Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2324-2330 ◽  
Author(s):  
Julie Bergeron ◽  
Emmanuelle Clappier ◽  
Isabelle Radford ◽  
Agnès Buzyn ◽  
Corinne Millien ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Event Free Survival ◽  
Chain Reaction ◽  
Free Survival ◽  
Maturation Arrest ◽  
Prognostic Analysis ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Polymerase Chain

TLX1 is a homeodomain transcription factor generally associated with a favorable outcome in T-cell acute lymphoblastic leukemia (T-ALL). However, the molecular mechanisms of TLX1 deregulation remain unclear and various transcript levels in the absence of 10q24 abnormalities have been reported. A reproducible and accurate delineation of TLX1+ T-ALL will be necessary for proper therapeutic stratification. We have studied 264 unselected T-ALLs (171 adults and 93 children) and show that T-ALLs expressing high levels of TLX1 (n = 35, 13%), defined as a real-time quantitative polymerase chain reaction (RQ-PCR) level of TLX1 greater than 1.00 ABL, form a homogeneous oncogenic group, based on their uniform stage of maturation arrest and oncogenetic and transcriptional profiles. Furthermore, TLX1-high T-ALLs harbor molecular TLX1 locus abnormalities in the majority (31/33), a proportion largely underestimated by standard karyotypic screening. T-ALLs expressing TLX1 at lower levels (n = 57, 22%) do not share these characteristics. Prognostic analysis within the adult LALA94 and GRAALL03 prospective protocols demonstrate a better event-free survival (P = .035) and a marked trend for longer overall survival (P = .059) for TLX1-high T-ALLs, while the expression of lower levels of TLX1 does not impact on prognosis. We propose that TLX1+ T-ALLs be defined as cases expressing TLX1/ABL ratios greater than 1 and/or demonstrating TLX1 rearrangement. Therapeutic modification should be considered for those patients.

scholarly journals Neuroblastoma mRNAs Predict Outcome in Children With Stage 4 Neuroblastoma: A European HR-NBL1/SIOPEN Study

2014 ◽  
Vol 32 (10) ◽  
pp. 1074-1083 ◽  
Author(s):  
Virginie F. Viprey ◽  
Walter M. Gregory ◽  
Maria V. Corrias ◽  
Andrei Tchirkov ◽  
Katrien Swerts ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Predictive Power ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Event Free Survival ◽  
Chain Reaction ◽  
Free Survival ◽  
Novel Treatment ◽  
Stage 4 ◽  
Polymerase Chain

Purpose To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. Methods RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy. Results High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value. Conclusion High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.

Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2077-2084 ◽  
Author(s):  
Martin Schrappe ◽  
Maria Grazia Valsecchi ◽  
Claus R. Bartram ◽  
André Schrauder ◽  
Renate Panzer-Grümayer ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Young Patients ◽  
Event Free Survival ◽  
Chain Reaction ◽  
Free Survival ◽  
Excellent Outcome ◽  
Favorable Prognostic Factor ◽  
Polymerase Chain ◽  
Standard Risk ◽  
Time Point

Abstract The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10−3 at day 78; and MRD high risk (MRD-HR) if ≥ 10−3 at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10−3 at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov; “Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia,” protocol identification #NCT00430118 for BFM and #NCT00613457 for AIEOP.

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.

Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome–positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1408-1413 ◽  
Author(s):  
Adrienne de Labarthe ◽  
Philippe Rousselot ◽  
Françoise Huguet-Rigal ◽  
Eric Delabesse ◽  
Francis Witz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Free Survival ◽  
Prospective Trials ◽  
Polymerase Chain ◽  
Philadelphia Chromosome Positive

AbstractThe combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

NUP214-ABL1 in adult T-ALL: the GMALL study group experience

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3556-3559 ◽  
Author(s):  
Thomas Burmeister ◽  
Nicola Gökbuget ◽  
Richard Reinhardt ◽  
Harald Rieder ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
T Cell ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Prognostic Impact ◽  
Significant Difference ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Pcr Method ◽  
Polymerase Chain

Abstract The NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia (T-ALL) has recently been identified as a possible target for imatinib and related tyrosine kinase inhibitors, but exact data regarding the prognostic impact and frequency of the several putative NUP214-ABL1 mRNA transcripts are still missing. We investigated 279 adult patients with T-ALL treated within the framework of the GMALL 5/93 and 6/99 therapy trials for NUP214-ABL1 by using a novel multiplex real-time, quantitative polymerase chain reaction (PCR). Eleven (3.9%) patients were NUP214-ABL1 positive, and 5 different transcripts were observed; 8 patients had a thymic immunophenotype, 1 had an early T-cell immunophenotype, and 2 had a mature T-cell immunophenotype. NUP214-ABL1-positive and -negative patients did not differ significantly in their major clinical features. In contrast to previous reports suggesting an adverse clinical course for NUP214-ABL1-positive patients, no significant difference in overall survival was observed. Based on the results, we have established and tested a novel PCR method for simplified detection of the NUP214-ABL1 fusion gene.

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

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.

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