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  • 1
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    Constitutive Activation of FLT3 Is a Positive Prognostic Factor in Infants with MLL-Rearranged Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1417-1417
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1417-1417
    Abstract: Constitutive activation of the FMS-related tyrosine kinase-3 (FLT3) is a common feature of acute leukemias which can be caused by activating mutations or by high expression levels. Aberrant FLT3 downstream signaling is mediated via the RAS/MAPK, PI-3-Kinase/AKT, and STAT5 pathways leading to proliferation, survival, and therapy resistance. In MLL-rearranged acute lymphoblastic leukemia (ALL) activating FLT3 tyrosine kinase domain mutations (TKDs) affecting codons D835 and I836 are frequently identified (Armstrong et al., 2003; Taketani et al., 2004). In addition, MLL-rearranged ALLs are consistently characterized by an exceptionally high FLT3 expression (Armstrong et al., 2002) which has been shown to be associated with ligand independent signaling (Stam et al., 2005). However, the prognostic impact of a constitutive activation of FLT3 in this ALL subset remains controversial. Here, we report on the FLT3 mutational status and gene transcription levels in a large cohort of 95 infants and 72 children with MLL-rearranged ALL. Results obtained were further complemented by a high resolution melting (HRM) screen for common activating NRAS and KRAS mutations at codons 12, 13, and 61. All patients were enrolled in the multicenter trials ALL-BFM 86, 90, 95, 2000, and AIEOP-BFM ALL 2009 as well as Interfant-99 and Interfant-06. In infants, FLT3-TKD mutations were identified in 12/95 patients (12.6%) including one novel insertion/deletion involving codons D835 to S838. In only 2/95 patients (2.1%) an alteration in the juxtamembrane domain of FLT3 was detected. Of the 12 infants with mutation only 2 suffered from a relapse, 2-years cumulative incidence of relapse (CIR) 18%± 12%. In children, only one FLT3 aberration (FLT3-TKD D835 mutation) was detected (1/72, 1.4%). FLT3 transcript levels were analyzed by quantitative real-time PCR in 124 patients (69 infants and 55 children) with available RNA. When we separated the infant cohort into two groups according to the median RQ value, FLT3high and FLT3low, the CIR was significantly different (CIR 19%±7% vs. 66%± 9%, Gray p=0.0001). Of the 6 patients with low FLT3 transcription level, but with presence of a mutation, only one had a relapse. These results indicate that activating FLT3 mutations may compensate for the high relapse risk of patients with a low FLT3 expression. Accordingly, we could show that the CIR was significantly reduced for infants with a low FLT3activation (low transcription, no mutation 19%±7%) compared to those with a high FLT3 activation (high transcription or mutation 75%±9%, Gray p 〈 0.0001, Figure 1). In multivariate analysis, the high prognostic impact of the FLT3 transcription level in infants was independent of age ( 〈 vs. ≥6 month), white blood cell count at diagnosis (WBC ≥ vs. 〈 300000), or prednisone response (poor vs. good). This influence of the FLT3 expression could not be seen in children: CIR 13%±7% for low transcription vs. 12%±7% for high transcription. The only other known recurrent mutations in pediatric MLL-rearranged ALL are activating N- and KRAS mutations at codons 12, 13, and 61 (Liang et al., 2006; Andersson et al., 2015). As RAS signaling is considered as a putative downstream target of FLT3, we investigated the frequency of these mutations and their impact in the context of the prognostic value of FLT3 activation. We identified non-synonymous N/KRAS mutations in 21/95 (22.1%) infants and in 10/72 (13.9%) children. The presence of activating RAS mutations correlated with a higher rate of relapse and a lower probability of event-free survival (pEFS). For infants alone, constitutive activation of N/KRAS resulted in a lower pEFS (43%±6% wt vs. 11%±8%, p=0.01), but there were no significant differences in the CIR (40%±6% wt vs. 51±12%, p=0.40). In summary, we confirm that MLL-rearranged infant ALL represents a biologically distinctive entity with unique molecular genetic features. However, in contrast to published studies, we report that hyperactivation of FLT3 signaling is associated with a good prognosis in MLL-rearranged infant ALL. Our data has important implications for the design of rational therapies in MLL-rearranged ALL as the use of small molecule FLT3 inhibitors may be disadvantageous in some infants depending on FLT3 expression levels and FLT3 and RAS mutational status. Figure 1. Cumulative incidence of relapse (CIR) at 3 years for infant MLL-rearranged ALL patients with high or low FLT3 activation. Figure 1. Cumulative incidence of relapse (CIR) at 3 years for infant MLL-rearranged ALL patients with high or low FLT3 activation. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1417.1417
    RVK:
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    Methotrexate-Associated Toxicity in Children with Down Syndrome and Acute Lymphoblastic Leukemia during Consolidation Therapy with High Dose Methotrexate According to ALL-BFM Treatment Regimen
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1378-1378
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1378-1378
