scholarly journals Frequency and Prognostic Impact of IKZF1 and Co-Existed Gene Alterations in Childhood B-ALL in Taiwan

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2750-2750
Author(s):  
Hsi-Che Liu ◽  
Ying-Jung Huang ◽  
Ting-Chi Yeh ◽  
Tang-Her Jaing ◽  
Chao-Ping Yang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Ras Pathway ◽  
Prognostic Profile ◽  
Minimal Residual ◽  
Gene Alterations

Introduction: IKZF1 deletion was firstly reported to be very frequent in Philadelphia (Ph) positive B-cell acute lymphoblastic leukemia (B-ALL), and continuously found in other B-ALL subtypes. IKZF1plus defined as the presence of any of CDKN2B, CDKN2A,PAX5 or PAR1 in the absence of ERG deletion and was reported to describe a new minimal residual disease (MRD)-dependent poor prognostic profile in B-ALL.1 We aimed to analyze the frequency and prognostic relevance of IKZF1 deletion with or without co-occurring gene alterations in Taiwanese children with B-ALL treated with TPOG-ALL-2002 protocol or MRD-directed TPOG-ALL-2013 protocol. Methods: Bone marrow samples at diagnosis from 561 children excluding Ph+ and infant ALL were analyzed. Detection of gene deletion was carried out with multiplex ligation dependent probe amplification (MLPA) kit (SALSA MLPA P335 and P327) and mutations of RAS pathway genes (NRAS, KRAS, and PTPN11) were assessed by Sanger sequencing. The outcome was analyzed on 259 patients treated with TPOG-ALL-2002 protocol and 158 patients treated with TPOG-ALL-2013 protocol. Results: IKZF1 deletions were present in 11.2% of 561 patients. DEL 4-7, DEL 1-8, and other variants were present in 50.8%, 14.3%, and 34.9%, respectively of 63 IKZF1-deleted patients. Co-existence of additional deletions with IKZF1 deletion was detected in 34.0% for CDKN2B, 37.3% for CDKN2A, 27.7% for PAX5, 2.1% forPAR1, and 8.0% for ERG. IKZF1plus comprised of 4.4% of 546 patients who had all the genes examined. Co-existed mutations of RAS pathway genes were detected in 5.0% for PTPN11, 13.3% for NRAS, and 10.0% for KRASin the IKZF1-deleted patients. The 5-year event-free survival (EFS) of IKZF1-undeleted patients was significantly better compared with IKZF1-deleted patients in TPOG-2002 cohort (82.5 ± 2.6% vs. 56.9 ± 9.1%, P = 0.002) as did TPOG- 2013 cohort (89.4 ± 3.9% vs. 59.1 ± 19.8%, P = 0.012). The 5-year overall survival (OS) of IKZF1-deleted patients was worse than that of patients with undeleted IKZF1 in TPOG-2013 cohort (58.3 ± 19.8% vs. 89.2 ± 4.2%, P = 0.004) but not in TPOG-2002 cohort (90.9 ± 5.0% vs. 86.9 ± 2.3%, P = 0.846). DEL 1-8 patients had an inferior 5-year EFS (33.3 ± 19.2%) compared with DEL 4-7 (63.3 ± 12.0%,) or DEL-others (60.0 ± 18.4 %) in TPOG- 2002 cohort (P = 0.003). No significant difference in OS was observed between patients among different IKZF1-deleted subtypes in TPOG-2002 cohort (P = 0.283) (Fig. 1A) but there was different in TPOG-2013 cohort (P = 0.003) (Fig. 1B). Patients with IKZF1 deletion alone had comparable 5-year EFS and 5-year OS compared with patients with IKZF1plus in TPOG-2002 cohort whereas patients with IKZF1 deletion alone had worse 5-year EFS (33.3 ± 27.2% vs. 80.0 ± 17.9%, P = 0.284) and 5-year OS (33.3 ± 27.2% vs. 80.0 ± 17.9%, P = 0.415) than that of KZF1plus in TPOG-2013 cohort. The prognostic impact of IKZF1 deletion with co-existed gene alterations in TPOG-2002 cohort was further analyzed as follows: IKZF1plus with ≧ 2 co-existed deletions had an inferior 10-year EFS (23.8 ± 20.3%) compared with patients with IKZF1 deletion alone (36.7 ± 17.5%) or IKZF1-undeleted patients (81.5 ± 2.7%) (P = 0.005) (Fig. 1C). Three patients carried both IKZF1 and ERG deletions had a superior 5-year EFS (100%) compared with IKZF1-deleted alone or IKZF1-undeleted patients (P = 0.005) (Fig. 1D). The 10-year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with RAS wild-type genes (66.6% ± 6.4% vs. 83.7% ± 2.6%, P = 0.011). In multivariate analysis, in addition to the initial white blood count > 50 x 109/L and KMT2A-rearranged, IKZF1 deletion (HR=2.609, 95% CI: 1.363-5.034; P = 0.004) and RAS pathway gene mutations (HR=2.360, 95% CI: 1.336-4.168; P = 0.003) were independent genetic predictors for inferior EFS. Co-existence of IKZF1 deletion with RAS pathway mutations had worst 5-year EFS (20.0% ± 12.6%, P < 0.0001, Fig. 1E), and 10-year OS (53.3% ± 17.6%, P = 0.042, Fig. 1F). Conclusions: Our results showed that IKZF1 deletion alone was associated with an inferior OS in MRD-directed TPOG-2013 treated cohort but not in TPOG-2002 cohort in which it became significant when co-existed with RAS pathway mutations. Reference: 1. IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol. 2018, 1240-1249. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1plus Defines a New Minimal Residual Disease–Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

