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  • American Society of Hematology  (7)
  • 1
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    Online Resource
    A Mutation Pentad Defined Outcome of De Novo and Cytogenetically Normal Acute Myeloid Leukaemia in Young Adults
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1400-1400
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1400-1400
    Abstract: Background. Cytogenetically normal acute myeloid leukaemia (CN-AML) occurs in 50% adult AML and is a group of diseases with diverse mutations and distinct clinical outcome. CEBPα, NPM1 and FLT3 mutations that are commonly seen in CN-AML have been incorporated into risk stratification. However, prognostic impacts of other gene mutations and their combinations in this AML subtype have remained unclear. In this study, we examined a cohort of young adults with de novo CN-AML who have received uniform treatment protocol in Hong Kong and identified a mutation pentad that might define their clinical outcome. Methodology. Young adults (18-60 years old) with de novo CN-AML, diagnosed from 1st August 2003 to 7th August 2018 in 8 regional hospitals in Hong Kong, were included. They received standard "7+3" induction (Daunorubicin 60-90 mg/m2 and Cytarabine 100 mg/m2) followed by up to 4 courses of high dose cytarabine consolidation (Cytarabine 3 gram/m2 for 4-6 doses). Decision on allogeneic haematopoietic stem cell transplantation (HSCT) was based on clinical grounds and gene mutations according to ELN recommendations. Next generation sequencing (NGS) was performed in diagnostic bone marrow (BM) in 362 patients for 36 recurrent mutated genes and analyzed by in-house bioinformatics pipelines. Relapse-free survival (RFS) was defined by the time from first complete remission (CR) to relapse or death and overall survival (OS) by the time from diagnosis to death. Patients were censored at last follow up. Survivals were evaluated by Kaplan-Meier analysis and compared by log-rank test. Multivariate analyses of clinical and genetic parameters were analyzed by Cox-regression. P-values of & lt;0.05 were considered statistically significant. Results. A total of 436 patients (Male=189; Female=247) were recruited. Their median age of onset was 49 years old (Range 18-60); median presenting white cell counts (WCC) was 21.85x109/L (range 0.25-411x109/L), median circulating blast % was 46% (range 1-99). 416 patients received induction of whom 90.1% achieved CR or CRi (N=375) after 1 (N=268), 2 (N=78) or ≥ 3 courses of induction (N=29). One hundred and sixty three patients received allogeneic HSCT at CR1 (N=102), CR2 (N=51), ≥ CR3 (N=2) and relapsed state (N=8). Eight mutations with ≥ 10% prevalence occurred in 79.8% patients (Figure 1). Univariate analyses showed that mutations of CEBPα, TET2, IDH2-R172K and RAS were not associated with treatment outcome and survival. Five genetic subgroups based on NPM1, FLT3 and DNMT3A mutations could be identified: NPM1 mutation only; NPM1 mutation and FLT3-ITD; All wildtype; FLT3-ITD only; DNMT3A irrespective of NPM1 and FLT3-ITD status. These subgroups showed distinct RFS and OS (Figure 2). Impacts of IDH1-R132 and IDH2-R140Q mutations were evaluated in these 5 subgroups. Interestingly, adverse impacts of IDH1-R132 on RFS and OS were only significant in the all wildtype subgroup and the adverse impact of IDH2-R140Q was only significant for RFS in the NPM1 mutation only subgroup. Conclusion. A mutation pentad comprising NPM1, FLT3, DNMT3A, IDH1-R132 and IDH2-R140Q seemed to define distinct prognostic subgroups in young adults with de novo CN-AML. A limited gene panel based on this pentad using conventional PCR may provide a practical and cost-effective means to guide post-remission therapy in these patients, especially in places where NGS may not be readily available. Acknowledgements: SK Yee Medical Foundation; Li Shu Fan Medical Foundation, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Blood Cancer Foundation Disclosures Leung: Curegenix: Research Funding; Servier: Research Funding; Merck: Research Funding; Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-130810
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 2
