scholarly journals Prognostic Relevance of Protocol Deviations in Children with Relapsed ALL Treated in the ALL-REZ BFM 2002 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 365-365
Author(s):  
Eleni Argyriadi ◽  
Ingo G. Steffen ◽  
Guenter Henze ◽  
Christiane Chen-Santel ◽  
Arend von Stackelberg
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Multivariate Analyses ◽  
Radiation Treatment ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Late Relapse ◽  
Prognostic Impact ◽  
Treatment Delays ◽  
Protocol Deviation ◽  
Prognostic Relevance

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common cancer affecting children and its cure rates are close to 90%. Nevertheless, relapsed ALL is still a major cause of cancer-associated deaths in children. Therefore, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002 was designed to improve the prognosis of children with relapsed ALL by introducing new chemotherapy elements. Little is known though about the prognostic relevance of deviations from the ALL protocols. This study aimed to investigate the characteristics of such protocol deviations and to determine their prognostic relevance for the relapsed disease. Methods: We performed a retrospective analysis of 686 children and adolescents up to 18 years of age with first relapse of ALL who were enrolled between 2002 and 2012 in the ALL-REZ BFM 2002 Study. Deviations were identified in terms of time and type. In order to investigate the prognostic importance of the time delay, the 90th percentile of delays between defined treatment elements (i.e. 15.5 days) was used as a cut-off point. Furthermore, deviations were categorized as avoidable (logistics, family/PI decisions) and non-avoidable (clear medical indication). The protocol deviation occurred during the course of therapy was therefore considered as a time-dependent variable. Disease-free survival, (DFS, induction failures excluded) and OS were analyzed using Kaplan-Meier estimate, log-rank test, Mantel-Byar test and Cox/logistic regression (univariate and multivariate analyses). Results: A total of 587 patients (86%) received the protocol therapy, whereas 99 patients (14%) underwent deviations during their treatment. Baseline characteristics were compared in both groups (Table 1). Deviations were categorized as: change of chemotherapy in 48% of the patients (n=47/99), stop of chemotherapy in 10 % (n=10/99), non-protocol compliant reaction to MRD findings in 28% (n=28/99) and change of radiation treatment in 14% (n=14/99). The cumulative incidence of protocol deviation was 6% and 15.5% at 3 and 9 months, respectively (Figure 1). The remission rate of patients with protocol deviation during induction was slightly lower compared to patients without such deviation (24/29, 83% vs. 579/657, 88%; P=0.38). The estimated 5-year probabilities of DFS and OS between the patients treated according to protocol therapy and those with deviations were significantly different (pDFS, Protocol therapy: 0.61 ± 0.02 vs. Deviation: 0.38 ± 0.05, P < 0.001; pOS, Protocol: 0.70 ± 0.02 vs. Deviation: 0.57 ± 0.05, P < 0.001; Figure 2, 3). In multivariate analyses protocol deviation, time point of relapse and immunophenotype turned out to be independent prognostic factors of the DFS (Table2). The hazard ratio of the protocol deviation was significant only in patients with the late relapse, whereas in patients with early/very early relapse no significant prognostic effect could be found [late (n=40): HR=2.53, 95%CI 1.53-4.21, P<0.001; early (n=29): HR=1.49, 95%CI 0.88-2.51, P=0.13; very early (n=25): HR=1.50, 95%CI 0.84-2.66, P=0.17]. Moreover, DFS probabilities were comparable for avoidable (n=63) and non-avoidable (n=31) deviations (0.43 ± 0.07 vs. 0.40 ± 0.09, P=0.9; Non avoidable: HR=1.19, 95%CI=0.68-2.10, P= 0.53). In terms of the time-related deviations, the extent of the delays between induction and beginning of consolidation therapy was not significantly associated with the DFS [≤90th percentile (n=319/603); pDFS: =0.60 ± 0.02 vs. >90th percentile (n=36/603); pDFS: 0.56 ± 0.08, P=0.3]. Treatment delays during other phases of the protocol were also not related to the outcome. Conclusion: While protocol deviations did not significantly affect remission rates in this study, they were significantly related to inferior DFS. Since a relevant part of the protocol deviations could be classified as avoidable, strict protocol compliance should lead to improved outcomes. The prognostic impact of protocol deviations was in particular relevant in patients with late relapse with generally rather chemosensitive diseases and better prognosis. In this analysis, treatment delays did not influence the outcome. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria.

Patient Stratification Based on Prednisolone-Vincristine-Asparaginase Resistance Profiles in Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (17) ◽  
pp. 3262-3268 ◽  
Author(s):  
M.L. Den Boer ◽  
D.O. Harms ◽  
R. Pieters ◽  
K.M. Kazemier ◽  
U. Göbel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Late Relapse ◽  
Early Event ◽  
Study Group ◽  
Increased Risk

Purpose: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. Patients and Methods: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. Results: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate ± SE was 69% ± 7.0%, 83% ± 4.4%, and 84% ± 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P ≤ .05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P = .03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known risk factors (P = .07). Conclusion: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.

