Characteristics and Prognostic Significance of CRLF2 High Expression and the Co-Existence with JAK1 Mutations and Ikaros Deletion in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3800-3800 ◽  
Author(s):  
Zheng Ge ◽  
Juan Liu ◽  
Run Zhang ◽  
Xing Guo ◽  
Jing-Yan Xu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
High Expression ◽  
Newly Diagnosed

Abstract Objective Cytokine receptor-like factor 2 (CRLF2) play an important role in differentiation and proliferation of lymphoid precursor cells through activation of JAK signaling pathway. Increased CRLF2 expression associates with mutations in JAK2, a combination that transforms hematopoietic cells, suggesting that mutants in JAK family members and CRLF2 may cooperate to contribute to acute lymphoblastic leukemia (ALL) pathogenesis. Moreover, the Ikaros deletion is also associated with the development of T-/B-cell ALL with poor outcome and relapse of high-risk leukemia. The aim of this study was to determine the clinical characterization and prognostic values of CRLF2 high expression and its concomitant expression with JAK1 mutations and Ikaros deletion in adult ALL patients. Methods Quantitative PCR (qPCR) was performed to detect the expression of CRLF2 in 133 newly diagnosed adult patients with ALL. Genomic DNA was amplified to detect the mutations of the exon 13, 14, 16, 18 and 19 of JAK1, and IKZF1 exons 4 through 7 deletions (△4–7) by direct sequencing or sequencing after cloning. The CD34, CD13, CD33 and other markers were detected on the leukemia cells from bone marrow of the patients by flow cytometry, and the correlations of the CRLF2 high expression with the clinical features, survival, and with co-expression of JAK1 mutations and Ikaros deletion were statistically analyzed with Pearson's chi-square test or Fisher's exact test and Kaplan–Meier curves analysis. Results CRLF2 high expression was detected in 22.8% of newly diagnosed adult ALL. The patients with CRLF2 high expression has significantly higher percentage of CD34, CD13 or CD33 positive than those with low expression（91.3% vs 62%, P=0.008; 76.2% vs 46.3%, P=0.016; 80.0% vs 37.9%, P=0.001), higher frequency of splenomegaly（60.0% vs 32.0%, P=0.040) in the adult ALL and shorter overall survival and event-free survival（9.5 months vs 16 months, P=0.029; 3 months vs 9 months, P=0.030）in the Philadelphia chromosome negative ALL. Moreover, the 4 JAK1 point mutations with amino acid changes were detected in the patients, which had significant CRLF2 high expression compared to that without mutation（75% vs 21.3%, P=0.037). The co-existence of CRLF2 high expression and IKZF1 exons 4-7 deletion (isoform Ik6) was found in 4 of 10 patients. Conclusion CRLF2 high expression predicts poor survival, and significantly co-exists with JAK1 mutation and Ikaros deletion in adult ALL patients. Our result also suggested that CRLF2, JAK1 and IKZF1 could be integrated in future prognostic model of adult ALL as possible markers for high-risk leukemia. Disclosures No relevant conflicts of interest to declare.

CD34+CD38-CD58- leukemia-Propagating Cells at Diagnosis Could Identify Patients at High-Risk for Relapse in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3795-3795
Author(s):  
Yuan Kong ◽  
Lan-Ping Xu ◽  
Yan-Rong Liu ◽  
Ya-Zhen Qin ◽  
Yu-Qian Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Peking University

Abstract Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph+ALL LPCs are enriched in the CD34+CD38-CD58- fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph+ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph+ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34+CD38-CD58- LPCs in Ph+ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph+ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P<0.1 were included as variables in the multivariate Cox regression model. The study was approved by the Ethics Committee of Peking University People’s Hospital. Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34+CD38-CD58- group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34+CD38-CD58- group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P=0.001]. Additionally, CD34+CD38-CD58- LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs. 5.3% [5.1-5.5%]; P<0.0001), worse LFS (30.2% [8.1-56.6%] vs. 78.7% [64.5-87.7%]; P=0.001) and OS (37.7% [12.6-63.2%] vs. 82.3% [68.5-90.4%]; P=0.0004). Multivariate analyses indicated that CD34+CD38-CD58- LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph+ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34+CD38-CD58- LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34+CD38-CD58- LPCs phenotype at diagnosis promises to benefit the adults with Ph+ALL in the future. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