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    Targeting Polo-like Kinase in Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2234-2234
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2234-2234
    Abstract: Acute myeloid leukemia (AML) carrying fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is associated with poor prognosis when treated with conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Despite much interest in tyrosine kinase inhibitor (TKI) targeting FLT3 activation, drug resistance is invariable and acquisition of secondary point mutation in the tyrosine kinase domain (TKD) of FLT3 was frequently reported. We have shown that genes encoding cell cycle regulators including polo-like kinase 1 (PLK1), cell division cycle 25 homolog A (CDC25A), cyclin B2 (CCNB2), and cyclin E1 (CCNE1) were up-regulated in sorafenib-resistant primary AML samples. In particular, PLK1, a member of the polo-like kinase family, has been found to express at several checkpoints critical for cell cycle progression. PLK1 inhibitors have recently been exploited for the treatment of both solid organ and haematological cancers. We hypothesized that aberrant cell cycle progression mediated by increased PLK1 expression might confer survival advantage to drug resistant AML cells and be targetable by PLK1 inhibition. In vitro treatment with PLK1 inhibitors volasertib and BI 2536 significantly inhibited the growth of 8 AML cell lines (KG-1, ML2, MOLM-13, MV4-11, Kasumi-1, NB4, THP-1 and OCI-AML3) with IC50 (all in nM) ranging from 48.7 - 98.4 (volasertib) and 35.1 - 81.6 (BI 2536). The growth inhibitory effects of PLK1 inhibition on two FLT3-ITD+ cell lines, MOLM-13 and MV411, correlated with induction of apoptosis and cell cycle arrest at G2/M phase. Moreover, both PLK1 inhibitors significantly suppressed the growth of a sorafenib resistant MOLM-13R cell line and sorafenib naïve MOLM-13N cell line. Introduction of FLT3-ITD alone or FLT3-ITD and TKD double mutations into Ba/F3 cell lines sensitized them to the growth inhibitory effects of PLK1 inhibitors. Primary FLT3-ITD+ AML cells obtained from patients at TKI resistance were shown to be more sensitive to PLK1 inhibitors than those obtained before treatment. The results suggested that the TKI resistant clones could be effectively targeted by PLK1 inhibition, providing an insight to the design of combination treatment with FLT3 inhibitors in FLT3-ITD+ AML. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2234.2234
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Lineage-Specific Sox7 Expression In Hematopoietic Progenitor Cells Derived From Human Umbilical Cord Blood
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4781-4781
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4781-4781
    Abstract: Abstract 4781 Introduction: The SOX (Sry-related HMG box) genes belong to a family of transcription factors containing a High-Mobility-Group box domain. In an initial screen of SOX genes in human leukemias, SOX7 is uniquely down-regulated in acute myeloid leukemia, myelodysplastic syndrome and chronic myelogenous leukemia but up-regulated in most cases of acute lymphoblastic leukemia. The observation led to the proposition that SOX7 may play a role in lineage differentiation in hematopoiesis. In this study, we examined SOX7 expression in human umbilical cord blood (UCB) with a view to understand its role in hematopoietic lineage specification. Methods: Mononuclear cells (MNC) were isolated from UCB and fractionated into CD34+, CD34-, CD34+CD38+ and CD34+CD38- populations by immunomagnetic selection and fluorescence activated cell sorting (FACS). 0.1–0.4 × 106 CD34+ UCB cells were transplanted intravenously into sub-lethally irradiated NOD/SCID mice with or without prior anti-CD122 antibody injection. Donor engraftment was assessed after 7–8 weeks and engrafting human cells were sorted for CD34+, CD33+, CD19+ expression. CD34+ UCB cells were also plated in colony-forming unit (CFU) assay. SOX7 expression was evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (Q-RT-PCR). Results: The relative SOX7 expression in CD34+ and CD34+CD38- UCB cells was 9.15±2.18 and 4.53±1.09 fold higher than in CD34- (P=0.0001) and CD34+CD38+ (P=0.014) respectively. SOX7 expression in CD34+ cells (arbitrarily set