Obesity and Body Weight Independently Predict Relapse and Survival in Preadolescents and Teenagers with Acute Lymphoblastic Leukemia (ALL). A Retrospective Analysis of Five Children Cancer Group (CCG) Studies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 992-992 ◽  
Author(s):  
Anna Butturini ◽  
Fred Dorey ◽  
Paul Gaynon ◽  
Cecilia Fu ◽  
Janet Franklin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Lymphoblastic Leukemia ◽  
Obese Patients ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Control Growth ◽  
Increased Risk ◽  
Leukemia Relapse

Abstract We analyzed data from 4356 patients with ALL diagnosed from 1988 to 1995 at age 2–20 years and enrolled in CCG studies 1881, 1891, 1922, 1882 or 1901. Patients with Down Syndrome and those with CNS disease at diagnosis were excluded. Obesity was defined as a body mass index (BMI)>95th percentile by the Center for Disease Control growth charts (www.cdc.gov/growthcharts). Obesity at diagnosis did not affect outcome in patients younger than 10 years but independently predicted 5y risk of leukemia relapse and event free survival (EFS) in the 1026 patients aged 10 years or older. Multivariate analysis in patients aged 10 years or older showed that obese patients had increased risk of leukemia relapse (hazard ratio-HR- 1.5, p=0.013) and of all the events (HR 1.5, p=0.009). Other independent predictors of poor outcome were high WBC at diagnosis and failure to achieve bone marrow M1 status by day 7 of therapy. Age had borderline significance; sex, race and type of therapy were not significant. To assess whether the effect of obesity on outcome was due to absolute body weight, we studied the effect of weight in Kg at diagnosis in patients aged 10 years or older. Patients >60kg had increased risk of leukemia relapse (HR 1.4, p=0.002) and of all the events (HR 1.4, p=0.006). High WBC at diagnosis and bone marrow status at day 7 maintained their significance; age, sex, race and therapy were not significant. The effects of obesity and weight on outcome only partially overlapped: obesity still predicted outcome when only patients <60 kg were analyzed as well as weight >60 kg predicted outcome when obese patients were excluded from the analysis. Obesity and weight >60 kg at diagnosis were not associated with differences in early toxic deaths, lenght of initial phases of therapy or days of hospitalization. In conclusion, preadolescents and teenagers with ALL who were either obese or >60 kg of weight at diagnosis had higher risk of leukemia relapse and poorer EFS.

scholarly journals CD2 antigen expression on leukemic cells as a predictor of event-free survival after chemotherapy for T-lineage acute lymphoblastic leukemia: a Children's Cancer Group study

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4288-4295 ◽  
Author(s):  
FM Uckun ◽  
PG Steinherz ◽  
H Sather ◽  
M Trigg ◽  
D Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Standard Risk

Abstract We examined the prognostic impact of CD2 antigen expression for 651 patients with T-lineage acute lymphoblastic leukemia (ALL), who were enrolled in front-line Childrens Cancer Group treatment studies between 1983 and 1994. There was a statistically significant correlation between the CD2 antigen positive leukemic cell content of bone marrow and probability of remaining in bone marrow remission, as well as overall event-free survival (EFS) (P = .0003 and P = .002, log-rank tests for linear trend). When compared with patients with the highest CD2 expression level (> 75% positivity), the life table relative event rate (RER) was 1.22 for patients with intermediate range CD2 expression level (30% to 75% positivity) and 1.81 for “CD2-negative” patients (< 30% positivity). At 6 years postdiagnosis, the EFS estimates for the three CD2 expression groups (low positivity to high positivity) were 52.8%, 65.5%, and 71.9%, respectively. CD2 expression remained a significant predictor of EFS after adjustment for the effects of other covariates by multivariate regression, with a RER of 1.47 for CD2- negative patients (P = .04). Analysis of T-lineage ALL patients shows a significant separation in EFS after adjustment for the National Cancer Institute (NCI) age and white blood cell (WBC) criteria for standard and high-risk ALL (P = .002, RER = 1.67). The determination of CD2 expression on leukemic cells helped identify patients with the better and poorer prognoses in both of these risk group subsets. For standard risk T-lineage ALL, CD2-negative patients had a worse outcome (P = .0007, RER = 2.92) with an estimated 5-year EFS of 55.9% as compared with 78.3% for the CD2-positive patients. Thus, CD2 negativity in standard risk T-lineage ALL identified a group of patients who had a worse outcome than high-risk T-lineage ALL patients who were CD2 positive. The percentage of CD2 antigen positive leukemic cells from T- lineage ALL patients is a powerful predictor of EFS after chemotherapy. This prognostic relationship is the first instance in which a biological marker in T-lineage ALL has been unequivocally linked to treatment outcome.

