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  • American Society of Hematology  (10)
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  • American Society of Hematology  (10)
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  • 1
    Online Resource
    Online Resource
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3494-3494
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3494-3494
    Abstract: Background: PIM1 is a somatic hypermutation gene in diffuse large B-cell lymphoma (DLBCL) and its inhibitors exhibit a great value in application in multiple types of lymphoma. Nevertheless, investigation on its genetic alterations, biological characteristics, clinical significance and response to drugs is still lacking. Methods: We integrated the genome sequencing (discovery cohort, n=162; validation cohort, n=1001) and transcriptome sequencing (discovery cohort, n=140; validation cohort, n=928) to capture more detailed insights into the potentially biological functions of PIM1 genetic alterations, and analyzed their relationship with biological characteristics and clinical value which provide a possibility for risk stratification and therapeutic exploitation for patients with DLBCL. Results: PIM1 mutations were identified in 28.4% of DLBCL patients and significantly correlated with higher IPI scores (P=0.013), disease relapse (P=0.031) and CNS and/or testis involvement (P=0.001), as well as inferior PFS (P=0.022) and OS (P=0.0022). Multivariate analysis revealed that PIM1 mutation status was an independent poor prognostic factor (HR=2.86; 95% CI, 1.40-5.84; P=0.004). The most frequent PIM1 mutation type was missense mutations (84.1%), followed by frameshift deletions and nonsense mutations. During the distribution of base substitutions, C & gt; T base substitution was predominant mutation type (54.4%), followed by C & gt;G transversion (29.3%). During different exons, exon 4 of PIM1 was most often mutated. PIM1 mutations significantly co-occurred with the mutations of SETD1B (P & lt;0.001) and CD79B (P=0.001), and was mutually exclusive to the SPEN mutation (P=0.024). We also explored the relationship between PIM1 mutations and genes distributed on previously reported signaling pathways in DLBCL and uncovered that mutations in MYD88 (P & lt;0.001) and PRDM1 (P & lt;0.001) involved in the NF-κB pathway were significantly enriched in the patients with PIM1 mutations. Unsurprisingly, patients with PIM1 mutations exhibited higher mutation frequencies in CD79B (P=0.001) involved in BCR pathway. PIM1 mutations were involved in immunoglobulin-related immune response, complement activation, B cell mediated immunity, B cell activation, antigen binding, and cytokine activity, which contributed to the signaling pathways of tumor microenvironment (e.g. cytokine-cytokine receptor interaction, chemokine signaling pathway, IL-17 signaling pathway, TNF signaling pathway), JAK-STAT and NF-κB. By MCODE analysis, five significant modules were obtained from the protein-protein interaction (PPI) network. Finally, a PIM1 mutation-related gene signature consisting of some independent prognostic factors was developed. According to the risk score, patients with high-risk score exhibited significantly shorter OS (P=0.0016) and PFS (P & lt;0.001). The areas under the curve (AUCs) for the predictions of 1-, 3-, and 5-year OS were respectively 0.69, 0.70, and 0.72, suggesting that the risk score based on the PIM1 mutation-related gene signature had satisfactory sensitivity and specificity. We further found that compared to patients with low-risk score, patients with high-risk score had higher sensitivity to some drugs of targeting the immune microenvironment, including TGFβ receptor inhibitors SB525334 (P & lt;0.0001) and SB505124 (P & lt;0.0001) and immunomodulator Lenalidomide (P=0.041), as well as NF-κB inhibitors Parthenolide (P & lt;0.0001) and TPCA-1 (P & lt;0.0001) and JAK inhibitors Ruxolitinib (P=0.014) and TG101348 (P=0.0053), accompanying with significantly lower IC50 values. In addition, another common chemotherapeutic drug