scholarly journals Risk-adapted treatment reduced chemotherapy exposure for clinical stage 1 pediatric testicular cancer

2020 ◽  
Author(s):  
yunlin ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Second Line ◽  
First Line ◽  
Risk Patients ◽  
Line Chemotherapy

Abstract Background: Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. For high-risk children, greater than 50% of them suffered relapse and progress during surveillance and adjuvant chemotherapy was administrated. Risk-adapted treatment might reduce chemotherapy exposure for those children.Methods: The decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as relapse rates of different groups during surveillance or after chemotherapy were collected from literatures. And a survey to urologist was performed to evaluate the toxicity of the first-line and second-line chemotherapy. Using decision analysis model, chemotherapy exposure between risk-adapted treatment and surveillance were compared based on this series of clinical utilities. One-way and two-way tests were administrated to check the feasibility.Results: In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤0.10 and the relapse rate of high-risk group ≥0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to first-line chemotherapy.Conclusions: Using decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients and precious evaluation after orchiectomy was critical to this process. Further clinical study was needed to validate this statement.

scholarly journals Risk-adapted treatment reduced chemotherapy exposure for clinical stage 1 pediatric testicular cancer

2020 ◽  
Author(s):  
yunlin ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Second Line ◽  
First Line ◽  
Risk Patients ◽  
Line Chemotherapy

Abstract Background: Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children.Methods: A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility.Results: In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤0.10 and the relapse rate of the high-risk group was ≥0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy.Conclusions: Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement.

scholarly journals Risk-adapted treatment reduced chemotherapy exposure for clinical stage 1 pediatric testicular cancer

2020 ◽  
Author(s):  
yunlin ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Second Line ◽  
First Line ◽  
Risk Patients ◽  
Line Chemotherapy

Abstract Background: Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. For high-risk children, greater than 50% of them suffered relapse and progress during surveillance and adjuvant chemotherapy was administrated. Risk-adapted treatment might reduce chemotherapy exposure for those children. Methods: The decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as relapse rates of different groups during surveillance or after chemotherapy were collected from literatures. And a survey to urologist was performed to evaluate the toxicity of the first-line and second-line chemotherapy. Using decision analysis model, chemotherapy exposure between risk-adapted treatment and surveillance were compared based on this series of clinical utilities. One-way and two-way tests were administrated to check the feasibility. Results: In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤0.10 and the relapse rate of high-risk group ≥0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to first-line chemotherapy. Conclusions: Using decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients and precious evaluation after orchiectomy was critical to this process. Further clinical study was needed to validate this statement.

scholarly journals Risk-adapted treatment reduced chemotherapy exposure for clinical stage I pediatric testicular cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yun-lin Ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Second Line ◽  
First Line ◽  
Risk Patients ◽  
Line Chemotherapy

Abstract Background Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children. Methods A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility. Results In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤ 0.10 and the relapse rate of the high-risk group was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy. Conclusions Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement.

scholarly journals Risk-adapted treatment reduced chemotherapy exposure for clinical stage 1 pediatric testicular cancer

2020 ◽  
Author(s):  
yunlin ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Second Line ◽  
First Line ◽  
Risk Patients ◽  
Line Chemotherapy

Abstract Background: Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. For high-risk children, greater than 50% of them suffered relapse and progress during surveillance and adjuvant chemotherapy was administrated. Risk-adapted treatment might reduce chemotherapy exposure for those children. Methods: The decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as relapse rates of different groups during surveillance or after chemotherapy were collected from literatures. And a survey to urologist was performed to evaluate the toxicity of the first-line and second-line chemotherapy. Using decision analysis model, chemotherapy exposure between risk-adapted treatment and surveillance were compared based on this series of clinical utilities. One-way and two-way tests were administrated to check the feasibility. Results: In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤0.10 and the relapse rate of high-risk group ≥0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to first-line chemotherapy. Conclusions: Using decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients and precious evaluation after orchiectomy was critical to this process. Further clinical study was needed to validate this statement.

scholarly journals Chemotherapy burden of risk-adapted treatment verse surveillance for clinical stage I pediatric testicular cancer: A decision tree model analysis

2020 ◽  
Author(s):  
yunlin ye ◽  
Zhuang-fei Chen ◽  
Jun Bian ◽  
Hai-tao Liang ◽  
Zi-ke Qin
Keyword(s):  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Low Risk ◽  
Stage I ◽  
Decision Analysis Model ◽  
Risk Patients

Abstract Background Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. For high-risk children, greater than 50% of them suffered relapse and progress during surveillance and adjuvant chemotherapy was administrated. Risk-adapted treatment might reduce chemotherapy burden for those children.Methods Using decision analysis model, we collected clinical utilities from literature and survey and compared chemotherapy exposure between risk-adapted treatment and surveillance.Results In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤ 0.10 and the relapse rate of high-risk group ≥ 0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to salvage chemotherapy.Conclusions Risk-adapted treatment might decrease chemotherapy-related toxicity for these high-risk patients and further clinical study was needed.

