Chemoresistance to Prednisolone as Treatment Stratification Criteria In the Adult ALL Therapeutic Approach of the Russian Acute Lymphoblastic Leukemia (RALL) Study Group

Abstract Abstract 4333 Adult acute lymphoblastic leukemia (ALL) differs from pediatric ALL by higher frequency of unfavorable biological features including cytogenetics (often t(9;22), rare t(12;21)), slower molecular response (MRD negativity is lower at day near +30 in adults - 47% vs 80%; Bruggemmann, Blood, 2006; Borowitz, Blood, 2010), more toxicity followed by less complience, all this translating in less efficacy. Another very important, early and simple predictor of antileukamia effect in ALL is prednisolone (PRD) sensitivity, that is to say tumor clearance within one week of prephase. It's a well documented fact in childhood ALL, but scarcely characterized in adults. 35% of adults with ALL are considered to be resistant to PRDN compaired to 10% children after evaluation of PB blast count on day +8 (Annino, Blood, 2002; Shrappe, Leukemia 2002), but few data exists about bone marrow blasts clearance. We initiated a prospective multicenter trial for Ph-negative ALL under the age of 55 based on: 1.evaluation of blast clearance in b/m after 7 days of PRD and its substitution by dexamethazone (DEXA) if blast count was 25% and more. 2. “no interruptions” protocol with 8 weeks induction and 5 consolidation phases followed by 2-years maintenance. 3. prolonged L-asparaginase application at 10.000 IU weekly in induction, once in two weeks in consolidations, twice a month in maintenance (total proposed dose 560.000 IU). The study started in April, 2009. 20 participating centers enrolled 77 patients (median age 27y (16-55), 44f, 33m, 61,5%=B-lin, 38,6%=T-lin; 41% with normal karyotype (NK)). 30,7% of patients were in the standrad 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)-), 69,3% - 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)+). The analysis was performed in June, 2010, and comprised 70 pts. The data on the day +8 b/m count was reported in 67 pts: 70% of them had b/m blasts 25% and more, thus were considered as non-responders to PRD (60 mg/m2) and were switched to DEXA (10 mg/m2). It's worth to note that the proportion of non-responders to PRD was almost equal in the SR and HR groups: 12 of 20 (60%) in SR and 35 of 47 (74,5%). CR rate was high in both risk groups (SR=95,5%; HR=89,4%) and immunological subsets (B=91,4%;T=91,6%). For the whole group of analysed patients (n=70) there were 5 induction deaths (7,1%) and 1 resistant leukemia (1,4%). Median of days without treatment during induction period was 8 days (0-56). Death in remission was reported in 2 of 64 CR pts (3,1%). Relapses occurred in 4/64 (4,2%). Within the short period of follow-up (14 mo) the probability of OS for 70 patients constituted 78,8%, DFS – 76,7%, continuous CR – 81,2%. The difference in DFS between PRD responders and non-responders was at borderline: 63,3% vs 93,8% (p=0,1), and statistically proved in pts with NK vs all other abnormalities: 100% vs 72% (p=0,03). Age, WBC, immunophenotype, risk group, time without treatment did not influence survival. We concluded that in adult Ph-negative ALL the proportion of non-responders to PRD is very high (70%), thus providing much poorer results than in children; sensitivity to PRD may still be used as very simple discriminative marker of unfavorable prognosis. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v120.21.2572.2572 ◽

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.

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Flow Cytometric Leukemic Blasts Detection in Cerebrospinal Fluid of Children with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.3799.3799 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3799-3799

Author(s):

Mette Levinsen ◽

Hanne Vibeke Marquart ◽

Line Groth-Pedersen ◽

Thomas Leth Frandsen ◽

Birgitte Klug Albertsen ◽

...

