Prognostic Significance of Blasts in the Cerebrospinal Fluid Without Pleiocytosis or a Traumatic Lumbar Puncture in Children With Acute Lymphoblastic Leukemia: Experience of the Dutch Childhood Oncology Group

2006 ◽  
Vol 24 (15) ◽  
pp. 2332-2336 ◽  
Author(s):  
D. Maroeska W.M. te Loo ◽  
Willem A. Kamps ◽  
Anna van der Does-van den Berg ◽  
Elisabeth R. van Wering ◽  
Siebold S.N. de Graaf
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lumbar Puncture ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Event Free Survival ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Significant Difference

Purpose To determine the significance of blasts in the CSF without pleiocytosis and a traumatic lumbar puncture in children with acute lymphoblastic leukemia (ALL). Patients and Methods We retrospectively studied a cohort of 526 patients treated in accordance with the virtually identical Dutch protocols ALL-7 and ALL-8. Patients were classified into five groups: CNS1, no blasts in the CSF cytospin; CNS2, blasts present in the cytospin, but leukocytes less than 5/μL; CNS3, blasts present and leukocytes more than 5/μL. Patients with a traumatic lumbar puncture (TLP; > 10 erythrocytes/mL) were classified as TLP+ (blasts present in the cytospin) or TLP− (no blasts). Results Median duration of follow-up was 13.2 years (range, 6.9 to 15.5 years). Event-free survival (EFS) was 72.6% (SE, 2.5%) for CNS1 patients (n = 304), 70.3% (SE, 4.7%) for CNS2 patients (n = 111), and 66.7% (SE, 19%) for CNS3 patients (n = 10; no significant difference in EFS between the groups). EFS was 58% (SE, 7.6%) for TLP+ patients (n = 62) and 82% (SE, 5.2%) for TLP− patients (n = 39; P < .01). Cox regression analysis identified TLP+ status as an independent prognostic factor (risk ratio, 3.5; 95% CI, 1.4 to 8.8; P = .007). Cumulative incidence of CNS relapses was 0.05 and 0.07 in CNS1 and CNS2 patients, respectively (not statistically significant). Conclusion In our experience, the presence of a low number of blasts in the CSF without pleiocytosis has no prognostic significance. In contrast, a traumatic lumbar puncture with blasts in the CSF specimen is associated with an inferior outcome.

Diagnostic Cerebrospinal Fluid Examination in Children With Acute Lymphoblastic Leukemia: Significance of Low Leukocyte Counts With Blasts or Traumatic Lumbar Puncture

2003 ◽  
Vol 21 (2) ◽  
pp. 184-188 ◽  
Author(s):  
Britta Bürger ◽  
Martin Zimmermann ◽  
Georg Mann ◽  
Joachim Kühl ◽  
Lutz Löning ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lumbar Puncture ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Event Free Survival ◽  
Cns Involvement ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Leukocyte Counts

Purpose: To determine the significance of leukemic blasts or traumatic lumbar puncture (TLP) in diagnostic CSF of children enrolled in the Berlin-Frankfurt-Münster (BFM) Acute Lymphoblastic Leukemia–BFM-95 trial. Patients and Methods: A total of 2,021 patients were retrospectively evaluated according to initial central nervous system (CNS) status. Patients were classified as follows: CNS1 (CNS negative, n = 1,605), CNS2 (≤ 5 WBC/μL CSF with blasts, n = 103), CNS3 (CNS positive, n = 58), TLP+ (TLP with blasts, n = 135), or TLP− (TLP without blasts, n = 111). Patients with CNS2 and TLP+ status were eligible for two additional doses of intrathecal (IT) methotrexate (MTX). CNS3 patients received additional IT MTX and cranial irradiation (18 Gy). Results: CNS2, CNS3, and TLP+ groups contained a higher percentage of patients with unfavorable characteristics. Cox regression analysis identified TLP+ and CNS3 status as prognostically significant (CNS3): risk ratio (RR) = 2.3; 95% confidence interval [CI], 1.4 to 3.6; P = .0005; TLP+: RR = 1.5; 95% CI, 1.02 to 2.2; P = .04. Overall 5-year event-free survival (EFS) is 79%, for CNS1 it is 80%, and for TLP− it is 83%. CNS2 patients have an EFS of 80%, but the cumulative incidence of relapses with CNS involvement is higher compared with CNS1 patients (0.10 v 0.04). TLP+ patients have a significantly reduced EFS (73%, P = .003) because of an increased incidence of CNS relapses. CNS3 patients suffer from more systemic and CNS relapses (EFS 50%). Conclusion: CNS2 patients have the same prognosis as patients with CNS1 status, whereas the EFS of TLP+ patients is inferior to CNS1 but superior to CNS3 patients (P = .001). Both subgroups may have benefitted from additional IT MTX.

