Results of the Randomized I-BFM-SG Trial „Acute Lymphoblastic Leukemia Intercontinental-BFM 2002“ in 5060 Children Diagnosed in 15 Countries on 3 Continents

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 872-872 ◽  
Author(s):  
Jan Stary ◽  
Martin Zimmermann ◽  
Myriam Campbell ◽  
Luis Castillo ◽  
Eduardo Dibar ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Oral Prednisone ◽  
Risk Groups ◽  
Intrathecal Methotrexate ◽  
Secondary Malignancy ◽  
Early Treatment Response ◽  
The Impact

Abstract Abstract 872 Introduction: ALL IC-BFM 2002 is one of the most successful projects developed by the I-BFM-SG, which is one of the world largest societies involving national leukemia groups. The trial evaluated in a randomized manner the impact on outcome of intensified late reinduction in the context of a newly developed risk stratification. The main goal of the trial was improvement of outcome of children with ALL in each of the 3 risk groups (RG). Patients & methods: From Nov 2002-Nov 2007, 5060 eligible pts aged 0–18 yrs with newly diagnosed ALL from Argentina (1270), Chile (558), Croatia (122), Cuba (151), Czech Republic (291), Hong Kong (155), Hungary (259), Israel (292), Poland (908), Serbia (266), Slovakia (137), Slovenia (36), Ukraine (421), Uruguay (96), and Moscow (98) were enrolled in the trial (http:clinicaltrials.gov “NCT00764907”). Stratification into 3 RGs was based on early treatment response (evaluated in PB on day 8 and in BM on days 15 and 33), age, initial WBC, and presence/absence of BCR/ABL or MLL/AF4. Standard Risk (SR) criteria were: < 1,000 blasts/μL in PB day 8 after 7 days of oral prednisone with 1 intrathecal methotrexate (IT-MTX) and age ≥ 1 yr and < 6 yr and initial WBC < 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (all criteria must be fulfilled). Intermediate Risk (IR) criteria were: < 1,000 blasts/μL in PB day 8 and age < 1 yr or ≥ 6 yr and/or WBC ≥ 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (or SR criteria but M3 marrow on day 15 and M1 marrow on day 33). High Risk (HR) criteria were: IR and M3 marrow on day 15, PB on day 8 ≥ 1,000 blasts/μL, M2 or M3 marrow on day 33, translocation t(9;22) [BCR/ABL] or t(4;11) [MLL/AF4] (at least one criterion must be fulfilled). The majority of infants < 1 yr were treated in studies Interfant 99 and Interfant 06. Treatment consisted of protocol I‘/I, SR/IR consolidation with 6-MP and MD MTX 2g/m2 × 4 (with additional IT-MTX in maintenance) for BCP-ALL, 6-MP and HD MTX 5g/m2 × 4 for T-ALL, HR consolidation with 3 HR polychemotherapy blocks. A randomized question was asked in late intensification: SR: would 2 shorter elements (protocol III × 2) be more effective than 1 longer (protocol II × 1) even though the cumulative dose of most drugs is not increased? IR: could the risk of failure be reduced by a third reintensification element (protocol III × 3)? HR: could the use of 3 reintensification elements (protocol III × 3) achieve the same or better results than the HR approach applied in BFM (3 HR blocks + protocol II × 1) or AIEOP (protocol II × 2)? Chemotherapy was concluded by maintenance therapy (6-MP/MTX), making up a total of 2 yrs overall treatment. Prophylactic CNS radiotherapy 12 Gy was applied in T-ALL and HR pts. Results: With median follow-up 4.9 yr, the 5-yr EFS was 74 ± 1% and 5-yr OS 82 ± 1% for the whole group of 5060 pts. The CR rate was 97%, 255 (5%) children died in remission. The 5-yr EFS/OS was 81 ± 1%/90 ± 1% in 1564 SR pts (30.9% of all pts), 75 ± 1%/83 ± 1% in 2650 IR pts (52.4%) and 55 ± 2%/62 ± 2% in 846 HR pts (16.7%). Randomization rate was 79% of those patients who survived for at least 20 weeks (planned timepoint of randomization). None of the experimental arms achieved significantly better EFS compared to standard treatment. CI of relapses at 5 yr was 18 ± 1% overall, CI for isolated BM relapse was 12 ± 1%, isolated and combined CNS relapse 4 ± 0.3%, isolated and combined testicular relapse 2 ± 0.2%. Secondary malignancy was diagnosed so far in 26 patients (5-yr CI 0.6 ± 0.1%). Significantly better EFS was achieved in BCP-ALL(75 ± 1%) in comparison with T-ALL (69 ± 1%), girls vs. boys (76 ± 1% vs 72 ± 1%), children aged < 10 yr vs ≥ 10 yr (77 ± 1% vs 65 ± 1%), M1/M2 BM D15 vs. M3(76 ± 1% vs 50 ± 3%). 140 pts with Ph+ALL achieved a EFS of 47 ± 4% Allogeneic HSCT in CR1 was done in 139 pts with 5 -yr DFS of 64 ± 4%. Conclusions: Although the experimental arm was no better than the traditional one across individual RGs, the majority of participating countries, many of them were new-comers to this intensive therapy, improved their treatment results against previous national studies. The trial confirmed the validity and feasibility of a simple risk stratification of ALL applied in a complex and heterogeneous multinational environment. Despite the great differences between individual countries, the trial set a firm stage for willing national leukemia groups to run collaborative clinical trials in ALL under the umbrella of I-BFM-SG. Supported by MSM0021620813 and MZ0FNM2005. Disclosures: No relevant conflicts of interest to declare.

Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002

2014 ◽  
Vol 32 (3) ◽  
pp. 174-184 ◽  
Author(s):  
Jan Stary ◽  
Martin Zimmermann ◽  
Myriam Campbell ◽  
Luis Castillo ◽  
Eduardo Dibar ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Standard Treatment ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Early Treatment Response ◽  
The Impact ◽  
Standard Risk

Purpose From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. Patients and Methods For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster [BFM] option). Results At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. Conclusion The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.

Host Pharmacogenetic Factors Significantly Contribute to Refinement of Prognosis in Children with Acute Lymphoblastic Leukemia (ALL): Result From the Malaysia-Singapore (Ma-Spore) ALL 2003 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 567-567 ◽  
Author(s):  
Yi Lu ◽  
Shirley Kow Yin Kham ◽  
Arrifin Hany ◽  
Ah Moy Tan ◽  
Thuan Chong Quah ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Risk Stratification ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Pediatric All ◽  
Induction Failure ◽  
Wbc Count ◽  
The Impact

Abstract Abstract 567FN2 The successful incorporation of risk-associated factors in contemporary treatment regimens has remarkably improved the treatment outcome of pediatric ALL. Currently, the most commonly used prognostic factors such as the age and white blood cell (WBC) count which are tightly correlated with certain cytogenetic/molecular subtypes, are mainly related to leukemic factors. Beyond that, host pharmacogenetic factors, i.e., how the host genetic makeup influences the metabolism of chemotherapeutic agents, are expected to have additional but smaller impact on treatment outcome. Modern, successful multi-agent chemotherapy incorporates more than 8 different chemotherapeutic agents to treat pediatric ALL. Variability in individual patients in handling these drugs arises from their pharmacogenetic factors. However, such pharmacogenetic variants are rarely evaluated in existing prognostication schema. We studied both tumor- and host pharmacogenetic factors to determine the impact of germline variations on the treatment outcome in the Malaysia-Singapore (Ma-Spore) ALL 2003 study essentially guided by the MRD-risk stratification. A total of 463 patients were included, with a median follow-up of 3.8 years (0-8.2). Genotyping was carried out for 20 germline polymorphisms in 11 genes (i.e., GSTM1, GSTT1, GSTP1, NQO1, MTHFR, MTHFD1, SLC19A1, ABCB1, TYMS, CCR5, and IL15). The genotypic influence on the event-free survival (EFS) probability was estimated by Cox regression, adjusted for patients' characteristics (including the ethnicity, sex, age, lineage, and initial WBC count) and cytogenetic subtypes. An event was defined as any of: induction failure (N=20), relapse (N=32, any site) or death (N=25, any cause). Only cytogenetic subtypes showed significant impact on the EFS (P=0.015). After adjusting for host-related and leukemic factors, ABCB1 3435C>T (rs1045642), CCR5 246A>G (rs1799987), and IL15 67276493G>C (rs17015014) were also found to significantly and independently affect the survival probabilities. Specifically, ABCB1 3435T/T and CCR5 246G/A predicted lower EFS probabilities compared to 3435C/C and 246G/G, respectively (P=0.012, HR=2.496, 95%CI=1.223-5.092, Fig.1a and P=0.033, HR=1.820, 95%CI=1.051-3.153, Fig.1b), while IL15 67276493G/C was associated with a higher survival probability compared to 67276493G/G (P=0.030, HR=0.545, 95%CI=0.315-0.942, Fig.1c). In addition, the risk increased with increasing number of risk genotypes (i.e., ABCB1 3435T/T, CCR5 246G/A, and IL15 67276493G/G, which were associated with the worst survival respectively; Fig.1d), implicating a cumulative adverse effect (P<0.001). Further analyses revealed that compared to the reference genotypes respectively, ABCB1 3435T/T particularly correlated with the highest risk of relapse (P=0.011); CCR5 246G/A was associated with a higher risk of failure of induction therapy (including induction failure and death during induction; P=0.022); and IL15 67276493G/C conferred a protection from septic death (P=0.041). We subsequently investigated whether these polymorphisms could still influence the outcome in cytogenetic groups with known prognosis. ABCB1 3435C/T and T/T in combination were predictive of a poorer survival in 184 patients with favorable subtypes including t(12;21), t(1;19), and hyperdiploidy (P=0.027, HR=5.271, 95%CI=1.211-22.944); CCR5 246G/A appeared to retain its significance in 29 patients with unfavorable subtypes including t(11q23)/MLL rearrangements and t(9;22) (P=0.052, HR=7.708, 95%CI=0.983-60.471); and in 229 patients without common chromosomal abnormalities, IL15 67276493C/C was associated with the best survival (P=0.027, HR=0.291, 95%CI=0.098–0.868). Our results suggest that risk assignment for contemporary ALL treatment can be refined by incorporating the host pharmacogenetic profile into existing strategy of risk stratification that uses mainly leukemic factors. Disclosures: No relevant conflicts of interest to declare.

