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  • 1
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    A Novel View of Bone Marrow As a “stem Cell sensor” of Tissue/Organ Damage -Evidence That in Vivo Exposure to the Neurotoxin Kainic Acid (KA) Induces Proliferation and Neural Specification of Developmentally Early Stem Cells Directly in Bone Marrow Before They Are Mobilized Into Peripheral Blood
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1192-1192
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1192-1192
    Abstract: Abstract 1192 Background. It is well known that various stem cells become mobilized into peripheral blood (PB) in response to tissue/organ injuries (e.g., heart infarct, stroke, or bleeding); however, the data on the immediate response of stem cells in BM during organ injuries are somewhat limited. We and others have demonstrated the presence of developmentally early stem cells in BM that we have named very small embryonic-like stem cells (VSELs). These Oct-4+SSEA-1+Sca-1+Lin–CD45– cells are kept quiescent in BM in the G0 phase of the cell cycle by erasure of the somatic imprint in the differentially methylated regions (DMRs) of some crucial paternally imprinted genes, (Igf2-H19, RasGRF1, and p57Kip2) that regulate proliferation of embryonic stem cells (Leukemia 2009;23:2042). These cells are mobilized into peripheral blood, for example, during heart infarct (J Am Coll Cardiol 2009;6:1–9.), stroke (Stroke 2009;40:1237–44.), or skin burns (Stem Cell Rev. 2012;8:184–94.). Hypothesis. We hypothesized that this population of BM-residing, small, quiescent, pluripotent cells should be able to respond to organ injury induced by a known neurotoxin, kainic acid (KA), in a brain damage model. We hypothesized that these quiescent cells would began to proliferate, expand, and become specified into the neural lineage. Experimental strategies. C57Bl6 mice were injected with increasing doses of KA and at various time intervals mice were sacrificed to harvest BM, PB samples, and brains for analysis. Brain damage was confirmed by histological analysis. The number of Sca-1+Lin–CD45– VSELs and Sca-1+Lin–CD45+ HSPCs was evaluated in BM and PB by FACS. The cell cycle status of VSELs and HSPCs was evaluated by FACS in cells isolated from mice that received bromodeoxyuridine (BrdU) after KA injection. By employing RQ-PCR, we also measured the expression of genes that regulate stem cell pluripotency (Oct-4, Nanog, Sox2, and Rex1) and regulate neuronal development (Nestin, βIII-tubulin, Olig1, Olig2, and GFAP). The expression of these genes was subsequently confirmed in sorted cells by immunohistochemical staining. The numbers of clonogenic CFU-GM and BFU-E progenitors residing in BM and circulating in PB were tested in methylcellulose cultures. Results. We found that 12 hrs after administration of KA (25 mg/kg bw) quiescent VSELs residing in BM enter the cell cycle: ∼2 ± 1% for control vs. 37 ± 6% for KA-treated cells. Interestingly, at the same time we did not observe significant changes in the proliferation rate of HSPCs (15±5% for control vs. 17±4% for KA-treated cells). The elevated number of VSELs in the cell cycle remained detectable for a few days and returned to control values (∼2%) after 1 week after KA administration. Furthermore, an increase in the number of cycling VSELs correlated with an increase in expression of pluripotent markers, according to RQ-PCR analysis. In parallel, 48 hrs after KA administration we observed the release from BM into PB of Sca-1+Lin–CD45–VSELs highly enriched for mRNAs characteristic of neural differentiation. Interestingly, while we observed a significant increase in VSEL number in BM and PB after KA-induced brain damage, no significant changes were observed for both BM-residing and circulating HSPCs. Conclusions. For the first time, we provide evidence that the compartment of developmentally early stem cells residing in BM responds robustly to brain damage induced by a neurotoxin. This effect seems to be specific for VSELs, as no significant changes were observed for HSPCs. The kinetics of changes in BM revealed that BM VSELs enter the cell cycle and, after they become specified into the neural lineage, egress from BM and enter the PB. Thus, our data provide novel evidence that developmentally early stem cells in BM “sense” the damage to brain tissue and respond to this type of organ injury. In parallel, we are studying the specificity of the response of BM-residing VSELs and HSPCs to other types of organ damage, such as heart infarct and acute limb ischemia. Disclosures: Ratajczak: Neostem Inc: Member of SAB Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1192.1192
