Genetic Markers Add Significant Prognostic Information to Age and WBC Count in High-Risk, Ph-Negative, B-Precursor Adult Acute Lymphoblastic Leukemia (ALL): Study of 96 Patients Treated According to Risk-Adapted Protocols from the Pethema Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3798-3798
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Eulàlia Genescà ◽  
Mireia Morgades ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Homozygous Deletion ◽  
Advanced Age ◽  
Prognostic Information ◽  
Independent Prognostic Significance ◽  
Multivariable Analyses ◽  
Wbc Count

Abstract Introduction Recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of ALL have been identified in genes involved in B-cell development, cell cycle regulation, proliferation, apoptosis and drug resistance. Their independent prognostic significance in adult ALL patients is controversial. The aim of this study was to analyze the prognostic significance of CNA in a series of 96 high-risk, Ph-negative, B-precursor adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods MLPA assays (MRC-Holland) were performed for the following genes: IKZF1, IKZF2, IKZF3, EBF1, CDKN2A/B, PAX5, ETV6, BTG1, RB1, hsa-miR-31, X/Y PAR1 region genes (CRLF2, CSF2RA, IL3RA) and 14q32.33 region genes (IGH D, MTA1, KIAA0284). Fragment analysis was made by Genescan in an ABI-3130 sequencer (Applied Biosystems). Data normalization provided a value indicative of the presence or absence of CNA: 0-0.20 homozygous deletion, 0.21-0.70 heterozygous deletion, 0.71-1.30 normal, 1.31-1.70 heterozygous duplication and 1.71-2.20 homozygous duplication. Univariable and multivariable analyses including the most relevant clinical parameters (age, WBC count, phenotype, cytogenetics, CNS involvement) were performed for CR attainment, CR duration and OS. Results The median age [range] of the 96 patients was 39 [15-72] years, 50 (52%) patients were males, with a median WBC count 14.3 x109/L [0.4-388]. Phenotype: early pre-B 19 (20%), common 51 (54%), pre-B 22 (24%), unknown 2 (2%). Cytogenetics: normal 18 (19%), hyperdiploid 5 (5%), hypodiploid 2 (2%), near haploid 6 (6%), t(1;19) 7 (8%), 11q23/MLL 11 (12%), complex 1 (1%), other 27 (29%), no growth 17 (18%). The most frequent CNA deletions involved CDKN2A/B (43/96, 45%), PAX5 (34/94, 36%), IKZF1 (32/95, 34%), hsa-miR-31 (25/96, 26%), 14q32.33 region (18/96, 19%), RB1 (17/96, 18%), EBF1(12/91, 13%) and X/Y PAR (10/96, 10%). The most frequent duplications involved X/Y PAR (11/96, 12%) and 14q32.33 region (7/96, 7%). The CR rate was 83% (80/96), the median (95%CI) of CR duration was 2.7 years (0-5.9) and the median (95%CI) of OS was 2.1 (1.0-3.2), being the median (range) follow-up of the series of 3.8 (0.6-8.0) years. Table 1 shows the results of univariable and multivariable analyses. By multivariable analyses advanced age and EBF1 deletions were significantly associated with less CR rate, WBC count and X/Y PAR duplication were associated with shorter CR duration, and advanced age and CDKN2A/Bdeletion were associated with shorter OS. Conclusions The CNA of EBF1, X/Y PAR1 genes and CDKN2A/Bhave independent prognostic significance in adult patients with high-risk, Ph-negative, B-precursor ALL. This study suggests that these genetic studies should be added to the initial work-up of these patients for more accurate prognostic assessment Supported by grants PI10/01417, RD12-0036-0029 from Instituto Carlos III, 2014 SGR225 (GRE) from Generalitat de Catalunya and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Abstract 3798. Table 1. Results of the univariable and multivariable studies. Variable CR rate CR duration OS P (univ) OR (95%CI) P (univ) HR (95%CI) P (univ) HR (95%CI) Age 0.011 0.93 (0.89 - 0.98) NS - 0.005 1.03 (1.01 - 1.05) WBC NS - <0.001 1.01 (1.00 - 1.01) NS - IKZF1 * NS - 0.048 - NS - EBF1 * 0.025 0.11 (0.02 - 0.54) NS - NS - CDKN2A/B * NS - NS - 0.014 2.32 (1.35 - 4.00) X/Y PAR** NS - 0.013 4.26 (1.64 - 11.09) NS - *Normal versus deleted; ** Normal versus duplicated; NS: not significant Disclosures No relevant conflicts of interest to declare.

