Presence Of MLL Rearrangements Research Articles

Evaluating Outcomes of Adult Patients with Acute Lymphoblastic Leukemia Treated on the GMALL Protocol

Background Chemotherapy based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established and commonly used protocol for ALL (Gökbuget 2012). Over the years evolving versions of the protocol have been developed with the aim of improving patient outcome (Apel 2014). In view of the recent advancements in the treatment of adult ALL we now analyzed our more recent data. Aims Assess the clinical outcomes of adult ALL patients treated on the GMALL protocol in real world settings, and establish prognostic parameters associated with long term survival and risk of relapse. Methods Retrospective analysis of all adult ALL patients who were treated with GMALL in our institution between the years 2008-2020. Demographic, clinical, cytogenetic, treatment, and transplant related data were collected using our institution's electronic medical records system. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to estimate overall survival (OS) and relapse-free survival (RFS). Hazard ratios and 95% confidence intervals were generated using a Cox proportional hazards model. Results The analysis comprised 81 evaluable patients with a median age of 36 years (range 18-73), 36% were adolescents and young adults (AYA). Forty-three were B-ALL (53%), 12 (15%) patients were Philadelphia chromosome positive ALL (Ph+ ALL), and 26 (32%) were T-ALL. Median duration of follow-up was 24.4 months (range 0.7-112.1 months), at the time of data analysis 51 patients (63.8%) were alive. Seventy patients (88%) attained a first remission (CR1) and 4 (5%) died during the first two induction phases. The 2-year and 5-year overall survival rates were 62% and 44%, respectively. Estimated 2-year and 5-year leukemia-free survival rates were 52% and 35%, respectively. Overall, disease relapse (31%), lethal infection (28%), and graft-versus-host disease (14%) accounted for most patient deaths. Of patients achieving CR1, 20 (29%) eventually relapsed after a median time of 9.8 months (range 1.1-69.3). Fifty-five patients (68%) underwent an allogeneic stem cell transplantation using matched sibling (47%), matched unrelated (31%), haploidentical (7%), partially mismatched (12%), and cord blood donors (3%). Of the 50 patients transplanted in CR1, 15 relapsed (30%) after a median time of 10.9 months (range 3.8-32.8). Multivariate analysis revealed that in terms of overall survival, increasing patient age was associated with inferior outcome [Hazard ratio (HR)=1.026, confidence interval (CI) 95%, 1.002-1.05, p=0.035) as was outcome for patients whose baseline cytogenetic analysis detected a higher number of clones (HR=2.69, CI 95%, 1.57-4.62, p=0.0002). T-ALL patients experienced longer survival compared with B-ALL (87 months versus 56 months, p=0.019) while patients transplanted using cord blood donors had inferior survival, 12.8 months, compared with matched sibling donors, 71.3 months, and fully matched unrelated donors, 73.4 months (p=0.001, and p=0.003, respectively). Relapse-free survival was significantly better in patients with T-ALL compared with B-ALL (90 months vs. 50 months, p=0.039), and in patients without t(12;21)(p13;q22) (75 months vs. 11.7 months, p=0.034). Gender, AYA status, extramedullary disease at diagnosis, initial white blood cell count, treatment delays, presence of MLL rearrangement, specific measurable residual disease modality used, GMALL risk category, and cytogenetic hyperdiploidy did not significantly impact on survival or disease relapse. Treatments for relapse following GMALL included blinatumomab (6), inotuzumab (3), nelarabine (3), and CAR-T (2). Conclusions While results are improving for patients treated on GMALL, a substantial patient segment still experiences relapse. It is conceivable that in the near future new novel therapeutic modalities for adult ALL involving the use of monoclonal antibodies and CAR-T cell therapy will help reduce relapse rates and further improve the current outcomes of patients treated on the GMALL protocol. Disclosures Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.