Keyword(s):

Bone Marrow ◽

Cerebrospinal Fluid ◽

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Leukocyte Count ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Newly Diagnosed ◽

Childhood All ◽

Blast Count

Abstract Background: Central nervous system (CNS)-directed treatment has reduced risk of CNS relapse for childhood acute lymphoblastic leukemia (ALL), which accounts for 30-40% of initial relapses. Compared with CNS-negative patients, patients with CNS leukemia (>5 leukocytes/µL cerebrospinal fluid (CSF) and lymphoblasts) suffer from more CNS+ relapses. Conventional cytology (CC) is specific (>95%), but nonsensitive (<50%), since leukocytes in CSF decay within few hours after lumbar puncture. Method: We prospectively assessed centralised multi-parameter flow cytometry (FCM) of fixated CSF versus local CC in Nordic/Baltic childhood ALL. Diagnostic samples from 172 children aged 0-18 years with de novo and eight children with relapsed ALL were investigated in 297 CSF samples from 180 patients. Kinetics of disappearance of leukemic cells in the CSF was evaluated until day 15. Antibody-combinations reflected the immunophenotype of leukemic blasts in bone marrow. Result: Of 172 newly diagnosed patients, 51 (30%) had CSF involvement by FCM, while CC was positive in 16 patients (9%) (p<0.001). CSF involvement was detected by both FCM and CC in four of eight patients with relapse (50%). Among newly diagnosed patients, samples positive by FCM and CC had higher leukemic blast count compared to samples positive by FCM only (medians: 0.545 (range: 0.005-4.801) versus 0.016 (range: 0.003-1.38) leukemic blasts/µL; p<0.001). Among newly diagnosed patients with samples positive by FCM and CC, the CSF blast count was related to the CSF leukocyte count (rs=0.82; p=0.001). Compared to newly diagnosed patients who were FCM-negative, those with FCM-positivity had higher WBC (median: 37 versus 9 x 109/L; p<0.001), were younger (medians: 3 versus 5 years, p=0.04), and more often had T-cell ALL (12/51 (24%) versus (6/121 (5%), p<0.001). Five (16%) of 31 newly diagnosed patients with FCM detected blasts at diagnosis and available data at day 15 still had CSF leukemic blasts on day 15. So far the two patients who later developed CNS and/or bone marrow relapse were positive by flow (1.38 and 0.178 blasts/µL), but CNS negative by CC or had CSF leukocyte count <5/µL and lymphoblasts on CC, respectively. Conclusion: Leukemic blasts are present in spinal fluid of one third of newly diagnosed ALL. CSF involvement is associated with other higher risk characteristics. The prognostic value of these findings awaits prospective evaluation. Disclosures No relevant conflicts of interest to declare.

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Cranial Irradiation Does Not Result in Pituitary-Gonadal Axis Dysfunction in Very Long-Term Male Survivors of Childhood Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v114.22.989.989 ◽

2009 ◽

Vol 114 (22) ◽

pp. 989-989

Author(s):

Niels J. van Casteren ◽

Rob Pieters ◽

Gert Dohle ◽

Manita van Baalen ◽

Sebastian Neggers ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Gonadal Function ◽

Free T4 ◽

Childhood All ◽

Male Survivors ◽

Igf I

Abstract Abstract 989 Poster Board I-11 Introduction: One of the risks of childhood cancer treatment is fertility impairment later in life. In the past a large proportion of children with acute lymphoblastic leukemia (ALL) has received cranial irradiation as part of their treatment. The aim of this study was to evaluate whether cranial irradiation negatively affects pituitary regulated gonadal function in male survivors of childhood ALL. Patients and Methods: We examined gonadal function, including Inhibin B, LH, FSH, testosterone, and pituitary axis function by measuring TSH, Free-T4 and IGF-I levels in 89 long-term male survivors of childhood ALL after a median follow-up time of 19 year (range 7-34 years). Results: Twenty-nine out of 89 male ALL survivors received cranial irradiation. Inhibin, FSH, LH, Testosterone, testicular volume as well as TSH and Free-T4 levels were not different in the cranial irradiated group as compared to the non-irradiated group (table 1). In contrast, IGF-I levels were significantly lower in the cranial irradiated group. Survivors treated with total body irradiation or testicular irradiation had significantly decreased gonadal function based on hormone levels. Conclusions: These data show that, in contrast to the negative influence on the growth hormone axis, cranial radiotherapy as part of ALL treatment does not have a deleterious long-term effect on the hypothalamic–pituitary-gonadal axis or pituitary-thyroid axis. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v116.21.3235.3235 ◽

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.