Absence of Chromosomal Abnormalities Corresponds to Better Survival in Adult Ph-Negative ACUTE Lymphoblastic Leukemia – Results of the Russian ACUTE Lymphoblastic Leukemia (RALL) Study Group.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2572-2572
Author(s):  
Elena Parovichnikova ◽  
Julia R Davidyan ◽  
Galina A Kliasova ◽  
Andrey N Sokolov ◽  
Vera V Troitskaya ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Normal Karyotype ◽  
Risk Groups ◽  
Treatment Schedule ◽  
Blast Count ◽  
The Impact

Abstract Abstract 2572 Adult ALL regardless recent advantages in adolescents and young adults is still considered to be a therapeutical problem. So called “a pediatric-like approach” applied in adult ALL is reported to be more reasonable even in the older adults (up to 55 y). RALL has initiated a prospective multicenter trial for adult Ph-neg ALL based on: 1) evaluation of b/m blast clearance after 7 days of Prednisolone (PRD) prephase and its substitution by Dexamethasone (DEXA) if b/m blast count was >25%; 2) continuous 2,5 years treatment schedule with prolonged L-asparaginase (Σ=590.000 IU); 3) evaluation of the impact of the late intensification (2 courses of HD of methotrexate and ARA-C) on MRD clearance. The study is registered on the ClinicalTrials.gov public site; NCT01193933. From Nov, 2008, till June, 2012, 24 centers enrolled 173 pts: median age 28 y (15–55), 71f/101m, 112 (64,7%) = B-lin, 54 (31,2%) = T-lin, 1 pt -undifferentiated AL (0,6%), 6 - uknown phenotype (3,5%), median LDH=848 ME (72–13061), median L=13,5 (0,6–556*109/l). Cytogenetics was evaluable in 58,3% of pts (n=101) and 46,5% of them (n=47) had normal karyotype (NK). Initial risk group was evaluated in 154 pts among whom 46 patients (29,9%) were in the standard risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-negative), 109 (60,1%) - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)-positive). 19/173 pts (11%) were not qualified. The analysis was performed in June, 2012. +8 day b/m blast count was reported in 149 pts and b/m blasts less than 25% were detected in 36,2% of pts. The portion of PRD non-responders was statistically different in SR and HR groups: 24/45 (53,3%) and 68/101 (67,3%) (p=0,01), confirming the initial risk groups identification. Induction results were obtained in 150 pts, and CR rate was identical in both risk groups (SR=86,9%; HR=84,1%) with total 12 induction deaths (8,0%) and 6 resistant leukemias (4,0%). With a median follow-up of 12 mo (1–36 mo) death in CR was reported in 9/132 (6,8%) pts. OS at 36 mo was 58,6%, DFS-68,3%. MRD analysis for clonal IgH and TCR rearrangements was carried out in 25 pts. And as in our previous studies (ASH 2006, abstr 2294) the clearance was slow with only 41,6% pts negative for MRD at day +133 (4mo) of the protocol. Two late intensification courses (day +157 = 5 mo) increased MRD negativity only up to 50%. Such slow MRD clearance did not correspond to higher relapse rate so far. Age, WBC, immunophenotype, LDH, risk group, +8 day b/m blast count, time to CR, time without treatment (<>8days), L-asparaginase cessation did not influence survival. OS and DFS differed in pts with NK vs all other abnormalities: 87,4% vs 57,9% (p=0,002) and 88,9% vs 66,5%, respectively (p=0,02). So, our data demonstrated that ALL-2009 protocol provided 58% 3-years overall survival and 68,3% DFS. In adult Ph-neg ALL normal karyotype predicts better survival. The MRD clearance is very slow while on this protocol. Disclosures: No relevant conflicts of interest to declare.