Socioeconomic Status Is Associated with Prognostic Factors in Childhood Acute Lymphoblastic Leukemia - Implications for Outcomes: A Report from the Children's Oncology Group

Introduction: Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Historical studies have found an association between ALL incidence with higher socioeconomic status (SES), though newer findings are contradictory for this association. Nevertheless, it has been well established that inferior outcomes in pediatric ALL are associated with lower SES. We sought to identify if specific ALL disease characteristics at diagnosis are associated with SES to determine if underlying biology plays a role in the known association between inferior outcomes and lower SES. Methods: Demographic and disease characteristics from children and young adults (aged 2-30 years) diagnosed with ALL 2004-2017 and treated on Children's Oncology Group (COG) frontline treatment protocols (N=4,726, AALL17D2) were matched 1:1 (by age, sex, race, and sampling year) and compared to National Health and Nutrition Examination Survey (NHANES) controls. SES for cases was defined using census data to determine the percent of population in a ZIP code living at or below the federal poverty threshold. SES for controls was defined by the individual's poverty income ratio. Chi-square testing and multivariate logistic regressions were performed, adjusting for sex, race/ethnicity, and age, to assess associations between SES and ALL, as well as specific risk-stratifying ALL disease characteristics, including cytogenetics and central nervous disease (CNS) involvement. Results: ALL patients (72% B-ALL, 28% T-ALL) were more likely to be male (62%), 58% were non-Hispanic white, 9% non-Hispanic black and 24% identified as Hispanic. By chi-square analysis, a difference in SES was identified between cases and controls (p<0.0001). This was further characterized by multivariate logistic regression, which found a positive significant association between ALL incidence and high SES, when using low SES as the reference group (OR 2.54, 95% CI 2.23-2.89, p < 0.0001). When disease characteristics were evaluated, there was an association between SES and CNS status, with presence of ALL involvement in the CNS (CNS 2 or 3 status) more strongly associated with low SES (p=0.0009). When stratified by sex and race, an association between low SES and CNS status at diagnosis remained among non-Hispanic white males and Hispanic males (p=0.008 and p=0.01, respectively). There was also an association between high SES and the presence of the favorable cytogenetic characteristic trisomy of chromosomes 4 and 10 (p=0.01), though this was not seen in a specific group when stratified by sex and race. Among non-Hispanic white males, an association was found between low SES and presence of rearrangement of the MLL gene, a poor prognostic cytogenetic characteristic in ALL (p=0.04). Among Hispanic males, an association was found between high SES and the presence of an ETV6-RUNX1 translocation status, a favorable prognostic cytogenetic characteristic in ALL (p=0.05). These associations were not seen when all cases were assessed together. We did not find an association between SES and immunophenotype, hypodiploidy, initial white blood cell count, or BCR-ABL1 fusion status Conclusions: To our knowledge, this is the first study to assess associations between SES and ALL disease characteristics that have known prognostic implications in disease outcome. We found that poor prognostic features of ALL including CNS involvement at diagnosis (regardless of sex and race) and presence of MLL rearrangement specifically in non-Hispanic white males, were both associated with low SES. In contrast, favorable prognostic features of ALL were associated with high SES, such as the presence of trisomy of chromosomes 4 and 10, and among Hispanic males the presence of an ETV6-RUNX1 translocation. Our study also replicated the association between ALL diagnosis and high SES, which has been a controversial finding. Nonetheless, our findings suggest that there may be biological factors that play a role in the known association between inferior ALL outcomes and low SES. Further studies to better elucidate this potential biologic role are needed as there may be important implications for future treatment options that could improve outcomes for children with ALL who have low SES, as well as improve disparate outcomes currently seen in ALL treatment. Disclosures No relevant conflicts of interest to declare.

Molecular Genetic Characterization of 3'-Deletion of MLL Gene in Infant Acute Leukemia.