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (2) ◽  
pp. 527-535 ◽  
Author(s):  
F M Uckun ◽  
M G Sensel ◽  
H N Sather ◽  
P S Gaynon ◽  
D C Arthur ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Improved Outcomes ◽  
B Lineage ◽  
The Individual

PURPOSE The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

scholarly journals Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3302-3304 ◽  
Author(s):  
Sima Jeha ◽  
Frederick Behm ◽  
Deqing Pei ◽  
John T. Sandlund ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Cd20 Expression ◽  
Therapy Studies

Abstract CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% ± 2.9% versus 78% ± 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.

scholarly journals Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3122-3133 ◽  
Author(s):  
A Reiter ◽  
M Schrappe ◽  
WD Ludwig ◽  
W Hiddemann ◽  
S Sauter ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Multicenter Trial ◽  
Low Risk ◽  
Event Free Survival ◽  
Free Survival ◽  
Risk Patients ◽  
To Receive

Abstract In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

Does ATRA Confirm to Play a Role in the Better Relapse Free Survival of Infants with Acute Lymphoblastic Leukemia?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1515-1515
Author(s):  
Larisa Fechina ◽  
Egor Shorikov ◽  
Olga Streneva ◽  
Olga Khlebnikova ◽  
Igor Vyatkin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Molecular Mechanisms ◽  
Treatment Approach ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Cox Regression Analysis