as 1.0) was down-regulated upon differentiation in CFU assay (CFU-GM/G: 0.09±0.06 fold, P=0.007; BFU-E: 0.05±0.03 fold, P=0.003). CD34+ cells engrafted into NOD/SCID mice as enumerated by human CD45+ cells in mouse BM (with anti-CD122: 51±6.3%; without anti-CD122: 28±9%; p=0.017) and gave rise to predominantly B-lymphoid (CD19+) (53.1±8.18%) and to a less extent myeloid (CD33+) (2.9±0.54%) differentiated cells. Prior injection with anti-CD122 antibody had no effect on lineage differentiation and the results were pooled. When SOX7 expression in engrafting myeloid and B-lymphoid differentiated cells (arbitrarily set as 1.0) were compared, it was significantly down-regulated in the myeloid series (0.28±0.08 fold, p = 0.036). Conclusion SOX7 is selectively expressed in human HSC from UCB. It is preferentially down-regulated during myeloid differentiation both in-vivo and in-vitro. The function of SOX7 during lineage specification and its link to myeloid malignancies is currently investigated in our laboratory. Acknowledgments The project was supported by a grant from the strategic Research Theme of cancer stem cells in the HKU. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4781.4781
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Novel Therapeutic Strategy Targeting NHE1 and Its Upstream Activators in Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 913-913
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 913-913
    Abstract: Increase in Tescalcin (TESC) gene expression and intracellular pH (pHi) have been associated with drug resistance in acute myeloid leukemia (AML). Tescalcin was shown to stabilize the membrane sodium/hydrogen exchanger (NHE1) that maintains a high pHi by H+ efflux in exchange for Na+. NHE1 has also been shown to be activated by PDGFR, PKC, calmodulin, p90-RSK and ROCK-RhoA, but their relevance to leukemogenesis and drug resistance in AML was unknown. We hypothesized that targeting NHE1 and its upstream activators might offer a novel and effective therapeutic strategy in AML. AML cell lines and mononuclear cell fraction from peripheral blood (PB) or bone marrow (BM) of AML patients (comprising primarily myeloblasts as shown by microscopic review of cytospin preparations) were treated with inhibitors for 3 days (concentrations: 0.1nM to 10mM) that target potential activators of NHE1. The anti-leukemia effects of these inhibitors were evaluated by PrestoBlue® Cell Viability Reagent as a measure of viable cell number. Their effects on pHi and apoptosis were evaluated by SNARF-1 and Annexin V/7-AAD staining respectively by flow cytometry. AML cell lines ML2, Kasumi-1, MOLM-13 and MV4-11 (IC50 in mM: 12.2, 13.1, 11.6 and 9.2 respectively) were more sensitive than KG1, NB4, THP-1 and OCI-AML3 (IC50 in mM: 30.7, 24.8, 119.2 and 49.4 respectively) to the growth inhibitory effects of NHE1 inhibitor, 5-(N,N-hexamethylene) amiloride (HMA), accompanied with a larger extent of cellular acidification and apoptosis induction in those 4 HMA-sensitive lines. To look for the upstream activators of NHE1 relevant to AML, the cell lines were treated with specific inhibitors targeting potential NHE1 activators. Both HMA-sensitive and insensitive cell lines were susceptible to the intracellular acidification and growth inhibition by PDGFR and p90-RSK inhibitors. Furthermore, FLT3 inhibitors, sorafenib and quizartinib, also reduced pHi of FLT3-ITD+ (Fms-Like Tyrosine Kinase 3 - Internal Tandem Duplication) AML cell lines, MOLM-13 and MV4-11, suggesting that FLT3-ITD might also activate NHE1, resulting in high pHi of FLT3-ITD+ AML. Different primary AML samples were treated with inhibitors to NHE1 (n=50), PDGFR (n=50) and p90-RSK (n=36) (Concentration: 100nM to 10mM) in vitro. Their response to the growth inhibitory effect of HMA, accompanied by effective pHi reduction (n=10), correlated with that of PDGFR and p90-RSK inhibitors (Pearson r=0.74, p & lt;0.001 and r=0.73, p & lt;0.001 respectively), supporting the proposition that these signaling pathways might be the critical and common activators of NHE1. Synergism of anti-leukemia effects could also be demonstrated between HMA and PDGFR inhibitors, calculated by Excess over Bliss Additivism (EOBA). To evaluate the clinical relevance of the