AbstractAbstract 2498 Background.MLL gene rearrangements are associated with unfavorable outcome in infant acute lymphoblastic leukemia (ALL) and have intermediate prognosis in infant acute myeloid leukemia (AML). Application of fluorescence in-situ hybridization (FISH) allows detecting not only conventional MLL rearrangements, but also concurrent 3'-deletion of MLL gene. However, detailed characteristics of infant leukemia carrying 3' MLL deletion remain unclear. Aim.To investigate molecular genetic features of MLL-rearranged infant acute leukemia with concurrent 3' MLL deletion. Methods.64 patients (27 boys and 37 girls) aged from 1 day to 11 months (median 6.6 months) including 44 ALL patients, 18 AML patients, 1 patient with acute bilineage leukemia and 1 patient with acute undifferentiated leukemia were enrolled in the current study. Chromosome banding analysis was done according to standard procedure. FISH analysis using LSI MLL Dual Color, Break Apart Rearrangement Probe (Abbott Molecular, USA) was performed on at least 200 interphase nuclei and on all available metaphases. Presence of MLL rearrangements was detected by FISH, reverse-transcriptase PCR. In 29 cases long-distance inverse PCR was additionally performed. In case of MLL rearrangement presence standard FISH pattern was defined as simultaneous detection of 3 different fluorescent signals: 1 fused (orange) signal, 1 green signal derived from 3' part of MLL gene, 1 red signal from 5' end of MLL (1F1G1R). MLL rearrangements with concurrent 3' MLL deletion led to 1F1R FISH pattern formation due to lack of green signal. Results.FISH revealed MLL rearrangements in 73% of ALL cases that was higher than frequency of 11q23 translocations detected by conventional cytogenetics — 55%. In MLL-positive cases we found 38 patients (81%) with standard FISH pattern, 7 ones (15%) with concurrent 3’-deletion of MLL gene and 2 (4%) with complex MLL rearrangements. Among patients with 3’ MLL deletions there were 1 case with 5’ MLL duplication (1F2R) and 1 case with 5’ MLL triplication (1F3R). Frequency of 3’-deletions were similar in ALL and AML patients (13% and 15%, respectively). We did not find more than one FISH pattern in bone marrow blast cells of each patient with 3’ MLL deletion. In this cohort of patients all blast cells carried concurrent 3’-deletion of MLL gene. Moreover, percentage of blast cells carrying MLL rearrangements did not differ significantly between patients with standard FISH pattern (median 97%, range 22–100%) and 3’-deletion (median 83%, range 13–99%) (p=0.206). 3’-deletion of MLL was not associated with breakpoint position in MLL gene and type of translocation partner gene. MLL translocation partner genes detected in patients with 3’ deletions were as follows AF4(n=2), MLLT3(n= 3), MLLT10(n=2). None of the patients with 3’-deletions had reciprocal fusion gene. Initial patients’ characteristics (age, sex, WBC count, immunophenotype, CNS-status, type of MLL partner gene) and treatment response parameters (day 8 peripheral blood blast cell count, day 15 bone marrow status, day 36 remission achievement, minimal residual disease status at time point 4) did not differ significantly between 2 groups. Although cumulative incidence of relapse was lower in patients with 3’-deletion as compared to patients with standard FISH pattern (0.31±0.04 and 0.55±0.01, respectively), difference between these two groups was not statistically significant (p=0.359). Conclusion.In our work we characterized rare subgroup of infant MLL-rearranged acute leukemia carrying concurrent 3' MLL deletion. Our data provide additional information of molecular genetic features of acute leukemia in children younger than one year. Disclosures:No relevant conflicts of interest to declare.

Minimal Residual Disease Monitoring by Quantification of Fusion Gene Transcripts In Infant with MLL-rearranged Acute Lymphoblastic Leukemia Treated by MLL-Baby Protocol