Influence of the fusion gene ETV6-RUNX1 in the prognosis of the Pediatric B- Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2515-2515
Author(s):  
Alejandro Contento-Gonzalo ◽  
Antonio Jimenez-Velazco ◽  
Alcala-Peña Magdalena ◽  
Manuel Barrios ◽  
Katie Hurst ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Rank Test ◽  
Prognostic Impact ◽  
Excellent Outcome ◽  
Log Rank Test ◽  
Significant Difference

Abstract Abstract 2515 INTRODUCTION AND OBJECTIVES: The ETV6-RUNX1 (TEL-AML1) rearrangement comes from the translocation of two chromosomes t(12;21)(p12;q22), and represents one of the most frequently detected anomalies (15–30%) in the B-precursor Acute Lymphoblastic Leukemia (B-ALL). It must be identified by polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH) methods, since this translocation is not detected by conventional cytogenetic techniques. The prognostic value of ETV6-RUNX1 is still a matter of controversy. Recently, the group of the St Jude Children's Hospital reported an excellent outcome in patients carrying the translocation, whereas the BMF group did not find any significant difference in the survival of ETV6-RUNX1 positive patients when compared to ETV6-RUNX1 negative. The aim of our study has been to determine the prognostic impact of the ETV6-RUNX1 rearrangement in patients diagnosed of B-ALL in our Hospital, after a long period of follow-up and with the same Spanish treatment protocols (from PETHEMA and SHOP groups). PATIENTS AND METHODS: All patients with B-ALL diagnosis from January 1997 to May 2011 were included in the study: in total, 114 patients with a mean of age of 6 ys (0.3–14). The type of leukemia was ALL common (83 patients), pro-B (17 patients), pre-B (13 patients) and mature (1 patient). All the children over 1 yr received treatment according to PETHEMA group protocols, adjusted to the risk. Children under 1 yr were treated following SHOP group protocols. Seventeen patients received an allogeneic transplantation. The main clinical features of the positive and negative patients for ETV6-RUNX1 are detailed in table 1. ETV6-RUNX1 assay was performed in our laboratory by RT-PCR, according to the European BIOMED project methodology. RESULTS: ETV6-RUNX1 was found in 31 of the 114 patients (27.2%). These patients showed a significantly higher frequency of myeloid antigens (p<0.001), and were always positive for CD10 (p=0.006). All cases of positive ETV6-RUNX1 were over 2 years old. No significant differences between positive and negative ETV6-RUNX1 were obtained when complete remissions (100 vs 80%), relapse (16 vs 20%) or deaths (10 vs 13%) were analyzed. Furthermore, estimation of disease free survival (DSF) at 14 ys for both groups were similar: 80 ± 8% for positive vs 66 ± 7% for negative (p=0.21, log-rank test). And the same happened for overall survival (OS): 87 ± 7% for positive vs 83 ± 5% for negative (p=0.4, log-rank test). DISCUSSION: In our series, including patients with B-ALL treated with similar protocols with long periods of follow-up, we could not find differences between positive and negative ETV6-RUNX1 patients. It is well known that the intensity of the chemotherapy regimen and the age of inclusion in different protocols may influence the prognosis. Therefore, at present, it is still a matter of discussion if previous reported differences in the B-ALL ETV6-RUNX1 positive group could be explained by a different stratification in risk groups or by different chemotherapy regimens. This work has been funded by a grant from AECC, Carmen Lavigne Prize 2010 Disclosures: No relevant conflicts of interest to declare.

IKZF1 (Ikaros) Deletions in BCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report

2009 ◽  
Vol 27 (31) ◽  
pp. 5202-5207 ◽  
Author(s):  
Giovanni Martinelli ◽  
Ilaria Iacobucci ◽  
Clelia Tiziana Storlazzi ◽  
Marco Vignetti ◽  
Francesca Paoloni ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Working Party ◽  
Prognostic Impact ◽  
Wild Type ◽  
Free Survival ◽  
Disease Free

Purpose The causes of the aggressive nature of BCR-ABL1–positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes. Patients and Methods Eighty-three patients with de novo adult Philadelphia chromosome (Ph) –positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy. Results A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04). Conclusion We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

scholarly journals Delays in Therapy Do Not Impact Survival in Childhood Acute Lymphoblastic Leukemia: A Report from the Learn Consortium

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1304-1304
Author(s):  
Ross Mangum ◽  
Tiffany M. Chambers ◽  
Andria Stevens ◽  
Robert C. Lynch ◽  
Evanette Burrows ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Age At Diagnosis ◽  
Primary Study ◽  
Prognostic Impact ◽  
Study Objective ◽  
Treatment Delays ◽  
The Impact