study, serum was obtained from medical patients treated with high dose amiloride (20 mg daily), an NHE1 inhibitor, for underlying congestive heart failure. Compared with the serum of healthy volunteers, the amiloride-containing serum significantly reduced the pHi (n=10, p=0.001), induced apoptosis (n=4, p=0.04) and potentiated the inhibitory effects of PDGFR inhibitors (n=4, p=0.04) in primary AML samples. NHE1 might be a potential target in drug-resistant AML and activated by PDGFR, PKC, p90-RSK or both in a patient-specific fashion. Therefore, employing specific inhibitors to target NHE1 and its upstream activators should be explored as novel therapeutic strategy in this group of patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.913.913
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Downregulation of SOX7 by DNA Methylation and Its Tumor Suppressing Role In Acute Myeloid Leukemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4189-4189
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4189-4189
    Abstract: Abstract 4189 Background: The SOX (Sry-related HMG box) gene family is a group of transcription factors containing in common a High-Mobility-Group (HMG) box domain which shares more than 60% homology to that in Sry. SOX proteins are involved in diverse embryonic processes and recently Sox7 was shown to regulate hematopoietic stem and progenitor cells during mouse development. In this study, we examined the expression, regulation and function of SOX7 in human acute myeloid leukemia with a view to understand its link to leukemogenesis. Method: Bone marrow (BM) or blood samples from patients with primary hematological malignancies, as well as cord blood obtained from normal Caesarian Sections were prospectively collected and mononuclear cells (MNC) fractions were obtained. Screening for SOX gene expression was performed by reverse-transcription polymer chain reaction (RT-PCR) and SOX7 expression in different experiments was further evaluated by quantitative real-time RT-PCR. Methylation of CpG islands around the sox7 transcription start site was studied by bisulphate DNA sequencing and methylation-specific PCR. Leukemic cell-lines (KG1, ML2, K562) and primary AML samples were treated with demethylating agent 5-aza-2′-deoxycytidine (5AdC). Cell proliferation of GFP or GFP-SOX7 expressing K562 cells was evaluated by SNARF-1 staining, cell-cycle analysis, 3H-thymidine incorporation and clonogenic assays. Apoptosis were evaluated by Annexin V/7-AAD assay. Canonical wnt activity of K562 cells expressing GFP or GFP-SOX7 was measured by TOP-FLASH dual luciferase assay. Result: The expression of 19 SOX genes was tested by RT-PCR in normal umbilical cord blood (UCB) as well as bone marrow or blood samples from patients with hematological malignancies. SOX7 was uniquely expressed in CD34+ cells from UCB (N=11) and most case of precursor B-cell acute lymphoblastic leukemia (ALL) (17 out of 20 tested) and a ALL derived cell line Nalm-20, but not any case of acute myeloid leukemia (N=22), myelodysplastic syndrome (N=16) or chronic myelogenous leukemia (N=13). In myeloid leukemia cell lines (KG1, ML2, K562) and primary AML samples, but not Nalm-20, the transcription start site of SOX7 contained CpG islands which were heavily methylated. Treating myeloid leukemic cell lines with 5AdC induced SOX7 expression. Enforced expression of SOX7 in K562 cells by lentiviral transduction significantly reduced cell proliferation as shown by cell growth in cultures (SOX7: 6.5-fold increase; GFP: 21.7-fold increase on Day 9, N=2), SNARF-1 staining (SOX7: 57.5%; GFP: 78.0% of total cells divided twice, N=2), 3H-thymidine incorporation assay (SOX7: 3987 cpm; GFP: 5767 cpm, N=2) and colony-forming unit (SOX7: 262±99 per 1000 input cells; GFP: 464±145 per 100 input cells, p=0.055). It also induced cell cycle delay in S/G2/M phases (SOX7: 53.4±0.35%; GFP: 44.4±2.28%, p=0.029). Apoptosis was not affected. SOX7 expression in K562 cells significantly reduced canonical-wnt activity as measured by TOP-FLASH dual luciferase assay (SOX7: 30.0±7.1-fold to FOP-FLASH; GFP: 130±18.8-fold to FOP-FLASH, p=0.0081). Conclusion: SOX7 expression in AML was regulated by promoter hypermethylation and its forced expression in K562 cells reduced cell proliferation and inhibited the canonical wnt signaling pathway. The pathogenetic link between SOX7 gene silencing and AML leukemogenesis is being investigated in our laboratory. Acknowledgments The project was supported by a grant from the strategic Research Theme of cancer stem cells in the HKU. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4189.4189