AbstractAbstract 2731 Background.Despite many attempts worldwide treatment results for infants with MLL rearrangements and especially MLL-AF4 remain unsatisfied. MLL-Baby protocol was developed for infant acute lymphoblastic leukemia (ALL). In this treatment approach conventional chemotherapy is augmented by administration of all-trans retinoic acid (ATRA). This treatment program is successfully applied for infant ALL within Russian Federation and Republic of Belarus (L. Fechina et al, ASH 2007 #2828). Minimal residual disease (MRD) is a strong tool for risk-adapted treatment. Majority of infants carry MLL rearrangements, so in this group MRD monitoring by quantification of fusion gene transcripts (FGt) is fast, easy and cost-effective approach. Objective.To evaluate the prognostic significance of MRD monitoring by FGt measurements in MLL-rearranged infant ALL, enrolled into MLL-Baby study. Methods.Twenty three infants with defined MLL translocation partner genes who received at least two ATRA courses were included in the current study. Median of follow-up period in the observed group was 41 months. Presence of MLL rearrangements was detected by FISH and confirmed by long-distance inverse PCR (C. Meyer et al, 2005). MRD detection in bone marrow (BM) was performed by real-time quantitative PCR and qualitative nested reverse-transcriptase PCR as previously described (A. Borkhardt et al.,1994, J. van Dongen et al., 1999, N. Palisgaard et al., 1998, J. Gabert et al, 2003) with sensitivity 1E–05. MRD-negativity was defined as absence of FGt in both assays. Among 23 infants there were 13 MLL-AF4-positive patients (pts), 4 MLL-MLLT10-positive pts, 3 MLL-EPS15-positive pts, 2 MLL-MLLT1-positive pts and one MLL-MLLT3-positive patient. BM samples were obtained at the time of diagnosis, on day 15 of remission induction (time point (TP) 1), at the end of remission induction (TP2) and after each course of ATRA administration (TP3-TP9). Informed consent was obtained in all cases. Results.All patients were MRD-positive at TP1. At TP2 two MLL-MLLT10-positive patients became MRD-negative. At TP3 other 4 pts (3 MLL-AF4-positive and 1 MLL-MLLT1-positive) converted to MRD-negativity. By TP4 18 pts were MRD-negative, while FGt were detected in 5 pts. 2 pts became MRD-negative before protocol II (at TP9), while 3 pts never achieved MRD-negativity. Retrospectively, we compared prognostic significance of MRD at each TP. TP4 was the earliest TP when discriminative data was obtained. According to the qualitative MRD results at this TP pts were divided into MRD-positive and MRD-negative groups. The first group consisted of 18 pts with different MLL translocation partner genes, while the second group included 5 MLL-AF4-positive pts, who remained MRD-positive at TP4. Groups did not differ in age at diagnosis, sex distribution, initial WBC count, immunophenotype, type of MLL partner gene, number of blast cells at day 8 of dexamethasone prophase, BM status on day 15, CNS disease, and achievement of hematological remission at day 36. Number of relapses was significantly higher in the second group (p=0.017). Odds ratio was 20.00 with 95% CI 1.61–247.99. In the first group there were 3 relapses (in one MLL-AF4-positive case and two MLL-EPS15-positive cases) while in the second group 4 relapses occurred. Cumulative incidence of relapse for pts who achieved MRD-negativity by TP4 was 0.17, for MRD-positive pts 0.80 (p=0.005). 7-years event-free survival in the first group was 0.82±0,09, in the second group 0.20±0.17 (p=0.008) (fig 1). Conclusions.MRD monitoring by FGt measurements has significant prognostic value in infants with MLL-rearranged ALL treated by MLL-Baby protocol. In our series achievement of MRD-negativity by TP4 corresponds to favorable outcome in infant ALL with MLL rearrangements treated by MLL-Baby protocol. Persistence of MRD-positivity at TP4 allows to define group with high incidence of relapse. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

BackgroundAberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required.Methodology/Principal FindingsWe carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients.Conclusions/SignificanceOur study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.

WT1 Gene Expression Limited Application for MRD Monitoring in AML Patients Carrying MLL Rearrangements.