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Chromothripsis-Mediated Structural Variations and Clonal Evolution In Recurrent Childhood High Hyperdiploid Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v122.21.233.233 ◽

2013 ◽

Vol 122 (21) ◽

pp. 233-233

Author(s):

Cai Chen ◽

Christoph Bartenhagen ◽

Michael Gombert ◽

Vera Okpanyi ◽

Vera Binder ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Copy Number ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Copy Number Variations ◽

Chromosome 3 ◽

Structural Variations ◽

Childhood All ◽

A Genome

Abstract High hyperdiploid acute lymphoblastic leukemia (HeH-ALL) is characterized by 51-67 chromosomes and nonrandom gains of specific chromosomes (X, 4, 6, 10, 14, 17, 18, and 21). It presents the most frequent numerical cytogenetic alteration in childhood pre B-cell ALL occurring in 25-30% of cases. Recurrent disease will affect 15-20%. Pre-leukemic HeH clones are generated in utero, but cooperating oncogenic lesions are necessary for overt leukemia and remain to be determined. Recently, a phenomenon termed chromothripsis has been described in which massive structural variations occur in a single aberrant mitosis. Whole or partial chromosomes are shattered and some fragments are lost in the process of rejoining. Thus, characteristically, chromosomal copy numbers oscillate between two copy number states. Chromothripsis has been suggested to be a tumor-driving alteration that may be present in 2-3% of all human cancers. Its role as a potential cooperating or initiating lesion in HeH-ALL has not been determined. We applied state-of-the-art whole-genome next-generation-sequencing to analyze structural variations in six pediatric patients with recurrent HeH-ALL. Matched sample sets taken at diagnosis, remission and/or relapse were compared. Paired end sequencing was carried out on a Genome Analyzer IIx or a HiSeq 2000 (Illumina), respectively. Reads were aligned against the human reference genome (GRCh37) using BWA. Translocations were detected by GASV. Copy number variations were analyzed by FREEC. Structural variations were validated by PCR/Sanger sequencing and FISH. Of the six patients analyzed, five harbored on average one interchromosomal translocation or intrachromosomal inversion, but one patient presented with massive genomic rearrangements (Figure). These affected chromosome 3, 11, 12 and 20. Ten copy number shifts on chromosome 3 oscillating between two copy number states (2 and 3) indicated that these rearrangements were caused by chromothripsis. Breakpoint sequencing revealed that one of the identified translocations (t(12;20)(p13.1;p12.3)), was indeed a three-loci-rearrangement composed of small fragments derived from chromosomes 3, 12 and 20. Characteristically for chromothripsis, the breakpoints clustered closely. Three breakpoints separated by 224 bp and 64 kb were located in the transducin (beta)-like X-linked receptor 1 (TBL1XR1) gene. Other genes repeatedly targeted included the MACRO domain-containing protein 2 (MACROD2) gene (a deacetylase involved in deacetylation of lysine residues in histones and other proteins), the KIAA1467 gene (a transmembrane protein of the integrin alpha FG-GAP repeat containing 3 (ITFG3) family), and a novel regulatory lincRNA (ENSG00000243276). MACROD2 was previously observed as a target of chromothripsis in a colorectal carcinoma. Thus, the characterized breakpoints may identify fragile genomic sites prone to chromothriptic rearrangement. DNA repair was effectuated by non-homologous-end-joining as typical addition of non-template nucleotides with microhomologies of two to four nucleotides at the breakpoints demonstrated. Copy number profiles of this patient showed that at least two distinct leukemic clones could be identified at diagnosis. One had acquired chromothriptic alterations and presented the dominant clone at relapse indicating chemotherapy resistance and tumor-driving potential. Prior whole-exome sequencing did not reveal mutations in known oncogenes or tumor suppressor genes. Therefore, loss of function or expression of genes affected by chromosomal rearrangements, such as TBL1XR1 that is recurrently mutated in childhood ALL with ETV6-RUNX1 translocation, may account for the tumor-driving effect. All leukemic cells at diagnosis showed conformity concerning number and pattern of whole chromosome gains demonstrating that chromothripsis was not an initiating oncogenic event, but occurred secondary to high hyperdiploidy. Further aberrations (t(4;7), loss of 4q) were gained by the chromothriptic clone and could be detected by FISH in minor subclones pointing at ongoing clonal evolution. Taken together, our study reveals chromothripsis as a novel assisting and tumor-driving lesion in HeH ALL. Chromothripsis in HeH-ALL. Copy number variations and translocations at diagnosis (left) and relapse (right). (magenta: chromothriptic translocations; green: other translocations) Disclosures: No relevant conflicts of interest to declare.