scholarly journals CD2 antigen expression on leukemic cells as a predictor of event-free survival after chemotherapy for T-lineage acute lymphoblastic leukemia: a Children's Cancer Group study

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4288-4295 ◽  
Author(s):  
FM Uckun ◽  
PG Steinherz ◽  
H Sather ◽  
M Trigg ◽  
D Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Standard Risk

We examined the prognostic impact of CD2 antigen expression for 651 patients with T-lineage acute lymphoblastic leukemia (ALL), who were enrolled in front-line Childrens Cancer Group treatment studies between 1983 and 1994. There was a statistically significant correlation between the CD2 antigen positive leukemic cell content of bone marrow and probability of remaining in bone marrow remission, as well as overall event-free survival (EFS) (P = .0003 and P = .002, log-rank tests for linear trend). When compared with patients with the highest CD2 expression level (> 75% positivity), the life table relative event rate (RER) was 1.22 for patients with intermediate range CD2 expression level (30% to 75% positivity) and 1.81 for “CD2-negative” patients (< 30% positivity). At 6 years postdiagnosis, the EFS estimates for the three CD2 expression groups (low positivity to high positivity) were 52.8%, 65.5%, and 71.9%, respectively. CD2 expression remained a significant predictor of EFS after adjustment for the effects of other covariates by multivariate regression, with a RER of 1.47 for CD2- negative patients (P = .04). Analysis of T-lineage ALL patients shows a significant separation in EFS after adjustment for the National Cancer Institute (NCI) age and white blood cell (WBC) criteria for standard and high-risk ALL (P = .002, RER = 1.67). The determination of CD2 expression on leukemic cells helped identify patients with the better and poorer prognoses in both of these risk group subsets. For standard risk T-lineage ALL, CD2-negative patients had a worse outcome (P = .0007, RER = 2.92) with an estimated 5-year EFS of 55.9% as compared with 78.3% for the CD2-positive patients. Thus, CD2 negativity in standard risk T-lineage ALL identified a group of patients who had a worse outcome than high-risk T-lineage ALL patients who were CD2 positive. The percentage of CD2 antigen positive leukemic cells from T- lineage ALL patients is a powerful predictor of EFS after chemotherapy. This prognostic relationship is the first instance in which a biological marker in T-lineage ALL has been unequivocally linked to treatment outcome.

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.

Treatment Outcome and Prognostic Factors for Infants With Acute Lymphoblastic Leukemia Treated on Two Consecutive Trials of the Children's Cancer Group

1999 ◽  
Vol 17 (2) ◽  
pp. 445-445 ◽  
Author(s):  
Gregory H. Reaman ◽  
Richard Sposto ◽  
Martha G. Sensel ◽  
Beverly J. Lange ◽  
James H. Feusner ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Historical Controls

PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (> 95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG-1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG-1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/μL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG-1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.

Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

2007 ◽  
Vol 25 (15) ◽  
pp. 2063-2069 ◽  
Author(s):  
Anna M. Butturini ◽  
Frederick J. Dorey ◽  
Beverly J. Lange ◽  
David W. Henry ◽  
Paul S. Gaynon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Prognostic Variables ◽  
Free Survival ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Cancer Group ◽  
Hazard Ratios ◽  
Nonobese Patients

PurposeTo evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL).Patients and MethodsWe retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002.ResultsThe 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% ± 2.4% v 77% ± 0.6% (P = .02) and 26 ± 2.4 v 20 ± 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients ≥ 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients ≥ 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity.ConclusionObesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

Overexpression of HIF1 Alpha Predicts Worse Overall and Event-Free Survival in Patients with Philadelphia Chromosome-Negative Precursor B-Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2508-2508 ◽  
Author(s):  
S. Konoplev ◽  
S.M. Kornblau ◽  
E. Schlette ◽  
H Lu ◽  
D. A Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Akt Signaling ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Data Set ◽  
Free Survival ◽  
Survival Signaling

Abstract Background: Low oxygen levels are a defining characteristic of solid tumors, but the role of hypoxia in leukemogenesis remains unclear. Recent reports indicate that the endosteum at the murine bone-bone marrow (BM) interface is hypoxic, and data in a rat model demonstrate that leukemic cells infiltrating bone marrow were markedly hypoxic compared with cells in the BM of healthy rats. Hypoxia triggers a complex cellular and systemic adaptation mediated primarily through transcription by hypoxia inducible factors (HIFs) including HIF-1a. Although hypoxia is the best-characterized mechanism of HIF activation in tumors, HIF activity also can be induced in tumor cells through activation of the PI3K/Akt-signaling pathway. In this study, we assessed AKT and HIF-1a expression in newly diagnosed precursor B-cell acute lymphoblastic leukemia (pre-B ALL) and correlated the results with overall and progression-free patient survival. Methods: We analyzed expression of phosphorylated AKT (pAKT) and HIF-1a in leukemic cells by immunohistochemical methods using archival fixed, paraffin-embedded BM biopsy specimens of newly diagnosed pre-B ALL and antibodies specific for pAKT (Cell Signaling Technology, Beverly, MA) and HIF-1a (BD Biosciences, San Jose, CA). The initial observations were confirmed by a Reverse Phase Protein Array (RPPA) data set generated from protein lysates prepared from fresh blood and BM aspirate samples from patients with newly diagnosed pre-B ALL. Results: There were 26 men and 27 women with a median age of 39 years (range, 17–77). The median follow-up was 17 months (range, 1–71). The median WBC was 5.7 × 109/L (range, 0.8–369 × 109/L), the median percentage of blasts in bone marrow was 88% (range, 21–97%). Conventional cytogenetic studies detected a normal karyotype in 13 patients and abnormal karyotype in 37 patients including the Philadelphia chromosome (Ph) in 15 patients; no analyzable metaphases were recovered in 5 patients. Fluorescence in situ hybridization for BCR/ABL rearrangement was performed in all patients and was positive in all 15 patients with Ph and in 1 patient with normal conventional cytogenetics. 50 patients received HYPER-CVAD therapy, 3 patients received augmented BFM therapy. 49 (92%) patients achieved complete remission with a median time to response of 3 weeks (range, 2–8 weeks), 12 of them relapsed. 17 patients died, including 6 patients in complete remission. 3 year overall survival was 56% (CI, 46–66%). HIF-1a expression was detected in 37 (70%) patients, including 10 patients with Ph-positive ALL. HIF-1a expression was associated with expression of pAKT (R=0.4479, p&lt;0.01), and was not associated with age, sex, WBC, percentage of blasts in blood or BM, platelet count, serum levels of albumin, beta-2-microglobulin, bilirubin, creatinine, LDH, or presence of the Ph. HIF-1a expression was associated with worse overall survival for the entire patient population (p=0.023). The negative prognostic impact of HIF-1a expression remained when only Ph-negative patients were analyzed (p=0.004), Fig 1. Patients with HIF-1a expression appear to have worse progression-free survival, but the difference did not reach statistical significance, p=0.39. These results were confirmed by RPPA data set generated from 104 patients with newly diagnosed Ph-negative ALL. HIF-1a overexpression was strongly associated with worse overall (p=0.026) and event-free (p=0.0178). No association of HIF-1a overexpression with other clinical or laboratory parameters was detected. Conclusions: This is the first report demonstrating that HIF-1a expression is associated with worse overall and event-free survival in Ph-negative pre-B ALL. These findings implicate that inhibition of AKT signaling or blockade of HIF-1α-mediated pro-survival signaling events may improve clinical outcomes in pre-B ALL. Analysis of the key pro-survival signaling pathways activated by hypoxia and HIF-1a is ongoing (Frolova et al., ASH 2008). Figure Figure