Gemcitabine was also predicted to be more sensitive for patients with high-risk score (P=0.047). Other targeted drugs such as Aurora kinase inhibitors VX-680 (P & lt;0.0001) and ZM-447439 (P=0.014), Bcl-2 inhibitors Obatoclax Mesylate (P=0.00036) and Navitoclax (P & lt;0.0001), and CDK inhibitors Roscovitine (P=0.0012), AT-7519 (P=0.0033), PHA-793887 (P & lt;0.0001) and THZ2-49 (P=0.0053) also exhibited higher drug sensitivity for patients with high-risk score. Conclusions: PIM1 mutations play a vital role in patient risk stratification and provide novel insights into therapeutic decision making for DLBCL patients with high-risk score. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6458-6459
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4496-4496
    Abstract: Abstract 4496 The Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of receptors on natural killer (NK) cells and play a role in hematopoietic stem cell transplantation (HSCT). KIR2DS4 gene is the most diverse stimulatory KIR loci and the only activating gene in haplotype A. The KIR2DS4 deleted variant differs from the normal KIR2DS4 sequence by a 22 bp deletion in exon 5, which causes a frame shift, yielding a truncated KIR2DS4 protein with loss of the transmembrane and cytoplasmic domains of the full-length KIR2DS4 protein. The deleted variant of KIR2DS4 is not anchored to the cell membrane but encodes a soluble form of the protein that is potentially secreted. To obtain the frequencies of 2DS4 allele in the Chinese-Han population and the impact of KR2DS4 alleles on the clinical outcomes of HSCT, a sequence based testing (SBT) and TOPO TA cloning system identifying and distinguishing alleles of the KIR2DS4 gene has been established. The method was applied to a total of 150 Chinese-Han individuals: 75 patients who received T-depleted HSCT to treat leukemia and their unrelated donors (URD). All patients were undergoing transplantation for CML (n=24), AML (n=19), ALL (n=29) and other malignancies (n=3). The majority (139) of the 150 samples (92.7%) were positive for KIR2DS4. Sequencing of most of the coding region of this gene identified four of the eight known KIR2DS4 alleles, KIR2DS4*00101, *003,*004, and *007.The KIR2DS4 deleted variant was found in 47.5% individuals. The ratio of deleted to non-deleted versions of KIR2DS4 was approximately 1:2 within this Chinese-Han population. Three KIR2DS4 novel alleles were identified. 44% individuals carried two group A haplotypes. The overall survival rates was lower in transplants where the donors carried two 2DS4 full-length allele (2DS4*001) in comparison with those where the donors carried less (0 or 1) 2DS4*001 allele (P=0.031). In transplantations where donors carried KIR2DS4-full length, the aGVHD rate was 42.9% (6 of 14). In contrast, if the donors carried only KIR2DS4-deletion or both 2DS4 deletion and full length alleles, the aGVHD rate was 4.8 % (1 of 21). Upon statistical analysis, 2DS4-full length donors had a significantly increased rate of aGVHD in URD transplantations (RR 9.0 [95% CI 1.2-66.9], P=0.01). These results demonstrated that Chinese Han population is distinct in 2DS4 allele frequencies in comparison to some other populations. The expression of the full length KIR2DS4 may increase the risk of aGVHD and contribute to a worse clinical outcome after URD-HSCT. These data would be beneficial for the selection of suitable donors. Moreover, our findings suggest that KIR genotyping, in addition to HLA typing, should be performed for prospective donors to improve the outcome of transplantation. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6008-6009
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6008-6009
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5231-5231
