Clinical Impact of NOTCH1 and/or FBXW7 Mutations, FLASH Deletion, and TCR Status in Pediatric T-Cell Lymphoblastic Lymphoma

2012 ◽  
Vol 30 (16) ◽  
pp. 1966-1973 ◽  
Author(s):  
Celine Callens ◽  
Frederic Baleydier ◽  
Etienne Lengline ◽  
Raouf Ben Abdelali ◽  
Arnaud Petit ◽  
...  
Keyword(s):  
T Cell ◽  
Residual Disease ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Good Prognosis ◽  
Disease Assessment ◽  
Free Survival ◽  
Mutational Status ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Prognosis Group

Purpose Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/Fmut), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Patients and Methods Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/Fmut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements. Results N/Fmut were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/Fmut and identified a poor prognosis group (P = .02). On multivariate analysis of N/Fmut, TCRγ ABD, and FLASH deletion, only N/Fmut was an independent factor for good prognosis. Conclusion Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.

scholarly journals Immature Immunoglobulin Gene Rearrangements Are Recurrent in B Precursor Adult Acute Lymphoblastic Leukemia Carrying TP53 Molecular Alterations

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 960
Author(s):  
Silvia Salmoiraghi ◽  
Roberta Cavagna ◽  
Marie Lorena Guinea Montalvo ◽  
Greta Ubiali ◽  
Manuela Tosi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Early Stage ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Disease Assessment ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Receptor ◽  
Molecular Alterations ◽  
Mutational Status

Here, we describe the immunoglobulin and T cell receptor (Ig/TCR) molecular rearrangements identified as a leukemic clone hallmark for minimal residual disease assessment in relation to TP53 mutational status in 171 Ph-negative Acute Lymphoblastic Leukemia (ALL) adult patients at diagnosis. The presence of a TP53 alterations, which represents a marker of poor prognosis, was strictly correlated with an immature DH/JH rearrangement of the immunoglobulin receptor (p < 0.0001). Furthermore, TP53-mutated patients were classified as pro-B ALL more frequently than their wild-type counterpart (46% vs. 25%, p = 0.05). Although the reasons for the co-presence of immature Ig rearrangements and TP53 mutation need to be clarified, this can suggest that the alteration in TP53 is acquired at an early stage of B-cell maturation or even at the level of pre-leukemic transformation.

scholarly journals Detection of minimal residual disease in T-cell acute lymphoblastic leukemia using polymerase chain reaction predicts impending relapse

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 739-747 ◽  
Author(s):  
GA Neale ◽  
J Menarguez ◽  
GR Kitchingman ◽  
TJ Fitzgerald ◽  
M Koehler ◽  
...  
Keyword(s):  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pcr Amplification ◽  
Leukemic Cells ◽  
Chain Reaction ◽  
Leukemic Clone ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Polymerase Chain

Abstract 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 (MRD) 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-delta (TCR-delta) 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-beta 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 10(4) 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.

scholarly journals DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T‐Cell Acute Lymphoblastic Leukemia

2016 ◽  
Vol 63 (7) ◽  
pp. 1185-1192 ◽  
Author(s):  
Magnus Borssén ◽  
Zahra Haider ◽  
Mattias Landfors ◽  
Ulrika Norén‐Nyström ◽  
Kjeld Schmiegelow ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Minimal Residual Disease ◽  
Prognostic Value ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Status ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

scholarly journals T-cell acute lymphoblastic leukemia

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 580-588 ◽  
Author(s):  
Elizabeth A. Raetz ◽  
David T. Teachey
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Disease Response ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Relapsed Disease ◽  
Modern Genomic

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease response. Although very similar regimens are used to treat T-ALL and B-ALL, distinctions in response to different elements of therapy have been observed. Similar to B-ALL, the key prognostic determinant in T-ALL is minimal residual disease (MRD) response. Unlike B-ALL, other factors including age, white blood cell count at diagnosis, and genetics of the ALL blasts are not independently prognostic when MRD response is included. Recent insights into T-ALL biology, using modern genomic techniques, have identified a number of recurrent lesions that can be grouped into several targetable pathways, including Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK. With contemporary chemotherapy, outcomes for de novo T-ALL have steadily improved and now approach those observed in B-ALL, with approximately 85% 5-year event-free survival. Unfortunately, salvage has remained poor, with less than 25% event-free and overall survival rates for relapsed disease. Thus, current efforts are focused on preventing relapse by augmenting therapy for high-risk patients, sparing toxicity in favorable subsets and developing new approaches for the treatment of recurrent disease.

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