scholarly journals Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children’s Oncology Group

2017 ◽  
Vol 35 (23) ◽  
pp. 2700-2707 ◽  
Author(s):  
Kristina K. Hardy ◽  
Leanne Embry ◽  
John A. Kairalla ◽  
Shanjun Helian ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Corticosteroid Treatment ◽  
Neurocognitive Functioning ◽  
Neurocognitive Outcomes ◽  
Leucovorin Rescue ◽  
B Lineage ◽  
The Impact

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

CD10− Pre-B Acute Lymphoblastic Leukemia (ALL): A Distinct High-Risk Subgroup of Adult ALL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1443-1443
Author(s):  
Beate Gleissner ◽  
Nicola Goekbuget ◽  
Harald Rieder ◽  
Dieter Hoelzer ◽  
Eckhard Thiel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Molecular Genetic ◽  
Treatment Strategies ◽  
Molecular Genetic Analysis ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Blood Cell Count ◽  
B Lineage

Abstract Introduction: Immunological subtyping and molecular genetic analysis enable risk-adapted treatment of acute lymphoblastic leukemia (ALL). Translocations involving the mixed lingeage leukemia (MLL) gene characterize one poor-prognosis subtype of adult B-lineage precursor ALL correlating with a CD19+/CD10−/cytoplasmic (cy) IgM− immunophenotype (pro-B ALL). Patients and Methods: Immunophenotyping was performed on 2,408 newly diagnosed ALL specimens indentifying pro-B ALL, TdT+/CD19+/CD10−/cyIgM−/surface(S)Ig−; c-ALL, TdT+/CD19+/CD10+/cyIgM−/SIg−; and pre-B ALL, TdT+/CD19+/CD10+/cyIgM+/SIg−. Ambiguous cases of CD10-positivity (5–15% CD10-positivity) were rechecked by a second antibody. BCR-ABL RT-PCR and cytogenetics were performed. CD10-negative blasts also underwent MLL-AF4 RT-PCR. FISH using directly labelled probes for MLL was done in selected cases. Patients were treated according the German Multicenter Adult ALL trials (GMALL) with MLL-rearrangement positive patients treated in the high-risk arm. Results: Immunophenotyping identified 70 CD10-negative pre-B ALL specimens (TdT+CD19+cyIgM+). Fifty-six of these 70 CD10-negative pre-B ALL specimens contained a sufficient amount of blasts for molecular analysis. A total of 46/56 CD10-negative pre-B ALL were assigned to MLL-rearrangement positivity, revealing either MLL-AF4 fusion by RT-PCR (n = 38) or an 11q23/MLL translocation by cytogenetics (n = 4) or FISH (n = 4). Looking at clinical characteristics, MLL-rearrangement-positive patients were characterized by a higher median white blood cell count (P = .0002) and their blasts showed frequently neuroglial antigen 2 chondroitin sulfate proteoglycan (P = .02). Forty CD10− pre-B ALL patients with molecular genetic and/or cytogenetic data were evaluable for the treatment response and outcome. A complete remission (CR) was achieved in 6 of 7 (86%) MLL-rearrangement-negative and in 27 of 33 (82%) MLL-rearrangement-positive patients (P = .06). CR was maintained by 2 of 6 (33.3%) MLL-rearrangement-negative and 7 of 27 (26%) MLL-rearrangement-positive patients. The probability of remission duration after 3 years was 0.37 (± 0.29 SE) in MLL-rearrangement-negative versus 0.28 (± 0.13 SE) in MLL-rearrangement-positive patients contributing essentially to the overall survival at 3 years after diagnosis of 0.15 (± 0.06 SE) in patients with CD10-negative pre-B ALL. Conclusion: Our data identify CD10− cytoplasmic Ig-positive pre-B ALL as a rare (2.2%) but distinct immunosubtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome with conventional intensified treatment strategies.

scholarly journals Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1731-1737 ◽  
Author(s):  
A Manabe ◽  
E Coustan-Smith ◽  
M Kumagai ◽  
FG Behm ◽  
SC Raimondi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Programmed Cell Death ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Fatal Outcome ◽  
Interleukin 4 ◽  
B Lineage