    Abstract: Background: Immune checkpoints, including PD-1/PD-L1, play an important role in immunosuppression in various malignancies. Elevated levels of soluble programmed death-ligand1 (sPD-L1) are associated with worse prognosis in multiple myeloma and diffuse large B cell lymphoma. Herein, the purpose of this study is to investigate the relationships between plasma sPD-L1 levels and clinical response in peripheral T-cell lymphomas (PTCLs) patients. Methods: Data from three cohorts, including 11 ALCL patients, 28 PTCL-NOS patients and 81 matched normal control tissues, were also obtained from the ONCOMINE database (https://www.oncomine.org) for PD-L1 gene expression array. The comparison dataset analysis of PD-L1 mRNA levels among diverse PTCL subtypes and matched normal control tissues was performed. Other 37 PTCLs patients and 20 healthy volunteers were also enrolled in this study. Peripheral blood from patients was collected prior to systemic therapy. Plasma levels of sPD-L1 and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in tissues was detected by immunohistochemistry (IHC). Clinical response for patients was evaluated. Results: ONCOMINE database analyses showed that the PD-L1 mRNA expression was upregulated in PTCLs, which were significantly higher in PTCLs compared to matched normal control tissues (1 cohort, P=0.029; 2 cohort, P=0.020 and 3 cohort, P=0.021). Among another cohort of 37 PTCLs patients and 20 healthy volunteers, the median sPD-L1 level was respectively 0.729 ng/ml for 20 healthy volunteers and 1.696 ng/ml for PTCLs patients, which was significantly higher than that in healthy volunteers (P=0.000). The median IFN-γ level of PTCLs patients was 4.555 pg/ml, and that the levels of sPD-L1 was positively correlated with the level of IFN-γ (P=0.000, r=0.849) for PTCLs patients. We found that patients with elevated LDH level, advanced stage and elevated β2-MG level had higher sPD-L1 levels than those with normal LDH level, early stage and normal β2-MG level. The sPD-L1 level was also positively correlated with LDH levels (P=0.003), clinical staging (P=0.045) and β2-MG level (P=0.045). Patients with high sPD-L1 level had lower overall response rate than those with low sPD-L1 level (88.9% vs 50.0%, P= 0.022), suggesting that sPD-L1 levels was an underlying plasma biomarker to predict the clinical response in PTCL patients. The median PFS for high and low sPD-L1 level groups was 42.7 months (95% CI, 27.9-57.6) and 53 months (95% CI, 33.7-72.3), respectively. As well, the median OS for high and low sPD-L1 level groups was 48.3 months (95% CI, 35.2-61.2) and 71 months (95% CI, 51.0-90.9), respectively. Survival data suggested that patients with high sPD-L1 levels tended to have shorter PFS and OS than those with low sPD-L1 levels. We also found that plasma sPD-L1 level appeared to have a positive relationship with tissue PD-L1 expression in PTCLs patients, and both of them had a high matched rate each other (90.9%). Conclusions: PTCLs patients had higher sPD-L1 level compared with healthy volunteers. High sPD-L1 level was correlated with worse clinical response, suggesting that sPD-L1 level was an underlying plasma biomarker to predict the prognosis for PTCLs patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9236-9237
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4117-4117
    Abstract: Purpose De novo CD5+ DLBCL is increasingly recognized as a distinct pathologic phenomenon with a specific clinical picture. However, De novo CD5+ DLBCL has not been studied on a large scale in China. In this study, we evaluated the frequency, clinicopathological characteristics of de novo CD5+ DLBCL and prognostic impact of CD5 expression, and patient survival in our center. Methods In this study, we retrospectively investigated 745 DLBCL cases treated at Tianjin medical university cancer institute and hospital between 2000 and 2017, sub-classifying them as germinal center B cell-like (GCB) and non-GCB type by immunohistochemical staining with CD10, BCL6 and MUM-1, and then comparing the prognosis. We used a cutof ≥50% tumor cells for CD5 to be considered positive. Results In the enrolled DLBCL patients, 64 (9.2%) were CD5+ and 631 (90.8%) were CD5-. There was no significant difference in age, sex, extranodal involvement, serum LDH, C-myc overexpression and CNS relapse between these two groups. In the CD5+group, the cell of origin was non-GCB type in 46 cases (71.9%); the ratio of non-GCB type in the CD5+ group was higher than that in the CD5-group (P=0.033). Comparison of the clinical characteristics of CD5+ vs CD5-DLBCL patients showed that CD5+ DLBCL patients were more frequently elderly ( 〉 60 years), and had B-symptoms, high performance status, stage III-IV, an IPI score 〉 2, and BM involvement. 