Abstract 4700 StatementWT1 gene expression (GE) is widely used for monitoring of minimal residual disease (MRD) in acute myeloid leukemia (AML) patients. Predictive value of WT1 GE in MLL-positive AML is not clear. Comparison of WT1 GE and fusion genes (FG), detected at RNA and DNA levels is rarely done. Here we present comparison of MRD data, assessed by WT1 GE, FG transcripts and MLL fusions alleles (MFA). Materials and methods27 samples from 5 MLL-positive AML patients (pts) were analyzed. Median age was 13 years (range 0.8-58 years). 5 samples were obtained at diagnosis, 21 samples during follow-up treatment, 1 at diagnosis of relapse. Initial diagnostics included cytomorphology, immunophenotyping of blast cells, cytogenetics. Presence of MLL rearrangements was detected by FISH, reverse-transcriptase PCR (RT-PCR) and confirmed by long-distance inverse PCR. Among 5 pts there were two MLL-MLLT4-positive cases, two MLL-MLLT10-positive. One patient carried MLL-MLLT3 fusion gene. Quantification of MFA in genomic DNA by patient-specific primers-probe combinations and detection of FG transcript kinetics in RNA/cDNA during treatment were performed by RQ-PCR as previously described (T. Burmeister et al, Leukemia 2006, 20; J. Gabert et al, Leukemia, 2003, 17, respectively). Due to high concordance rate (96%) between qualitative results obtained by FG transcript and MFA detection, these results were combined into one group named as standard methods (SM) of MRD monitoring. Sample was defined as positive if only one result obtained by SM was positive. Sample was defined as negative if both results assessed by FG transcript and MFA were negative. Quantification of WT1 was performed in bone marrow (BM) samples by real-time quantitative PCR (RQ-PCR) with normalization to ABL gene. Additionally, BM samples taken from 14 pts without hematological malignancies were investigated. WT1 threshold level (TL) calculation was based on ROC curve analysis. TL was defined as value with maximal sensitivity and specificity. ResultsROC analysis of WT1 GE revealed an area under curve (AUC) of 0.890 (95% CI 0.800-0.990). TL was set at 32 with sensitivity of 62% and specificity of 100%. Value of TL was equal to upper level of WT1 normalized copy number (NCN) in BM of 14 pts without hematological malignancies (median 10, range 0-32 WT1 copies/104ABL copies). In AML pts it was detected 13 WT1-positive samples (48%). 21 samples (78%) were positive by SM. 6 samples (22%) were negative both by SM and WT1 GE. Discrepant results were found in 8 samples (30%) (table 1). These discrepant results were observed in follow-up samples only. Qualitative concordance between SM and WT1 GE was 70% in our series.Table 1WT1 positiveWT1 negativeSM Positive138SM Negative06 ConclusionsBased on the ROC curves analysis it was not found particular TL of WT1 NCN that clearly distinguishes MRD-negative pts from those with positive MRD, detected by SM. Applicability of WT1 NCN quantification for MRD monitoring in the assessed MLL-rearranged AML samples appears to be limited because of relatively high percentage of false-negative samples. Discrepant results could be explained by high variability of WT1 GE during antileukemic therapy, and presence of WT1 GE in normal BM. Thus WT1-negative results should be considered as truly MRD-negative with great caution and have to be confirmed by FG transcript and/or MFA quantifications. Disclosures:No relevant conflicts of interest to declare.

MLL rearrangements in pediatric acute lymphoblastic and myeloblastic leukemias: MLL specific and lineage specific signatures

BackgroundThe presence of MLL rearrangements in acute leukemia results in a complex number of biological modifications that still remain largely unexplained. Armstrong et al. proposed MLL rearrangement positive ALL as a distinct subgroup, separated from acute lymphoblastic (ALL) and myeloblastic leukemia (AML), with a specific gene expression profile. Here we show that MLL, from both ALL and AML origin, share a signature identified by a small set of genes suggesting a common genetic disregulation that could be at the basis of mixed lineage leukemia in both phenotypes.MethodsUsing Affymetrix® HG-U133 Plus 2.0 platform, gene expression data from 140 (training set) + 78 (test set) ALL and AML patients with (24+13) and without (116+65) MLL rearrangements have been investigated performing class comparison (SAM) and class prediction (PAM) analyses.ResultsWe identified a MLL translocation-specific (379 probes) signature and a phenotype-specific (622 probes) signature which have been tested using unsupervised methods. A final subset of 14 genes grants the characterization of acute leukemia patients with and without MLL rearrangements.ConclusionOur study demonstrated that a small subset of genes identifies MLL-specific rearrangements and clearly separates acute leukemia samples according to lineage origin. The subset included well-known genes and newly discovered markers that identified ALL and AML subgroups, with and without MLL rearrangements.

Incidence and Spectrum of MLL Gene Rearrangements in Pediatric Acute Leukemias in Poland