    Abstract: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents. Children with Down syndrome (trisomy 21) have a 30-times higher risk of acquiring ALL and pose up to 5% of all pediatric ALL patients. Moreover, many Down syndrome-ALL patients (DS-ALL) suffer from severe toxicity during chemotherapy, especially after application of high dose methotrexate (HD-MTX). Severe toxicities often result in MTX dose reduction, which may be associated with a higher probability of relapse. Systematic and comprehensive toxicity data in a large cohort of uniformly treated DS-ALL patients are lacking. In order to extend our knowledge on MTX-associated toxicities in DS-ALL, we analyzed clinical data from 103 DS-ALL and 1109 Non-DS-ALL (NDS-ALL) patients diagnosed between 1995 and 2016 treated according to German ALL-BFM protocols (ALL-BFM 1995, ALL-BFM 2000 and AIEOP-BFM ALL 2009). We only included patients for whom both therapy and toxicity data were available. We focused on toxicity after HD-MTX administration during the 8-week HD-MTX consolidation in which patients receive 4 courses of intravenous HD-MTX (5 g/m2 each) plus intrathecal MTX in addition to 6-mercaptopurine (25 mg/m2/d). As of 2004, it was recommended for DS-ALL to administer the first MTX course with a reduced dose of 0.5 g/m2 and subsequently increase the dose if no severe toxicity occurs. Toxicity grading was performed according to CTC 2.0. From the 103 DS-ALL patients four switched to high risk treatment and in one patient only incomplete data on toxicity were available. For these patients data could not be analyzed throughout the complete consolidation therapy. From the remaining 98 patients, 42 (43%) received MTX in a dose of 5 g/m2 ± 10%, six (6%) in a dose between 0.551 - 4.499 g/m2 and50 (51%) received a dose of 0.5 g/m2 ± 10% in the first MTX-block. In contrast, 1061 of 1109 (96%) NDS-ALL received an MTX dose of 5 g/m2. One DS-ALL patient died due to a severe infection after the second MTX block and in two DS-ALL patients HD-MTX consolidation was stopped due to severe infections after the first and the third MTX block, respectively. In contrast, HD-MTX was stopped for two NDS-ALL patients due to toxicity (neurotoxicity and infection) after the second and third course, respectively. All five patients received a first MTX dose of 5 g/m2. No NDS-ALL patient died during HD-MTX therapy. After receiving an MTX dose of 5 g/m2 DS-ALL showed significantly higher rates of grade 3/4 leukopenia, stomatitis, thrombocytopenia and infections as compared to NDS-ALL after the first course (Figure A). Reduction of the initial MTX dose to 0.5 g/m2 significantly reduced the rate of stomatitis, thrombocytopenia and leukopenia in DS-ALL by more than 40% (Figure B). However, these patients still suffered significantly more often from grade 3/4 stomatitis and infections compared to NDS-ALL who received full dose MTX (Figure C). Moderate MTX dose escalation for DS-ALL who tolerated a low MTX dose in the first course and received a higher MTX dose in the second course (median MTX dose 1 g/m2) did not result in an increased rate of toxicity as compared to the first course. Importantly, for DS-ALL a reduced MTX dose of 0.5 g/m2 in the first MTX block was not associated with a higher five year-cumulative risk of relapse (CIR) compared to a dose of 5 g/m2 (CIR 0.08±.05 vs. 0.16±0.05, p=.37). Differences in MTX plasma levels at 42 h and 48 h after start of the MTX infusion did not explain the higher rate of toxicity in DS-ALL as compared to NDS-ALL as most DS-ALL patients who received a low MTX dose presented with significantly lower MTX plasma level than NDS-ALL controls who received high dose MTX (Figure D). Additionally, DS-ALL with MTX plasma levels lower than median level ( 〈 0.320 µmol/l) showed significantly higher rates of grade 3/4 stomatitis and infections than NDS-ALL with higher plasma levels (≥0.320 µmol/l, Figure E). Within the DS-ALL group high MTX plasma level were associated with significantly higher rates of grade 3/4 stomatitis and thrombocytopenia (Figure F). In summary, MTX dose reduction in the first MTX course led to significantly decreased toxicity in DS-ALL without increasing the risk of relapse, although toxicity was still higher as compared to NDS-ALL. As low MTX plasma levels in DS-ALL were associated with less toxicity, lower cut-offs for higher leucovorine doses and forced diuresis may further reduce MTX toxicity in this highly vulnerable group of patients. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-112114
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 3
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    The Strong Prognostic Effect of Concurrent Deletions of IKZF1 and PAX5, CDKN2A, CDKN2B or PAR1 in the Absence of ERG Deletions (IKZF1plus) in Pediatric Acute Lymphoblastic Leukemia Strongly Depends on Minimal Residual Disease Burden after Induction Treatment
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 131-131
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 131-131
    Abstract: Technical advances in the field of genomic analyses have stimulated a large number of discovery studies on etiological and clinical endpoints in acute lymphoblastic leukemia (ALL) to provide new avenues for preventive strategies, diagnostics and treatment. Recently, deletion of IKZF1 (IKZF1del) was described as a poor prognostic factor in pediatric ALL (Mullighan CG et al., 2012). In our trial AIEOP-BFM ALL 2000 patients with IKZF1del had a lower 5-year event-free survival (EFS; 0.69±0.05 vs. 0.85±0.01; P 〈 0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (CIR; 0.21±0.04 vs. 0.10±0.01; P=0.001) (Dörge P et al., 2013). IKZF1delwas an independent prognostic factor in this modern protocol. However, on its own, and even in association with minimal residual disease (MRD) levels, its relatively mild prognostic strength limited incorporation in clinical