46.9% of the CD5+ patients, compared to 9.4% CD5-DLBCL patients, showed BM involvement at diagnosis. Almost 84.4% of CD5+DLBCL patients had concurrent overexpression (≥50% of the tumor cells) of antiapoptotic Bcl-2, an unfavorable biomarker. This frequency was significantly higher than that in CD5-DLBCL patients (67.2%, P=0.032). Similarly, the P53 positive rate (≥50% of the tumor cells) of CD5+DLBCL (46.9%) is significantly higher than that of CD5-DLBCL (17.6%, P=0.011). Univariate Cox analysis identified the following prognostic factors: CD5 positive, age 〉 60 years, IPI≥3, BM/PB involvement, performance status and stage (III or IV). Intensive chemotherapy was not identified as significantly prognostic by univariate analysis. The CD5+GCB group showed no significant differences compared to CD5-GCB group for both PFS and OS, whereas the CD5+ non-GCB DLBCL and CD5- non-GCB DLBCL showed significantly worse prognosis compared to other groups. (P 〈 0.001, PFS and OS, respectively) (Fig.1A; 1B; 1C; 1D) In CD5+ DLBCL, PFS and OS in patients treated with rituximab were significantly better than those without rituximab. Three-year PFS was 41.1% for the former and 15.4% for the latter (P=0.036, Fig. 1E), and three-year OS were 60.7 and 46.2% (P=0.047, Fig. 1F). Next, we evaluated the therapeutic responses of different chemotherapy regiments. A total of 20 patients received treatment with R-CHOP and 24 patients received DA-EPOCH-R. Patients treated with R-CHOP showed similar PFS and OS compared with intensive treatment group (Fig. 1G,1H). Of the 631 cases of CD5- DLBCL, only 111 cases (17.6%) showed p53 overexpression. In contrast, p53 was overexpressed in 30 (46.9%) of 64 CD5+ DLBCL. As shown in Fig. 1, PFS and OS in patients with overexpression of either p53 or CD5 alone were significantly different from those in patients with p53- /CD5- DLBCL. However, patients with p53 and CD5 co-overexpression had the worst PFS and OS (P 〈 0.001, PFS and OS, respectively) (Fig. 1I, 1J). These data suggest that the negative prognostic impact of p53 and CD5 overexpression was augmented when both variables existed. In fact, all 30 patients with p53 and CD5 co-overexpression died within 40 months of diagnosis. Conclusion In summary, in this study we show that de novo CD5+ DLBCL, which occurs at a frequency (9.2%), was associated with unfavorable clinicopathologic variables and with inferior survival following R-CHOP and DA-EPOCH-R treatment. CD5+ DLBCL has a high frequency of p53 overexpression and CD5 augments the negative effect of p53 overexpression in DLBCL. Fig. 1 PFS (A) and OS (B) of patients with DLBCL according to the presence or absence of CD5. PFS (C) and OS (D) for the four DLBCL groups: CD5+ GCB DLBCL, CD5+ non-GCB DLBCL, CD5- GCB DLBCL and CD5- non-GCB DLBCL. PFS (E) and OS (F) of CD5+ DLBCL in the chemotherapy group and in the R-chemotherapy group. PFS (G) and OS (H) in CD5+ DLBCL treated with RCHOP and DA-EPOCH-R regimens. PFS (I) and OS (J) in patients with de novo DLBCL stratified according to p53 and CD5 immunostaining status. Figure 1 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9264-9265
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2801-2801