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    Cladribine Alone and in Combination with Cyclophosphamide or Cyclophosphamide and Mitoxantrone in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): Long-Term Follow-up of the the Polish Adult Leukemia Group (PALG CLL2) Study,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3915-3915
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3915-3915
    Abstract: Abstract 3915 Purpose. In 2006 we have published an early report of the prospective, randomized, multicenter study (PALG CLL2) comparing the efficacy and toxicity of cladribine alone and in combination with cyclophosphamide (CC) or cyclophosphamide plus mitoxantrone (CMC) in 508 previously untreated patients with progressive and advanced CLL (Blood. 2006;108:473–9). In this early analysis we found that CMC induced higher CR rate than CC (36% vs. 21%, p=0.004), but no differences in overall response (OR), progression-free survival (PFS) and overall survival (OS) among treatment groups were observed. The aim of the present study was to verify whether long-term follow-up might change originally published data on PFS or/and OS as well as to compare the rate of late complications including secondary neoplasms and Richter's syndrome. Methods. In PALG CLL2 study PFS was defined as the time from the end of first–line therapy to disease progression or death from any cause. OS was measured from the time of randomization to death or last contact. OS and PFS were calculated according to the method of Kaplan and Meier and compared between groups by the log-rank test. Only patients with pathologically-proven tumours diagnosed after chemotherapy initiation were considered as having secondary neoplasms or Richter's syndrome. Frequencies of secondary tumours were compared by chi2 test. Results. The median time of follow-up as of Januar y 2011 was 45.6 months (95% CI: 39.9–51.4). The results of comparison of survival times and late complications in different study arms are shown in Table 1 and Figure 1. Conclusions. Long term results for 508 r andomized patients confirm that cladribine alone, CC and CMC regimens produce comparable PFS and OS in previously untreated progressive CLL. The risk of secondary tumours does not differ in the investigated treatment groups. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3915.3915
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
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    Correlation Between Serum Ofatumumab Concentrations, Baseline Patient Characteristics and Clinical Outcomes in Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ofatumumab.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3433-3433
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3433-3433
    Abstract: Abstract 3433 Poster Board III-321 Introduction Monoclonal antibody (mAb) therapies represent an important clinical advance for patients (pts) with CLL, yet little is known about the pharmacokinetics (PK) and pharmacodynamics of mAb therapy in these pts. Ofatumumab is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity in vitro. Ofatumumab is being evaluated in a pivotal trial for pts with fludarabine-refractory CLL also refractory to alemtuzumab (FA-ref; n=59) or less suitable for alemtuzumab due to bulky ( 〉 5 cm) lymphadenopathy (BF-ref; n=79). Overall response rate (ORR; primary endpoint) was 58% in FA-ref and 47% in BF-ref pts at an interim analysis; median progression-free survival (PFS) was 5.7 and 5.9 months, respectively. We evaluated relationships between baseline factors and ofatumumab PK and between PK parameters and treatment outcomes from the pivotal trial. Patients and Methods Pts received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee over 24 weeks of therapy. Blood samples for PK analysis were collected at Dose 1, Dose 8 (last weekly dose), and Dose 12 (last monthly dose). A population PK model was employed that included data from a previous study (Coiffier et al, Blood 2008;111:1094). For Dose 1, Cmax was determined; for Doses 8 and 12, Cmax, Cmin, AUC, clearance (CL), volume of distribution (Vss) and t½ were determined. The relationships between baseline pt characteristics and disease factors and PK parameters were evaluated by multivariate regression