stratification strategies so far. The present study was undertaken to evaluate the prognostic effect of concurrent recurrent genetic aberrations in association with IKZF1del to further refine a high-risk genetic signature for pediatric ALL treated on AIEOP-BFM protocols. For this purpose, we studied a cohort of 1100 German patients with B-cell precursor ALL treated on AIEOP-BFM ALL 2000 with available characterization of genetic aberrations at initial diagnosis by MLPA (MLPA SALSA kit P335; MRC-Holland) and a PCR assay for detection of ERG deletions (ERGdel; Zaliova M et al., 2014). Validation of results was conducted by use of an independent cohort of 417 Italian patients from the same trial. BCR/ABL1-positive patients were excluded from outcome analysis. When single marker analyses were conducted, IKZF1del was the strongest determinator of outcome in the discovery as well as the validation cohort. When IKZF1del was analyzed in combination with PAX5, CDKN2A, CDKN2B, and PAR1 deletions, patients with an additional deletion to that of IKZF1 had the worst EFS and highest CIR in absence of ERGdel and, consequently, were grouped as IKZF1plus (definition: presence of IKZF1del and at least an additional deletion in PAX5, CDKN2A, CDKN2B or PAR1 in the absence of ERGdel). This group comprised 6% of B-lineage ALL patients and had a very poor clinical outcome: 5y-EFS 50%±0.06 compared to 86%±0.01 in IKZF1plus-negatives (p 〈 0.0001); 5y-CIR 45%±0.06 compared to 11%±0.01 (p 〈 0.0001) and was an independent prognostic factor in multivariate analyses including MRD, slow early response, prednisone response, ETV6/RUNX1 status, and WBC (≥100.000/µl) (hazard ratio for an event: 3.39; 95% CI 2.09 – 5.48; p 〈 0.0001). Surprisingly, stratified analysis by MRD demonstrated that the effect of IKZF1plus was restricted to those patients still carrying MRD loads of at least 10E-4 after induction treatment: standard-risk group 5y-EFS 94%±0.06 compared to 38%±0.09 in intermediate-risk and 27%±0.13 in high-risk patients (p 〈 0.0001); standard-risk group 5y-CIR 6%±0.10 compared to 62%±0.10 in intermediate risk and 55%±0.17 in high-risk patients (p 〈 0.0001). Hierarchical clustering of gene expression profiles of IKZF1plus patients did not demonstrate association specific to the different MRD risk groups. Similarly, analysis of whole exome and transcriptome data from material at initial diagnosis in a very restricted number of patients could not demonstrate insights into the observed differences. Newly identified very poor prognostic ALL subgroup – termed IKZF1plus – represented worse outcome compared to that of IKZF1del or others as a sole marker. The differential prognostic effect of IKZF1plus at different MRD levels without currently discernable molecular explanations suggest a quantitative mechanism with higher levels of leukemic cell burden during the early treatment phases predisposing to evolution of a treatment resistant leukemic clone under exposure towards genotoxic chemotherapeutic agents. Potential explanations for these differences in treatment response may be undetected sub-clones already present at diagnosis or underlying germline genetic variation associated with treatment response. Further analyses will be required to better understand this phenomenon. However, due to its strength, the definition of IKZF1plus is likely to aid in the practical implementation of newly detected markers for risk stratification in childhood ALL in a clinical setting. Support: EU FP7 (ENCCA, TRANSCALL), IGA MZ NT/13170-4 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.131.131
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    Poor Prognosis in Children with ABL-Class Fusion Positive B-Cell Acute Lymphoblastic Leukemia Treated According to AIEOP-BFM Protocols
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1351-1351
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    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1351-1351
    Abstract: ABL-class fusions other than BCR-ABL1 (or Ph+) are found in 2-3% of precursor B-cell acute lymphoblastic leukemia (pB-ALL) in children and adolescents. Occasional reports suggest that this rare ALL subtype has a poor prognosis and patients can benefit from treatment with tyrosine kinase inhibitors (TKIs). Aim of this retrospective study is to investigate the presenting features, treatment response and outcome in ABL-class fusion positive cases identified within large cohorts of patients treated in AIEOP-BFM ALL trials. This retrospective survey of ABL-class fusion positive pB-ALL other than Ph+ ALL was performed in patients aged 1-17 years at the diagnosis, treated from October 2000 to August 2018 according to the AIEOP-BFM (Associazione-Italiana- di- Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols in Austria, Australia, Czech Republic, Germany, Israel, Italy and Switzerland. While ABL-class fusions screening was not required by protocols, it was performed in some patients, according to centers' policies, usually after poor early treatment response. Overall, 46 ABL-class fusion positive cases with ABL1 fusions (N=15), ABL2 fusions (N=5), CSF1R fusions (N=3) and PDGFRB rearrangements (N=23) were identified. Compared with other pB-ALL children and adolescents, the ABL-class fusion positive cases presented with higher proportions of patients aged 10 years or older (52.2 vs. 22.2, P & lt; .0001), hyperleukocytosis (WBC ≥100x109/l, 41.3 vs. 6.3, P & lt; .0001), or poor minimal residual disease (MRD) response ( & gt;5x10-4 levels were observed in 65.2% vs. 18%, P & lt; .0001 of patients after induction treatment phase IA and in 45.7% vs. 4.8%, P & lt; .0001 after consolidation phase IB). For the entire cohort of 46 cases, the 5-year probability of event-free survival (EFS) was 49.1+8.9% and that of overall survival (OS) 69.6+7.8%; the cumulative incidence of relapse (CI) was 25.6+8.2% and treatment-related mortality 20.8+6.8%. Although not prescribed by the protocols, 13 patients received a TKI during different phases of treatment (TKI group), by choice of treating physicians, generally due to poor early treatment response. Eight TKI patients with high MRD levels at the end of induction phase IA received the TKI during consolidation phase IB, and six of them achieved either a low positive or negative MRD level at the end of consolidation phase IB. Nine of the 13 patients treated with TKIs underwent hematopoietic stem cell transplantation (HSCT) and only 1/9 (TKI+HSCT) relapsed. Thirty-three cases did not receive any TKI (no-TKI group) and eight of them relapsed; 6/17 patients treated with chemotherapy only, versus only 2/16 who underwent HSCT. Overall, 25 patients underwent HSCT, and of them 3 relapsed and 6 died of treatment-related complications. In patients with a WBC higher or lower than 100x109/L, the 5-year EFS was 36.8+12.7% vs. 59.9+11.6%, respectively (P= .21), and the 5-year OS was significantly lower in patients with a high WBC (48.8+12.9% vs. 87.4+6.8%, P= .036). This difference was more pronounced in the no-TKI group with a 5-year EFS 27.8+13.6% vs 61.8+12.7%, (P= .07), and an OS of 36.7+14.6% vs 94.4+5.4%, respectively (P= .0015). Presenting features, treatment response and outcome in this cohort of ABL-class fusion positive patients are markedly similar to those of patients with Ph+ ALL included in the EsPhALL studies. Our results suggest that TKIs and HSCT may be beneficial in reducing the risk of relapse. Thus there is an urgent need for large international cooperative controlled studies to investigate the impact of TKI, in combination with an appropriate chemotherapy backbone and the role of HSCT. To this purpose, an early identification of patients with ABL-class fusion positive acute lymphoblastic leukemia will be necessary. Disclosures Izraeli: sightdx: Consultancy; novartis: Honoraria; prime oncology: Speakers Bureau. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-126523
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 5
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    Analyses of a Pair of Concordant Twins with Infant ALL and Discordant Clinical Outcome Reveals Immunoescape As a Mechanism of Disease Persistence in MLL-Rearranged Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3791-3791
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3791-3791
    Abstract: MLL-fusion is the most common genetic abnormality in acute lymphoblastic leukemia (ALL) of infancy and occurs in approximately 80% of the cases. Infant ALL represents a biologically distinctive entity with a highly immature pro-B immunophenotype associated with a particularly unfavorable prognosis due to a high proportion of early relapses. This may be due to the survival of dormant residual disease protected by the bone marrow niche. We have characterized a pair of monozygotic twin sisters diagnosed with ALL in early infancy. Tumor cells from both children carried the t(11;19) translocation (MLL-ENL fusion) and both patients were treated according to the ALL-BFM 2000 protocol. Despite good initial treatment responses in both twins, one sister developed very early relapse (twin A) and succumbed to the disease. The other went into continuous complete remission (twin B) and, as of today, is alive after 9 years. The clinical data of the 2 patients are presented in Table 1. Diagnostic bone marrow (BM) aspirates of both sisters were injected into the femoral bones of NOD SCID gamma (NSG) mice. Survival of xenografted mice bearing twin A was significantly longer due to a lower proliferative capacity of twin A as compared to twin B cells. In vivo Bromodeoxyuridine (BrdU) assays revealed that twin B cells were proliferating equally fast in BM and spleen, while in twin A cells, the BM markedly suppressed entry into S-phase. Flow cytometry from xenograft BM identified a large CD34+ population in twin A cells that was almost absent in twin B cells. Furthermore, BM of twin A xenografts showed a CD34+/CD38-/CD19- stem cell like population undetectable in twin B animals. Most interestingly, injection of minimal residual disease (MRD) negative remission bone marrow (PCR for Ig-gene rearrangements and the MLL-fusion gene) of both sisters into NSG mice resulted in a full-blown xenograft leukemia in animals bearing twin A but not twin B. Taken together, these data suggest that fatal relapse in twin A may be due to a quiescent stem cell like population kept in check by unknown mechanisms. Next, we performed gene expression analyses on xenografted leukemias from twin A (initial, leukemia amplified from remission BM, relapse) and from twin B (initial). STRING analysis of gene expression differences revealed that, amongst other findings related to cell cycle regulation and DNA-repair, twin A cells downregulated genes indicating a reduced interferon pathway activity (CXCL10, IFI30, TRAIL, STAT1, OAS1, MX1) and several genes connected to TYRO protein kinase binding protein (TYROBP) shown previously to regulate the activity of natural killer (NK) cells. This suggests that twin A cells may evade immunosurveillance as a mechanism of disease persistence. 