Abstract Abstract 1515 Treatment achievements in infant's acute lymphoblastic leukemia (ALL) are still very modest. Despite of many attempts, the creation of novel, based on the molecular mechanisms, clinically approved and safe therapy strategies for this group of patients (pts) seems to be slow, so far. We also have developed a new treatment approach for infants with acute leukemia – MLL-Baby protocol, which includes 1 or 2 weeks ATRA consecutive courses at the dosing schedule of 25 mg/m2/d adjusted to age, started immediately after induction completion, alternating with standard chemotherapy and/or simultaneously applied with re-inductions. Rationale for ATRA application and MLL-Baby details were introduced in our previous report (ASH 2007 Abstract #2828). We have described there a small group of 19 primary diagnosed ALL infants, who underwent MLL-Baby protocol treatment in comparison to the group treated by standard chemotherapy with 20 months (mo.) median of follow up. ATRA-containing regimen has been shown well tolerated and improved early relapse free survival (RFS) significantly. Aim. To re-assess the ATRA efficacy in more representative group of pts with longer time of follow up. From September 2003 108 pts with primary ALL younger 12 mo. were non-randomly allocated either to ATRA (+) treatment approach (MLL-Baby) – 75 pts or ATRA (-) standard chemotherapy (mainly ALL-MB) – 33 pts due to decision of the treating physicians from 24 participating clinics in Russia and Belarus. Parents' informed consent was signed in all cases. The trial was approved by Ethics Committees. Both ATRA (−) and ATRA (+) groups were similar by the initial characteristics: median age 6 (1–11) and 6 (0–11) mo.; m/f ratio 12/21 and 25/50; initial WBC 96,7 (0,7–940) and 83,9 (1,6–2058) per microliter respectively, although CNS involvement seems to be more frequent in ATRA (+) group: 4 (12%) and 18 (24%) pts correspondingly. MLL rearrangements (MLL pos.) were found in 15 (53,6%) from 28 examined ATRA (−) pts and in 53 (70,7%) from 75 ATRA (+) pts. BI phenotype predominance was evident in ATRA (+) group - 39 (52,7%) out of 74 examined pts. The number of pts who have achieved CR was equally high in both schedules: 28 (84,9%) and 67 (89,3%) but the relapses rates remains significantly different: 16 (57,1%) and 16 (23,8%) pts in ATRA (-) and ATRA (+) groups respectively (p=0,001). Eight years RFS is 0,36 ± 0,08 and 0,59 ± 0,06 (p=0,02); cumulative incidence of relapses (RCI) is 0,62 ± 0,01 and 0,31 ± 0,004 (p=0,03) in ATRA (−) and ATRA (+) groups correspondingly, although EFS: 0,54 ± 0,06 vs. 0,33 ± 0,08 (p=0,17) and OS: 0,59 ± 0,06 vs. 0,36 ± 0,08 (p=0,09), median of follow up - 36 mo. (2 - 105), did not differ significantly between 2 groups ATRA (+) and ATRA (−) respectively due to the high proportion of induction and remission deaths. Among 75 pts treated by MLL-Baby – 7 (9,3%) died in induction and 7 (10,4%) out of 67 pts who achieved CR died in remission with median time to death – 2 mo., mostly because of severe infections. Out of 46 MLL pos. pts from ATRA (+) group who achieved CR, 14 (30%) pts relapsed, RFS is 0,59 ± 0,08 and RCI 0,40 ± 0,007. In contrast, in ATRA (−) group the relapse incidence in MLL pos. pts was very high - 12 (80%) out of 15 pts who achieved CR (p=0,008), RFS is 0,20 ± 0,10 (p=0,01) and RCI 0,80 ± 0,01 (p=0,02) correspondingly. In univariate analysis the following risk-factors: age < 6 mo. (p=0,001); MLL rearrangements (p=0,004) and dexamethasone response on Day 8 (p=0,01) have a significant negative impact on EFS in group of pts treated by MLL-Baby. Cox-regression analysis confirms the negative value of the same risk-factors: MLL pos. status with Hazard Ratio (HR) 3,8 (95% CI 1,32-10,9) p=0,01; age HR 3,18 (95%CI 1,5–6,8) p=0,003 and Day 8 response HR 3,16 (95% CI 1,4–7,1) p=0,005. Conclusions. The updated results in our cohort of 75 patients demonstrated that ATRA confirms effectiveness in the relapses prevention in infants suffering from ALL, if used in combination with standard chemotherapy without any escalation and bone marrow transplantation. Although the molecular mechanisms of ATRA effect are still poorly understood and need to be deeply explored, it might be recommended for randomization within representative international studies, particularly to the MLL rearranged infant's ALL. Great efforts in non-relapse mortality reduction should be applied by all participating clinics. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evaluation of pulse wave velocity for predicting major advanced cardiovascular events in patients with chronic myocardial infarction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Z Meiszterics ◽  
T Simor ◽  
R J Van Der Geest ◽  
N Farkas ◽  
B Gaszner
Keyword(s):  
Myocardial Infarction ◽  
Regression Analysis ◽  
Cardiovascular Events ◽  
Pulse Wave ◽  
Cox Regression ◽  
Event Free Survival ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Abstract Introduction Increased aortic pulse wave velocity (PWV) as a strong predictor of major advanced cardiovascular events (MACE) has a prognostic relevance in patients after myocardial infarction (MI). Several non-invasive methods have been proposed for the assessment of arterial stiffness, but the PWV values show significant differences according to the applied techniques. Cardiac magnetic resonance imaging (CMR) provides an accurate method to measure PWV and infarct size in patients after MI. Purpose Calculated PWV values of CMR based phase-contrast (PC) and invasively validated oscillometric methods were compared in this prospective observational study. We aimed to evaluate the cut-off PWV values for each method, while MACE predicted and validated the prognostic value of high PWV in post-infarcted patients in a 6-year follow-up. Methods 3D aortic angiography and PC velocity imaging was performed using a Siemens Avanto 1,5 T CMR device. Oscillometric based Arteriograph (AG) was used to assess PWV using direct body surface distance measurements. The comparison between the two techniques was tested. Patients received follow-up for MACE comprising all-cause death, non-fatal MI, ischemic stroke, hospitalization for heart failure and coronary revascularization. Event-free survival was analysed using Kaplan-Meier plots and log-rank tests. Univariable and multivariable Cox regression analysis was performed to identify outcome predictors. Results 75 patients (56 male, 19 female, average age: 56±13 years) referred for CMR were investigated, of whom 50 had coronary artery disease (CAD) including 35 patients with previous MI developing ischaemic late gadolinium enhancement (LGE) pattern. AG and CMR derived PWV values were significantly correlated (rho: 0,343, p&lt;0,05), however absolute PWV values were significantly higher for AG (median (IQR): 10,4 (9,2–11,9) vs. 6,44 (5,64–7,5); p&lt;0,001). Bland Altman analysis showed an acceptable agreement with a mean difference of 3,7 m/s between the two measures. In patients with CAD significantly (p&lt;0,01) higher PWV values were measured by AG and CMR, respectively. During the median follow-up of 6 years, totally 69 MACE events occurred. Optimized PWV cut-off values for MACE prediction were calculated (CMR: 6,47 m/s; AG: 9,625 m/s) by receiver operating characteristic analysis. Kaplan-Meier analysis in both methods showed a significantly lower event-free survival in case of high PWV (p&lt;0,01, respectively). Cox regression analysis revealed PWV for both methods as a predictor of MACE (PWV CMR hazard ratio (HR): 2,6 (confidence interval (CI) 1,3–5,1), PWV AG HR: 3,1 (CI: 1,3–7,1), p&lt;0,005, respectively). Conclusions Our study showed good agreement between the AG and CMR methods for PWV calculation. Both techniques are feasible for MACE prediction in postinfarcted patients. However, different AG and CMR PWV cut-off values were calculated to improve risk stratification. FUNDunding Acknowledgement Type of funding sources: None. Agreement between the two methods Kaplan-Meier event curves for MACE