Prognostic Significance Of Copy Number Alterations In B-Lineage Adult Acute Lymphoblastic Leukemia Patients Enrolled In Risk-Adapted Protocols From The Pethema Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2556-2556
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Mireia Morgades ◽  
Ramon Guardia ◽  
Josep Sarrá ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Advanced Age ◽  
Copy Number Alterations ◽  
Gene Deletions ◽  
B Lineage ◽  
Wbc Count

Abstract Introduction In the last years genome wide profilings have identified recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of Acute Lymphoblastic Leukemia (ALL). These studies have identified deletions in B-cell development genes (IKZF1, EBF1, PAX5, TCF3, etc.), cell cycle regulation genes (CDKN2A/B, RB1, TP53, etc.), glucocorticoid resistance genes (BTG1, CREBBP) and growth factor receptors genes (CRLF2, CSF2RA, IL3RA) among others. Some of these CNA (i.e. IKZF1, CDKN2A, CRLF2) have been reported to have prognostic significance in several pediatric series but there are very few data regarding their impact in B-lineage adult ALL. Our aim was to analyze the frequency and prognostic significance of CNA in a series of 125 B-lineage adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods Bone marrow or peripheral blood (with significant blast burden) samples from 125 B-lineage adult ALL patients enrolled in risk-adapted protocols from the PETHEMA Group were analyzed at diagnosis. MLPA assays (MRC-Holland) were performed for the following genes: IKZF1, IKZF2, IKZF3, EBF1, CDKN2A/B, PAX5, ETV6, BTG1, RB1, hsa-miR-31, X/Y PAR1 region genes (CRLF2, CSF2RA, IL3RA) and 14q32.33 region genes (IGH D, MTA1, KIAA0284). Fragment analysis was made by Genescan in an ABI-3130 sequencer (Applied Biosystems). Data normalization provided a value indicative of the presence or absence of CNA: 0-0.20 homozygous deletion, 0.21-0.70 heterozygous deletion, 0.71-1.30 normal, 1.31-1.70 heterozygous duplication and 1.71-2.20 homozygous duplication. Results The median age [range] was 40 [15-74] years, 71 (57%) males, median WBC count 12.11 x109/L [0.4-388]. Immunophenotype: pro-B 14 (11%), common 71 (58%), pre-B 26 (21%), mature-B 10 (8%), unavailable 2 (2%). Cytogenetics: normal 16 (13%), hyperdiploid 6 (5%), hypodiploid 2 (2%), t(9:22) 20 (16%), t(1;19) 8 (6%), 11q23/MLL 11 (9%), 8q24/C-MYC 7 (5%), complex 1 (1%), iAMP21 2 (2%), other translocations or deletions 31 (25%), no growth 20 (16%). CNA frequencies of the 125 patients are shown in the table. IKZF1 deletions were significantly associated with EBF1 deletions, high WBC count and Philadelphia (Ph) chromosome. In the IKZF1 deleted cohort whole gene deletions were as frequent as Ik6 isoforms (28% each). A high codeletion rate was detected in genes located in 9p (CDKN2A/B with PAX5, CDKN2A/B with hsa-miR-31 and PAX5 with hsa-miR-31). CDKN2A/B also showed concomitant deletions with ETV6 while PAX5 showed codeletions with BTG1. CDKN2A/B and PAX5 deleted patients had higher WBC counts than non-deleted individuals. Clinical follow-up data was available for 123 patients of the whole series and for the 105 patients of the Ph-negative cohort. Multivariate analysis showed that advanced age, BTG1 deletions and EBF1 deletions were negative prognostic factors for achieving Complete Remission (CR) and WBC count and IKZF1 deletions significantly reduced CR duration in both cohorts. Interestingly, there were significant differences in relapse rates between whole and partial gene IKZF1 deletions. IKZF1 haploinsufficient patients had a probability of CR duration at 3 years of 83% ± 30% vs. 6% ± 12% of partial gene deletion carriers. Advanced age and IKZF1 deletions were predictors for overall survival in the Ph-negative cohort and age>30 years, IKZF1 deletions and hsa-miR-31 deletions were associated with poor prognosis in the whole series. Conclusions In B-lineage adult ALL, deletions of IKZF1, EBF1, BTG1 or hsa-miR-31 are markers with prognostic significance in addition to age and WBC count. Patients with partial IKZF1 gene deletions have a significantly higher probability of relapse than those with whole gene loss. These genetic abnormalities could help to better define prognostic subgroups in adult patients with B-lineage ALL. Supported by the grants PI10/01417 and RD12-0036-0029 from Instituto Carlos III and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Disclosures: No relevant conflicts of interest to declare.

Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia.

1985 ◽  
Vol 3 (4) ◽  
pp. 477-484 ◽  
Author(s):  
D K Kalwinsky ◽  
P Roberson ◽  
G Dahl ◽  
J Harber ◽  
G Rivera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Periodic Acid ◽  
Prognostic Significance ◽  
Time To Failure ◽  
Prognostic Information ◽  
Biological Features ◽  
Wbc Count

Improvements in therapy for childhood acute lymphoblastic leukemia (ALL) have led us to reevaluate the prognostic significance of lymphoblast characteristics at diagnosis. From application of univariate and multivariate statistical methods, we determined the relationship of five blast cell features to treatment outcome in 250 patients who were enrolled in two clinical trials at this center from May 1979 through April 1982. Karyotype ploidy, lymphoblast morphology, and immunophenotype were each significantly related to prognosis as measured by time to failure, while periodic acid-Schiff reactivity and glucocorticoid receptor number lacked prognostic implication for this patient population. In addition, clinical features of initial WBC count, age, and race were also significant independent variables in predicting treatment response. By multivariate analysis, both ploidy and morphology contributed prognostic information to a clinical model based on WBC count, age, and race. If the model was adjusted for impact of ploidy, however, French-American-British morphology no longer contributed additional prognostic information. Our findings suggest that many traditional biological features used to estimate prognosis in ALL can be discarded in favor of clinical features (leukocyte count, age, and race) and cytogenetics (ploidy) for planning of future clinical trials.

Growth Differentiation Factor-15 in Patients with Light Chain (AL) Amyloidosis Has Independent Prognostic Significance and Adds Prognostic Information Related to Risk of Early Death and Renal Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 306-306 ◽  
Author(s):  
Efstathios Kastritis ◽  
Ioannis Papassotiriou ◽  
Evangelos Terpos ◽  
Athanassios Akalestos ◽  
Erasmia Psimenou ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Significance ◽  
Early Death ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Prognostic Information ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Hematological Response ◽  
Independent Prognostic Significance