Background: In general, modern clinical trials for pediatric acute lymphoblastic leukemia (ALL) have intensified therapy compared with therapy in prior decades. While survival rates now approach 90%, increased treatment intensity has heightened the risk of complications such as serious infections or organ toxicities, which may in turn lead to dose modifications and/or treatment delays. There is a paucity of data on the prognostic impact of cumulative delays during the intensive phases of ALL therapy. Methods: We performed a retrospective chart review of patients between the ages of 1-21 years with newly diagnosed ALL who were treated at two large academic pediatric hospitals that are part of the Leukemia Electronic Abstraction of Records Network (LEARN). Eligible patients were those diagnosed with B- or T-lineage ALL who received chemotherapy treatment at least through the start of maintenance therapy. Exclusion criteria included disease relapse prior to start of maintenance, Down syndrome, or clinical features requiring highly intensified frontline therapy. The primary study objective was to determine the impact of treatment delays on relapse-free survival (RFS) and overall survival (OS). A secondary objective was to investigate associations between delays and patient clinical characteristics. Results: A total of 537 patients were eligible for analysis. Of these 537, 32 were analyzed separately as an "extreme toxicity" subgroup, due to excessive treatment-related morbidities prior to the start of maintenance requiring significant therapy modification. The remaining 505 were divided into quartiles based on their duration of delay, with the highest quartile experiencing >64 days of delay to start of maintenance. Most patients experienced some delay (median 40 days, range 0-154 days). Patients in the highest quartile were characterized by an older mean age at diagnosis (7.8 versus 6.7 years, p=0.0254), treatment on a more intensified regimen (p<0.001), and higher likelihood of Hispanic or Asian race/ethnicity (p=0.033). These patients did not have a significantly lower RFS (4.7 vs. 4.8 years; p=0.701; Figure 1A Kaplan-Meier [KM] p=0.67) or OS (4.8 vs. 4.9 years; p=0.24) compared to patients in the other three quartiles. Patients in the extreme toxicities group did demonstrate a significantly inferior RFS (2.9 vs. 4.7 years; p<0.001; Figure 1B KM p<0.0001)) and OS (3.2 vs. 4.9 years; p<0.001) compared with the remainder of patients. Patients in the extreme toxicities group were more likely to be Hispanic or black (p=0.039), have T-ALL (p=0.043), have received higher intensity therapy (p=0.005), and have a higher mean age at diagnosis (11.8 vs 7.0 years; p<0.0001). Conclusions: Due to the intensity of modern ALL therapy, treatment delays are common. Our data suggest that prolonged delays in treatment prior to the start of maintenance therapy do not impact survival, but that extreme toxicities requiring significant alterations in therapy are associated with significantly poorer RFS and OS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

Abstract We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

scholarly journals Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1079-1086 ◽  
Author(s):  
AT Look ◽  
PK Roberson ◽  
DL Williams ◽  
G Rivera ◽  
WP Bowman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dna Content ◽  
Proportional Hazards Model ◽  
Lymphoblastic Leukemia ◽  
Sheep Erythrocyte ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Current Therapy ◽  
Prognostic Impact ◽  
Dna Index

Using flow cytometric techniques, we determined the pretreatment distribution of DNA content in propidium iodide-stained leukemic blasts from 205 children with “standard-risk” acute lymphoblastic leukemia (ALL). Risk assignment was based on an initial WBC count less than 100 X 10(9)/L, no thymic mass, no meningeal leukemia, and lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. A single aneuploid leukemic line was detected in 74 cases (36.1%): 70 hyperdiploid and four hypodiploid. For hyperdiploid cases, the DNA index (DI, or ratio of the DNA content of leukemic v normal G0/G1 cells) ranged from 1.06 to 2.0 (median, 1.20). A secondary leukemic line with hyperdiploid cellular DNA content was identified in 21 cases with diploid primary lines. Children whose primary leukemic line showed a DI greater than or equal to 1.16 (n = 57) had significantly better responses to treatment than did those with either a diploid DI (n = 130; P = .002) or values in the range of 1.01 to 1.15 (n = 14; P = .001). The relative risk of failure for hyperdiploid cases with DI greater than or equal to 1.16, corresponding to greater than or equal to 53 chromosomes, was one-third that of the other two groups. Treatment responses of patients with both diploid and hyperdiploid lines were identical to those associated with single diploid lines, but significantly worse than those associated with single hyperdiploid lines with DI greater than or equal to 1.16 (P = .016). The most favorable prognostic variables selected by a Cox proportional hazards model were: DI greater than or equal to 1.16 (P = .001), white race (P = .022), WBC less than or equal to 25 X 10(9)/L (P = .032), age between 2 and 9 years (P = .075), and hemoglobin less than 7.0 g/dL (P = .094). DNA index greater than or equal to 1.16 retained its significant prognostic impact even after adjustment for other variables (P = .001). With the combination of DI greater than or equal to 1.16 and WBC less than or equal to 25 X 10(9)/L, one can identify a group of children with ALL who have a low probability of relapse when treated with current therapy. If they remain disease-free after longer follow-up, it may be advisable to treat them with less intensive, hence less toxic, chemotherapy than patients with higher WBC counts or lower DI values.

scholarly journals Prognostic impact of absolute lymphocyte counts at the end of remission induction in childhood acute lymphoblastic leukemia

Cancer ◽  
2013 ◽  
Vol 119 (11) ◽  
pp. 2061-2066 ◽  
Author(s):  
Jeffrey E. Rubnitz ◽  
Patrick Campbell ◽  
Yinmei Zhou ◽  
John T. Sandlund ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Prognostic Impact ◽  
Absolute Lymphocyte Counts
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