analysis. Associations between PK and ORR or PFS were explored using univariate and multivariate logistic regression or Cox regression analyses. Results 90% of the 154 pts received 8 weekly infusions of ofatumumab and 55% received all 12 infusions. PK parameters were similar between FA-ref and BF-ref pts. In multivariate analysis, higher Cmax at Dose 1 was significantly associated with lower % of bone marrow infiltration (p 〈 0.001), lower Rai stage (p=0.002), lower lymphocyte count (p=0.006), smaller BSA (p 〈 0.001) and lower total bilirubin (p=0.013). The majority of responders and non-responders were still receiving treatment at Dose 8; thus, this dose represents an informative time point for analysis. Baseline factors that influenced PK parameters at Dose 8 are shown in the table. Based on univariate analyses, higher Cmax and Cmin at Dose 8 were associated with increased likelihood of response (Table); in addition, significantly higher Cmax, Cmin and AUC were observed in responders versus non-responders (p 〈 0.05 for each; data not shown). Higher Cmax, AUC and Cmin and lower CL at both Doses 8 and 12 were significantly correlated with longer PFS (p 〈 0.05 for each). Based on exploratory multivariate analyses, PK parameters were not independent predictors of ORR or PFS. Conclusions These data demonstrate that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. The pivotal study is ongoing, and further analyses of associations between disease-related factors, PK and treatment response will be performed at study completion. Such analyses will help us to better understand the response kinetics of biological therapy and to optimize the dose. Disclosures Österborg: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Biilmann Ronn:Genmab: Employment. Jewell:GlaxoSmithKline: Employment, Equity Ownership. Kipps:Physicians' Educational Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Mayer:GlaxoSmithKline: Consultancy. Stilgenbauer:GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Hellmann:Novartis, BMS: Consultancy, Honoraria. Robak:GlaxoSmithKline, Roche: Advisory Board, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau. Hillmen:GlaxoSmithKline: Consultancy, Honoraria for Advisory Boards. Trneny:GlaxoSmithKline: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Kozak:GlaxoSmithKline, Amgen: Consultancy. Chan:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Losic:Genmab: Employment, Stock Ownership. Davis:GlaxoSmithKline: Employment, Stock ownership. Wilms:Genmab: Employment, Equity Ownership. Russell:Genmab: Employment, Equity Ownership. Wierda:Genmab, GlaxoSmithKline: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3433.3433
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
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    Polymorphisms of Mir-34b/c, Mir-146a and Mir-196a-2 and Predisposition to Chronic Lymphocytic Leukemia and Monoclonal B-Cell Lymphocytosis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4585-4585
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4585-4585
    Abstract: Abstract 4585 Since microRNAs control expression of protein-coding oncogenes and tumor suppressor genes, functional microRNAs single nucleotide polymorphisms (SNPs) may modulate the risk of tumorigenesis including susceptibility to chronic lymphocytic leukemia (CLL). In this case-control study we investigated whether pri-miR-34b/c rs4938723 (T-to-C), miR-196a2 rs11614913 (C-to-T) and miR-146a rs2910164 (G-to-C) SNPs influence predisposition to CLL or monoclonal B-cell lymphocytosis (MBL). miR-34 family members are direct transcriptional targets of tumor suppressor p53, and miR-34b/miR-34c have been recently proposed as regulators of TCL1 (T-cell leukaemia/lymphoma 1) expression in CLL. A rs4938723 SNP in the promoter region of pri-miR-34b/c might affect transcription factor GATA binding and pri-miR-34b/c expression. Alterations in miR-196a2 and miR-196a2 may represent common cancer predisposition pathways as miR-196a2 rs11614913 and miR-146a rs2910164 have been recently associated with altered risk of different solid tumors including breast, lung, prostate and liver cancers. Additionally, we verified the impact of these microRNA SNPs on prognostic factors and clinical course of CLL. Genotyping was performed using PCR-based assays in a total of 561 Caucasians including 195 patients with CLL, 166 patients with MBL and 200 healthy control individuals. The assessed minor allele frequencies (MAFs) of the investigated