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    Clinicopathologic Features and Outcome of Chinese Patients with Myelofibrosis
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3174-3174
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3174-3174
    Abstract: Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) comprising primary myelofibrosis (PMF) and myelofibrosis developing from either polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF). Methods Two hundred and sixty-seven consecutive patients with MF (PMF, N=206); post-PV MF, N=26; post-ET MF, N=35) diagnosed between January 1988 and December 2013 at seven regional hospitals in Hong Kong were prospectively followed up. Data on the clinicopathologic features and treatment outcome were collected. Results The median duration of follow-up was 45 (1 – 247) months. The median overall survival (OS) was 65 months (95% confidence interval, CI: 56.3–73.7). The 5-year and 10-year OS were 52.2% and 26.7% respectively. On univariate analysis, factors associated with an inferior OS included age 〉 65 years (hazard ratio ,HR, =1.81; 95% CI:1.33–2.48; P 〈 0.001), the presence of constitutional symptoms (HR=1.52; 95% CI:1.11–2.08; P=0.009), hemoglobin 〈 10 g/dL (HR=1.71; 95% CI:1.25–2.35; P=0.001), circulating blasts ≥ 1% (HR=1.55; 95% CI:1.13–2.16; P=0.007), platelet 〈 100 x 109/L (HR=2.51; 95% CI:1.79–3.53; P 〈 0.001), high risk IPSS (HR=3.09; 95% CI: 1.78–5.37; P 〈 0.001), intermediate-2 risk DIPSS (HR=2.37; 95% CI: 1.38–4.06; P=0.002), high risk DIPSS (HR=2.92; 95% CI:1.51–5.64; P=0.001), transfusion dependence within the first year of diagnosis (HR=2.61; 95% CI:1.92–3.55; P 〈 0.001), transfusion dependence after the first year of diagnosis (HR=2.42; 95% CI:1.61–3.54; P 〈 0.001), palpable hepatomegaly at diagnosis (HR=1.44; 95% CI:1.06–1.96; P=0.02) and secondary AML (HR=1.75; 95% CI:1.24–2.47; P=0.001). On multivariate analysis, post-PV MF (P=0.03), platelet 〈 100 × 109/L (P=0.001), high risk IPSS (P=0.009), transfusion dependence within the first year (P=0.001), transfusion dependence after the first year (P=0.02), and transformation to secondary acute myeloid leukemia (AML) (P=0.007) were independent risks associated with inferior OS. On univariate analysis, factors associated with increased risk of secondary AML include age ≤ 55 years (odds ratio [OR] = 2.61; 95% CI:1.33–5.12; P=0.005), circulating blasts ≥ 1% (OR=2.24; 95% CI:1.18–4.26; P=0.01), transfusion dependence within the first year (OR=5.57; 95%:2.16–14.88; P 〈 0.001), transfusion dependence after the first year (OR=5.57; 95% CI:2.16–14.88; P 〈 0.001), hepatomegaly (OR=4.05; 95% CI:2.03–8.10), splenomegaly (OR=3.71; 95% CI:1.09–9.26; P=0.04), abnormal karyotypes (OR=3.3; 95% CI:1.14–9.56; P=0.02), and the presence of unfavourable karyotypes (OR=4.9; 95% CI: 1.22–19.96). On multivariate analysis, transfusion dependence within the first year of diagnosis (P=0.04), transfusion dependence after the first year of diagnosis (P=0.003) and hepatomegaly (P=0.006) were independent risks associated with secondary AML. The 5-year and 10-year risks of leukemic transformation were 17.1% and 29.7 respectively. Factors associated with inferior leukemia-free survival (LFS) on univariate analysis included post-ET MF (HR=2.15; 95% CI: 1.03–4.50; P=0.04), presence of constitutional symptoms (HR=1.85; 95% CI:1.04–3.31; P=0.04), circulating blasts ≥ 1% (HR=2.89; 95% CI:1.62–5.16; P 〈 0.001), platelet count 〈 100 x 109/L (HR=2.56; 95% CI: 1.35–4.84; P=0.004), transfusion dependence within the first year of diagnosis (HR=3.05; 95% CI: 1.70–5.50; P 〈 0.001), transfusion dependence after the first year of diagnosis (HR=6.49; 95% CI: 2.33–18.10; P 〈 0.001), hepatomegaly (HR=3.21; 95% CI:1.69–6.08; P 〈 0.001) and unfavorable karyotype (HR=3.01; 95% CI:1.08–8.35; P=0.03). On multivariate analysis, male gender (P=0.05), presence of