High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1028-1034 ◽  
Author(s):  
Anja Troeger ◽  
Ludmila Glouchkova ◽  
Birgit Ackermann ◽  
Gabriele Escherich ◽  
Roland Meisel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Death Receptor ◽  
High Expression ◽  
Cell Precursor ◽  
Relapse Free Survival ◽  
Free Survival ◽  
The Impact ◽  
Very High

Abstract CD40 and CD27, members of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we prospectively assessed the impact of CD40 and CD27 on outcome in 121 children treated according to the CoALL06-97 protocol. Expression of both CD40 and CD27 was found to be significantly higher in low- than in high-risk patients as defined by standard clinical risk parameters such as age and white blood cell count. In addition, in multivariable analysis, a very high percentage of CD40+ blasts at diagnosis was identified as an independent favorable prognostic factor for relapse-free survival. Of note, high CD40 expression particularly protected against late relapse. In B cells, CD40 is known to enhance both antigen-presenting capacity and sensitivity to proapoptotic signals. Yet, although CD40 ligation does result in significant up-regulation of CD80/CD86 in our cohort, it is up-regulation of the death receptor CD95 that significantly correlates with the percentage of CD40+ blasts. Thus very high expression of CD40 on BCP-ALL blasts is an independent prognostic marker indicative of superior relapse-free survival that may in part be due to CD40-dependent death receptor up-regulation.

scholarly journals Impact of Blinatumomab Treatment on Bone Marrow Function in Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5607
Author(s):  
Hagop M. Kantarjian ◽  
Gerhard Zugmaier ◽  
Monika Brüggemann ◽  
Brent L. Wood ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Survival Benefit ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Survival Prognosis ◽  
Free Survival ◽  
Bone Marrow Function

Association of blinatumomab treatment with myelosuppression was examined in this study. Peripheral blood counts were assessed prior to, during, and after blinatumomab treatment in patients with relapsed/refractory Philadelphia chromosome-negative (Ph−) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL; n = 267) and Ph+ BCP-ALL (n = 45) from the TOWER and ALCANTARA studies, respectively, or chemotherapy in patients with Ph− BCP-ALL (n = 109) from the TOWER study; all the patients with relapsed/refractory BCP-ALL and responders achieving complete remission (CR) or CR with partial/incomplete hematological recovery (CRh/CRi) were evaluated. Event-free survival (EFS) and overall survival (OS) were assessed in patients achieving CR and CRh/CRi. Median leukocyte, neutrophil, and platelet counts increased during two blinatumomab cycles but remained low longer after chemotherapy. Among the responders, there was a trend that a greater proportion of patients achieved CR with blinatumomab (Ph−, 76.5%; Ph+, 77.8%) versus with chemotherapy (Ph−, 63.6%). In the TOWER study, the survival prognosis for patients achieving CRh/CRi versus CR with blinatumomab was more similar (median OS, 11.9 (95% CI, 3.9–not estimable (NE)) vs. 15.0 (95% CI, 10.4–NE) months, p = 0.062) than with chemotherapy (5.2 (95% CI, 1.6–NE) vs. 18.9 (95% CI, 9.3–NE) months, p = 0.013). Blinatumomab treatment, with only temporary and transient myelosuppression, resulted in a greater survival benefit than chemotherapy.

scholarly journals Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3302-3304 ◽  
Author(s):  
Sima Jeha ◽  
Frederick Behm ◽  
Deqing Pei ◽  
John T. Sandlund ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Cd20 Expression ◽  
Therapy Studies

Abstract CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% ± 2.9% versus 78% ± 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.

scholarly journals IKZF1plus Defines a New Minimal Residual Disease–Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

2018 ◽  
Vol 36 (12) ◽  
pp. 1240-1249 ◽  
Author(s):  
Martin Stanulla ◽  
Elif Dagdan ◽  
Marketa Zaliova ◽  
Anja Möricke ◽  
Chiara Palmi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Prognostic Profile ◽  
Minimal Residual

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

Deletion of CDKN2A/B is associated with inferior relapse free survival in pediatric B cell acute lymphoblastic leukemia