    Abstract: Background: The NT5E-adenosine axis constitutes one of the most promising immunosuppressive pathways in immune-oncology. NT5E is also named as CD73, which catalyzes the conversion of AMP to adenosine, and then the extracellular adenosine within tumor microenvironment bindings to A2a adenosine receptor (A2aR) to further dampen T cell-mediated immune responses and promote tumor immune escape. Several anti-CD73 or anti-A2aR antibodies are being evaluated in different types of malignancies in clinical trials. However, the prognostic significance and effect of NT5E-adenosine axis in diffuse large B-cell lymphoma (DLBCL) remain unclear. Methods: Multiplexed immunofluorescence staining, and a professionally and automatically assessed computer-assisted platform were applied to localize and quantify the markers from the DLBCL tumor and microenvironment cells. Gene expression status was analyzed according to the microarray data. The associations among marker expression patterns or their correlations with clinicopathological characteristics were estimated with the χ2 test and two-tailed Spearman analyses. Co-culture system of CD73 positive DLBCL cells and primary CD8 positive T cells was applied to evaluate the effect of NT5E-adenosine axis in DLBCL. Results: We found that CD73 was widely expressed on tumor and immune cells in DLBCL tissue. The CD73 positive rate on tumor cells was 52.31%, and CD73 expression on tumor cells was significantly associated with several clinicopathologic parameters, including IPI score (p = 0.020), LDH levels (p = 0.016) and Ki67 expression (p = 0.014). The A2aR positive rate on tumor-infiltrating lymphocytes (TILs) was 43.08%, and A2aR expression on TILs was significantly correlated with several clinicopathologic parameters, including IPI score (p = 0.036), clinical stage (p = 0.011), B symptom (p = 0.024) and Ki67 expression (p = 0.036). No significant difference in OS was observed in 233 DLBCL patients stratified by their CD73 gene expression status according to the microarray data (p = 0.267). There was also no significant effect of total CD73 protein expression on OS for the patients. However, a significant difference in OS was found when the patients were stratified by the CD73 expression on tumor cells, and the median survival times of the patients with CD73+/Pax-5+ and those with CD73-/Pax-5+ were 57.8 months (95% CI: 46.4-69.3) and 73.5 months (95% CI: 65.9-81.2), respectively. Patients with CD73+/Pax-5+ experienced significantly poorer outcomes than those with CD73-/Pax-5+ (p = 0.027). Furthermore, the median survival times of the patients with A2aR+ TILs and those with A2aR- TILs were respectively 53.3 months (95% CI: 40.6-66.0) and 74.5 months (95% CI: 67.5-81.5), and patients with A2aR+ TILs also had a significantly shorter survival time than those with A2aR- TILs (p = 0.003). Spearman's analysis revealed that CD73+/Pax-5+ tumor cells were positively correlated with A2aR+ TILs (R=0.395, p = 0.001). In a cohort, we found that 24 exhibited CD73-/Pax-5+ as well as A2aR- TILs, and 21 exhibited CD73+/Pax-5+ as well as A2aR+ TILs. Patients with CD73+/Pax-5+ and A2aR+TILs had poorer survival than those with CD73-/Pax-5+ and A2aR- TILs (p = 0.001). Residual patients were further classified into 2 groups, in which 7 exhibited CD73-/Pax-5+ as well as A2aR+ TILs, and 13 displayed CD73+/Pax-5+ as well as A2aR- TILs. There was a significant difference in survival among these four groups, and patients with CD73+/Pax-5+ and A2aR+ TILs had the worst outcome, with a 5-year OS rate of 57.1% (p = 0.017). We also found that CD73 positivity on tumor cells weakened the favorable prognosis for patients, which was correlated with the presence of CD8+ TILs. Patients with CD73+/Pax-5+ and CD8+ TILslow had the worst clinical outcome, with a 5-year OS rate of 50%. In contrast, patients with CD73-/Pax-5+ and CD8+ TILshigh had the best clinical outcome, with a 5-year OS rate of 100% (p = 0.002). Co-culture system displayed that CD73 being expressed on the DLBCL cells suppressed the growth of CD8 positive T cells through A2aR, but not A2aR negative T cells. Conclusions: Our findings uncovered that DLBCL patients with CD73+ on tumor cells as well as A2aR+ on TILs exhibited inferior survival and NT5E-adenosine axis inhibited the growth of CD8 positive T cells, supporting the potential combination strategies using CD73/A2aR immunosuppressive blockades as treatment options for DLBCL patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3805-3806
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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