51Chromium-release assays with IL-2 stimulated allogeneic NK cells from two healthy donors and the xenografted twin cells showed that twin A cells were significantly less sensitive to NK cell mediated lysis as compared to twin B cells. Whether the tumor cells also display differential susceptibility to antibody-dependent cell-mediated cytotoxicity is currently investigated. While the extensive genomic characterization of the twin leukemias is under way, we show evidence from xenograft experiments, gene expression profiles and functional in vitro experiments that dormant residual cells in MLL-rearranged ALL can evade immunosurveillance. These findings serve as a rationale to employ immunotherapeutic approaches in infant ALL patients in order to improve their dismal prognosis. Finally, we report the first monozygotic twin pair with MLL-rearranged ALL and discordant clinical outcomes. This provides a unique opportunity and a model to gain insight into the clonal composition of infant leukemia and the origins of leukemia relapse. Table 1: Patient characteristics of the MLL-ENL positive twin pair. WBC, white blood cells; BM, bone marrow; CNS, central nervous system; MRD, minimal residual disease. Parameter Twin A Twin B Age at diagnosis (days) 98 147 WBC (initial)/µl 334.000 103.000 Blasts (Peripheral Blood) % 97 91 Blasts (BM) % 98 97 CNS involvement Not determined Negative Immunophenotype Pro-B Pro-B Cytogenetics t(11;19) t(11;19) Prednisone-Response Poor Good Blasts (BM), day 15 % 32 1 MRD day 33 Negative Negative MRD day 78 Negative 〈 10-4 * Event-free survival 227 days 〉 9 years Time to relapse 227 days n/a Overall survival 390 days 〉 9 years *low positive, not quantifiable Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3791.3791
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 6
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    CD79a Is Associated with Central Nervous System Infiltration of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 386-386
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 386-386
    Abstract: Despite the advances in the treatment of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), infiltration of the central nervous system (CNS) remains a clinical challenge. Certain cytogenetic subtypes such as E2A-PBX1-and BCR-ABL-positive BCP-ALL confer a higher risk for CNS involvement initially and for CNS relapse. Novel strategies to predict CNS and to eradicate leukemic cells from the CNS are subjects of ongoing research. In order to identify targets with diagnostic and therapeutic relevance, comparative RNA-sequencing was performed with patient derived xenograft (PDX) blasts from 5 E2A-PBX1-positive patients, recovered from the bone marrow (BM) and from the CNS of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Differential gene expression analysis revealed the upregulation of various genes of the pre-B cell receptor complex, particularly the signaling component CD79a (Igα) in blasts recovered from the CNS as compared to blasts from the BM. We then investigated the impact of CD79a on CNS infiltration in vivo and in patients. CD79a was downregulated by short-hairpin RNA (shRNA) mediated knockdown in the E2A-PBX1 positive cell line 697. Proliferation rates of 697-shCD79a cells and control-transfected 697 cells (697-shCtrl) in vitro were similar. Furthermore, NSG mice injected with 697-shCD79a cells showed comparable survival times, as well as similar blast infiltration in spleen and BM as animals injected with 697-shCtrl cells. However, downregulation of CD79a led to a significantly lower number of CNS-positive mice (4/15, 26%) as compared to control animals (7/10, 70%) (p=0.0486, Figure A). This indicates that CD79a is not critically involved in proliferation and peripheral engraftment, but in CNS infiltration of E2A-PBX1 positive 697 cells in vivo. To test if CD79a also affects CNS involvement in BCR-ABL-positive leukemia, a murine/murine transplantation model was used. B-cells isolated from CD79a-knockout (CD79a-KO) or wildtype mice (CD79a-Ctrl) were stably transfected with a BCR-ABL fusion gene and cultured independent of cytokines, thereby inducing malignant transformation. Both cell lines were subsequently injected into recipient NSG mice (n=8/group) and leukemic development was followed. The experiment was terminated when all control mice had developed leukemic symptoms and mice were analyzed for leukemic engraftment. A further CD79a-KO group was included for survival analysis. Median spleen volume as a surrogate of leukemic infiltration was significantly lower in mice injected with CD79a-KO as compared to CD79a-Ctrl cells (0.35 cm³ vs. 0.06 cm³; p=0.0001). Median blast percentages in spleens and BM were also markedly reduced (75.3% vs. 5.8%; p=0.0001 and 61.0% vs. 4.5%; p=0.0001, respectively). Importantly, none of the animals in the CD79a-KO group showed blasts in the CNS as assessed by histology whereas blasts were present in all of the animals in the CD79a-Ctrl group. Finally and most importantly, NSG-mice injected with CD79a-KO cells showed a highly significant prolongation in median survival as compared to mice with CD79a-Ctrl cells (29 days vs. 95 days; p=0.0001, Figure B). Altogether, these data suggest that in a model of BCR-ABL-positive leukemia, absence of CD79a impacts the engraftment of blasts in vivo, in the CNS and other leukemic niches. To further validate our findings in patient material, we measured CD79a protein expression in PDX cells from an E2A-PBX1- and a BCR-ABL-positive patient serially transplanted into NSG mice for three passages. For both entities and in all passages, CNS blasts showed a higher CD79a expression than blasts isolated from the bone marrow. In order to assess if CD79a can be used as a marker to predict CNS involvement in patients, CD79a mRNA levels were measured in a selected cohort of 98 pediatric BCP-ALL patients, which contained 26 CNS-positive patients matched to 72 CNS-negative patients. CNS-positive patients showed significantly higher mRNA levels of CD79a than CNS-negative patients (p=0.0225, unpaired t-test, Figure C) suggesting that CD79a may be of value as a potential diagnostic marker for initial CNS involvement in BCP-ALL. Our results indicate a role of CD79a in proliferation and CNS infiltration of BCP-ALL blasts in experimental settings and patients. We intend to prospectively evaluate CD79a as a prognostic marker, which may also be a therapeutic target in CNS-positive BCP-ALL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114595