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 Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3510-3518 ◽  
Author(s):  
Shannon L. Maude ◽  
Sarah K. Tasian ◽  
Tiffaney Vincent ◽  
Junior W. Hall ◽  
Cecilia Sheen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Mammalian Target Of Rapamycin ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Human Leukemia ◽  
Xenograft Models

Abstract CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)–like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.

scholarly journals A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (INCB18424-269/AALL1521): Dose-Finding Results from the Part 1 Safety Phase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 555-555 ◽  
Author(s):  
Sarah K. Tasian ◽  
Albert Assad ◽  
Deborah S Hunter ◽  
Yining Du ◽  
Mignon L. Loh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Multi Agent

Abstract Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

High Musashi-2 Expression Is an Unfavorable Prognostic Factor in Adult B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2508-2508
Author(s):  
Qitian Mu ◽  
Yungui Wang ◽  
Bing Chen ◽  
Wenbin Qian ◽  
Haitao Meng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Myelogenous Leukemia ◽  
High Expression ◽  
Expression Level ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Hes1 Expression

Abstract Abstract 2508 Background: Musashi-2 (MSI2) can inhibit translation of the mRNA encoding NUMB, the NOTCH signaling inhibitor, and play a vital role in the maintenance of hematopoietic stem cells. Musashi-1 (MSI1), another isoform of Musashi family, positively regulates NOTCH1 expression. Recent studies have demonstrated that MSI2 expression was up-regulated during chronic myelogenous leukemia (CML) progression and its high expression was associated with poor outcome of CML and acute myeloid leukemia (AML). However, the prognostic significance of MSI2 expression and the relation between MSI2 and NOTCH1 expressions in acute lymphoblastic leukemia (ALL) remain unknown. Methods: In this study, real-time PCR was used to measured expression levels of MSI2 and NOTCH1 signaling related genes in 116 B-ALL and 24 T-ALL patients, in whom more than 70% leukemic cells were morphologically detected in bone morrow (BM) at diagnosis. Clinical and Molecular data in relation with MSI2 expression level were analyzed. Results: In our B-ALL cohort, although MSI2 expression was not associated with gender, age, white blood cell (WBC), t(9;22)/BCR-ABL and IK6 variant of IKZF1, patients with high MSI2 expression had inferior overall survival (OS) (P=0.007) and event free survival (EFS) (P=0.002) than patients with low MSI2 expression. Multivariate analysis showed that high MSI2 expression was an independently prognosic factor in OS (P=0.001, HR=2.641, 95%CI, 1.494–4.668), EFS (P<0.001, HR=2.562, 95%CI, 1.513–4.218) and RFS (P=0.043, HR=2.057, 95%CI, 1.023–4.137). Moreover, MSI2 expression level had a positive correlation with that of NOTCH1 (P<0.001), but not c-MYC (P=0.432) or HES1 (P=0.509). Similarly, NOTCH1 expression level in patients with high MSI2 expression (0.98, range 0.02 to 13.58) was significantly higher than that in patients with low MSI2 expression (0.42, range 0.01 to 3.55, P=0.001), but c-MYC and HES1 expression levels between patients with high MSI2 expression and low MSI2 expression showed no significant differences (both P>0.05). Conclusion: Our data suggests MSI2 high expression can indicate poor prognosis in adult B-ALL accompanying with elevated NOTCH1 expression but not activating NOTCH1 downstream pathway. Disclosures: No relevant conflicts of interest to declare.

CD34+CD38-CD58- Candidate Leukemia-Initiating Cells Are Clinically Relevant With The Unfavorable Prognosis In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 354-354
Author(s):  
Yuan kong ◽  
Ying-Jun Chang ◽  
Yan-rong Liu ◽  
Ya-zhe Wang ◽  
Qian Jiang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Mrna Levels ◽  
Imatinib Resistance ◽  
Self Renewal ◽  
Philadelphia Chromosome Positive