Objectives and aims of the study: The MLL oncogene on chromosome 11q23 undergoes various translocations in acute leukemias. MLL gene rearrangements are associated with worse outcome in infant acute lymphoblastic leukemia (ALL), while t(4;11) is a high-risk factor in children with ALL > 1 year of age. The prognostic value of MLL gene rearrangements in acute myeloid leukemia (AML) remains to be determined. In this study, we aimed at comprehensive analysis of the incidence and spectrum of MLL gene rearrangements in a large cohort of pediatric acute leukemias in Poland.Material and Methods: The study group comprised 355 children including 271 patients with de novo ALL, 24 children with relapsed ALL, 56 children with AML, three children with relapsed AML and a patient with acute bi-lineage leukemia. The presence of MLL rearrangements was determined with split-signal fluorescent in situ hybridization (FISH). Partner genes rearranged to MLL locus were identified with long-distance inverse PCR at the genomic DNA level.Results: MLL rearrangements were found in 18 patients with de novo ALL, 12 infants and six children > 1 year of age (6.6%). They included 12 t(4;11) with MLL-AFF1 fusion, two t(11;19) with MLL-MLLT1 fusion, one t(9;11) with MLL-MLLT3 fusion and one t(10;11) translocation with two gene fusions MLL-MLLT10 and PIWIL4-MLL. MLL rearrangements were also present in two patients with relapsed ALL. MLL rearrangement characterized 11 patients with de novo AML [four t(9;11) with MLL-MLLT3 fusion, one t(11;19) with MLL-ELL fusion, one (1;11) with MLL-EPS15 fusion, and a single t(1;11;17)] and one patient with secondary AML after ALL treatment [t(11;19)], which comprises 22% of all AML patients. This incidence is higher than usually described in literature (approximately 10–15%). Interestingly, in patient with t(1;11;17) two in-frame gene fusions were identified: MLL-MLLT11 and MYO18A-MLL, with the latter previously not reported. MLL gene rearrangement [t(9;11)], was also found in one of three relapsed AML cases. In a patient with acute bi-lineage leukemia both lymphoblasts and myeloblasts displayed t(4;11) translocation. Interestingly MLL-AFF1 fusion in this patient was accompanied by the fusion of the distal part of MLL to KIAA0999 gene on chromosome 11q23.3.Conclusions: In ALL patients MLL gene rearrangements are most frequent in infants (80% of cases) and very infrequent in older children (< 2%). Application of split-signal FISH as a screening for MLL gene rearrangements revealed unprecedentedly high incidence of these aberrations in childhood AML. Molecular analysis of MLL gene fusions and breakpoints shows several different mechanisms leading to these chromosome aberrations.

Clinical relevance of FLT3 gene abnormalities in Brazilian patients with infant leukemia

Infant leukemia (IL) is characterised by the presence of MLL rearrangements and a poor outcome. FLT3 gene is consistently highly expressed in MLL+ patients. To correlate the clinical aspects of IL with FLT3 sequence alterations, we have analysed 159 children included in the Brazilian Collaborative Study Group of Infant Acute Leukemia. FLT3-D835 mutations and FLT3-ITD were detected by PCR-RFLP assay and standard PCR amplification, respectively. Mean age at diagnosis was 11.3 months. Overall, 7.5% (ITDs n = 6 and D835 n = 6) of patients contained FLT3 mutations. FLT3 mutated cases exhibited significantly higher white blood cells (WBC) than wild-type patients (p = 0.013). Median overall survival time was 9.2 months (SE 3.3, 95% CI 2.8–15.6). Variables with significant poorer outcomes were age <6 months (p = 0.0043), MLL+ (p = 0.0292), AML subtype (p = 0.0008), high WBC (p = 0.0179) and FLT3-D835 mutation (p = 0.042). The concomitant presence of FLT3 and MLL abnormalities displayed the worst survival (p = 0.0032). Cox regression analysis, with survival as endpoint, showed that leukemia subtype and WBC were independent prognostic factors. Although FLT3 mutations were not a frequent genetic abnormality in this cohort, they might be prognostically important in IL, but this will need to be confirmed in the analyses of larger patient cohorts.

A transgenic mouse model for TEL-JAK2-induced B-cell lymphoma/leukemia

(o1 year of age) the pro-B phenotype was not associated with sensitivity to Ara-C, but the number of infants with pre-B or common phenotypes was small. Thus, Ara-C sensitivity in ALL seems to be associated with age (i.e. o1 year) and immunophenotype, but not with the presence of MLL rearrangements. Possibly, sensitivity to Ara-C as observed in childhood AML M4/M5 cells is associated with the M4/M5 FAB type rather than with young age. In conclusion, the present study does not provide data to support that MLL rearrangements are directly involved in the increased sensitivity to Ara-C as detected in infant ALL and M4/M5 AML.