Integrated Use of Minimal Residual Disease Classification and IKZF1 Alteration Status Accurately Predicts 79% of Relapses In Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 272-272 ◽  
Author(s):  
Esmé Waanders ◽  
Vincent H.J. van der elden ◽  
Ellen van der Schoot ◽  
Frank N. van Leeuwen ◽  
Simon V. van Reijmersdal ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 272 The response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). Even though MRD classification clearly identifies patients at low or at high risk for relapse, it also results in a large intermediate group (50 to 60% of patients), which still contains approximately half of all relapse cases. To improve risk stratification, we evaluated the added value of the IKZF1 alteration status, recently identified as a prognostic factor, in precursor-B-ALL patients. In an unbiased cohort of 131 uniformly treated precursor-B-ALL patients, we determined MRD levels at 42 and 84 days after treatment initiation using RQ-PCR analysis of Ig/TCR rearrangements. Based on these levels, patients were divided into three groups: MRD-Low (MRD-L), MRD-Medium (MRD-M) and MRD-High (MRD-H). IKZF1 alterations at diagnosis were determined using multiplex ligation-dependent probe amplification and genomic sequencing. We confirmed the strong prognostic significance of MRD classification, which was independent of IKZF1 status. Importantly, in the large MRD-M group (n=81; 62% of patients) containing 46% of the relapsed patients, IKZF1 alteration status identified 8 out of 11 relapsed patients (72%). The 9 year relapse-free survival (RFS) for IKZF1 mutated patients in this MRD-M group was 27% compared to 96% for patients wild-type for IKZF1 (P<0.001). Based on these results, we defined a new parameter integrating both MRD and IKZF1 status. The favorable risk group included patients classified as MRD-L or MRD-M with IKZF1 wild-type (n=104; 5 relapses), whereas the high risk group consisted of MRD-H patients or MRD-M patients with IKZF1 alterations (n=27; 19 relapses). This parameter showed stronger prognostic value than each of the established risk factors alone (Hazard Ratio[95%CI]: 24.98[8.29-75.31]). Importantly, whereas MRD and IKZF1 status alone identified only 46% and 54% of relapses, respectively, their integrated use allowed prediction of 79% of all relapses with 93% specificity. In conclusion: The use of a new parameter integrating MRD and IKZF1 status results in an unprecedented sensitivity in upfront relapse prediction and has a high potential for future risk stratification, particularly for patients originally classified as non-high-risk, such as the large group of MRD-M patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparative Value of the Assessment of Minimal Residual Disease in Peripheral Blood at Days 8 and 15 By Flow Cytometry in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5270-5270
Author(s):  
Marie Loosveld ◽  
Vanessa Nivaggioni ◽  
Isabelle Arnoux ◽  
Denis Bernot ◽  
Chantal Fossat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, but treatments' progress now allowsto obtain prolonged remission or curein over 90% of the patients. Consequently, therapeutic de-escalation is now an objective for future treatment protocols, providing that biomarkers allow to reliablyidentifygood responders. Among such indicators, low levels of Minimal Residual Disease (MRD) obtained early after induction chemotherapy stand out as good candidates. The latter can be investigated usingmultiparameterflow cytometry (MFC) or real-time polymerase chain reaction (RT-PCR) for immunoglobulins or T-cell receptors (IG TCR) rearrangements. In this study we report the impact on survival of two early points of peripheral blood (PB) MRD assessment by MFC at days 8 and 15 on a cohort of 125 children with B-ALL enrolled in the French FRALLE trial and compared to molecular MRD in the bone marrow (BM) at day 35. Patients and methods. The study enrolled 67 boys and 58 girls and the duration of the study allowed for a median follow up of 52,1months. Median age at diagnosis was 57 months old (range 18 to 196), 101 children were between 1 to 10 years old and 24 were older than 10. Complete blood counts (CBC) at diagnosis showed a median of 6.7x109/L leucocytes (range 0.47 - 151x109/L) and 33% blasts (range 0 to 97%). One hundred and eight children had less than 50x109/L leucocytes while 17 had higher counts. EGIL classification at diagnosis allowed to classify patients as three B-I, 94 B-II, 27 B-III and 1 B-IV. Cytogenetic analyses were performed for 118 patients who