Abstract Growth differentiation factor-15 (GDF-15) is a member of the TGF-beta family, which is involved in several pathological conditions, including inflammation, cancer, cardiovascular, pulmonary and renal diseases. GDF-15 has prognostic value in patients with cardiovascular disorders and adds prognostic information to conventional prognostic factors, such as NT-proBNP and high-sensitivity troponin (hs-TnT). Cardiac involvement is the most important determinant of prognosis in patients with AL amyloidosis and cardiac biomarkers have major prognostic importance in AL. The aim of the study was to explore the value of GDF-15 in patients with AL amyloidosis. We measured the circulating levels of GDF-15, NT-proBNP and hs-TnT in 77 patients with newly diagnosed AL amyloidosis, before and 3 months post frontline treatment. GDF-15 was measured by a novel pre-commercial immunoassay (Roche Diagnostics). Patients' median age was 68 years; most patients had cardiac (61%) or renal involvement (74%); 61% had NT-proBNP >1284 pg/ml and 46% had hsTnT>54 ng/ml. Median eGFR was 57 ml/min/1.73m2, 52% had eGFR <60 ml/min/1.73m2, while 12% required dialysis at the time of treatment initiation. All patients received primary therapy with bortezomib- (49%) or lenalidomide-based regimens (51%). Median levels of GDF-15 were 3594 pg/ml (range 626-71,475pg/ml); 95% of patients with AL had GDF-15 levels >1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease). GDF-15 correlated with NT-proBNP (r=0.538, p<0.001), hs-TnT (r=0.447, p=0.02) and eGFR (r=-0.570, p<0.001). Patients with GDF-15 levels within the upper quartile (>7575 pg/ml) had a very poor outcome (median overall survival (OS) 3 months) compared to patients with GDF-15 levels below the upper quartile (p=0.01; see the Figure). Among other cardiac markers, hs-TnT >54 ng/ml (12 vs >48 months, p=0.001) and NT-proBNP >1284 pg/ml (11 vs >48 months, p<0.001) were also associated with shorter OS. Higher cut-off levels for NT-proBNP and hs-TnT did not discriminate patients at high risk for early death more accurately. In a multiple logistic regression model which included GDF-15, NT-proBNP and hs-TnT, only GDF-15 in the upper quartile (HR: 8.427, 95% CI 1.73-41.1, p=0.008) was independently predictive of early death at 3 months. Similar results were obtained when these biomarkers were treated as continuous variables. Regarding OS, GDF-15 had independent prognostic significance in a multivariate model that included both NT-proBNP and hs-TnT. We also evaluated changes in the levels of GDF-15, NT-proBNP and hs-TnT in patients who received lenalidomide after 3 months of treatment. In these patients NT-proBNP often increases without obvious deterioration of cardiac function, thus complicating the assessment of cardiac response early, during the course of therapy. GDF-15 levels did not change significantly either in patients with hematological response (p=0.998) or those without hematological response (p=0.774). However, NT-proBNP levels increased substantially both in those with hematological response (p=0.05) and in those without hematological responses (p=0.013). Similarly, hs-TnT levels increased in non-responders (p=0.006) and did not change in patients with hematological response (p=0.251). As GDF-15 reflects heart and renal defects, we further evaluated whether GDF-15 could be associated with the risk of progression to ESRD and need for dialysis. Using ROC analysis, GDF-15 >median was identified to better discriminate patients which had a shorter time to dialysis (29 months vs not reached, p=0.001, see the Figure; with 38% vs. 8% progressing to ESRD, respectively). eGFR< 60 ml/min/m2 was also a strong predictor of ESRD (p=0.004). However, in multivariate analysis which included GDF-15 >median, eGFR <60 ml/min/m2 and proteinuria >5 g/day, only GDF-15 was independently associated with a higher risk of ESRD requiring dialysis (HR: 4.25, 95% CI 1.01-18, p=0.045). In conclusion, GDF-15 is a novel biomarker with prognostic implications for different outcomes in patients with AL; it is associated with a high risk of early death, with OS and also with renal outcome. More importantly GDF-15 adds prognostic information independent of the traditional cardiac biomarkers and thus, its measurement in larger series of patients is recommended. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Prognostic Significance of Complex Karyotype in Philadelphia Chromosome-Negative (Ph−) Acute Lymphoblastic Leukemia (ALL) in Adults Is Related with Risk Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3501-3501 ◽  
Author(s):  
Isabel Granada ◽  
Juan-Manuel Sancho ◽  
Albert Oriol ◽  
Mireia Morgades ◽  
Concepción Bethencourt ◽  
...  
Keyword(s):  
High Risk ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Complex Karyotype ◽  
Increased Risk ◽  
Wbc Count ◽  
Standard Risk