scholarly journals Chemotherapy burden of risk-adapted treatment verse surveillance for clinical stage I pediatric testicular cancer: A decision tree model analysis

2019 ◽  
Author(s):  
Yunlin Ye ◽  
Hong-chao Li ◽  
Ji Zhang ◽  
Hai-tao Liang ◽  
Zike Qin ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
High Risk ◽  
Testicular Cancer ◽  
Decision Analysis ◽  
Relapse Rate ◽  
Risk Group ◽  
Clinical Stage ◽  
Low Risk ◽  
Stage I ◽  
Risk Patients

Abstract Background Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. This study was to compare chemotherapy exposure between risk-adapted treatment and surveillance in CS1 pediatric testicular cancer.Methods We collected clinical utilities from literature and survey. Using decision analysis model, we compared chemotherapy exposure between risk-adapted treatment and surveillance and sensitivity analysis was performed.Results In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤0.10 and the relapse rate of high-risk group ≥0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to salvage chemotherapy.Conclusion Decision analysis demonstrated that risk-adapted treatment was associated with lower exposure of chemotherapy for patients with CS1 pediatric testicular cancer. This might decrease chemotherapy-related toxicity for these high-risk patients and further clinical study was needed.

Second-line chemotherapy in advanced biliary tract cancer: Who may benefit?

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 381-381
Author(s):  
Massimiliano Salati ◽  
Francesco Caputo ◽  
Luigi Marcheselli ◽  
Margherita Rimini ◽  
Andrea Spallanzani ◽  
...  
Keyword(s):  
High Risk ◽  
Biliary Tract Cancer ◽  
Risk Group ◽  
Daily Practice ◽  
High Risk Group ◽  
Second Line ◽  
First Line ◽  
Tract Cancer ◽  
Ecog Ps ◽  
Line Chemotherapy

381 Background: No established second-line treatment (2L) is available for patients (pts) with advanced biliary tract cancer (ABC) failing gemcitabine/platinum first-line chemotherapy (CT). However, 20-40% of pts are offered 2L CT in daily practice. We evaluated the impact of clinical and biochemical parameters on survival of ABC in order to identify factors aiding in 2L treatment selection. Methods: Medical records of consecutive ABC pts treated with 2L CT between 2005 and 2018 at the Modena Cancer Centre were reviewed. Log-rank test and multiple Cox proportional hazard regression were performed to assess the prognostic significance of covariates on OS. A prognostic score was developed from the multivariate model. Results: A total of 98 pts were identified and included in the analysis. Median (m) age was 63 years, 52% of pts were female, 75% had ECOG PS of 1-2. 72% of pts received first-line gemcitabine/platinum combination. In the 2L setting, 70% of pts received a doublet and the most common regimen was FOLFIRI (26%), followed by FOLFOX (20%) and fluoropyrimidine monotherapy (19%). Disease control rate was 39%, with 7% of objective responses. mOS and mPFS were 7.2 months and 3.5 months, respectively. At both univariate and multivariate analysis ECOG PS > 0 ( P= 0.002), peritoneum involvement ( P< 0.001), LDH > 430 UI/L ( P< 0.001), albumin < 3.5 g/dL ( P= 0.001), gamma-GT > 100 UI/L ( P= 0.001), PFS to first-line < 6 months ( P= 0.025), Na+ < 140 mEq/L ( P= 0.010), absolute lymphocyte count < 1000/uL ( P= 0.030) were significantly associated with shorter OS. By assigning to each of the 8 variables weight = 1, three different risk groups were identified: low-risk group (0-2 factors), intermediate-risk group (3-4 factors) and high-risk group (5-8 factors). mOS was 18, 9.4, and 2.9 months in the low-, intermediate-, and high-risk group, respectively ( P< 0.001). Conclusions: Our 2L study confirms the prognostic value of ECOG PS, PFS to first-line and peritoneal carcinomatosis, identifies novel biochemical prognosticators and proposes a readily-available and inexpensive score to risk stratify patients both in daily practice and clinical trials.

Relapsed Hodgkin Lymphoma in Older Patients: A Comprehensive Analysis From the German Hodgkin Study Group

2013 ◽  
Vol 31 (35) ◽  
pp. 4431-4437 ◽  
Author(s):  
Boris Böll ◽  
Helen Goergen ◽  
Nils Arndt ◽  
Julia Meissner ◽  
Stefan W. Krause ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Prognostic Score ◽  
Treatment Strategies ◽  
Study Group ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Early Relapse ◽  
Risk Patients

Purpose Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown. Patients and Methods We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis. Results We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies. Conclusion OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.