Survival in Patients with Newly Diagnosed Myeloma Undergoing Therapy with Lenalidomide and Dexamethasone: Impact of High-Risk Cytogenetic Risk Status on Outcome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 95-95 ◽  
Author(s):  
Prashant Kapoor ◽  
Shaji Kumar ◽  
Rafael Fonseca ◽  
Martha Q. Lacy ◽  
Thomas E Witzig ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Plasma Cell ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Impact ◽  
Standard Risk

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

Increased Incidence of Osteonecrosis (ON) with a Dexamethasone (DEX) Induction for High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report from the Children’s Oncology Group (COG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 898-898 ◽  
Author(s):  
Leonard A. Mattano ◽  
James B. Nachman ◽  
Meenakshi Devidas ◽  
Naomi Winick ◽  
Elizabeth Raetz ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Initial Study ◽  
Intrathecal Methotrexate ◽  
High Dose ◽  
Historical Comparison ◽  
Randomized Design ◽  
Age Cohort ◽  
Methotrexate Dose ◽  
Grade 3 ◽  
The Impact

Abstract Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design: induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), and interim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX. Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those <13y received continuous DEX. In 10/2006 the study was amended due to an unexpectedly high ON incidence in patients 10–12y receiving continuous DEX (28% @ 18 months) compared with historical controls given discontinuous DEX (3.4%). Subsequently all patients ≥ 10y have received discontinuous DEX; it is too early to assess the impact of this change. A comprehensive interim ON analysis was completed 4/2008 (reported as 24-month cumulative incidences). Overall ON incidence is 10.4% (110/1647), and is higher for those age ≥ 10 vs. <10y (15.2 vs 2.6%, p<0.0001, RHR=6.38); 99/110 cases of ON occurred in the older cohort. Among all patients, ON incidence is higher in DEX vs. PRED regimens (11.6 vs 8.7%, p=0.014, RHR 1.64); rates are similar for Capizzi MTX vs. HD-MTX regimens (10.4 vs 9.8%). Among patients ≥ 13y, incidence is higher in DEX vs. PRED regimens (18.9 vs 9.9%, p=0.02, RHR 1.97). There is no difference between regimens for children <10y. Among randomized RER patients ≥ 10y, incidence is higher in DEX vs. PRED regimens (17.2 vs 12.6%, p=0.006, RHR=1.79). For historical comparison, ON incidences by age cohort for RER patients on AALL0232 regimen PC (PRED + Capizzi MTX) vs. CCG-1961 regimen D (double DI with discontinuous DEX) were: <10y 4.1±3.4 vs. 2.0±1.4%, 10–12y 21.9±10.6 vs. 7.1±2.8%, and ≥ 13y 7.1±10.1 vs. 6.6±3.8%. To address these findings, the study was amended 6/2008. Patients ≥ 10y will be non-randomly assigned to induction PRED; the induction steroid randomization will continue for younger patients. Patients of all ages will receive discontinuous DEX during DI and PRED pulses during maintenance. Of note, compared with CCG-1961 the AALL0232 augmented BFM backbone was non-randomly modified in several ways that may affect ON incidence, including the use of pegaspargase during induction, a higher 15 mg intrathecal methotrexate dose for those age ≥ 9y, and monthly DEX instead of PRED maintenance pulses. Heightened awareness among caregivers may also have led to increased recognition and reporting of this toxicity. Using CTCAE v3.0 criteria, clinical ON severity among the 110 patients is: 3% grade 1, 60% grade 2, 35% grade 3, and 2% grade 4. Data regarding surgical intervention are being collected. These findings will directly influence the design of future trials in an effort to lessen the incidence and burden of this toxicity.