SNPs were as follows: for rs4938723 SNP C allele frequency was 0.37 in CLL, 0.36 in MBL and 0.30 in controls, for rs11614913 SNP T allele frequency reached 0.43 in CLL, 0.42 in MBL and 0.39 in controls, and for rs2910164 SNP C allele frequency was 0.29 in CLL, 0.30 in MBL and 0.26 in controls. Logistic regression analysis did not detect significant associations of CLL or MBL with studied genotypes or alleles (p 〉 0.05). Moreover, none of the tested genetic variants was found to influence CLL patients’ progression-free survival (PFS) or overall survival (OS) with median follow-up time from diagnosis of 3.0 (0–13.9) years. In conclusion, our data suggest that investigated SNPs in pri-miR-34b/c, miR-146a and miR-196a-2 genes are not likely to play a major role in the susceptibility to CLL and MBL or in clinical outcome of CLL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4585.4585
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An International Pivotal Trial
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 328-328
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 328-328
    Abstract: Background: The prognosis for patients with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky ( & gt;5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) is poor. The overall response rate (ORR) to salvage therapy for such patients is approximately 20% with a median survival of 9 mo (Tam et al, Leuk Lym, 2007). New effective treatments are needed for these patients. Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even in malignant B cells with low CD20 expression levels. We report on a planned interim analysis of an international, multicenter, pivotal study of ofatumumab in patients with DR and BFR CLL. Methods: Patients with DR or BFR CLL received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2000 mg). Patients were premedicated with paracetamol, antihistamine and glucocorticoid. The primary end point was ORR (1996 NCI-WG response criteria) assessed by an Independent end points Review Committee (IRC) over a 24 wk period. Overall survival (OS) and safety were also evaluated. Results: This interim analysis included all 138 treated patients (DR, n=59; BFR, n=79: Table); 54% received all 12 infusions and 90% received □8 infusions. The ORR (99% CI) based upon IRC assessment was 51% (34, 68%) for the DR group and 44% (30, 59%) for the BFR group; 1 patient had CR. Additionally, a considerable number of patients had stable disease (Table). Median time to next CLL therapy was 9 mo for the DR group and 8 mo for the BFR group (Table); clinical progression was typically due to worsening lymphadenopathy. The median OS was about 14 mo for the DR group and 15 mo for the BFR group (Table); based upon a landmark analysis at wk 12, response was significantly correlated with longer survival for both groups. Updated efficacy results will be presented at the meeting. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the DR group and 38% in the BFR group, which were grade 3 (no grade 4) in 7% and 3%, respectively (only 1 grade 3 event was considered a serious adverse event). These events generally subsided with subsequent infusions. The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR; 4% in BFR group). Early death (within 8 wks from start of treatment) occurred in 2 patients (3%) in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group (PD, n=1; sepsis, n=1; myocardial infarction, n=1). No patient tested developed antibodies to ofatumumab. Conclusions: These results demonstrate the effectiveness of ofatumumab in patients with double-refractory CLL or bulky fludarabine-refractory disease. Ofatumumab was well tolerated with no unexpected toxicities. This monoclonal antibody potentially represents an active treatment option with clinical benefit for patients with very poor prognosis who have exhausted standard treatment options. The encouraging single-agent activity in patients with refractory CLL warrants further investigation of ofatumumab in earlier disease settings, in combination with other agents, as maintenance, and in other B-cell malignancies. Table DR (n=59) BFR (n=79) CI=confidence interval; NR=not reached Characteristic Median(range) Age, yrs 64 (41–86) 62 (43–84) No. of prior treatments 5 (1–14) 4 (1–16) % of patients Rai Stage III/IV 54 70 Binet Stage C 51 65 ECOG performance status 0 44 30 1–2 53 67 Lymph node or CT lesion & gt;5cm 93 100 Prior rituximab-containing regimen 59 54 ORR (%) (99% CI) 51 (34, 68) 44 (30, 59) Complete response 0 1 Partial response 51 43 Stable disease 39 43 Progressive disease 3 10 Median (95% CI) Time to next CLL therapy, mo 9.0 (7.3, 10.7) 7.9 (7.1, 9.3) Overall survival, mo 13.7 (9.4, NR) 15.4 (10.2, 20.2)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.328.328