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 7
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    Co-Targeting of CD38 and CD47 in T Cell Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-40
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-40
    Abstract: Antibody application is a promising therapy in hematological malignancies including acute lymphoblastic leukemia (ALL). Unlike for B-cell precursor (BCP-ALL), immunotherapeutic interventions in T-cell ALL (T-ALL) are practically non-existent. Most T-ALL patient samples show substantial surface expression of CD38. Moreover, mice bearing T-ALL patient-derived xenograft (PDX) samples treated with daratumumab (Dara) monotherapy displayed prolonged survival and MRD-negativity in 50% of cases as opposed to animals treated with chemotherapy (Vogiatzi et al., Blood, 2019). Besides CD38, elevated surface expression of CD47 has been described in T-ALL (Chao et al., 2011). CD47 acts as a "don't-eat-me" signal protecting cancer cells from macrophage-dependent phagocytosis. In this study, we explored the efficacy of Dara and a CD47 blocking antibody (Fc-modified version of Hu5F9-G4, termed Hu5F9-IgG2σ) alone or in combination in T-ALL. In vitro phagocytosis assays with M-CSF derived M0 (CD64+, CD80-, CD163+) macrophages from healthy donors were evaluated in T-ALL cell lines. Cells labelled with a pH-dependent dye became fluorescent upon engulfment by macrophages and formation of the acidic phagolysosome, which was automatically measured as an absolute cell count. The highest count was set as 100% in each experiment and all other values expressed as percentages relative to that. Treatment of MOLT-13 cells with Dara or Hu5F9-IgG2σ increased median phagocytosis from 5% in control to 23% and 27%, respectively (p=0.008 for both, Figure 1A). However, combined treatment resulted in a maximal increase of median phagocytosis in MOLT-13 cells (p=0.004 compared to Dara and p=0.008 compared to Hu5F9-IgG2σ, Figure 1A). Similar results were obtained in HSB-2 and P-12 cells (p=0.037/0.004 for HSB-2, p=0.011/0.001 for P-12). In addition, phagocytosis was determined in 12 PDX samples from random T-ALL patients. Hu5F9-IgG2σ alone showed a modest increase in median phagocytosis compared to control (19% vs. 6%, p & lt;0.001) and Dara increased phagocytosis to 43% (p & lt;0.001). Combination therapy, however, led to a maximal rise of median phagocytosis in all samples (p & lt;0.001 compared to all others). Phagocytosis was also determined in 16 relapsed/refractory (r/r) T-ALL-PDX samples, in which a maximal median phagocytosis upon combination of Dara and Hu5F9-IgG2σ was also observed (2% in control, 37% in Dara and 14% in Hu5F9-IgG2σ, p & lt;0.001/p=0.02/p=0.02, respectively). The extent of phagocytosis correlated with CD38 and CD47 surface expression on T-ALL cells and, in part, also with expression of signal regulatory protein α (SIRPα) on macrophages, the interacting partner of CD47. A maximal increase in phagocytosis was also observed when applying Hu5F9-IgG2σ in 1/10 of the concentration of Dara, confirming its high efficacy. The effects of the Dara/ Hu5F9-IgG2σ combination were also examined in vivo in phase II-like preclinical trials containing different patients in one experiment. Six random T-ALL-PDX samples were injected into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and subjected to therapy with Dara and Hu5F9-IgG2σ alone or in combination. In order to mimic minimal residual disease (MRD), antibody therapy was started one day post injection. Mice subjected to Dara displayed prolonged survival in 4/6 (67%) animals compared to control (p=0.007), whereas animals treated with Hu5F9-IgG2σ showed significantly prolonged survival in all cases (p=0.007, Figure 1B). Interestingly, mice not responding to Dara benefitted from Hu5F9-IgG2σ monotherapy and the combination had no further survival advantage in this MRD model. In a second approach, eight r/r T-ALL PDX samples were used, and the same therapy was started upon overt leukemia (1% human blasts in peripheral blood). Compared to control, mice treated with Dara in this overt leukemia and r/r setting showed no survival benefit, while animals subjected to Hu5F9-IgG2σ showed a trend towards a prolonged survival (5/8 cases, 63%, p=0.08). Most importantly, the combination of both agents resulted in a statistically significant survival prolongation in 7/8 cases (88%, p=0.010, Figure 1C). Altogether, we show that combining Dara with CD47 blockade increases phagocytosis in vitro in three T-ALL cell lines and 28 PDX samples. Our in vivo data suggest that this combination is a highly promising therapeutic strategy, especially in the relapsed/refractory setting. Figure Disclosures Cario: Jazz Pharmaceuticals: Consultancy, Other: travel support; Novartis: Consultancy, Other: travel support. Kulozik:bluebird bio, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bourquin:Servier: Other: Travel Support. Schewe:Sobi: Other: was an advisory board member; Bayer: Other: was an advisory board member; Jazz: Other: was an advisory board member; OSE pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-140270