Abstract Different from acute myeloblastic leukemia, the prognostic significance of complex karyotype (CK) is not well known in adults with ALL. A recent study showed that CK (≥5 chromosomal abnormalities) confer an increased risk of treatment failure and poor survival (Moorman, 2007). The aim of study was to analyze the possible prognostic influence of CK in Ph- adult (≥15yr) ALL patients treated with risk-adapted protocols from the Spanish PETHEMA Group. The cytogenetic studies were reviewed following the ISCN criteria (2005). CK was defined as the finding of 3 or more structural chromosomal abnormalities. Patients were included in three different trials: ALL-96 for standard-risk (SR) ALL, and ALL-93 or ALL-AR03 for high-risk (HR) ALL. Patients with Burkitt’s ALL were not included in these trials. Patients included: 237. SR: n=44, 25 males, WBC count 12x109/L (SD: 14), 5 patients with CK (11.4%), 39 non-complex karyotype and normal karyotype (non- CK) (88.6%). HR: n= 193, 107 males, WBC count 58x109/L (SD: 77), 25 patients with CK (13%), 168 non- CK (87%). Complete remision (CR), disease free survival (DFS) and overall survival (OS) according to karyotype group and trial are showed in Table: When CK was defined as the finding of ≥ 5 structural chromosomal abnormalities (n=11, SR=3, HR=8), DFS and OS were also significantly shortened in patients with SR ALL and CK (p=0.007 and p=0.001, respectively), but not in patients with HR ALL. Complex karyotype (defined as ≥ 3 or ≥5 structural chromosomal abnormalities) did not have any prognostic relevance in adults with high-risk Ph- ALL, whereas a significant short survival observed in standard-risk patients with complex karyotype.

Microarray-Based Genomic Profiling Facilitates Genetic Subgrouping and Detects Critical Submicroscopic Aberrations Associated with Prognosis in Pediatric Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1444-1444
Author(s):  
Marilyn L Slovak ◽  
Ya-Hsuan Hsu ◽  
Jennifer A Otani-Rosa ◽  
Jennifer A Jahn ◽  
Zunyan Dai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Neutral Loss ◽  
Genomic Profiling ◽  
Prognostic Information ◽  
Old Patients