Salvage Therapies in Patients with High-Risk Relapse After Fludarabine, Cyclophosphamide, Rituximab (FCR) for Chronic Lymphocytic Leukemia: The French CLL Intergroup Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1796-1796
Author(s):  
Luc-Matthieu Fornecker ◽  
Therese Aurran-Schleinitz ◽  
Anne-Sophie Michallet ◽  
Bruno Cazin ◽  
Jehan Dupuis ◽  
...  
Keyword(s):  
High Risk ◽  
Second Line ◽  
Complex Karyotype ◽  
First Line ◽  
Second Line Therapy ◽  
High Risk Patients ◽  
First Line Therapy ◽  
Line Therapy ◽  
Ultra High Risk ◽  
Risk Patients

Abstract Abstract 1796 Introduction: FCR chemoimmunotherapy is recommended as first line therapy for fit cll patients. Since the 2007 EBMT guidelines based on the previously published trials using FCR, the definition of high risk CLL has evolved, to include biologic parameters (TP53 disruption by deletion/mutation, high b2-microglobulin level, IgVH unmutated, complex karyotype), refractoriness (progression during fluda-based regimen or within 6mo of completion), and also remission duration (high risk if PFS after FCR <24mo, ultra-high risk if TTNT <24–36mo with TP53 del/mut). However, few data are available regarding the characteristiscs, response rate and outcome of CLL patients treated in second line after FCR first line. Patients and methods: In this multicentric retrospective study, we collected data from 117 patients who relapsed after FCR first line therapy and received second-line therapy (according to NCI2008 guidelines). Results: At the time of initial FCR therapy: patients characteristics were as follows: Binet B/C 87.2%, unmutated IgVH 52.2%, del11q 25.6% (n=30/81 with FISH available), del17p 6.8% (n=8/87 with FISH available), bulk>5cm 22%, complex karyotype 21% (n=12/57 with karyotype available). FCR yielded 93% ORR, with 66% clinical CR, 27% PR, and 7% failed to respond. Median PFS and TTNT were 27mo and 32.5mo, respectively. At the time of relapse: patients characteristics were as follows: del11q 16.4% (n=19/65 with FISH available), del17p 19% (n=22/77), bulk>5cm 26%, complex karyotype 44% (n=24/54 with karyotype available). According to FCR remission duration, 11.1% of patients were considered as truly FCR-refractory, 47% had PFS<24mo, 34.2% had TTNT<24mo. TTNT<24mo after FCR was correlated to age>65y, del17p (20% vs 0%) and complex karyotype (38% vs11%), but not with gender, IgVH status, del11q, or bulk>5cm. Based on FCR-refractoriness, or TTNT<24mo and/or del17p, 53 patients were considered as ultra-high risk (45.3%). Various regimen were used for second-line treatment after FCR: R-bendamustine (n=47, 40.2%), alemtuzumab-based therapy (single agent or with chemo/dexa, n=22, 18.8%), R-CHOP (n=15, 12.8%), FCR (n=14, 12%), and other miscellaneous regimens (as follows: R-alkylator (n=6, 5.1%), R-DHAP (n=4, 3.4%), R-methylprednisolone (n=3, 2.6%), or investigational drugs (n=6, 5.1%)). Thus, 74.3% of patients received a second course including rituximab-based chemotherapy. Overall response rate was 78.4%, with 13.8% clinical CR, 64.6% PR, and 21.6% failure/stable disease. 14 pts (12%) underwent stem cell transplantations, 8 had maintenance therapy ongoing (ofatumumab, alemtuzumab, or lenalidomide). With regards to factors defining high-risk relapse, distribution of salvage therapies was as follows: As expected, a second course of FCR was seldom used in high-risk patients. Among ultra-high risk patients, 30.3% received R-benda, 11.3% Alem-based Rx, 32% R-CHOP and 18% the miscellaneous regimens described above. After second-line therapy, median PFS was 12 months, median TTNT was 14mo, and median OS was 36mo (20 deaths). On univariate analysis, complex karyotype (p=0.04) but not del17p (p=0.1), PFS<24mo (p=0.028) and TTNT<24mo (p=0.04) correlated with OS. Regarding treatment, OS was significantly improved in R-bendamustine-treated patients, as compared to alem-based or CHOP regimen (p=0.01). Most importantly, patients who received an allogeneic transplant benefited from significantly prolonged OS (at 4y, 70% vs 40%, p=0.03). Of note, only one patient treated with R-benda received allotransplant. Conclusions: This study shows that there are no consensus for second line therapy after FCR. Second line trials after FCR therapy are warranted. Definition of high-risk subsets of patients at relapse after FCR is of upmost importance in the management of CLL, to compare second-line strategies. Our data suggest that R-bendamustine is an efficient regimen even in high-risk patients (complex karyotype, PFS<24mo, TTNT<24mo). These data are important since this immunochemotherapy is now used as the backbone for combination with new compounds (ibrutinib, GS1101, GDC-199). Disclosures: Aurran-Schleinitz: Roche: Honoraria. Leblond:Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria.

