Detection of Minimal Residual Disease in T-Cell Acute Lymphoblastic Leukemia Using Polymerase Chain Reaction Predicts Impending Relapse

• Published in: Blood 1991-08, Vol.78 (3), p.739-747
• Main Authors: Neale, Geoffrey A.M., Menarguez, Javier, Kitchingman, Geoffrey R., Fitzgerald, Thomas J., Koehler, Maria, Mirro, Joseph, Goorha, Rakesh M.
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Blotting, Southern; Bone Marrow - immunology; Bone Marrow - pathology; DNA, Neoplasm - genetics; Gene Rearrangement; Gene Rearrangement, T-Lymphocyte; Hematologic and hematopoietic diseases; Humans; Leukemia-Lymphoma, Adult T-Cell - diagnosis; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - immunology; Medical sciences; Molecular Sequence Data; Oligonucleotide Probes; Polymerase Chain Reaction - methods; Prognosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V78.3.739.739

After achieving remission, approximately one-third of patients with T-cell acute lymphoblastic leukemia (T-ALL) relapse due to the resurgence of residual leukemic cells that cannot be detected in remission by morphologic methods. Thus, the early detection of residual disease is highly desirable to monitor the efficacy of therapy, or to institute an alternative mode of therapy. Toward this aim, we have examined the applicability of polymerase chain reaction (PCR) amplification in the detection of minimal residual disease (MRP) in bone marrow samples from patients with T-ALL in morphologic remission. Two different approaches were taken to identify leukemic clone-specific sequences that could be used as targets for PCR amplification. The first technique used T-cell receptor-δ (TCR-δ) gene rearrangements that were sequenced directly after PCR amplification of leukemic DNA. This method was successful in generating clone-specific probes for 76% of T-ALL patients screened. An alternative method was used to clone and sequence a TCR-β chain gene from leukemic cells to generate a specific probe. The PCR assays that we used were specific for each patient's leukemic clone, and were capable of routinely detecting one leukemic cell in 104 normal cells. Using these sensitive PCR-based assays, we found no evidence for persistence of the leukemic clone in any of the bone marrow samples from four T-ALL patients who are in long-term (3.9+ to 8.1 + years) remission. In contrast, we detected residual disease in clinical remission samples from two patients who subsequently relapsed. In one patient, where we had appropriate samples, we observed a dramatic expansion of the leukemic clone 3 months before clinical relapse. These results suggest that PCR-based assays for detection of MRD in T-ALL patients have great potential in predicting impending relapse, and in determining the efficacy of the anti-leukemic therapy. These methods may also allow the identification of long-term survivors.