Implication of Genetic Variations of Ikzf1, ARIDB5, and CEBPE Genes In the Risk of Childhood Acute Lymphoblastic Leukemia In Korea

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3235-3235
Author(s):  
Dong Kyun Han ◽  
Hee Nam Kim ◽  
Min Ho Shin ◽  
Minenori Eguchi-Ishimae ◽  
Mariko Eguchi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Asian Countries ◽  
Childhood All ◽  
Genomic Variations ◽  
Genotype Frequencies ◽  
The Impact

Abstract Abstract 3235 Background: Recent western studies have showed the implication of the germline genomic variations in IKZF1 gene at 7p12.2, ARIDB5 gene at 10q21.2, and CEBPE gene at 14q11.2 on the risk of childhood acute lymphoblastic leukemia (ALL); the most significant association was observed in the single nucleotide polymorphism (SNP) rs4132601 which located at 3' region of the IKZF1. IKZF1 plays important role in lymphocyte differentiation, proliferation and function, ARIDB5 in embryogenesis and growth regulation, and CEBPE in regulation of myelopoiesis. Genomic variants in these genes are therefore considered to be involved in transcriptional regulation and differentiation of B cell progenitors. However, there have been no reports on the role of germline variations in leukemogenesis of childhood ALL in Asian countries. The aim of this study is to show the impact of these genetic variants on childhood ALL in Korea. Patients and Methods: To examine the association between genetic variations (IKZF1 rs4132601, ARIDB5 rs7089424, and CEBPE rs2239633) and the risk of childhood ALL, we here analyzed 228 children with ALL and 508 healthy individuals in Korea. Results: In ARIDB5 rs7089424, TG and GG genotypes were significantly associated with a risk for ALL (odds ratio [OR], 1.63; 95% confidential interval [CI], 1.07–2.48; P=0.02 for TG genotype, OR, 2.69; 95% CI, 1.42–5.07; P=0.002 for GG genotype). The allele incidence of ARIDB5 rs7089424 was also significantly associated with a risk for ALL (OR, 1.66; 95% CI, 1.24–2.22; P=0.0006). CEBPE rs2239633 TT genotype showed a significant association with a decreased risk for ALL (OR, 0.54; 95% CI, 0.33–0.90; P=0.02 for TT genotype). The allele incidence of CEBPE rs2239633 was also associated with a decreased risk for ALL (OR, 0.77; 95% CI, 0.61–0.97; P=0.02). There was no significant association between IKZF1 rs4132601 polymorphism and a risk for ALL in this study. Conclusion: These results suggest that genomic variations of ARIDB5 and CEBPE may play an important role in the risk for childhood ALL in Korea, compared with findings from western countries showing a significant relation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other SNPs or other Asian countries are warranted in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

MiR-125b Cooperates with BCR-ABL and Enhances Therapy Resistance in Childhood Ph+ ALL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 78-78
Author(s):  
Marina Lipkin Vasquez ◽  
Nicola Zanesi ◽  
Stefano Volinia ◽  
Ramiro Garzon ◽  
Giovanni Cazzaniga ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Poor Responder ◽  
Intrathecal Methotrexate ◽  
Patient Groups