Abstract Abstract 1444 Objective: Risk-adapted therapeutic categories in acute lymphoblastic leukemia (ALL) take into account several key parameters, including cytogenetics. Because accurate conventional chromosome (CC) studies in ALL are hampered by low mitotic indexes and poor chromosome morphology, fluorescence in situ hybridization (FISH) and other molecular methods such as RT-PCR are currently used to complement karyotyping. We evaluated the contribution of oligo/SNP microarrays for providing additive genetic information in ALL that is not obtained by karyotype studies. Methods: Specimens from 24 children and young adults (12 M;12 F), including 3 patients with Down syndrome (DS), were processed for pre-B ALL cytogenetics work-up plus SNP/Oligo microarray. The median age was 4 y (range, 2–21 y); 23 patients had a pre-B-cell immunophenotype. Unstimulated CC (n=23) and pre-B ALL FISH studies (n=20) were performed using standard protocols. Genomic DNA was extracted from the residual bone marrow samples and processed for genome-wide copy number analyses on the Cytoscan HD oligo/SNP microarray (Affymetrix). Results: CC detected abnormalities that allowed prognostic subgrouping in 19 (83%) of 23 patients tested; the 24th patient was not tested with CC but showed an ETV6-RUNX1 fusion on FISH. Microarray genomic profiling allowed genetic subgrouping in the 4 cases with suboptimal or non-informative CC results. Overall, microarray detected a median of 5 additional copy number aberrations (CNAs) per patient (range, 1–27), including 18 additional CNAs in a T-cell ALL patient with only deletion 9p detected by CC and FISH. The 4 most common deletions detected by array involved CDKN2A (n=10, including 4 biallelic deletions) and ETV6, SESN1/6q16.1, and IKZF1 (6 cases each); sporadic deletions involved genes affecting B-cell development, cell cycle progression, DNA repair, and tumor progression were also seen. Five of the 7 patients with ETV6-RUNX1 translocation also showed deletions or disruptions at or near these 2 loci, suggesting the presence of the “cryptic” t(12;21). No balanced translocations were detected. Clonal diversity was easily detectable by microarray; however, a case with 64 chromosomes and a case with both 2n and 4n clones were difficult to interpret. At least 1 extended area of copy neutral loss-of heterozygosity (>5 Mb) was seen in 8/24 (33%) cases, including a 17q region that encompassed IKZF3; however, in most cases the significance of these CN-LOH changes was not clear. Significant “high risk” prognostic alterations identified by array but not detected by CC included 3 CRLF2-rearragements (found in 2 of the 3 DS patients) and disruption of the IKZF1 locus (6 patients). IKZF1 deletions were detected in a 5-y-old DS-ALL patient with CRLF2-P2PY8, a 20-y-old DS-ALL patient with high hyperdiploidy, an 18-y-old patients with IGH-CRLF2 confirmed by FISH (CC failed), another 18-y-old patient with a normal karyotype, and 1 patient each with iAMP(21) and dic(9;20) ALL. Conclusion: Submicroscopic IKZF1 deletions have been associated with drug resistance and a high risk of treatment failure in ALL, signifying critically important prognostic information needed for clinical management. Accordingly, OligoSNP arrays provide a comprehensive approach for accurately identifying clinically significant abnormalities in ALL that may be missed by routine chromosome study and targeted FISH panels alone. Array testing is a highly sensitive complementary molecular cytogenetic assay that should be offered to newly-diagnosed ALL patients, especially when CC is non-informative, to facilitate genetic subgrouping and define tumor markers that may help monitor a patient's clinical course. Disclosures: No relevant conflicts of interest to declare.

Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

1996 ◽  
Vol 14 (1) ◽  
pp. 18-24 ◽  
Author(s):  
M Smith ◽  
D Arthur ◽  
B Camitta ◽  
A J Carroll ◽  
W Crist ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Risk Category ◽  
Treatment Assignment ◽  
Uniform Approach ◽  
Wbc Count

PURPOSE To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored a workshop in September 1993. Participants included representatives from the Childrens Cancer Group (CCG), Pediatric Oncology Group (POG), Dana-Farber Cancer Institute (DFCI), St Jude Children's Research Hospital (SJCRH), and the CTEP. METHODS Workshop participants presented and reviewed data from ALL clinical trials, using weighted averages to combine outcome data from different groups. RESULTS For patients with B-precursor (ie, non-T, non-B) ALL, the standard-risk category (4-year event-free survival [EFS] rate, approximately 80%) will include patients 1 to 9 years of age with a WBC count at diagnosis less than 50,000/microL. The remaining patients will be classified as having high-risk ALL (4-year EFS rate, approximately 65%). For patients with T-cell ALL, different treatment strategies have yielded different conclusions concerning the prognostic significance of T-cell immunophenotype. Therefore, some groups/institutions will classify patients with T-cell ALL as high risk, while others will assign risk for patients with T-cell ALL based on the uniform age/WBC count criteria. Workshop participants agreed that the risk category of a patient may be modified by prognostic factors in addition to age and WBC count criteria, and that a common set of prognostic factors should be uniformly obtained, including DNA index (DI), cytogenetics, early response to treatment (eg, day-14 bone marrow), immunophenotype, and CNS status. CONCLUSIONS The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

1991 ◽  
Vol 9 (12) ◽  
pp. 2183-2192 ◽  
Author(s):  
C M Rubin ◽  
M M Le Beau ◽  
R Mick ◽  
M A Bitter ◽  
J Nachman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Childhood All ◽  
Wbc Count