were partitioned as follows: low risk n=47, intermediate risk n=55 and high risk n=16 (Harrisson CJ et al., BJH, 2010). Eighty-three patients were in the low risk group and 42 in the high-risk group as described by the FRALLE protocol. Seven patients of the 64 tested had an IKZF1 deletion. During the duration of the study, 20 patients relapsed and 8 died. Corticosensitivitywas defined by less than 1x109/L PB blasts on day 8 andchemosensitivity by less than 5% BM blasts on day 21 on BM smears. PB MRD was assessed in MFC with a single five or ten colors tube adapted to each patient's leukemia associatedimmunophenotypeon a backbone of CD45, CD19, CD10 and CD38. Statistical analyzes examined factors impacting disease-free survival (DFS) using Log rank test and Kaplan-Meier using theMedcalc® software (Ostend, Belgium). P values <0.05 were considered significant. Results None of diagnosis features had any significant impact on DFS: age (p=0,95), risk group (p=0,17), EGIL classification (p=0,55), cytogenetics (p= 0,87), leucocyte count (p=0,36) nor IKZF1 deletion (p=0,2). Of the 125 patients, 9 were corticoresistant, 79 corticosensitive and 37 not evaluable because of less than 1x109/L leucocyte at diagnosis.Corticosensitivity had no impact on DFS (p=0,11). Conversely,chemosensitivity had a significant positive impact on DFS (p= 0,009). Day 8 PB MRD did not oultlineany significantly different DFS, whether considering detectable vs undetectable MRD (p=0.65) or MRD levels (logwisefrom >10-1 to <10-4, p=0,22). Conversely, PB MFC at day 15 appeared highly discriminant. Considering notdetectablevs detectable MRD, 4 years DFS was 91,6+3% vs. 67,6+9% p=0,0013 (Figure 1). Further refining the thresholds of MRD logwisedid not modify the significance (p=0.004; Figure 2). Indeed, DFS at 48 months was 61+15 % (n=16) for MRD >10-3, 74+11% ( n=18) for MRD <10-3->10-4 and 92+3% ( n=91) for MRD<10-4. Comparison of PB MFC MRD on day 15 with day 35 BM molecular MRD showed concordance in 72% of the cases (83 negative/negative and 7 positive/positive, 48 months DFS 94.6+2.7% and 38+20% respectively). Eight patients were negative in PB but positive in BM (DFS 62.5+17%).Twenty seven where positive in PB but negative in BM (DFS 83.5+7.6%).These differences were statistically highly significant (p <0.0001). Conclusion This study demonstrates that even in the good prognosis context of childhood ALL, early MRD retains a highly significant prognostic value. It is of importance that this result was obtained not only on day 35 BM but interestingly, even earlier on day 15 PB. This less invasive procedure can easily be applied, especially for children. It should allow to detectgood responders, with MFC MRD levels below 10-4 for whom a de-escalation of chemotherapy could be considered. Conversely, the detection of blasts by MFC in day 15 PB is worrisome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia

2020 ◽  
Vol 11 ◽  
pp. 204062072092757 ◽  
Author(s):  
Seth E. Karol ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Disease Stratification ◽  
Cure Rates ◽  
Minimal Residual

Although cure rates for pediatric acute lymphoblastic leukemia (ALL) have now risen to more than 90%, subsets of patients with high-risk features continue to experience high rates of treatment failure and relapse. Recent work in minimal residual disease stratification and leukemia genomics have increased the ability to identify and classify these high-risk patients. In this review, we discuss this work to identify and classify patients with high-risk ALL. Novel therapeutics, which may have the potential to improve outcomes for these patients, are also discussed.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2321-2321
Author(s):  
Sebastian Giebel ◽  
Beata Stella-Holowiecka ◽  
Malgorzata Krawczyk-Kulis ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 2321 Poster Board II-298 The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT. Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases. With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009). CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease At 3 Months, Combined to the Presence of IKZF1 Deletion in B-Lineage or Absence of NOTCH1 pathway Mutation in T-Lineage, Recapitulates the Disease Risk Assessment in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia - A GRAALL Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 572-572 ◽  
Author(s):  
Kheira Beldjord ◽  
Elizabeth Macintyre ◽  
Véronique Lhéritier ◽  
Marie-Laure Boulland ◽  
