Despite improvements in treatment modalities, approximately one-third of children with acute lymphoblastic leukemia (ALL), and two-thirds of patients with acute myeloid leukemia (AML) are not presently being cured. Following hematologic relapse, 80% of the patients expire within 6 months. At diagnosis, patients have a tumor burden of approximately one billion leukemic cells, and at the present time it is not known how effective cytoreductive therapy is. This is because residual leukemic blasts representing <5% of the bone marrow cell population may remain unseen by conventional morphological examination, and other methods of detection of residual leukemic cells are either insufficiently sensitive to significantly improve on this detection level, or require considerable technical expertise and can only be applied to small numbers of samples. It is possible that early detection of minimal residual disease (MRD) when the leukemic burden is low would allow intervention with alternative treatment strategies that may improve the patient's possibility of survival. The polymerase chain reaction (PCR) represents a technique that is potentially applicable to this problem. The sensitivity of the technique is sufficient to detect one cell in 100,000, and if specificity for the leukemic clone can be achieved then use of this technique will significantly improve our ability to detect occult leukemic cells. Leukemic clone specificity can be achieved through the use of immunoglobulin and T cell receptor gene rearrangements which can be found in almost 100% of B and T lineage ALLs, and in about 20% of AMLs. The dynamics of the leukemic cell population during remission will therefore be investigated utilizing the PCR to detect minimal residual disease. They will attempt to determine if detectable residual leukemic cells are a harbinger of impending relapse. Methods will be developed to make the PCR technique generally applicable to leukemias with gene rearrangements by identifying primers from immunoglobulin and T cell receptor genes that can be used for this purpose. With such primers, they will examine serial DNA samples from a large number of patients, some of whom remain in continuous remission and some of whom have relapsed. Patients undergoing autologous and allogeneic bone marrow transplantation will be examined before and after infusion of marrow. Overall, these studies should shed considerable light on the dynamics of the leukemic cell population during clinical remission, and determine whether the PCR can be used to predict impending relapse. A positive outcome of these experiments may allow future modifications in therapeutic modalities that are geared toward the actual level of leukemic cells in the body.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052259-04
Application #
2094672
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-07-01
Project End
1996-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Stow, Patricia; Key, Laura; Chen, Xiaohua et al. (2010) Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 115:4657-63
Coustan-Smith, Elaine; Campana, Dario (2010) Immunologic minimal residual disease detection in acute lymphoblastic leukemia: a comparative approach to molecular testing. Best Pract Res Clin Haematol 23:347-58
Pui, Ching-Hon; Robison, Leslie L; Look, A Thomas (2008) Acute lymphoblastic leukaemia. Lancet 371:1030-43
Campana, Dario (2004) Minimal residual disease studies in acute leukemia. Am J Clin Pathol 122 Suppl:S47-57
Neale, G A M; Coustan-Smith, E; Stow, P et al. (2004) Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 18:934-8
Pui, C H; Relling, M V; Sandlund, J T et al. (2004) Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol 83 Suppl 1:S124-6
Neale, Geoffrey A M; Campana, Dario; Pui, Ching-Hon (2003) Minimal residual disease detection in acute lymphoblastic leukemia: real improvement with the real-time quantitative PCR method? J Pediatr Hematol Oncol 25:100-2
Campana, Dario; Coustan-Smith, Elaine (2002) Advances in the immunological monitoring of childhood acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 15:1-19
Campana, D; Neale, G A; Coustan-Smith, E et al. (2001) Detection of minimal residual disease in acute lymphoblastic leukemia: the St Jude experience. Leukemia 15:278-9
Chen, X; Pan, Q; Stow, P et al. (2001) Quantification of minimal residual disease in T-lineage acute lymphoblastic leukemia with the TAL-1 deletion using a standardized real-time PCR assay. Leukemia 15:166-70

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