scholarly journals Changing the Fate of Children with Acute Lymphoblastic Leukemia (ALL) in a Limited Resources Setting

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5075-5075
Author(s):  
Yajaira Valentine Jimenez-Antolinez ◽  
Julia Esther Colunga Pedraza ◽  
José Eduardo Mares-Gil ◽  
Emma Lizeth Estrada ◽  
Jesus Mauricio Gonzalez-Diaz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Relapse Rate ◽  
Lymphoblastic Leukemia ◽  
Limited Resource ◽  
Outcome Evaluation ◽  
Event Free Survival ◽  
Free Survival ◽  
Early Relapse

Introduction Pediatric acute Lymphoblastic Leukemia (ALL) patients have about 90% overall survival (OS) in developed countries. However, many children in low-middle income countries (LMIC) do not have access to appropriate drugs at optimal doses, a multidisciplinary medical team, laboratory resources for diagnosis and follow-up, and appropriate support therapy for morbidities and treatment-related toxicities. A 50-60% five-year OS has been reported in children with ALL in Mexico, and our center is not the exception. This low survival rate has pushed Mexican centers to develop strategies highlighting collaboration between centers with economic, research and teaching resources ("Mexico en Alianza con St. Jude MAS"), and outpatient treatment. However, each center must adapt their chemotherapy protocol to its own supplies and possibilities. We report the results of a risk adapted therapy protocol in a limited-resource treatment setting. Materials and Methods All pediatric patients with a diagnosis of ALL from January 2017 to December 2018 were classified according to risk as shown in Figure 1. Depending on risk classification, modifications to the induction, consolidation and intermediate maintenance regimens were made. The higher the risk, the higher the intensity of the regimen, as defined by the number of anthracycline doses, the presence or absence of high-dose methotrexate, and the duration of the consolidation and maintenance phases (Table 1). Demographic data is reported using distribution analysis, and the Kaplan-Meier method is used to analyze and predict overall survival, event-free survival (EFS) and relapse. Our results were compared with previous results from our institution. Results There were 35 male and 25 female patients; median age at diagnosis was 5.5. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 57 (95%), and 3 (5%) patients, respectively, with a follow-up of 16 (8-30) months. Twenty-three (38%), 21 (35%), and 16 (26%) children were classified as high, intermediate and low risk ALL, respectively. After one week of corticosteroids 46 (77%) of patients had a good response. At the end of induction 53 patients had an evaluable MRD (88%), out of which 9 were positive (17%). Median follow-up was 16 (0.6-30) months. Mortality at induction was 6 (10%) patients. Very early relapse was observed in 3(5%) of patients. Estimated 2-year relapse rate was 6%, event-free survival was 84.1%, and OS was 85%. A comparison of results obtained with previous regimens (protocols 1 and 2) and the risk-adapted treatment (protocol 3) is observed in Table 2. Conclusions The implementation of a modified chemotherapy regimen based on adjusted stratification risk was associated to improved responses as reflected by MRD. A decrease in very early relapse rate to 5%, without increasing the toxicity and death during induction was observed. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and to standardize therapy. Long-term follow-up of this patient group is required to compare OS and EFS at 5 years. This is a preliminary report, but it seems that we are changing the fate of Mexican children with ALL. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