Preemptive Bone Marrow Transplantation and Event-Free Survival in Fanconi Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3624-3624
Author(s):  
Nicholas Economou Khan ◽  
Philip S. Rosenberg ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Fanconi Anemia ◽  
Marrow Transplantation ◽  
Standard Care ◽  
Bone Marrow Failure ◽  
Event Free Survival ◽  
Free Survival ◽  
Increased Risk ◽  
The Mean

Abstract Background: Fanconi anemia (FA) is a primarily autosomal recessive bone marrow failure and cancer predisposition syndrome associated with mutations in the FA/BRCA DNA damage response pathway. The median age at diagnosis of FA is 7 years; the diagnosis is often made due to recognition of characteristic birth defects. Over half of patients with FA develop severe bone marrow failure (BMF) by age 50 years, one in ten develop acute myeloid leukemia (AML), and one in four develop a solid tumor (ST) as their first event. Successful allogeneic bone marrow transplantation (BMT) is potentially curative of FA's hematologic manifestations but introduces risks of transplant-related mortality (TRM) and morbidity. We hypothesized that preemptive bone marrow transplantation (PE-BMT) for individuals diagnosed prior to the development of BMF, AML, or ST, would increase event-free survival (EFS) if the risks associated with transplantation were sufficiently low. Methods: We developed a mathematical decision model (Markov) of EFS with the assumption that successful PE-BMT would eliminate the risks of BMF and AML, but would introduce a procedural risk of TRM. We modeled the EFS of PE-BMT at variable ages at decision ranging from birth to 30 years, and without and with an increase in the rate of ST following BMT above the level in untransplanted patients with FA. We developed our model using empirical estimates of the age-specific conditional probabilities of BMF, AML, and ST (Alter et al, BJH, 2010), and a 4.4-fold estimated increased risk of ST following BMT (Rosenberg et al, Blood, 2005). We tested the sensitivity of the model over a range of values for TRM and an increased risk of ST following BMT, and evaluated the model using TreeAge Pro 2014 (TreeAge Software, Inc, Williamstown MA, http://www.treeage.com). Results: Children diagnosed at age 7 years receiving standard care could expect to live an additional 16 years before experiencing BMF, ST, or AML, and thus survive free of an event until an average age of 23 years. If those children instead received PE-BMT with a 10% risk of TRM, they could expect to survive an additional 29 years and be cancer-free until an average age of 36 years. However, if PE-BMT were to increase the rate of ST 4.4-fold, PE-BMT would only increase the mean EFS by 2 years over standard care, until an average age of 25 years. PE-BMT would increase the mean EFS at all ages if TRM was ≤10% and the risk of ST was the same as in untransplanted patients. PE-BMT would decrease the mean EFS when performed after age 9 years if there was 10% TRM and a 4.4-fold increased rate of ST. PE-BMT at age 18 years with 10% TRM would increase the mean EFS if it did not affect the trajectory to ST, but would decrease the mean EFS if it modestly increased the rate of ST (≥2.2-fold). Conclusions: PE-BMT in patients with FA may provide an event-free survival benefit so long as the risk of TRM appears to be low (≤10%) and the regimen has little or no impact on the development of ST. The decision was particularly sensitive to the increase in ST following BMT. Our model suggests that older ages at decision, higher risks of TRM, and greater relative risks of ST following transplant would lead to PE-BMT being a less desirable strategy. Our estimates of event-free survival may be used to inform shared decision making between providers and families, with attention paid to patient values and the morbidity associated with BMT. Disclosures No relevant conflicts of interest to declare.