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 8
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    Preclinical Evidence for the Efficacy of CD79b Immunotherapy in B Cell Precursor Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2388-2388
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2388-2388
    Abstract: Patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) have a favorable prognosis, yet current treatment protocols are based on intensive cytotoxic chemotherapy and therapy options are limited when patients relapse. Novel immunotherapy approaches are therefore needed. We recently reported that the preB cell receptor signaling unit CD79a (known as Igα) is crucial for BCP-ALL engraftment in vivo, particularly in the central nervous system (CNS) employing BCR-ABL + and E2A-PBX1 + patient derived xenograft (PDX) models (Lenk et al., Communications Biology, 2021). CD79a forms a heterodimer with CD79b (known as Igß), which is also expressed on the surface of mature B cells as part of the B cell antigen receptor. Accordingly, the CD79b antibody drug conjugate (ADC) Polatuzumab Vedotin (PolVed) has shown therapeutic efficacy in the treatment of refractory/relapsed (r/r) diffuse large B cell lymphoma. Moreover, CD79a/CD79b may also be present on the cell surface at the pro/pre B cell stage. We therefore hypothesize that CD79b can serve as a therapeutic target in BCP-ALL. First, to substantiate that CD79b is important for BCP-ALL engraftment in vivo, a murine/murine transplantation model was applied. B cell precursors were isolated from mice harboring CD79b with a non-functional signaling domain (CD79b-ITAM-KO) or wildtype mice, malignantly transformed with a BCR-ABL fusion construct and transplanted into NSG-mice. Whereas control cells caused overt leukemia in all animals within 25 days, no animal injected with CD79b-ITAM-KO cells had developed leukemia by the time of sacrifice at 162 days (P & lt;0.001). To investigate the frequency of surface (s)CD79b expression in BCP-ALL patients, we measured sCD79b levels via flow cytometry in diagnostic samples of pediatric BCP-ALL patients with different cytogenetic backgrounds. We detected sCD79b-positivity (defined as ≥10% sCD79b + BCP-ALL cells) in 23/94 patients including BCR-ABL +, E2A-PBX1 +, MLL-rearranged (MLLr), TEL-AML1 + and B-other BCP-ALL patients indicating a population of sCD79b + patients within different cytogenetic BCP-ALL subgroups (Figure 1a). To validate CD79b as a therapeutic target, we applied an unconjugated monoclonal CD79b antibody (CD79b-mAB) to PDX mice bearing either pediatric BCR-ABL + or E2A-PBX1 + PDX samples with high sCD79b expression (49.6% sCD79b + cells and 37.7% sCD79b + cells, respectively). Treatment was initiated one day after BCP-ALL injection, modelling a minimal residual disease (MRD) situation. Therapy with CD79b-mAB (1mg/kg) resulted in a mild reduction of leukemia burden in the spleen (SP) and bone marrow (BM) of PDX mice and a significant reduction of CNS-involvement in both PDX-models as compared to control treated mice (P & lt;0.05 and P & lt;0.01, respectively). To test the hypothesis that treatment of BCP-ALL with a CD79b-ADC outperforms CD79b-mAB, we applied PolVed (1mg/kg) in NSG mice bearing the same E2A-PBX1 + and BCR-ABL + PDX cells. PolVed therapy resulted in a significant reduction of BCP-ALL engraftment in SP, BM and CNS (P & lt;0.01, respectively) and a significant survival prolongation compared to control treated mice in both models (P & lt;0.01, respectively). Of note, 4/5 PolVed-treated E2A-PBX1-PDX animals were free of leukemia by the time of sacrifice (236 days) (Figure 1B). To test the efficacy of PolVed on different BCP-ALL subgroups, we conducted a preclinical phase II-like PDX study, using sCD79b high and sCD79b low PDX samples (defined by sCD79b-expression above or below the median) (5E2A-PBX1 +, 3 BCR-ABL +, 2 MLLr, 1 E2A-HLF + and 1 ETV6-NTRK3 +). Two NSG mice per patient were injected with PDX cells, randomly assigned into treatment groups and PolVed therapy was initiated when 1% PDX-cells were detected in the peripheral blood, modelling an overt leukemia situation. sCD79b low PDX mice did not respond to PolVed treatment (Figure 1c), but we detected a response to therapy and a significant survival prolongation in 5/6 sCD79b high PDX samples irrespective of the cytogenetic background (P & lt;0.05) (Figure 1d). Taken together, our data indicate that a subgroup of BCP-ALL patients is sCD79 + positive and may respond to PolVed treatment. Therefore, we suggest CD79b as a novel therapeutic target in BCP-ALL and propose PolVed as a potential therapeutic agent in r/r disease. *LL and DW contributed equally to this work Figure 1 Figure 1. Disclosures Lenk: OSE Immunotherapeutics: Research Funding. Richter: HTG Molecular Diagnostics, Inc.: Current Employment, Research Funding. Schrappe: SHIRE: Other: research support; JazzPharma: Honoraria, Other: research support; Servier: Honoraria, Other: research support; SigmaTau: Other: research support; Novartis: Honoraria; JazzPharma: Honoraria; Novartis: Honoraria, Other: research support; Servier: Honoraria; Amgen: Other: research support. Cario: Novartis: Other: Lecture Fee. Brüggemann: Incyte: Other: Advisory Board; Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Schewe: Jazz Pharmaceuticals: Other: Advisory Board; SOBI: Other: Advisory Board; Bayer: Other: Advisory Board; OSE Immunotherapeutics: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-148429
