in the near future. (van de Loosdrecht et al. Blood. 2008;111(3):1067-77).
  4. Antibody-based therapies
    - Several parameters that affect the efficacy of Mylotarg (CD33 immunotoxin) in acute myeloid leukemia patients have been defined, including drug efflux, CD33 expression levels, renewed CD33 expression, and tissue distribution of Mylotarg, including penetration in bone marrow (Walter et al. Blood. 2007;109(10):4168-70; van der Velden et al. Leukemia. 2004 May;18(5):983-8).

For more information, please contact dr. Vincent H.J. van der Velden.
Telephone: +31 (0)10 70.44253
E-mail: v.h.j.vandervelden@erasmusmc.nl