2018 ◽  
Vol 36 (12) ◽  
pp. 1240-1249 ◽  
Author(s):  
Martin Stanulla ◽  
Elif Dagdan ◽  
Marketa Zaliova ◽  
Anja Möricke ◽  
Chiara Palmi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Prognostic Profile ◽  
Minimal Residual

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

Prognostic Role of Minimal Residual Disease in Mature B-Cell Acute Lymphoblastic Leukemia of Childhood

2007 ◽  
Vol 25 (33) ◽  
pp. 5254-5261 ◽  
Author(s):  
Lara Mussolin ◽  
Marta Pillon ◽  
Valentino Conter ◽  
Matilde Piglione ◽  
Luca Lo Nigro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chemotherapy Cycle ◽  
Prognostic Impact ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

PurposeTo study the prevalence of t(8;14) at diagnosis and the response kinetics to treatment of minimal residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) patients and determine its impact on prognosis.Patients and MethodsA total of 68 children affected by de novo B-ALL enrolled onto the Berlin-Frankfurt-Muenster–based Italian Association of Pediatric Hematology and Oncology LNH-97 clinical protocol were studied. Bone marrow aspirate from each patient was analyzed for the presence of t(8;14)(q24;q32) by long-distance polymerase chain reaction at diagnosis, after the first chemotherapy cycle, and after subsequent cycles until negative for MRD. Morphologic and immunophenotypic analyses were reviewed centrally.ResultsA total of 47 patients (69%) were positive for t(8;14)(q24;q32). MRD response kinetics was determined in 39 patients. All of them reached clinical complete remission and most (31 of 39) became MRD negative after the first chemotherapy cycle. The 3-year relapse-free survival (RFS) was 38% (SE = 17%) in patients MRD positive after the first chemotherapy cycle compared with 84% (SE = 7%) in MRD-negative patients (P = .0005), whereas there was no difference in RFS for children who reached a clinical complete remission after the first chemotherapy cycle versus those who did not (RFS = 72% and SE = 9%; RFS = 79% and SE = 11%, respectively; P = .8). In multivariate analysis, MRD was shown to be predictive of higher risk of failure.ConclusionOur study demonstrated that MRD carries a negative prognostic impact in B-ALL patients and suggests that a better risk-adapted therapy, possibly including the use of anti-CD20 monoclonal antibody, should be considered in selected patients.

scholarly journals Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stephanie L. Rellick ◽  
Gangqing Hu ◽  
Debra Piktel ◽  
Karen H. Martin ◽  
Werner J. Geldenhuys ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Tumor Cells ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Adherent Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

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