scholarly journals Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 761-761
Author(s):  
Uma H. Athale ◽  
Maneka Puligandla ◽  
Kristen E. Stevenson ◽  
Barbara L. Asselin ◽  
Luis A. Clavell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Dana Farber Cancer Institute ◽  
Induction Failure

Abstract Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant. Results: Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]). Conclusion: DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. Overall and event free survival Overall and event free survival Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group.

1997 ◽  
Vol 15 (6) ◽  
pp. 2222-2230 ◽  
Author(s):  
J Nachman ◽  
H N Sather ◽  
P S Gaynon ◽  
J N Lukens ◽  
L Wolff ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Early Response ◽  
Response To Therapy ◽  
Intensive Chemotherapy ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Avascular Necrosis Of Bone

PURPOSE Compared with previous Children's Cancer Group (CCG) acute lymphoblastic leukemia (ALL) trials, therapy based on the Berlin-Frankfurt-Munster (BFM) 76 trial has effected an improvement in event-free survival (EFS). In an attempt to improve EFS further, CCG investigators formulated an augmented BFM (A-BFM) regimen that provides prolonged, intensified postinduction chemotherapy relative to the CCG-modified BFM regimen. PATIENTS AND METHODS We tested A-BFM in 101 patients with ALL and unfavorable presenting features that showed slow early response (SER) to induction therapy who attained remission on day 28. Their outcome was compared with that of 251 concurrent patients with unfavorable presenting features, a rapid early response to therapy (RER), and remission by day 28, treated with CCG-BFM with or without cranial radiation (CRT). RESULTS The 4-year EFS rate from the end of induction for SER patients treated with A-BFM was 70.8% +/- 4.6%. Seventeen patients remain in continuous remission beyond 5 years. Vincristine (VCR) neurotoxicity developed in 50% of patients, but was rarely debilitating. Allergies to Escherichia coli L-asparaginase (L-ASP) occurred in 35% of patients. Avascular necrosis of bone (AVN) developed in 9% of patients. In comparison, a concurrent RER group treated with standard BFM +/- CRT had a 4-year EFS rate of 73.1% +/- 4.6%. CONCLUSION The toxicity of A-BFM is significant, but acceptable. Compared with historical control SER patients treated with CCG-modified BFM, A-BFM therapy appears to produce a significant improvement in EFS. This is the first study to show that intensive chemotherapy, as given in the A-BFM regimen, can abrogate the adverse prognostic significance of SER.

Ten Year Follow up Analysis of the OSHO Phase III Trial (AML 96) Comparing Different Application Modes of AraC in Patients below 60 Years with Acute Myeloid Leukemia (AML): No Impact of AraCApplication Mode on Remission Rate, Toxicity, Disease-Free Survival or Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Difference

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) &gt; 109/l and median platelets (plt) &gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p&lt;10−6) and for EFS (p&lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (&gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p&lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

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