Treatment outcomes for childhood acute lymphoblastic leukemia in low-middle income country before minimal residual disease risk stratification

2021 ◽  
Vol 75 ◽  
pp. 102040
Author(s):  
Sara Makkeyah ◽  
Ayat Manzour ◽  
Azza Tantawy ◽  
Ashraf Mohamed ◽  
Fatma Ebeid ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Treatment Outcomes ◽  
Minimal Residual Disease ◽  
Disease Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Middle Income Country ◽  
Middle Income ◽  
Minimal Residual

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.

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 Minimal Residual Disease Assessment of Remission after Induction Therapy Is Superior to Morphologic Assessment for Risk Stratification in Childhood Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group (COG)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 758-758
Author(s):  
Sumit Gupta ◽  
Meenakshi Devidas ◽  
Si Chen ◽  
Cindy Wang ◽  
Mignon L. Loh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Laboratory Services ◽  
Minimal Residual

Abstract Background: Minimal residual disease (MRD) assessment after initial therapy is integral to modern risk stratification in both precursor B and T lineage acute lymphoblastic leukemia (B-ALL and T-ALL). While MRD is used to determine depth of remission, remission is still defined, both in clinical practice and clinical trials, according to morphological assessment. We aimed to determine the outcomes of children, adolescents and young adults with discordant assessments of remission by morphology vs. by MRD, and in doing so, the extent to which morphologic assessment of remission contributes to risk assessment in this population. Methods: We identified a cohort of patients age 1-30.99 years enrolled on frontline COG trials for B-ALL [standard risk (SR): AALL0331; high risk (HR) AALL0232] and T-ALL (AALL0434) that underwent bone marrow assessment of remission at the end of induction therapy (Day 29). Morphologic response was assessed by local centers and was categorized according to traditional criteria: M1 (<5% leukemic blasts - remission) vs. M2 (5-25%) vs. M3 (>25%). MRD was measured by flow cytometry at one of two central laboratories. We determined predictors of MRD discordance and compared event free survival (EFS) between those with discordant vs. concordant morphology/MRD remission assessments. Results: Day 29 remission assessments and central MRD data were available on 9,350 patients, 7,857 (84%) with B-ALL (AALL0331: N=5049; AALL0232: N=2808) and 1,493 (16%) with T-ALL. Table 1 shows the distribution of end induction marrow morphology vs. flow cytometry results. Few patients with M2/M3 marrows had discordant low MRD values. For example, of 84 patients with M3 morphology, only 2 (2.4%) had MRD <5%. Of 202 patients with M2/M3 morphology, 23 (11.4%) had MRD<1% and 9 (4.5%) had MRD<0.1%. Subsequent analyses of discordance were thus restricted to patients with M1 morphology but flow cytometry consistent with failure to achieve remission (MRD>=5%). Using this definition, discordance was uncommon among subjects with B-ALL (66/7,748; 0.9%) but significantly more common in T-ALL (97/1,400; 6.9%; p<0.0001). Among subjects with B-ALL and M1 morphology, significant predictors of discordance (MRD>=5%) in multivariable regression included variables traditionally associated with poor response: age >=10 years [odds ratio (OR)=1.7, 95th percentile confidence interval (CI) 1.1-2.8; p=0.03), presenting white blood cell count >=50,000/microliter (OR=2.1, CI 1.3-3.6; p=0.004), and unfavorable compared to favorable cytogenetics (OR=31, CI 8.9-109; p<0.0001). In B-ALL, subjects with end induction M1 morphology but discordant MRD (>=5%) had modestly superior 5-year EFS when compared to those with M2 morphology and MRD >=5% (33.1%±6.2% vs. 22.0%±6.9%; p=0.03), but EFS was significantly inferior to those with M1 morphology and concordant MRD (<5%) (33.1%±6.2% vs. 86.8%±0.4%; p<0.0001) (Figure 1). In T-ALL, the 5-year EFS of subjects with M1 morphology/discordant MRD was not significantly different from those with M2 morphology and MRD >=5% (80.3%±7.3% vs. 62.7%±13.5%; p=0.13); outcomes of both groups were superior to their equivalents with B-ALL, in keeping with known slower disease clearance kinetics in T-ALL. Conclusions: Patients in morphologically defined remission but with MRD >=5% have outcomes similar to those who fail to achieve morphological remission. These results suggest that, in addition to measuring depth of remission, MRD should replace morphology in defining remission in subjects with ALL, with consequent implications for risk stratification, treatment assignment and eligibility for experimental agents. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Borowitz:HTG Molecular: Consultancy; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding. Wood:Juno: Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement.