Abstract We investigated the effects of interleukin-4 (IL-4) on the survival of leukemic and normal B-cell progenitors cultured on bone marrow stroma. IL-4 (at 100 U/mL) was cytotoxic in 16 of 21 cases of B-lineage acute lymphoblastic leukemia, causing reductions in CD19+ cell numbers that ranged from 50% to greater than 99% (median 83.5%) of those in parallel cultures not exposed to the cytokine. All nine cases with the t(9;22)(q34;q11) or the t(4;11)(q21;q23), chromosomal features that are often associated with multidrug resistance and a fatal outcome, were susceptible to IL-4 toxicity. IL-4 cytotoxicity resulted from induction of programmed cell death (apoptosis); there was no evidence of cell killing mediated by T, natural killer, or stromal cells. IL-4 cytotoxicity extended to a proportion of normal B-cell progenitors. After 7 days of culture with IL-4 at 100 U/mL, fewer CD19+, CD34+ normal lymphoblasts (the most immature subset) survived: in five experiments the mean (+/- SEM) reduction in cell recoveries caused by IL-4 was 60.0% +/- 6.0%. By contrast, reductions in recovery of more differentiated bone marrow B cells (CD19+, CD34-, surface Ig+) were low (6.6% +/- 2.2%; P < .001 by t-test). Our findings indicate that IL-4 is cytotoxic for human B-cell precursors and support clinical testing of IL-4 in cases of high-risk lymphoblastic leukemia resistant to conventional therapy.

scholarly journals Leukemic cell growth in SCID mice as a predictor of relapse in high- risk B-lineage acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 873-878 ◽  
Author(s):  
FM Uckun ◽  
H Sather ◽  
G Reaman ◽  
J Shuster ◽  
V Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
B Lineage ◽  
Human Leukemic Cells ◽  
Overt Leukemia

Mice with severe combined immunodeficiency (SCID) provide a model system to examine the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells. The relation between leukemic cell growth in this model and the treatment outcome in patients from whom cells were derived has not been established. Leukemic cells from 42 children with newly diagnosed high-risk B- lineage acute lymphoblastic leukemia were inoculated intravenously into CB.17 SCID mice. Mice were killed at 12 weeks or when they became moribund as a result of disseminated leukemia. All mice were necropsied and subjected to a series of laboratory studies to assess their burden of human leukemic cells. Twenty-three patients whose leukemic cells caused histopathologically detectable leukemia in SCID mice had a significantly higher relapse rate than the 19 patients whose leukemic cells did not (estimated 5-year event-free survival: 29.5% v 94.7%; 95% confidence intervals, 11.2% to 50.7% v 68.1% to 99.2%; P < .0001 by log- rank test). The occurrence of overt leukemia in SCID mice was was a highly significant predictor of patient relapse. The estimated instantaneous risk of relapse for patients whose leukemic cells caused overt leukemia in SCID mice was 21.5-fold greater than that for the remaining patients. Thus, growth of human leukemic cells in SCID mice is a strong and independent predictor of relapse in patients with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Novel Chromosomal Rearrangements and Sequence Mutations in High-Risk Ph-Like Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 67-67
Author(s):  
Kathryn G. Roberts ◽  
Ryan D Morin ◽  
Jinghui Zhang ◽  
Martin Hirst ◽  
Richard C. Harvey ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Cytokine Receptor ◽  
Negative Regulator ◽  
Rna Seq ◽  
Kinase Signaling ◽  
Rt Pcr ◽  
B Lineage

