Risk-Directed Treatment Intensification Significantly Reduces the Risk of Relapse Among Children and Adolescents With Acute Lymphoblastic Leukemia and Intrachromosomal Amplification of Chromosome 21: A Comparison of the MRC ALL97/99 and UKALL2003 Trials

2013 ◽  
Vol 31 (27) ◽  
pp. 3389-3396 ◽  
Author(s):  
Anthony V. Moorman ◽  
Hazel Robinson ◽  
Claire Schwab ◽  
Sue M. Richards ◽  
Jeremy Hancock ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Survival Rates ◽  
Chromosome 21 ◽  
Treatment Intensification ◽  
Runx1 Gene ◽  
Increased Risk ◽  
First Remission ◽  
Risk Of Relapse

Purpose To evaluate the effect on outcome of intensifying therapy for patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21). Patients and Methods We report two cohorts of patients treated on Medical Research Council ALL97 or United Kingdom (UK) ALL2003. iAMP21 was identified retrospectively in ALL97 and was not used to guide therapy. However, in UKALL2003, iAMP21 was determined prospectively, and patients were allocated to the most intensive treatment arm (regimen C), which included augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first remission transplantation. The presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for the RUNX1 gene. Results iAMP21 was identified in 2% of patients with B-cell precursor ALL treated on UKALL2003 and ALL97. The event-free survival, relapse, and overall survival rates at 5 years for iAMP21 patients treated on ALL97 and UKALL2003 were 29% and 78%, 70% and 16%, and 67% and 89%, respectively (all P < .01). Patients treated on ALL97 had an increased risk of relapse compared with patients treated on UKALL2003 (hazard ratio, 7.2; 95% CI, 2.91 to 17.87; P < .001). Conclusion iAMP21 patients with ALL benefitted from receiving more intensive therapy in UKALL2003. In UKALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy (regimen C), and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely.

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439 ◽  
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

Abstract The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Amplification of RUNX1 gene in two new cases of childhood B-cell precursor acute lymphoblastic leukemia: A case report

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e21000-e21000
Author(s):  
A. Fauzdar ◽  
A. Mahajan ◽  
D. Jain ◽  
M. Mishra ◽  
V. Raina
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Fish Analysis ◽  
Cell Precursor ◽  
Childhood All ◽  
Mll Gene ◽  
Runx1 Gene

e21000 Background: Chromosome abnormalities of leukemia cells have important prognostic significance in childhood acute lymphoblastic leukemia (ALL). B-cell precursor acute lymphoblastic leukemia (BCP-ALL) ETV6/RUNX1 (alias TEL/AML1) is most frequent i.e. 15 - 35% in the children with 2 - 18 age group. We report two new cases with Pre B- cell ALL without ETV6/RUNX1 rearrangement, showing amplification of AML1 gene detected by FISH analysis. Methods: Bone marrow samples were analyzed for chromosomal abnormalities with conventional G-banding techniques and interphase fluorescence in situ hybridization (FISH) using probes to detect BCR/ABL t(9;22)(q34-q11) fusion, cryptic TEL/AML1 t(12:21)(p13-q22) and MLL rearrangement for del 11q23. Results: In first case a 3-year girl with four copies of AML (RUNX1) gene were observed in 95% of the cell with normal two copies of TEL (ETV6) gene in both interphase and metaphase FISH. We observed BCR-ABL negative translocation and no MLL gene rearrangement in all the interphase cells after doing FISH. We got a normal 46XX karyotype from bone marrow with conventional cytogenetics (CC) in the same patient. In second case, a 4-year male we observed four copies of AML and two copies of TEL gene in more than 80% of cells. In this patient, we got BCR-ABL negative translocation and three copies of MLL gene without any rearrangement through FISH. We got normal 46XY karyotype in the same patient through CC. Conclusions: In both the patients, we observed hyperdiploidy detected with four copies of RUNX1 gene showing tetrasomy of chromosome 21 detected with metaphase FISH analysis whereas G-banding shows normal diploidy. Bone marrow karyotype in combination with molecular cytogenetic techniques like FISH should be done for improvement in sensitivity and accurate cytogenetic analysis in childhood ALL patients for proper identification of prognostic group for optimum treatment. This is one of the few reported studies worldwide for amplification of RUNX1 gene from Indian subcontinent in childhood BCP-ALL. No significant financial relationships to disclose.

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1332-1339 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Olle Björk ◽  
Anders Glomstein ◽  
Göran Gustafsson ◽  
Niels Keiding ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Control Group ◽  
Cox Regression Analysis ◽  
Cell Counts ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P = .00003), high WBC at diagnosis (P = .03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P = .002), and high average neutrophil counts during maintenance therapy (P = .0009), with a significant interaction between sex and randomization group (P = .0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P = .001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P < .0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P = .03; boys 19.3 v 18.0 U/mL, P = .04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21)

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2327-2330 ◽  
Author(s):  
Anthony V. Moorman ◽  
Susan M. Richards ◽  
Hazel M. Robinson ◽  
Jon C. Strefford ◽  
Brenda E. S. Gibson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Survival Data ◽  
Lymphoblastic Leukemia ◽  
White Cell Count ◽  
Fold Increase ◽  
Chromosome 21 ◽  
Newly Diagnosed ◽  
First Remission ◽  
The Uk

Abstract Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.

scholarly journals Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease

Blood ◽  
2015 ◽  
Vol 125 (9) ◽  
pp. 1383-1386 ◽  
Author(s):  
Christine J. Harrison
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
White Cell Count ◽  
Intensive Therapy ◽  
Chromosome 21 ◽  
Structural Rearrangements ◽  
Cell Precursor ◽  
High Relapse Rate ◽  
Complex Structural ◽  
Standard Risk

Abstract Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia. Breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21 underlie the mechanism giving rise to iAMP21. Patients with iAMP21 are older (median age 9 years), with a low white cell count. They have a high relapse rate when treated as standard risk. Recent studies have shown improved outcome on intensive therapy. Molecular targets for therapy are being sought.