scholarly journals Conventional and Flowcytometric Minimal Residual Disease Based Risk Stratified Post Remission Therapy Improves Survival in Ph-Negative Pediatric Acute Lymphoblastic Leukemia- Single Centre Experience from South India

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4119-4119
Author(s):  
Rema Ganapathy ◽  
Aswathy Ashok Beenakumari ◽  
Syamaprasad Vinayakumar ◽  
Remya Sudevan ◽  
Renjitha Bhaskaran ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Algorithm ◽  
Middle Income ◽  
Middle Income Countries ◽  
Minimal Residual

Abstract Background: Children with Acute Lymphoblastic Leukemia (ALL) in Low Middle income countries(LMIC) face major challenges including treatment abandonment and poor overall survival (OS) and event-free survival (EFS).The preliminary data and results of outcome of Pediatric ALL from our pediatric hematology-oncology center which follows BFM based ALLtreatment protocol has been published in 2015 in ASH forum.Due to non availability of Polymerase chain reaction (PCR)based Minimal residual disease(MRD)analysis, we use multiparametric flowcytometry (FCM) based MRD analysis for remission assessment and risk stratification in our patients. Within resource constraints, we present evidence that outcomes comparable with that seen in high income (HIC)and upper middle income countries(UMIC) can be achieved with a post remission therapy guided by a risk stratification incorporating FCM MRD. Methods: Following IRB approval,an ambidirectional cohort study was performed using clinical information and outcomes of all patients aged 1to 14 years treated for newly diagnosed B- or T-ALL between January 1,2015 and December 31, 2020. AIEOP BFM ALL 2009 protocol with modifications was followed as the institutional protocol in all patients.The treatment algorithm is mentioned in Figure 1. Patients who underwent multiparametric FCM MRD analysis at the end of Induction IA and whose 6 months follow up details were available were included in the analysis. Patients with Ph positive ALL and those who died during Induction IA were excluded. FCM MRD analysis was performed after Induction IA on Day 33.MRD level above 0.01% was considered positive.MRD assessment was repeated following Induction IB on Day 74 in patients who had MRD positivity on Day 33. At the end of Induction IB patients were risk stratified into High risk(HR) and non High risk(Non HR).HR features included Hypodiploidy(&lt;45chromosomes), Positivity for MLL/AF4 or t(4:11),poor prednisolone response(absolute blast count in peripheral blood ≥1 x 10^9/l on Day 8 of initiation of prednisolone) and non remission on Day33. Patients who had persistent MRD positive on Day74 were reallocated to high risk. Treatment with HR protocol was initiated for high risk patients whenever financially manageable.Statistical analysis was done using SPSS version 21 OS and EFS were assessed by Kaplan-Meier method Patients were censored at last follow-up. Results: Median follow-up time was 33.5(4-102) months . Study had 102(n=102) consecutive Ph negative patients who underwent induction therapy. Six patients (5.88%) died during induction IA;96(n=96) children who continued treatment were included in further analysis. The mean age at diagnosis was 6(1-14) years .Forty seven (48.95%)patients were male..B-ALL n=84(87.5%) and T ALL n=12.(12.5%). Four patients(4.16%) had CNS disease at diagnosis. Three children (3.13%) had high risk cytogenetics.Ten children (10.42%)in the cohort had poor prednisolone response. Five patients(5.20%) didnot achieve morphological remission on Day33. Fifteen (15.63%) patients were risk stratified as HR during IA. Four more (4.16%) were reallocated to HR in view of persistent MRD positivity after Induction IB. At median follow-up, the OS was 95.35%±2.65(95% CI 90.16-100.54) and the EFS 94.48%±2.74 (95% CI, 89.11%-99.84%).Female gender predicted better EFS (p=0.042).The EFS of patients without CNS disease at presentation was significantly better(93.5% Vs 23.2% p=0.000). The EFS at median follow up of patients in re HR cohort was 64.19% Vs 97.81% in non HR (p=0.010). EFS by risk stratification is shown in Figure II. Conclusion:Our study suggests that FCM MRD can be successfully incorporated into the treatment algorithm in a resource limited setting. With FCM MRD were able to identify an additional subset of HR patients who otherwise would have been stratified into non HR group. In a prospective cohort , FCM MRD could be tested at an earlier time point in IA induction to facilitate identification of early drug responsive patients with lowest risk of relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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