Abstract Abstract 67 Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and relapsed B-lineage ALL remains a leading cause of cancer death in young people. Recent genomic analyses by our group and others identified a unique subtype of BCR-ABL-negative, high-risk B-ALL, with deletion or mutation of IKZF1 and a gene expression profile similar to BCR-ABL1-positive ALL (Ph-like ALL). Up to 50% of Ph-like patients harbor rearrangements of the cytokine receptor gene, CRLF2, with concomitant JAK mutations detected in ∼30%. However, the nature of genetic alterations activating kinase signaling in the remaining cases is unknown. To identify novel genetic alterations in Ph-like ALL, we performed transcriptome sequencing (RNA-seq) on 11 cases of Ph-like B-ALL (10 from the P9906 Children's Oncology Group trial and 1 from the St Jude Total XV study), and whole genome sequencing (WGS) on two of these. Using multiple complementary analysis pipelines including deFuse, Mosaik, CREST and CONSERTING, we identified novel rearrangements, structural variations and sequence mutations dysregulating cytokine receptor and kinase signaling in 10 cases. Putative rearrangements and sequence mutations were validated using RT-PCR, genomic PCR and Sanger sequencing. The spectrum of alterations included 3 cases with known IGH@CRLF2 rearrangement, 2 cases with the NUP214-ABL1 rearrangement, 1 case each with the in-frame fusions EBF1-PDGFRB, BCR-JAK2 or STRN3-JAK2, and 1 case with a cryptic IGH@-EPOR rearrangement. Detailed analysis of RNA-seq data revealed a 7.5 kb insertion of EPOR downstream of the enhancer domain in the IGH@ locus, which was not detected by fluorescence in situ hybridization. WGS identified an in-frame activating insertion in the transmembrane domain of IL7R (L242>FPGVC) in 1 index case, and recurrence screening identified similar IL7R sequence mutations in 8 cases from the P9906 cohort (N=188). This patient also harbored a focal homozygous deletion removing the first two exons of SH2B3 that was not evident by SNP array analysis. SH2B3 encodes LNK, a negative regulator of JAK2 signaling. Notably, all patients harbor genetic lesions affecting B-lymphoid development (e.g IKZF1), suggesting these events cooperate to drive B-lineage ALL. To determine the frequency of each fusion, candidate RT-PCR was performed on 231 cases from the COG AALL0232 trial of high-risk B-ALL, 40 (17%) of which were identified as Ph-like using Predictor Analysis of Microarrays (PAM). The EBF1-PDGFRB fusion was detected in 3 additional patients, each containing an intact PDGFRB kinase domain. No additional cases of NUP214-ABL1, BCR-JAK2, or STRN3-JAK2 were identified. Phosphoflow analysis on 3 primary ALL samples demonstrated increased CKRL phosphorylation in the NUP214-ABL1 case and tyrosine phosphorylation in the cases with BCR-JAK2 and STRN3-JAK2 fusions. Importantly, this activation was reduced with the tyrosine kinase inhibitors (TKI) imatinib, dasatinib and the T315I inhibitor XL228 in cells harboring the ABL1 fusion, and the JAK2 inhibitor, XL019, in the JAK2-rearranged samples. Furthermore, the novel EBF1-PDGFRB fusion transformed Ba/F3 cells to growth factor independence, induced constitutive activation of pSTAT5, pAkt, pERK1/2, and responded with low IC50 values to imatinib, dasatinib and the specific PDGFRB/FGFR inhibitor, dovitinib. Using complementary genomic approaches we show that rearrangements, sequence mutations and DNA copy number alterations dysregulating cytokine receptor and kinase signaling are a hallmark of Ph-like ALL. These data support the screening of patients at diagnosis to identify those with Ph-like ALL, characterize the genomic lesions driving this phenotype, and to determine those that may benefit from TKI treatment. Disclosures: Hunger: Bristol-Myers Squibb: Author's children own stock in BMS, Membership on an entity's Board of Directors or advisory committees.

Kinase-Activating Fusions in Pediatric High-Risk B-Lineage Acute Lymphoblastic Leukemia (ALL): a Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1729-1729
Author(s):  
Thai Hoa Tran ◽  
Marian H. Harris ◽  
Jonathan V. Nguyen ◽  
Traci M. Blonquist ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Chromosomal Rearrangements ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Philadelphia Chromosome ◽  
B Lineage