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

scholarly journals Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3105-3112 ◽  
Author(s):  
MB Diccianni ◽  
J Yu ◽  
M Hsiao ◽  
S Mukherjee ◽  
LE Shao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Risk Of Death ◽  
Increased Risk ◽  
Cell Acute Lymphoblastic Leukemia ◽  
First Remission ◽  
First Relapse

Abstract In T-cell acute lymphoblastic leukemia (T-ALL), p53 gene mutations were found in 12 of 51 patients in first relapse (24%). In a retrospective study, bone marrow samples at diagnosis were obtained from 9 of the 12 relapsed patients with p53 mutation; only one patient was found to harbor a p53 mutation at diagnosis. No further p53 mutations were identified in 18 unpaired diagnosis T-ALL samples. This is the first report of a p53 mutation in T-ALL at diagnosis. p53 mutations in relapsed T-ALL were clinically relevant. Patients with p53 mutations experience a shorter duration of survival than those patients without p53 mutations. Additionally, patients with p53 mutations were significantly less likely to have achieved a complete second remission from reinduction therapy than those patients without p53 mutations and experience a shorter duration of survival from relapse even when a second reinduction is obtained. Though primarily identified only at relapse, p53 mutations were also associated with a decreased duration of first remission and overall decrease in survival from diagnosis. Patients with p53 mutations had a 3.8-fold increase in risk of death than those patients without p53 mutations. These findings suggest that p53 mutation is associated with poor clinical outcome that is characterized by (1) a shortened duration of survival after first relapse; (2) a reduced response to reinduction therapy; (3) a shortened duration of first remission; and, hence, (4) an overall decreased duration of survival and increased risk of death.

scholarly journals How I treat acute lymphoblastic leukemia in older adolescents and young adults

Blood ◽  
2015 ◽  
Vol 125 (24) ◽  
pp. 3702-3710 ◽  
Author(s):  
Emily Curran ◽  
Wendy Stock
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Survival Rates ◽  
Age Groups ◽  
Disease Free Survival ◽  
Current Approach ◽  
Adolescent And Young Adult

Abstract At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients.

Genetically Defined Racial Differences Underlie Risk of Relapse in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 14-14
Author(s):  
Jun J. Yang ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
Meenakshi Devidas ◽  
Xueyuan Cao ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
American Indian ◽  
American Indians ◽  
Lymphoblastic Leukemia ◽  
Prognostic Features ◽  
Increased Risk ◽  
Hispanic Patients ◽  
Racial Ethnic ◽  
Risk Of Relapse

Abstract The effect of race or ethnicity on cure and survival outcomes among children with acute lymphoblastic leukemia (ALL) is controversial. For those studies that have demonstrated variability in survival associated with race or ethnicity, the cause of these differences remains unclear. We therefore used genome-wide germline single nucleotide polymorphism (SNP) genotypes to quantitatively estimate racial ancestral composition in children with ALL and examined associations between ancestries and the probability of ALL relapse. To infer population genomic structures, we applied principal components analysis (PCA) to genotypes at 219,955 germline SNPs in 893 individuals: 683 patients with ALL (450 from St. Jude Children’s Research Hospital [St. Jude] Total XIIIB and Total XV studies and 233 from Children’s Oncology Group [COG] P9906 protocol), and 210 HapMap samples (60 CEU, 60 YRI, 90 CHB/JPT, serving as references for white, black, and Asian races, respectively). The top ranked principal component (PC1) separated self-reported black patients (n=92) and the YRI HapMap group from all other racial/ethnic groups; PC2 separated self-reported Asian patients (n=19) and the CHB/JPT HapMap samples from non-Asian populations. PC3, on the other hand, primarily captured genetic variation characteristic of American Indian ancestry (assessed using publicly available data from American Indians, n=105). Interestingly, Hispanic patients with ALL (n=75) showed a continuous cline between the American Indians and whites, displaying a gradient of these two ancestries among Hispanics. The relationships between ancestries (PC1, PC2, and PC3) and outcome were assessed in the St. Jude cohort first and validated in the COG cohort, using Fine and Gray’s regression test and after stratification for risk-adapted treatment. Of the top three PCs, only PC3 exhibited a significant association with cumulative incidence of relapse in St. Jude (P=0.038), with higher PC3 values linked to higher risk for relapse. This relationship between PC3 and relapse was validated in the COG cohort (P=0.003), which included more Hispanic patients than the St. Jude cohort. When the St. Jude and COG cohorts were combined, only the American Indian/Hispanic-informative PC3 (not PC1 or PC2) was related to relapse (P=4.5×10−4). Further, PC3 remained significant even after accounting for self-reported race/ethnicity (P=0.044), or when the analysis was restricted to self-reported white patients (P=0.006). The proportions of patients with high risk clinical or biological features (i.e. high leukocyte count, unfavorable age, unfavorable genetic subtypes, and minimal residual disease at the end of induction therapy) did not differ between the high and low PC3 groups (PC3 &gt; or &lt; 0.005). Therefore, the higher relapse rates in patients with higher proportions of American Indian ancestry are not derived from overrepresentation of unfavorable prognostic features in this group. In a multivariate analysis, PC3 remained significantly associated with the risk of relapse (P=0.041) after adjusting for known risk factors, indicating a possible independent prognostic value of PC3. In conclusion, germline genetic variation that is related to American Indian ancestry is associated with increased risk of leukemia relapse, providing evidence for a genetic basis for racial/ethnic differences in cancer treatment outcome.

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