2018 ◽  
Vol 60 (2) ◽  
pp. 433-441 ◽  
Author(s):  
M. Kathiravan ◽  
Minu Singh ◽  
Prateek Bhatia ◽  
Amita Trehan ◽  
Neelam Varma ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 3982-3988 ◽  
Author(s):  
Michael N. Dworzak ◽  
Angela Schumich ◽  
Dieter Printz ◽  
Ulrike Pötschger ◽  
Zvenyslava Husak ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Induction Treatment ◽  
Cell Precursor ◽  
Anti Cd20 ◽  
The Impact

Abstract CD20 is expressed in approximately one- half of pediatric acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We observed that it is occasionally up-regulated during treatment. To understand the impact of this on the potential effectiveness of anti-CD20 immunotherapy, we studied 237 CD10+ pediatric BCP-ALL patients with Berlin-Frankfurt-Munster (BFM)–type therapy. We analyzed CD20 expression changes from diagnosis to end-induction, focusing on sample pairs with more than or equal to 0.1% residual leukemic blasts, and assessed complement-induced cytotoxicity by CD20-targeting with rituximab in vitro. CD20-positivity significantly increased from 45% in initial samples to 81% at end-induction (day 15, 71%). The levels of expression also increased; 52% of cases at end-induction had at least 90% CD20pos leukemic cells, as opposed to 5% at diagnosis (day 15, 20%). CD20 up-regulation was frequent in high-risk patients, patients with high minimal residual disease at end-induction, and patients who suffered later from relapse, but not in TEL/AML1 cases. Notably, up-regulation occurred in viable cells sustaining chemotherapy. In vitro, CD20 up-regulation significantly enhanced rituximab cytotoxicity and could be elicited on prednisolone incubation. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction, and this translates into an acquired state of higher sensitivity to rituximab. This study was registered at http://www.clinicaltrials.gov as #NCT00430118.

CD20 up-Regulation in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia during Induction Treatment Translates into Higher Rituximab-Sensitivity.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 906-906
Author(s):  
Andishe Attarbaschi ◽  
Angela Schumich ◽  
Georg Mann ◽  
Oskar A. Haas ◽  
Helmut Gadner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Induction Treatment ◽  
Cell Precursor ◽  
The Impact

Abstract CD20 is expressed in about one half of childhood acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We recently observed that this phenotypic marker is further up-regulated in some patients during remission induction treatment containing corticosteroids for up to 5 weeks. To understand the impact of this phenomenon on the potential effectiveness of anti-CD20 immunotherapy (i.e., Rituximab), we studied 237 CD10-positive childhood BCP-ALL patients consecutively enrolled onto the trial AIEOP-BFM-ALL 2000. The analysis included the assessment of CD20 expression changes from diagnosis to the end of induction therapy and complement-induced cytotoxicity by CD20-targeting with Rituximab in-vitro. CD20-positivity significantly increased from diagnosis to the end of induction therapy with respect to the number of positive cases as well as to the levels of expression. After completion of induction therapy, one half of cases showed ≥ 90% CD20pos. leukemic cells, as opposed to 5% at diagnosis and 20% after 2 weeks of chemotherapy. Notably, up-regulation occurred in viable cells sustaining chemotherapy, most probably as a consequence of steroid-induced modulation of gene expression. Rituximab-cytotoxicity was significantly enhanced by CD20 up-regulation and depended on high expression levels. Importantly, CD20 up-regulation was frequent in high-risk patients (mainly poor prednisone responders), patients with high minimal residual disease levels at the end of induction therapy, and patients who suffered later from relapse, but not in TEL/AML1-positive cases. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction therapy and this translates into an acquired state of higher sensitivity to Rituximab.

scholarly journals Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia

Blood ◽  
2020 ◽  
Vol 135 (12) ◽  
pp. 921-933 ◽  
Author(s):  
Malwine J. Barz ◽  
Jana Hof ◽  
Stefanie Groeneveld-Krentz ◽  
Jui Wan Loh ◽  
Annabell Szymansky ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Induction Treatment ◽  
Clinical Effects ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Poor Outcomes