Abstract Background. Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a diverse spectrum of chromosomal rearrangements resulting in novel chimeric fusions associated with poor prognosis when treated with conventional chemotherapy. These fusions are observed more frequently in NCI High-Risk (HR) B-ALL compared with NCI Standard Risk (SR) patients. They often activate ABL and JAK-STAT signaling pathways and have demonstrated sensitivity to the relevant tyrosine kinase inhibitors (TKIs) in in vitro assays and ex vivomodels. The objective of this study was to determine the frequency of NCI HR B-ALL patients enrolled on DFCI ALL Consortium Protocol 05-001 with a kinase-activating fusion that would be amenable to TKI therapy and to describe their associated clinical characteristics and outcomes. Methods. Between 2005-2011, 219 NCI HR, Philadelphia chromosome (Ph)-negative, B-ALL patients were enrolled on DFCI ALL Consortium Protocol 05-001, 105 of whom had sufficient material to undergo kinase fusion testing by validated multiplex reverse transcription polymerase chain reaction (RT-PCR) assays. A total of 35 kinase fusions of ABL-class (ABL1, ABL2, PDGFRB, CSF1R), JAK2 and CRLF2 rearrangements were examined. IGH@-CRLF2 and EPOR rearrangements were not assessed. Fusion products were predicted by NCBI BLAST algorithms, confirmed by singleplex PCR and Sanger sequencing and aligned using CLC Main Workbench Version 7.6.1. IKZF1 deletion (del) status had previously been assessed by multiplex ligation-dependent probe amplification (MLPA). Fisher's exact test and the Wilcoxon rank sum test were used to compare patient characteristics to those with and without any identified fusion for categorical and continuous variables respectively. Event-free survival (EFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared using a log rank test. Univariate and multivariable Cox proportional hazards models of EFS were constructed. Results. Among 105 NCI HR, Ph-negative, B-ALL patients, 16 (15%) were found to harbor an ABL-class fusion (ETV6-ABL1: n=1; FOXP1-ABL1: n=1; SFPQ-ABL1: n=1; ZC3HAV1-ABL2: n=1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n=8; PAX5-JAK2: n=4). Sixty-nine percent of patients with an identified fusion (Fusion +) had a concomitant IKZF1 del (n=11). Features associated with fusion-positivity were age of 10 years or older (p=0.003), male sex (p=0.03), Hispanic ethnicity (p=0.01) and IKZF1 del (p=0.0005) (Table 1). Fifty percent of Fusion+ patients experienced an event (induction death (n=1); induction failure (n=1); or relapse (n=6)) compared to 24% of patients without a fusion. The 5-year EFS and OS were 48% (95% CI 22-70%) and 68% (95% CI 39-85%) for Fusion+ patients compared to 78% (95% CI 67-85%) and 88% (95% CI 79-93%) for those without fusions (Figure 1). In univariate analysis, fusion-positivity (HR: 2.66, p=0.02) and IKZF1 del (HR: 3.21; p=0.0018) were each significantly associated with inferior EFS, while age and presenting leukocyte count were not. In multivariable analysis, IKZF1 del, but not fusion-positivity, retained statistical significance (HR: 2.64, p=0.02). Conclusion. Fifteen percent of NCI HR, Ph-negative, B-ALL patients enrolled on DFCI ALL Consortium 05-001 were found to have a kinase-activating fusion. Fusion+ patients frequently harbored concomitant IKZF1 deletion and had an inferior outcome. Future studies should focus on developing clinical strategies to rapidly identify these patients at diagnosis and to test whether the addition of the relevant TKIs to their treatment will improve their outcome. Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

scholarly journals Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 571-577 ◽  
Author(s):  
Arndt Borkhardt ◽  
Giovanni Cazzaniga ◽  
Susanne Viehmann ◽  
Maria Grazia Valsecchi ◽  
Wolf Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Dna Index ◽  
Childhood All ◽  
Pediatric All ◽  
Aml1 Gene ◽  
B Lineage ◽  
The Impact

The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 <1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 552-552 ◽  
Author(s):  
Nathalie Dhédin ◽  
Anne Huynh ◽  
Sébastien Maury ◽  
Reza Tabrizi ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
White Blood Count ◽  
Prognostic Impact ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Unrelated Donors ◽  
B Lineage

Abstract Purpose The pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials. Patients and methods In these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis). Results Among the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1). Conclusion In adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial. ND and AH contributed equally to the work. Disclosures: No relevant conflicts of interest to declare.

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