constitutional symptoms (P=0.04) and unfavorable karyotypes (P=0.01) were independent risks associated with inferior LFS. Eighteen patients underwent allogeneic haematopoietic stem cell transplantation (HSCT) (matched sibling, N=14; matched-unrelated, N=4), with 15 patients achieving complete remission. Seven patients relapsed with subsequent progression to secondary AML. Acute and chronic graft-versus-host disease occurred in seven (39.9%) and six (33.3%) patients respectively. Transplant-related mortality occurred in three patients. The 5-year and 10-year OS following HSCT was 51.5%. Conclusion Findings of this study complement current prognostic models in guiding treatment decisions at diagnosis and during the course of MF. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3174.3174
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 7
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    The Use of Clofarabine and Cytarabine Combination (CLARA) As Salvage Therapy for Relapsed and/or Refractory Acute Myeloid Leukemia (AML)
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1518-1518
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1518-1518
    Abstract: Abstract 1518 Patients with relapsed and/or refractory acute myeloid leukemia (AML) have a very dismal outcome and treatments are largely unsatisfactory. Salvage therapy is often limited by drug resistance and organ toxicities in patients who have already been exposed to multiple lines of chemotherapy. Clofarabine is a second generation nucleoside analogue with multiple mechanisms of action including inhibition of ribonucleotide reductase, suppression of DNA polymerase, direct DNA incorporation and induction of apoptosis. In this study, we evaluated the clinical outcome of patients with relapsed and/or refractory AML who received combination treatment of clofarabine and cytarbine (acronym CLARA) at Queen Mary Hospital in Hong Kong. The treatment with CLARA comprised clofarabine 40 mg/m2 and cytarabine 2 gm/m2 given intravenously for five days. For patients who relapsed after allogeneic hematopoietic stem cell transplantation (HSCT), CLARA was followed by the infusion of either BM or mobilized peripheral blood stem cells (PBSC) from the original donor and immunosuppression (cyclosporine A at 1.5 mg/kg twice daily) was given from day 8 after HSC infusion. All patients received standard anti-microbial prophylaxes and G-CSF support during neutropenia. Remission status was confirmed by bone marrow examination. Since 2009, a total of 55 patients have been recruited of whom 19 received CLARA at relapse after allogeneic HSCT. The median age of the patients was 45 years (range 20–64) and cytogenetic categorizations were favorable (N=7); intermediate (N=29) and unfavorable (N=14) in 50 evaluable patients. There were a median of two regimens (range 1–4) and five courses (range 1–12) of chemotherapy before CLARA. All patients developed grade 4 hematologic toxicity and 20% (no. of patients: grade 1–2=8; grade 3= 3) and 60% (grade 1–2=23; grade 3–4=10) developed dermatologic and liver toxicities. Six patients including three who relapsed after HSCT (out of 19 patients=16%) and three non-transplant patients (out of 36 patients=8%) died of treatment related mortality after CLARA (overall 11%). Twenty-seven patients (49%) achieved complete remission (CR) or CR with insufficient hematologic recovery (CRi). Patients who received CLARA for relapse post-HSCT had a higher CR/CRi (12 out 19 patients=63%) than the non-transplant patients (15 out of 36 patients=42%). The respective median disease-free (DFS) and overall-survivals (OS) of the post-HSCT relapse and non-transplant patients were 9.6 and 5.0 months (DFS) and 11.5 and 8.0 months (OS). CLARA is an effective salvage regimen for both post-HSCT relapse and non-transplant patients with tolerable side-effects. The optimal consolidation and maintenance strategies after CLARA would have to be further defined. Acknowledgments: Clofarabine was provided by a compassionate program from Sanofi-aventis Hong Kong Ltd. Disclosures: Off Label Use: Clofarabine.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1518.1518
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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