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CITED2 Facilitates Apoptosis Induced By Histone Deacetylase Inhibitor SAHA In Human Pediatric Pre-B Acute Lymphoblastic Leukemia Cells

Blood ◽

10.1182/blood.v122.21.2913.2913 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2913-2913

Author(s):

Jinwei Du ◽

Shigemi Matsuyama ◽

Yu-Chung Yang

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Side Effects ◽

Mononuclear Cells ◽

Bone Marrow Cells ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Dependent Manner ◽

Mouse Development ◽

Childhood All ◽

Normal Peripheral Blood

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, representing 31% of all tumors, and about 85% of children with ALL have B-cell ALL. Although the survival rate is approaching 90%, ALL remains the main cause of death from disease in children and young adults. The activity of histone deacetylases (HDAC) in childhood ALL is increased compared with that in normal peripheral blood mononuclear cells or bone marrow cells. Treatment of mice engrafted with T or B-ALL cells with HDAC inhibitor (HDACi) increases the acetylation of Histone 3 and Histone 4 and prolongs survival of these mice. <>Vorinostat (Suberoylamilide Hydroxamic Acid, SAHA) was the first HDACi approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma. Currently, several clinical trials are being conducted to evaluate its effects on other cancers, including ALL. However, some patients are resistant to HDACi therapy, and concerns regarding toxic side effects of HDACi exist due to the roles of HDACs in multiple pathways. Therefore, identification of new therapeutic targets is required which could improve the efficacy of HDACi by reducing the dose of HDACi administered without compromising the treatment benefits but alleviating the side effects of HDACi. <>CBP/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)–rich tail 2 (CITED2) is a cytokine-inducible gene that plays various roles during mouse development and, in particular, is essential for normal hematopoiesis. While the role of CITED2 in the pathogenesis of leukemia is currently unclear, dysregulation of CITED2 has been implicated in various types of leukemia, including ALL, in which downregulation of CITED2 is frequently observed. In this study, we tested the hypothesis that CITED2 may enhance the sensitivity of human pediatric pre-B ALL cells to HDACi SAHA. <>SAHA treatment of NALM-6 and 697 cells (human pediatric pre-B ALL cell lines) significantly induced apoptosis and cell cycle arrest in a dose dependent manner. The protein level of CITED2 was not affected by SAHA treatment. Although overexpression of CITED2 alone only slightly increased apoptosis, it significantly enhanced apoptosis resulted from SAHA treatment in both NALM-6 (15.1% versus 39.2%) and 697 cells (9.4% versus 14.6%) as assessed by annexin V/Propidium Iodide double staining and flow cytometry analysis (Figure 1). Accordingly, compared with control (i.e. NALM-6 cells transduced with GFP), overexpression of CITED2 also greatly reduced mitochondrial membrane potential of NALM-6 cells caused by SAHA treatment. To explore the potential mechanisms underlying enhanced apoptosis by overexpression of CITED2 in NALM-6 cells treated with SAHA, we determined the levels of pro- and anti- apoptotic proteins by Western blot and real-time quantitative PCR. We found that SAHA treatment increased the levels of pro-apoptotic molecules Bak, Puma, and Noxa, and decreased the levels of anti-apoptotic molecule Bcl-xL and apoptosis inhibitors XIAP and survivin. Importantly, overexpression of CITED2 markedly increased the protein levels of pro-apoptotic molecules Bak and Bim. Furthermore, knockdown of Bim by shRNA significantly attenuated apoptosis in Cited2 overexpressing NALM-6 cells treated with SAHA. Taken together, these results suggest that modulation of the CITED2 activity may confer its cooperative effect with SAHA in pre-B ALL cells and warrant future evaluation of such a combination in inducing apoptosis of primary ALL cells. Disclosures: No relevant conflicts of interest to declare.