Thibaut Leguay ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Disease Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cns Involvement ◽  
Risk Patients ◽  
Minimal Residual

Abstract Abstract 572 Aim. In recent series of adults with acute lymphoblastic leukemia (ALL), the GRAALL (ASH 2009, abstract 577) and other cooperative groups have confirmed the strong prognostic value of Ig/TCR minimal residual disease (MRD) on patient outcome. Despite this, age, WBC, CNS involvement, recurrent chromosomal translocations, and early response to steroids and chemotherapy remain frequently used to tailor post-remission therapy and envision allogeneic stem cell transplantation (SCT) in most adult ALL trials. We updated our MRD study, now with 262 patients who all achieved complete remission (CR) after the first induction and were assessed for MRD after induction (MRD1, at 6 weeks) and consolidation (MRD2, at 12 weeks). One hundred and fifty-eight patients had Philadelphia chromosome (Ph)-negative B-cell precursor ALL (BCP-ALL), while 104 had T-cell ALL (T-ALL). Since 107 of the BCP-ALL (68%) were studied for IKZF1 deletion and 90 of the T-ALL patients (87%) for NOTCH1/FBXW7 mutations, we were able to reassess the MRD significance according to these newly described oncogenic markers. These two covariates (i.e. MRD and IKZF1/NOTCH1/FBXW7 genetics) allowed us to redefine a much simpler yet more powerful stratification of disease risk in both BCP- ALL and T-ALL subsets. Methods. All 262 patients studied (median age, 31.5 years) were treated in the GRAALL-2003 and GRAALL-2005 trials. Although they were younger and had more frequently circulating blasts, other characteristics and outcome did not differ from patients treated in the same trials but not assessed for MRD. Ig/TCR MRD levels were determined according to Euro-MRD guidelines (Leukemia 2007;21:604). IKZF1 deletions were assessed by multiplex multi-fluorescent PCR. NOTCH1/FBXW7 mutations were assessed as previously described (Blood 2009;113:3918). Multivariate backward stepwise selection Cox models were used for the cumulative incidence of relapse (CIR), disease-free (DFS) and overall survival (OS) endpoints, after censoring transplanted patients at SCT. Models were always adjusted on age (35-year cutoff), WBC (30 and 100 G/L cutoff for BCP- and T-ALL, respectively), CNS involvement, and trial. Additional BCP-specific covariates included CD20 expression, t(4;11) and t(1;19) translocations, and IKZF1 deletion. Additional T-specific covariates included cortical immunophenotype according to the EGIL classification, TLX1 overexpression, and NOTCH1/FBXW7 mutation. Finally, allogeneic SCT was re-evaluated in the newly defined risk subsets, as a time-dependent covariate. Results. An initial multivariate analysis revealed that among blood response after 1 week of steroid, bone marrow response after 2 weeks of therapy, and molecular response at both MRD1 and MRD2 time-points, the MRD2 level was the main and sole independent predictor of relapse (P=0.003). In BCP-ALL patients, persistent MRD2 and IKZF1 deletion were the only two independent factors identified, the presence of at least one factor defining 51% high-risk patients with 52% versus 15% CIR (HR, 3.8; P= 0.008), 41% versus 81% DFS (HR, 3.6; P= 0.005), and 54% versus 80% OS (HR, 3.9; P= 0.015) at 4 years. Allogeneic SCT in first CR significantly decreased relapse incidence and prolonged DFS in these new high-risk BCP-ALL patients (HR, 0.23 and 0.40; P= 0.016 and 0.05, respectively). In T-ALL patients, persistent MRD2 and lack of NOTCH1/FBXW7 mutation were the only two independent factors identified, the presence of at least one factor defining 49% high-risk patients with 64% versus 12% CIR (HR, 6.4; P= 0.002), 36% versus 88% DFS (HR, 6.4; P= 0.002), and 41% versus 95% OS (HR, 7.3; P= 0.015) at 4 years. SCT had no significant effect on relapse incidence and DFS in these new high-risk T-ALL patients. Conclusion. In adult patients with Ph-negative ALL treated with the pediatric-inspired GRAALL regimen, IKZF1 deletion in BCP-ALL, NOTCH1/FBXW7 mutation in T-ALL, and MRD at 3 months in both subsets replace all classical risk factors, leading to a new simplified prognostic scoring system based only on IKZF1 and NOTCH1/FBXW7 genetics and MRD clearance. This new risk score identifies approximately half of the patients as good-risk, with a relapse incidence as low as 10–15%. It will be validated and used prospectively in the next generation of GRAALL trials, to stratify both new drug evaluation and SCT in first CR. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document