Augmented Berlin-Frankfurt-Muenster (ABFM) regimen for children with standard-risk acute lymphoblastic leukemia (SR-ALL) and slow early response (SER)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9511-9511
Author(s):  
Y. H. Matloub ◽  
A. Angiolillo ◽  
B. Bostrom ◽  
L. Stork ◽  
S. P. Hunger ◽  
...  
Keyword(s):  
Negative Impact ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Event Free Survival ◽  
Eligibility Criteria ◽  
Standard Regimen ◽  
Free Survival ◽  
E Coli ◽  
Cancer Group ◽  
Standard Risk

9511 Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p <0.001 and 02 respectively (N Engl J Med 1998; 338:1663–71). Methods: Therefore, COG-1952 and COG- 1991, studies for patients with SR-ALL, assigned the slow early responders to augmented therapy, while others were randomized according to the study design. Study eligibility criteria were similar for both, and included newly diagnosed children with National Cancer Institute SR criteria. COG-1952 accrued a total of 2,027 patients and COG-1991 accrued 3,054. In COG-1952 patients were deemed SER if their day-7 marrow had >5% blasts, and their day-14 marrow >25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had >25% blasts and their day-14 marrow had >5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy. No significant financial relationships to disclose.

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.

Obesity Independently Predicts Event Free Survival (EFS) in Adults with BCR-ABL-Negative Acute Lymphoblastic Leukemia (ALL). A Retrospective Analysis of Two GIMEMA Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1828-1828 ◽  
Author(s):  
Anna Butturini ◽  
Marco Vignetti ◽  
Stefania Gubbiotti ◽  
Giovanna Meloni ◽  
Monica Recchia ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Multivariate Analysis ◽  
Acute Lymphoblastic Leukemia ◽  
Pulmonary Toxicity ◽  
Lymphoblastic Leukemia ◽  
Obese Patients ◽  
Event Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Pediatric All

Abstract Obesity predicted decreased EFS in pediatric ALL (ASH 2004, Abstract#992). Here we report the effect of obesity, defined as body mass index &gt;30, in 906 adults enrolled in two GIMEMA trials. The first study (1996–2001) included 45 obese (9.5%) and 426 non-obese patients. Obese patients were older, received lower total doses of vincristine (VCR) and daunomicin (DNR) and had more hepatic and pulmonary toxicity during induction than not-obese patients; the incidence of toxic deaths and complete remissions (CR) were similar. By multivariate analysis, obesity, high WBC, age &gt;30y and presence of BCR-ABL at diagnosis independently predicted EFS. Hazard ratios (HR) for any events were respectively 1.506 (1.059–2.142, p=0.0228), 1.002 (1.001–1.003, p=0.0022)), 1.015 (1.006–1.025, p=0.0014) and 1.8 (1.4–2.4, p&lt;0.0001). The effect of obesity on EFS was present across all levels of WBC, but was observed prevalently in BCR-ABL-negative patients. 3y-EFS in obese vs non-obese patients was 22.9% vs 39.5% (p=0.0064) in BCR-ABL negative patients and not significantly different (14% vs 22%, p=0.77 n.s.) in BCR-ABL positive patients. These results were verified in the following study started in 2000, which included 50 obese (11%) and 385 non-obese patients. In this study, obese patients received 28% and 21% less than the planned doses of VCR and DNR respectively; also they were more likely than non-obese patients to be &gt;30 y of age and BCR-ABL-positive. The incidence of toxicity, toxic deaths and CR were similar in obese and non-obese patients. In the BCR-ABL negative patients, obesity tended to predict EFS. 2y-EFS was 26.6% in the obese and 49.4% in the non-obese patients (p=0.067). By multivariate analysis HR for any events of obesity, WBC&gt;50 and age&gt;30 were respectively 1.53 (0.92–2.58, p=0.107), 1.64 (1.12–2.39, p=0.012) and 1.74 (1.19–2.54, p=0.004). In conclusion, obesity seems associated with a poorer EFS in patients with BCR-ABL negative ALL; this might be caused by the lower doses of chemotherapy obese patients receive. Studies aimed to clarify chemotherapy pharmacokinetics, toxicity and efficacy in obese patients are warranted.

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