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Translocation ETS leukemia-acute myeloid leukemia 1 (TEL-AML1) gene fusion in childhood acute lymphoblastic leukemia

Paediatrica Indonesiana ◽

10.14238/pi49.5.2009.270-5 ◽

2009 ◽

Vol 49 (5) ◽

pp. 270

Author(s):

Sri Mulatsih ◽

Yeow Liang ◽

Allen Yeoh ◽

Sutaryo Sutaryo ◽

Sunarto Sunarto

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Gene Fusion ◽

Lymphoblastic Leukemia ◽

Risk Groups ◽

Molecular Characteristics ◽

Rt Pcr ◽

Cross Sectional ◽

Childhood All ◽

Diagnostic Quality ◽

Aml1 Gene

Background Acute lymphoblastic leukemia (ALL) in childrenis a heterogeneous disease with different subtypes based on their cellular and molecular characteristics. This condition wouldinfluence the treatment outcome and subsequent risk for relapse. Accurate assignment of individual patients to risk groups is a critical issue for better outcome. TEL-AML1 gene fusion is themost frequent in childhood ALL.Objective The aim of this study was to investigate the incidenceofTEL-AML1 children with ALL in Sardjito Hospital.Methods This was a cross sectional study. In this preliminarystudy, we used nested reverse-transcriptase polymerase chainreaction (RT-PCR) to analyze the present of TEL-AML1 genefusion in bone marrow sample of childhood ALL patients.Results We analyzed 41 samples. Out of these, 30 (73%) wereamplified. Twenry three out of 30 ALL patients with good medicalrecord were analyzed for this gene fusion. Out of 30 patients, there were five patients (17%) with TEL-AML1-positive gene fusion and 25 (83%) were TEL-AML1-negative. Among five patients with TEL-AML1-positive gene fusion, four patients (80%) were one year to less than 10 year old. All of the patients (100%) were with leukocyte < 50x109/L.Conclusions TEL-AML1 gene fusion was found in 17 % ofsamples. This gene fusion was more frequent in standard risk group (based on age and leukocyte). These data must be clarified with more samples. RT-PCR must be apply in all center as one part of improving diagnostic quality, especially in managing leukemia patients.

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Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Blood ◽

10.1182/blood-2018-99-111546 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4014-4014 ◽

Cited By ~ 8

Author(s):

Marie-Anne Couturier ◽

Xavier Thomas ◽

Francoise Huguet ◽

Céline Berthon ◽

Célestine Simand ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Disease Risk ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Philadelphia Chromosome ◽

New Drugs ◽

Molecular Response ◽

Complete Molecular Response

Abstract Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce. This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study. There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib. The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively. At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up. The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

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The Frequencies of ETV6-RUNX1 Fusion and Hyperdiploidy (>50 chromosomes) in Children with Acute Lymphoblastic Leukemia Are Lower in Far East Than the West..

Blood ◽

10.1182/blood.v114.22.3064.3064 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3064-3064

Author(s):

Der-Cherng Liang ◽

Lee-Yung Shih ◽

Chao-Ping Yang ◽

Iou-Jih Hung ◽

Hsi-Che Liu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Meta Analysis ◽

Far East ◽

Hong Kong Chinese ◽

Event Free Survival ◽

The West ◽

Childhood All ◽

Free Survival

Abstract Abstract 3064 Poster Board III-1 Both ETV6-RUNX1 (TEL-AML1)fusion and hyperdiploidy (>50 chromosomes) of lymphoblasts are favorable outcome predictors in childhood acute lymphoblastic leukemia (ALL). In 433 children with ALL diagnosed at our hospitals between 1997 and 2007 in Taiwan, the frequency of ETV6-RUNX1 fusion was 15.8%, and the frequency of hyperdiploidy (>50 chromosomes) was 14.1%, both were lower than those of the West. While ETV6-RUNX1 fusion had borderline favorable impact on outcome (p=0.053-0.061), hyperdiploidy showed significant favorable impact on event-free survival (91.1% vs 76.6 %, p= 0.016) in our patients. A meta-analysis from literature enrolled reports in which the case numbers and frequency of ETV6-RUNX1 fusion or hyperdiploidy in childhood ALL were described. It revealed that the frequency of ETV6-RUNX1 fusion in childhood ALL in Far East (Japan, Korea, Hong Kong, Chinese in Singapore, and Taiwan) was 14.2% (127/893, range 10-17%), significantly lower than 21.8% (152/697, range 19-27%) in the West (USA, Germany, Italy, France and Chile) (p < 0.0001). The frequency of hyperdiploidy in Japan and Taiwan was 15.2% (140/921, range 13-20%), significantly lower than 31.6% in the West (977/3,158, range 19-34%) (USA, UK and Germany) (p < 0.0001). So far as we know, there were several articles, including ours, addressing that the frequency of ETV6-RUNX1 fusion in childhood ALL was lower in a Far East country. This is the first meta-analysis to demonstrate that the frequency of ETV6-RUNX1 fusion in childhood ALL in Far East was lower than that in the West. There was no report on that the frequency of hyperdiploidy in Far East was lower than that in the West. This is also the first meta-analysis to demonstrate that the frequency of hyperdiploidy in childhood ALL in Far East is significantly lower than that in the West. The nature of these differences, probably due to racial, needs further study. In Far East, with both a lower frequency of ETV6-RUNX1 fusion, and a lower frequency of hyperdiploidy, it warrants renewed effort to cure a higher proportion of children with ALL. Disclosures No relevant conflicts of interest to declare.