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 9
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    The IL7R-Antagonist OSE-127 Blocks Acute Lymphoblastic Leukemia Development Via a Dual Mode of Action
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1045-1047
    Details
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1045-1047
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2022-162261
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 10
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    IL7R Targeting Using OSE-127 Shows Robust Anti-Leukemic Activity in B-Cell Precursor Acute Lymphoblastic Leukemia Xenografts
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1313-1313
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1313-1313
    Abstract: Despite the favorable prognosis of B cell precursor acute lymphoblastic leukemia (BCP-ALL), relapse remains a clinical challenge. Antibody-based immunotherapies like Blinatumomab have improved BCP-ALL outcome, yet these can quickly turn ineffective due to CD19 antigen escape. Therefore, novel targeted immunotherapy options are urgently needed. We previously showed that high IL7R expression associates with adverse outcome in BCP-ALL patients and that IL7R targeting using laboratory-grade blocking antibodies significantly reduced leukemic burden in E2A-PBX1 and BCR-ABL patient derived xenografts (PDX) (Alsadeq et al., Blood, 2017; Abdelrasoul et al., Nat. Commun., 2020). Here we used the humanized monoclonal antibody OSE-127, a full IL7R antagonist which is not internalized by target cells and prevents IL7R heterodimerization and subsequent downstream signaling (Belarif et al., Nat. Commun. 2018, Belarif et al. JCI, 2019). Importantly, OSE-127 has recently been positively evaluated in a phase 1 study conducted in 63 healthy volunteers receiving either a single dose or two doses two weeks apart (EUDRACT 2018-001832-22). OSE-127 demonstrated an excellent safety and tolerability profile showing no signs of lymphopenia, cytokine release syndrome or T-cell compartment alterations. Based on these preclinical and clinical results, we investigated the anti-leukemic efficacy of OSE-127 immunotherapy in PDX models of BCP-ALL. First, to identify patients that may benefit from IL7R-immunotherapy, we measured IL7R surface expression in diagnostic BCP-ALL patient samples of different cytogenetic subgroups via flow cytometry. We detected IL7R-positivity (defined as ≥10% IL7R + BCP-ALL cells) in 52% (49/94) of patient samples including BCR-ABL + (25%; 5/20), TEL-AML1 + (41%; 7/17) and B-other (40%, 8/20) samples. Particularly high numbers of IL7R + patients were found in the E2A-PBX1 + and MLL-rearranged (MLLr) BCP-ALL subgroups (79%; 19/24 and 85%; 11/13 IL7R + patient samples, respectively). Next, we tested the efficacy of OSE-127 in NSG mice injected with PDX cells from two different E2A-PBX1 + patients (63.0% and 89.6% IL7R-positive blasts, respectively) modelling an MRD-situation by starting treatment one day after injection of PDX cells. While 100% of control animals developed overt leukemia, 0% of the OSE-127-treated animals developed the disease, with 10/10 and 7/10 mice per PDX-group being MRD-negative by the time of sacrifice. Of note, OSE-127-therapy was also effective in corresponding PDX models when therapy was initiated upon detection of 1% BCP-ALL cells in the peripheral blood, modelling an overt leukemia situation (P & lt;0.0001 in both cases). To investigate the efficacy of OSE-127 in a variety of BCP-ALL samples, we conducted a preclinical phase II-like study using PDX from different cytogenetic patient subgroups (8E2A-PBX1 +, including 1 matched diagnostic/relapse sample, 1 BCR-ABL, 1 MLLr and 1 ETV6-NTRK3). Two mice per PDX were injected, randomly assigned to control or OSE-127 treatment groups and therapy was initiated when & gt;1% blasts were detected in the peripheral blood. Response to OSE-127 was detected in 9/11 (82%) PDX samples in vivo, including BCR-ABL +, MLLr and E2A-PBX1 +-relapse samples. Accordingly, OSE-127 immunotherapy led to a significant increase in median overall survival (85 days versus 55 days; P=0.0122). Of note, OSE-127 therapy response associated with IL7R expression levels on BCP-ALL cells and no significant downregulation of the IL7R antigen was observed upon OSE-127 treatment. Taken together, our data demonstrate that IL7R-targeting using OSE-127, which has already demonstrated a good safety profile in healthy volunteers, is an efficient approach for BCP-ALL immunotherapy and may be particularly beneficial for patients with high IL7R-expression and/or relapsed/refractory disease after CD19-directed therapy. Disclosures Lenk: OSE Immunotherapeutics: Research Funding. Baccelli: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Corallo: OSE Immunotherapeutics: Current Employment. Schrappe: SHIRE: Other: research support; JazzPharma: Honoraria, Other: research support; Servier: Honoraria, Other: research support; Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria. Cario: Novartis: Other: Lecture Fee. Brüggemann: Incyte: Other: Advisory Board; Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Poirier: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Schewe: OSE Immunotherapeutics: Research Funding; Bayer: Other: Advisory Board; SOBI: Other: Advisory Board; Jazz Pharmaceuticals: Other: Advisory Board.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-150323
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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