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
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    A Randomized, Multicenter Study (PALG CLL4/ ML 21283) Of Maintenance Treatment With Rituximab Versus Observation After Induction Treatment With Rituximab, Cladribine, and Cyclophosphamide (RCC) Regimen In Patients With Progressive Chronic Lymphocytic Leukemia: Interim Analysis
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1640-1640
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1640-1640
    Abstract: RFC (rituximab, fludarabine, cyclophosphamide) regimen showed extraordinary clinical activity in untreated CLL patients, with high rates of overall response (ORR), complete remission (CR), progression-free survival (PFS) and prolonged overall survival (OS). Recent reports suggest also high activity of rituximab combination with cladribine, and cyclophosphamide (RCC regimen) in previously treated CLL patients. The use of rituximab maintenance after induction treatment may prolong response duration in patients with CLL. The aim of current multicenter, open-label, randomized, two arm phase III b PALG CLL4/ ML 21283 study was to assess the effect of maintenance treatment with rituximab vs. no further treatment, after induction therapy with RCC regimen in previously untreated patients with progressive CLL. The initial induction treatment included rituximab 500mg/m2 on day 1 (375 mg/m2 the first cycle), cladribine (2-CdA) 0,12 mg/kg/day i.v.- days 2-4, cyclophosphamide 250mg/m2 on days 2 to 4, for six cycles. After response assessment was performed 8 weeks after last induction cycle, patients who obtained a CR or a PR were randomized 1:1 to either rituximab maintenance or observation. Rituximab maintenance was started 12 weeks after the last induction cycle and included 8 doses of rituximab at 375 mg/m2 i.v., given in 12 weeks intervals. Six centers entered a total of 128 patients to the study. Baseline demographics, disease characteristics, and prognostic factors were balanced between the two arms. Median patient age was 58 (range 31-74) years, and 37% of patients had advanced CLL stage (3 or 4 according to Rai classification). Following induction phase 22.6% of patients obtained CR, 51.6% of patients had PR while the remainder did not respond to RCC therapy rates. Median PFS in the total study population reached 36 months. In terms of safety and tolerability during induction with RCC regimen grade 3-4 neutropenia developed in 64.8% of patients and major infections were reported in 7.8%. Grade 3-4 thrombocytopenia in 10.94% and anemia 10.16% of patients were noted. During second maintenance/observation phase of the study in grade 3-4 adverse events were observed in 16 (48.5%) patients receiving maintenance with rituximab and in 9 (27.3%) patients in observation arm, p= 0.076. Grade 3-4 neutropenia and febrile neutropenia was significantly more common in maintenance arm (36%) than in observation arm (9%) (p=0.017). However, there was no significant difference regarding the rate of major grade 3-4 infections that were reported in 3% of patients in the maintenance arm as compared to 12% of patients in observation arm (p=0.36). Grade 3-4 thrombocytopenia or anemia were observed in 6% vs 0% (p=0.49) and 0% vs 3% (p=1.0) of patients, in maintenance and observation arm, respectively. In conclusion, early analysis of this study shows moderate toxicity of maintenance with rituximab in patients who achieved response after rituximab-based immunochemotherapy. Although severe neutropenia is more common in patients receiving rituximab immunotherapy as maintenance treatment in CLL this seems not to be followed by increased rate of major infections. Disclosures: Robak: ROCHE: Consultancy, Honoraria, Research Funding. Off Label Use: Cladribine is not registersed by FDA and EMA for the treatment of CLL, but is approved for the treatment of this disease in Poland. Rituximab is not approved for maintenance treatment in CLL but is approved in follicular lymphoma. Fidecka:Roche: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1640.1640
    RVK:
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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