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Results of PETHEMA LAL-BR-01 Protocol for Low-Risk (LR) Acute Lymphoblastic Leukemia (ALL) In Children

Blood ◽

10.1182/blood.v116.21.4334.4334 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4334-4334

Author(s):

Josep-Maria Ribera ◽

Albert Oriol ◽

Mireia Morgades ◽

Pilar Bastida ◽

Olga Garcia ◽

...

Keyword(s):

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Normal Karyotype ◽

Complete Response ◽

Low Risk ◽

Response To Treatment ◽

Intrathecal Therapy ◽

Childhood All ◽

Additional Tool

Abstract Abstract 4334 Background and objectives. Children with ALL and low-risk (LR) features have a survival over 80%. The study of minimal residual disease (MRD) is an additional tool for best risk definition and for optimal selection of post-remission treatment. The results of PETHEMA LAL-BR-01 for low-risk childhood ALL (LR-ALL) including sequential MRD evaluation are presented. Patients and Method. Baseline LR-ALL criteria included age 1–9 yr., B-precursor ALL, WBC count <50×109/L, no CNS involvement and absence of hypodiploidy, t(9;22) (BCR-ABL) or 11q23 (MLL) rearrangements. Induction therapy included VCR, DNR, PDN, ASP and CPM (4 weeks), followed by reinduction-consolidation (R-C), consolidation with intensification (C-I) (both including HD-MTX and HD-ARAC among other drugs), maintenance (MP and MTX) with reinductions (with VCR, PDN and ASP)(M-R) during the first yr., and maintenance (M) without reinductions during the second year. CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone). Patients with slow cytologic response (>1× 109 peripheral blood blasts/L on day 8 or >20% bone marrow blasts on day 14), or MRD>0.1% after induction, or MRD >0.01% after R-C or at the 1st or 1.5 yr of therapy were moved to a high-risk (HR) protocol. Results. By April 2010, 176 pts (mean (SD) age 4 (2) yr., 96 males) were evaluable. Baseline ALL characteristics: WBC 8 (SD 6) ×109/L, common ALL 144 (35%), pre-B 30 (17%), hyperdiploidy >50 chromosomes 32 (19%), TEL/AML1 40/140 (29%), normal karyotype 41(24%). Treatment response (172 pts): induction death 2 (infection in both), abandon 2, and complete response (CR) 168 (98%). Five patients were moved to a HR protocol because of slow cytologic response (n=4) or MRD >0.1% at the end of induction (n=1). During consolidation and maintenance 4 pts relapsed and 4 were moved to HR protocol because of MRD>0.01%. Out of 104 pts who completed therapy, 4 relapsed. Seven out of 9 patients moved to the HR protocol (including the 5 pts transferred due to high MRD level) are in first CR and the remaining 2 relapsed. With a median follow-up of 3 (0.1-8.3) yr, 6-yr probabilities of CR duration, overall survival and event-free survival were 92±5%, 97±3% y 87±5%, respectively. The most frequent toxicity was due to infections, and was observed in all phases of the protocol, especially in induction. Dose modifications were documented in 6% of induction cycles, 15% of R-C, and 18% of C-I, in 27% of the patients during M-R and in 25% of the patients during M phase. Conclusions. 1. Most LR-ALL pts achieved a durable CR. 2. Most patients shifted to a HR protocol on the basis of slow response to treatment or MRD positivity maintained CR with HR protocol. 3. Toxicity was acceptable, although frequent dose reductions were required. Supported in part by grants P-EF09 from FJC and RD06/0020/1056 from RTICC. Disclosures: No relevant conflicts of interest to declare.

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