Abstract Abstract 78 The treatment improvements in the past two decades led childhood acute lymphoblastic leukemia (ALL) cure rates reach over 80%, but children who carry the Philadelphia (Ph+) chromosome still have high risk of relapse due to therapy resistance. Different results with large series of patients have shown that an earlier remission after induction with glucocorticoids and intrathecal methotrexate is correlated to a better outcome. Besides, the minimal residual disease (MRD) risk measured after induction is also correlated to the therapy response, indicating that an early response can predict Ph+ ALL overall outcome. Several studies have shown that Ph+ ALL is heterogeneous in terms of clinical parameters even if all patients carry BCR-ABL and most of them carry the oncogenic isoform of IKAROS. They respond differently to the treatment, which suggests the presence of additional mechanisms involved in leukemogenesis. In an attempt to find secondary genetic abnormalities that may be responsible for the Ph+ ALL chemo resistance and heterogeneity, we studied the miRNA expression profile in two patient groups discriminated by the initial therapy response. We included samples from 78 consecutive Ph+ ALL children diagnosed in Italy between 2000 and 2010. The miRNA signature was analyzed by miRNA array using Applied Biosystems Array-Cards comparing two patient groups differentiated according to MRD and prednisone response. A particular miRNA profile was found in the poor responder group and it was confirmed using specific miRNA single assays from AB. Specially the miR-125b was up to ten-fold overexpressed compared to the good responder group (p =.006). To investigate the functional role of miR-125b in Ph+ ALL we used BCR-ABL positive cell lines (3 ALL and one CML in blast-crisis) to create a xenograft leukemia model and induced miRNA upregulation by direct inoculation of synthetic miR-125b (premiR). Tumors injected with premiR-125b (n=14) were significantly bigger than the scrambled oligonucleotide (n=10) and mock controls (n=4) (p=.04). After two weeks the premiR-125b tumors grew six-fold more than controls and average tumor weights for the scrambled oligonucleotides and the premiR-125b inoculated mice were 0.63 g and 1.56 g, respectively (p =.01). Further, we determined whether miR-125b protects the tumor cells from apoptosis after treatment with Dexamethasone. While tumors injected with scrambled molecules were 70% reduced after 10 days of corticoid treatment, tumors injected with premiR-125b were only 30% reduced (p=.05). Together, these results suggest that miR-125b acts as an oncogene in Ph+ ALL and its overexpression accelerates the role of BCR-ABL, increasing therapy resistance and leukemia aggressiveness. Additional studies will be necessary to understand why this miRNA is overexpressed in some patients and how it acts in cooperation with BCR-ABL to induce leukemia. In the future, novel therapies using miRNAs as targets can emerge as strategies to be added to the anti-tyrosine kinase drugs in order to improve treatment response and survivor in Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

Effects of G-CSF On Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2564-2564
Author(s):  
Jordan Basnett ◽  
Adam Cisterne ◽  
Kenneth F Bradstock ◽  
Linda J Bendall
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Microarray Analysis ◽  
Environmental Changes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Extracellular Matrix Components ◽  
The Impact