scholarly journals Impact of IKZF1 Deletions and IKZF1 Plus in Pediatric Acute Lymphoblastic Leukemia Outcome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4091-4091
Author(s):  
Maria Sara Felice ◽  
Patricia Laura Rubio ◽  
Myriam Ruth Guitter ◽  
Jorge Gabriel Rossi ◽  
Jorge Alberto Digiorge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Relapse Rate ◽  
Copy Number ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Rank Test ◽  
Copy Number Alterations ◽  
Risk Patients ◽  
Pediatric All

Abstract Introduction: Survival of children with acute lymphoblastic leukemia (ALL) has improved in the last decades, achieving approximately 80% in Argentina. However, relapses remain the most frequent adverse event and the identification of patients with higher risk need to be refined. Deletions in IKZF1(IKZF1del) in addition with deletion of CDKN2A, CDKN2B,PAX5 or PAR1 region define a new subgroup of patients (IKZF1plus) with higher relapse rate and poor survival. Objectives: To analyze the characteristics of patients with IKZF1del and IKZF1plus, assessing the impact of the copy number alterations in several genes on survival of pediatric ALL treated with ALLIC strategy. Methods: This is a retrospective analysis performed in the population of patients admitted from October 2009 to May 2018. Samples of 432 patients with diagnosis of ALL were collected and analyzed by MLPA P-335 (MRC-Holland) for copy number alterations of IKZF1, EBF1, JAK2, CDKN2A, CDKN2B, PAX5, ETV6, BTG1, RB1 genes and PAR1 region. IKZF1plus cases were defined as those with IKZF1del with at least one additional deletion in: PAX5, CDKN2A, CDKN2B, PAR1 region. Patients were treated with 2 consecutive ALLIC protocols, according to studies stratification. Patient characteristics were compared with chi-square and Wilcoxon-sum-rank-test. Survival probability was analyzed with Kaplan-Meier calculation and survival results compared with Log-rank-test. Results: IKZF1 was not deleted in 345 cases, IKZF1del was detected in 87 cases and 47 of them were defined as IKZF1plus. Statistically significant higher WBC, MRD+ positivity on day 15, day 33 and week 12, more BCR-ABL+ and high-risk group cases, null response and higher relapse rate were observed in the IKZF1del group (total) when comparing with IKZF1 not del, and also when comparing IKZF1plus vs IKZF1 not del + IKZF1del only. EFS (SE) and DFS (SE) probabilities were: 73 (4)% and 75 (3)% for IKZF1 not del, 66 (9)% and 70 (9)% for IKZF1del, and 20 (10)% and 21 (10)% for IKZF1plus, respectively (p<0.00001).DFS of the standard-risk group was not influenced by the presence of only 1 case of IKZF1del detected in this risk-group of patients. However, DFS of intermediate-risk patients was 41 (11)% for IKZF1plus while 70 (7)% and 73 (4)% were achieved for IKZF1del and IKZF1 not del respectively (p=0,0083). Therefore, high-risk patients with IKZF1plus achieved DFS of 12 (19)% vs 65 (7)% and 50 (21)% for IKZF not del and IKZF1del respectively (p=0.0085). DFS of patients with IKZF1del + CDKN2Adel was 30 (10)% and CDKN2A not deleted 67 (9)% (p=0.0433). DFS of patients with IKZF1del + CDKN2Bdel was 42 (12)% and 66 (9)% for CDKN2B not del. DFS of cases with IKZF1del in addition to deletion of ETV6, BTG1, EBF1 orJAK2 did not show statistically significant differences when comparing with IKZF1del + normal copy number of these genes. In addition, DFS of cases with RB1del was 36 (13)% while cases without RB1del showed 70 (3)% (p=0.0071). Conclusions: 1- Patients with IKZF1del and IKZF1plus disclosed biological features related to poor outcome. 2- IKZF1plus was associated with a poor outcome in intermediate and high-risk groups according to ALLIC stratification. 3- The addition of CDKN2Adel to IKZF1del influence the outcome. However, CDKN2Bdel did not show the same effect. 4- Copy number alterations of ETV6, BTG1, EBF1 or JAK2 did not demonstrate prognostic impact. 5- RB1 showed negative influence in survival. 6- Identification of patients with IKZF1plus at diagnosis could be very useful for improving risk-group stratification of pediatric ALL patients. Disclosures No relevant conflicts of interest to declare.

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