Abstract Activating mutations in cytosolic 5′-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.

scholarly journals Classification and Quantification of Oncogenic Ikaros Isoforms in B Cell Precursor Acute Lymphoblastic Leukemia By RNA-Seq

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-3
Author(s):  
Guangsi Zhang ◽  
Cao Panxiang ◽  
Fang Wang ◽  
Xue Chen ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Sequence Homology ◽  
Lymphoblastic Leukemia ◽  
Low Frequency ◽  
Ras Signaling ◽  
Rna Seq ◽  
Cell Precursor ◽  
The Impact

Background Ikaros, encoded by IKZF1, is a critical transcriptional factor in the B cell development, and the oncogenic isoforms could contribute to leukemia transformation and poor outcome in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Truncated oncogenic isoforms lacking DNA binding domains could be originated from intragenic deletion and alternative splicing, and act as dominant-negative manner. Because of the variable transcripts and sequence homology of IKZF1, there are still challenges to identify the ikaros isoforms by traditional PCR. Methods Here, we developed an integrated pipeline to adapt the classification and qualification of oncogenic ikaros isoforms. Reads were aligned to the reference using the Hisat2. The classification of ikaros isoforms can be visualized and inferred by counting the specific junction reads from ggsashimi plotting. Then we applied SUPPA to each annotation gtf generated by Stringtie to obtain the possible focal alternative splicing events and percentage spliced in (psi or ψ) denoting the abundance or fraction of the oncogenic isoforms (Figure 1). Results Oncogenic ikaros isoforms (Figure 2) were found in 20.2% (53 of 263 cases) BCP-ALL patients by PCR technology. The IK6 and IK10 transcripts accounted for 64% (32 of 53 cases) and 32% (16 of 53 cases), respectively, in addition to two patients harbored both IK6 and IK10 (Table 1). The truncated oncogenic transcripts of IKZF1 often occurred in Ph+ and Ph-like BCP-ALL, which always were characterized by JAK-STAT or RAS signaling activation. The BCR-ABL1 (40%), PAX5 rearrangement (11%), EBF1-PDGFRB (8%), and ABL1-class fusion (6%) were the most recurrently co-occurred gene fusions (Table 1). By the integrated pipeline for RNA-seq analysis, the sensitivity and the specificity have achieved 94.3% and 100% for IK6 and IK10. Intriguingly, although IK7, IK8 and IK9 have been seldom identified in BCP-ALL, we revealed that IK7, IK8 and IK9 were recurrently presented with low frequency by RNA-seq. In order to eliminate the impact of sequence homology to junction reads between exons, we aligned the first and last 20bp base of all exons of ikaros family genes and found low homology among them (Figure 3). Theoretically they were unlikely false positives caused by sequence mismatches, which were also evidenced by the presence of dim bands corresponding to the appropriate products from most PCR results, but further significance of those oncogenic transcripts with low frequency in BCP-ALL remains to be discovered, especially in relapse or refractory cases. Discussion Through the visualization of junction reads, we can easily infer the subtype of the oncogenic ikaros isoforms, which could also be extrapolated to other frequently truncated genes, such as ERG and BTK in BCP-ALL. Moreover, the revised SUPPA pipeline can quantify the expression level of oncogenic transcripts by the value of TPM and psi-value. In this study, we provide a paradigm to exquisitely classify and quantify alternative splicing transcripts through junction reads. Keywords: B cell precursor acute lymphoblastic leukemia, isoforms, IK6, IK10, IKZF1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Blinatumomab in Children and Adolescents with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: A Real-Life Multicenter Retrospective Study in Seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Centers

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 426
Author(s):  
Giuliana Beneduce ◽  
Antonia De Matteo ◽  
Pio Stellato ◽  
Anna M. Testi ◽  
Nicoletta Bertorello ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Life Experiences ◽  
Lymphoblastic Leukemia ◽  
Real Life ◽  
High Rate ◽  
Cell Precursor ◽  
Free Survival ◽  
Multiagent Chemotherapy

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

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