Abstract Abstract 2564 G-CSF is commonly used to treat chemotherapy-induced neutropenia and for the mobilization of hematopoietic stem cells for transplantation in patients with leukemia. Administration of G-CSF has profound effects on the bone marrow microenvironment including the cleavage of molecules required for the maintenance of lymphopoiesis, including CXCL12 and VLA-4. We have recently reported that G-CSF results in the dramatic suppression of B-lymphopoiesis. This, together with previous reports by ourselves, and others, showing that disruption of CXCL12 or VLA-4 slow the progression of B-lineage ALL lead us to consider that G-CSF may similarly antagonize the progression of ALL. To explore this possibility, we examined the impact of G-CSF administration on six human ALL xenografts using a NOD/SCID mouse model. Mice were engrafted without radiation and G-CSF commenced when 1% of the bone marrow consisted of ALL cells. G-CSF was administered twice daily for 10 days, at which time all animals were culled and leukemia assessed in the blood, bone marrow and spleens. Surprisingly G-CSF was found to increase disease progression in two of xenografts investigated (1345 and 0398, referred to as G-CSF responsive xenografts hereafter), while the remainder demonstrated a small reduction in leukemia, with one showing a statistical significant decrease. No evidence for a direct mitogenic effect of G-CSF could be demonstrated in any of the xenografts using exogenous G-CSF in vitro cultures in the presence or absence of human or murine stromal support. Consistent with these findings, and previous reports, little to no G-CSF receptor was detected by flow cytometry or microarray analysis of xenografts. Microarray analysis of the xenografts revealed significant differences in gene expression between the G-CSF responsive xenografts and the remainder of the samples. A total of 83 genes were expressed at a higher level and 127 genes at a lower level in the G-CSF responsive xenografts. The more highly expressed genes included cell cycle regulators (eg cyclin A1), adhesion molecules (eg ALCAM), extracellular matrix components and surface receptors. Perhaps the most interesting was the exclusive expression of the acetylcholine receptor (cholinergic receptor, nicotinic, beta 4, nAChRb4) in the G-CSF responsive cases. Analysis of a large public dataset of childhood ALL samples revealed significantly higher expression of this gene in ALL samples with rearranged MLL (p<0.03). However, small numbers of cases in all ALL subgroups had greater than an 2 fold higher expression compared to normal B cell progenitors. The role of nAChR in the response of ALL cells to micro-environmental changes induced by G-CSF remains to be determined, however, nAChR has known roles in cell proliferation and inhibition of apoptosis. Furthermore G-CSF is known to induce acetylcholine production in other tissues. In summary, G-CSF inhibited leukemia progression in the majority of patient xenografts, however, in a subset of samples G-CSF accelerated disease progression. Clinically, G-CSF administration to ALL patients has not been associated with any major adverse outcomes. However our data suggest that a small subset of patients may experience accelerated disease. Identification of features associated with adverse responses to G-CSF will permit the identification of patients for whom G-CSF may present a risk for increased disease progression. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Cell Transplant Co-Morbidity Index (HCTCI) and Multiple Myeloma (MM) Survival After Autologous Hematopoietic Cell Transplantation (AHCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4217-4217
Author(s):  
Anuj Mahindra ◽  
Ayman A Saad ◽  
Mei-Jie Zhang ◽  
Xiaobo Zhong ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Co Morbidity ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4217 Background: AHCT improves survival (OS) in newly diagnosed MM patients (pts) in large randomized trials. These trials have limited eligibility to younger, healthier pts. Selection of older pts and those with co-morbid illness for AHCT is problematic. HCT-CI, originally developed as predictor of post-allogeneic transplant outcomes, maybe valuable in stratifying risk of transplant related mortality (TRM) risk and OS in the AHCT setting. We investigated the relative impact of HCT CI along with other patient and MM related variables on outcomes after AHCT in a large cohort of transplant recipients. Methods: Outcomes of 1156 MM pts receiving AHCT after high dose Melphalan (MEL) between 2007 and 2010 reported to the CIBMTR (Center for International Blood and Marrow Transplant Research) were analyzed. HCTCI scores and individual comorbidities were prospectively reported at time of AHCT. Median follow up of survivors was 26 month. The impact of HCTCI and other potential prognostic factors including Karnofsky performance status (KPS) on OS were studied in multivariate Cox regression models. Results: HCTCI score was 0, 1, 2, 3, >3 in 42%, 18%, 13%, 13% and 14% respectively. Most common co-morbidities included pulmonary, diabetes, obesity, psychiatric, cardiac, renal and prior solid tumor. Using consolidated HCTCI scores, patients were stratified initially into 3 risk groups – HCTCI 0 (42%) vs. HCTCI 1–2 (32%) vs. HCTCI >2 (26%). Males and Caucasians were more likely to have greater HCTCI score. Higher HCTCI was associated with lower KPS <90 (33% in HCTCI 0 cohort vs. 50% in HCTCI >2). HCTCI score >2 was associated with MEL dose reduction to 140 mg/m2 (22% vs. 10% in score 0 cohort). Cytogenetic risk and MM related factors were not correlated with HCTCI. TRM at 12 month was 2%, 2%, and 3% for 3 risk groups. With extremely few TRM events, multivariate analysis did not suggest an impact of HCTCI. OS was 95%, 92%, 92% at 1 year and 87%, 81%, 80% at 2 year, respectively. OS was inferior for HCTCI >2 cohort (RR of death 1.48, p=0.02) and HCTCI cohort 1–2 (RR 1.37, p=0.04) compared with HCTCI 0 cohort. There was no significant difference in OS between HCTCI >2 vs. HCTCI 1–2 (p=0.64). Therefore the latter 2 groups were combined as the HCTCI >0 cohort [N=667] and compared with HCTCI=0 [N=489] in multivariate models. HCTCI >0 predicted inferior OS (RR of death= 1.41, p=0.01). Other significant predictors of inferior survival were KPS <90 (RR of death 1.61, p<0.01), IgA subtype (RR 1.64, p<0.01), >1 pretransplant regimen (RR 1.47, p<0.01), resistant MM at AHCT (RR 1.78, p<0.01). Major cause of death in both groups was progressive MM. Conclusion: In clinical practice, higher HCTCI score was associated with MEL dose reduction. Mortality after AHCT is predominantly related to MM progression/relapse with low incidence of TRM. Higher HCTCI scores were independently associated with inferior OS. KPS remains an important tool for risk stratification. Disclosures: No relevant conflicts of interest to declare.

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