Abstract Background The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has been greatly improved in the modern era of imatinib. Nevertheless, relapse is still a major cause of treatment failure in human Ph+ALL. Leukemia-initiating cells (LICs) are presumed to be responsible for relapse in leukemia. Therefore, we conducted a study to identify the candidate LICs that are responsible for disease progression and its clinical significance in patients with Ph+ALL. Aims To investigate the leukemia-initiating and self-renewal capacities of CD34+CD38-CD58- cells and determine the prognostic significance of CD34+CD38-CD58- phenotype in patients with Ph+ALL treated in Peking University Institute of Hematology. Methods The leukemia-initiating potential and self-renewal capacity of the sorted CD34+CD38-CD58-, CD34+CD38-CD58+,CD34+CD38+CD58- and CD34+CD38+CD58+ compartments were investigated in vivo using sublethally irradiated and anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice by intra-bone marrow–injection. Furthermore, we prospectively analyzed whether the identified CD34+CD38-CD58- compartment at diagnosis correlates with minimal residual disease (MRD) after therapy and clinical outcomes in 63 adult patients (18-60 years) with de novo Ph+ALL. Results Xenotransplantation of the sorted CD34+CD38-CD58- cells led to a repopulation of human B-ALL in primary and secondary recipient mice, which were phenotypically and clonally derived from the original Ph+ALL patients analyzed by flow cytometry, as well as quantitative real-time RT-PCR and fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities. Furthermore, the candidate CD34+CD38-CD58- LICs phenotype at diagnosis (n=16) significantly correlated with a lower complete remission rate and higher MRD frequency monitored by BCR-ABL mRNA levels in BM of Ph+ALL patients. Additionally, it directly correlated with higher cumulative incidence of relapse (CIR, 60% ± 1.97% vs. 15.51% ± 0.30%, P=0.002) and unfavorable disease-free survival (DFS, 33.75%±12.64% vs. 71.31%±7.17%, P=0.009) at 3-year. The CD34+CD38-CD58- group exhibited a higher rate of BCR-ABL mutations conferring higher level imatinib resistance than the other group (43.75% vs. 17.02%, P=0.04). Multivariate analyses revealed that CD34+CD38-CD58- phenotype at diagnosis was an independent risk factor for relapse (HR=4.35, P=0.009) and DFS (HR=3.38, P=0.008) in adult Ph+ALL. Summary/Conclusion Both the xenotransplantation data as well as the clinical correlation studies show that CD34+CD38-CD58- compartment enrich for leukemia-initiating cells in adult Ph+ALL. CD34+CD38-CD58- phenotype at diagnosis independently correlates with an adverse prognosis, which promises to be an efficient tool for relapse prediction and risk-stratification treatment in adult Ph+ALL patients. Acknowledgments This work was supported by grants from National Natural Science Foundation of China (grants no. 30800483&81230013) and Beijing Municipal Science and Technology Program (grant no.Z111107067311070). Disclosures: No relevant conflicts of interest to declare.

scholarly journals P190BCR-ABL1 in a Patient with Philadelphia Chromosome Positive T-Cell Acute Lymphoblastic Leukemia: A Rare Case Report and Review of Literature

2021 ◽  
pp. 1040-1050
Author(s):  
Samah Kohla ◽  
Sarah EL Kourashy ◽  
Zafar Nawaz ◽  
Reda Youssef ◽  
Ahmad Al-Sabbagh ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Rare Case ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Cytogenetic Abnormality ◽  
Rare Case Report ◽  
Philadelphia Chromosome Positive

T-acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) is rare and aggressive leukemia. Philadelphia chromosome positive (Ph+) is the most common cytogenetic abnormality in chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Ph+ T-ALL is exceeding rare and has a therapeutic and prognostic significance. The incidence and outcome of Ph+ T-ALL are unknown. Differentiation between Ph+ T-ALL/LBL and T-cell lymphoblastic crises of CML may be difficult. We report a rare case of adult de novo T-ALL with significant monocytosis, having Ph+ with (P190 <i>BCR-ABL1</i>) as a cytogenetic abnormality. He was treated with ALL induction chemotherapy and imatinib and achieved complete remission, then relapsed twice and expired shortly after the last CNS relapse.

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (2) ◽  
pp. 527-535 ◽  
Author(s):  
F M Uckun ◽  
M G Sensel ◽  
H N Sather ◽  
P S Gaynon ◽  
D C Arthur ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Improved Outcomes ◽  
B Lineage ◽  
The Individual

PURPOSE The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

scholarly journals Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3816-3816 ◽  
Author(s):  
Ryan J. Daley ◽  
Sridevi Rajeeve ◽  
Charlene C. Kabel ◽  
Jeremy J. Pappacena ◽  
Sarah E. Stump ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hypersensitivity Reactions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

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