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

CD58-Negtive Leukemia Initiating Cells Are Independently Associated with High Risk of Relapse in B-Precursor Acute Lymphoblastic Leukemia: A Comprehensive Clinical and Biological Profiling Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1397-1397
Author(s):  
Yuan Kong ◽  
Yanrong Liu ◽  
Honghu Zhu ◽  
Qian Jiang ◽  
Hao Jiang ◽  
...  
Keyword(s):  
High Risk ◽  
Expression Profile ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Lymphocyte Function ◽  
The Impact

Abstract Abstract 1397 Background: Using neonatal NOD/SCID/IL2rγnull xenotransplantation model, we previously demonstrated that CD34+CD38+CD19+ cells as well as CD34+CD38−CD19+ cells have the capacities to initiate B-precursor ALL (B-ALL) in vivo and to self-renew, that is, leukemia initiating cells(LICs) are enriched in the CD34+CD19+phenotype in human B-ALL (Kong Y et al. Leukemia 2008; 22: 1207–1213). Nevertheless, in order to distinguish B-ALL initiating cells from their normal compartment, further markers have to be identified. CD58 (lymphocyte function–associated antigen 3), a cell surface adhesion molecule binding to CD2, plays a critical role in the attachment of cytotoxic T lymphocytes and non-specific killer cells to their targets. Recent data give evidence that diffuse large B cell lymphoma patients with poor expression of CD58 appear to be more aggressive by escaping from immune-surveillance of the host. However, the prognostic relevance of CD58 expression on B-ALL initiating cells is largely unknown. Objectives: To investigate the expression profile of CD58 on CD34+CD19+B-ALL initiating cells. To evaluate the prognostic significance of CD58 expression on LICs in human B-precursor ALL. Materials and methods: Using a cohort of 139 patients (including pediatric and adult patients) with CD34+ B-ALL, the expression profile of CD58 on LICs(CD34+CD19+ phenotype) were examined by multicolor flow cytometry (FCM) at diagnosis. A total of 1,050,000 events were routinely collected. More than 20% of LICs with CD58 expression were defined as CD58-positive LICs (CD34+CD19+CD58+ phenotype, abbreviated by CD58+LICs), all other cases were defined as CD58-negtive LICs (CD34+CD19+CD58−phenotype, abbreviated by CD58−LICs). Furthermore, the impact of CD58−LICs at diagnosis on the clinical outcome was prospectively investigated. The study was approved by the Ethics Committee of Peking University People's Hospital and written informed consent was obtained from all subjects. Results: Among the newly diagnosed B-ALL patients, 119 cases were detected with CD58+LICs and the remaining 20 cases with CD58−LICs. The expression of CD58 on LICs at diagnosis was inversely related to the age, WBC at diagnosis and NCCN risk group of the B-ALL patients (P=0.002, P=0.015 and P=0.009, respectively). CD58+LICs group had a higher complete remission(CR) rate after one course induction than CD58−LICs group (87.39% vs. 65.00%, P=0.019).Cumulative incidence of relapse (CIR) at 2-year in the CD58+LICs group was significantly lower than that in the CD58−LICs group (18.20% ± 0.15% vs. 72.00% ± 1.30%, P<0.0001). CD58+LICs group resulted in superior survival compared to CD58−LICs group (2-year disease-free survival(DFS), 77.95% ± 4.36% vs. 28.00% ± 10.58%, P<0.0001; 2-year overall survival(OS), 75.61% ± 5.53% vs. 42.4% ± 11.50%, P = 0.0016). Multivariate analysis revealed CD58−LICs at diagnosis as independent risk factor affecting relapse (HR=3.413, P=0.001) and DFS (HR=2.857, P=0.004) in B-ALL patients. By summing up the risk factors(RF) defined as CD58 status on LICs (CD58+LICs=0,CD58−LICs=1),age(<18 years=0,≥18 years=1) and NCCN risk group (Standard risk=0, High risk=1), two prognostic groups (Low risk group: RF≤1;High risk group: RF>1)could be discriminated, which differed significantly with regard to 2-year CIR(9.18%±0.14% vs. 49.94%±0.67%, P<0.0001), 2-year DFS (90.82%±5.65% vs. 39.83%±7.97%, P<0.0001) and 2-year OS(91.21%±3.87% vs. 45.27%±7.89%, P<0.0001), respectively. Conclusions: CD58-negtive leukemia initiating cells at diagnosis independently correlate with unfavorable prognosis. Combined analysis of CD58 status on CD34+CD19+leukemia initiating cells at diagnosis, age and NCCN risk group may help to optimize currently available prognostic stratification model in B-ALL. Acknowledgments: This work was supported by grants from National Natural Science Foundation of China (30800483) and Beijing Municipal Science and Technology Program (Z111107067311070). Disclosures: No relevant conflicts of interest to declare.

Characteristics and Prognostic Significance of CRLF2 High Expression and the Co-Existence with JAK1 Mutations and Ikaros Deletion in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3800-3800 ◽  
Author(s):  
Zheng Ge ◽  
Juan Liu ◽  
Run Zhang ◽  
Xing Guo ◽  
Jing-Yan Xu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
High Expression ◽  
Newly Diagnosed

Abstract Objective Cytokine receptor-like factor 2 (CRLF2) play an important role in differentiation and proliferation of lymphoid precursor cells through activation of JAK signaling pathway. Increased CRLF2 expression associates with mutations in JAK2, a combination that transforms hematopoietic cells, suggesting that mutants in JAK family members and CRLF2 may cooperate to contribute to acute lymphoblastic leukemia (ALL) pathogenesis. Moreover, the Ikaros deletion is also associated with the development of T-/B-cell ALL with poor outcome and relapse of high-risk leukemia. The aim of this study was to determine the clinical characterization and prognostic values of CRLF2 high expression and its concomitant expression with JAK1 mutations and Ikaros deletion in adult ALL patients. Methods Quantitative PCR (qPCR) was performed to detect the expression of CRLF2 in 133 newly diagnosed adult patients with ALL. Genomic DNA was amplified to detect the mutations of the exon 13, 14, 16, 18 and 19 of JAK1, and IKZF1 exons 4 through 7 deletions (△4–7) by direct sequencing or sequencing after cloning. The CD34, CD13, CD33 and other markers were detected on the leukemia cells from bone marrow of the patients by flow cytometry, and the correlations of the CRLF2 high expression with the clinical features, survival, and with co-expression of JAK1 mutations and Ikaros deletion were statistically analyzed with Pearson's chi-square test or Fisher's exact test and Kaplan–Meier curves analysis. Results CRLF2 high expression was detected in 22.8% of newly diagnosed adult ALL. The patients with CRLF2 high expression has significantly higher percentage of CD34, CD13 or CD33 positive than those with low expression（91.3% vs 62%, P=0.008; 76.2% vs 46.3%, P=0.016; 80.0% vs 37.9%, P=0.001), higher frequency of splenomegaly（60.0% vs 32.0%, P=0.040) in the adult ALL and shorter overall survival and event-free survival（9.5 months vs 16 months, P=0.029; 3 months vs 9 months, P=0.030）in the Philadelphia chromosome negative ALL. Moreover, the 4 JAK1 point mutations with amino acid changes were detected in the patients, which had significant CRLF2 high expression compared to that without mutation（75% vs 21.3%, P=0.037). The co-existence of CRLF2 high expression and IKZF1 exons 4-7 deletion (isoform Ik6) was found in 4 of 10 patients. Conclusion CRLF2 high expression predicts poor survival, and significantly co-exists with JAK1 mutation and Ikaros deletion in adult ALL patients. Our result also suggested that CRLF2, JAK1 and IKZF1 could be integrated in future prognostic model of adult ALL as possible markers for high-risk leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 409-409
Author(s):  
Petra Breithaupt ◽  
Barbara Meissner ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
André Schrauder ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
High Risk ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Risk Group ◽  
Independent Predictor ◽  
Lymphoblastic Leukemia ◽  
Time Points ◽  
Pediatric All

Abstract Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of <10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

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