Leukemia Research - Articles in Press

Retraction notice to “Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines” [Leuk. Res. 30 (2006) 313–321] - Corrected Proof

2012-02-22

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). Reason: Fig. 3a of this paper had previously been published in Int J Cancer, 118 (2006), 765–772. doi:10.1002/ijc.21389 and should have been appropriately cited as such.

Post-transcriptional modulation of C/EBPα prompts monocytic differentiation and apoptosis in acute myelomonocytic leukaemia cells - Corrected Proof

2012-02-20

Abstract: CCAAT/enhancer binding protein alpha (C/EBPα) induction induces monocytic differentiation even in acute myeloid leukaemia (AML). In this study, the induction/activation of C/EBPα in myelomonocytic AML was investigated using a combination of all-trans retinoic acid (ATRA) and RAD001 (Everolimus), a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Combining these agents increased PU.1, C/EBPɛ and C/EBPα expression, increased the p42/p30 C/EBPα ratio, and decreased C/EBPα phosphorylation at serine 21, and was accompanied by growth inhibition, induction of CD11b expression and apoptosis in AML cell lines. Thus, agents that induce sufficient levels of C/EBPα expression might be useful in treating AML.

Vitamin D protects acute lymphoblastic leukemia cells from dexamethasone - Corrected Proof

2012-02-20

Abstract: Vitamin D deficiency has been linked with increased cancer risk, and vitamin D has been shown to be cytotoxic to some cancer cells in vitro. In the present study we evaluated whether vitamin D would have antiproliferative or cytotoxic effects on human pre-B acute lymphoblastic leukemia cells. Contrary to our hypotheses, calcitriol, the active form of vitamin D, had no effect on leukemia cell proliferation. Calcitriol actually had a modest effect to impair dexamethasone cytotoxicity and induction of apoptosis. Further studies are needed to evaluate the effects of vitamin D on leukemia cells in vivo.

Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling - Corrected Proof

Jing Yang, Takayuki Ikezoe, Chie Nishioka, Goichi Honda, Akihito Yokoyama — 2012-02-20

Abstract: We found recombinant human soluble thrombomodulin (rTM) induced growth arrest and differentiation of THP-1 cells by activating JNK/c-Jun signaling. Further activation of JNK by 1,25-(OH)2D3 significantly enhanced rTM-mediated growth arrest and differentiation of THP-1 cells. Importantly, forced expression of domains 1, 2 and 3 of TM (TMD123) induced growth arrest and differentiation of leukemia cells freshly isolated from individuals with AMLs of M4/M5-French-American-British classification subtypes, but not those with less advanced AML. Further studies indicated that the epidermal growth factor-like domain of TM was critical for the anti-leukemia effects of TM and these effects were independent of protein C activation.

Acute myeloid leukemia targeting by myxoma virus in vivo depends on cell binding but not permissiveness to infection in vitro - Corrected Proof

2012-02-20

Abstract: Some oncolytic viruses, such as myxoma virus (MYXV), can selectively target malignant hematopoietic cells, while sparing normal hematopoietic cells. This capacity for discrimination creates an opportunity to use oncolytic viruses as ex vivo purging agents of autologous hematopoietic cell grafts in patients with hematologic malignancies. However, the mechanisms by which oncolytic viruses select malignant hematopoietic cells are poorly understood. In this study, we investigated how MYXV specifically targets human AML cells. MYXV prevented chloroma formation and bone marrow engraftment of two human AML cell lines, KG-1 and THP-1. The reduction in human leukemia engraftment after ex vivo MYXV treatment was dose-dependent and required a minimum MOI of 3. Both AML cell lines demonstrated MYXV binding to leukemia cell membranes following co-incubation: however, evidence of productive MYXV infection was observed only in THP-1 cells. This observation, that KG-1 can be targeted in vivo even in the absence of in vitro permissive viral infection, contrasts with the current understanding of oncolytic virotherapy, which assumes that virus infection and productive replication is a requirement. Preventing MYXV binding to AML cells with heparin abrogated the purging capacity of MYXV, indicating that binding of infectious virus particles is a necessary step for effective viral oncolysis. Our results challenge the current dogma of oncolytic virotherapy and show that in vitro permissiveness to an oncolytic virus is not necessarily an accurate predictor of oncolytic potency in vivo.

Development of a multiplex PCR assay for the detection of genomic copy number changes in myelodysplastic syndromes - Corrected Proof

2012-02-17

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic malignancies characterized by ineffective hematopoiesis . The International Prognostic Scoring System (IPSS) introduces cytogenetic abnormalities together with cytopenia and percentage of marrow blasts as independent prognostic factors for both survival and progression to AML . However, using conventional cytogenetics (CC), chromosomal abnormalities are detected in about 50% of primary MDS and 80% of secondary MDS. Moreover, CC results are often not available for all myelodysplastic patients. FISH (fluorescent in situ hybridization) approaches have been proposed, mostly dedicated to the search of a 5q deletion, a monosomy 7 or a 7q deletion, but there is no consensus regarding the probes to be used for such an approach, nor regarding the prognostic significance of defects when detected by FISH as compared to conventional karyotype. In order to overcome these problems, we designed a dedicated multiplex PCR assay (quantitative multiplex PCR of short fluorescent fragments or QMPSF) to measure the copy number of genes located in several regions involved in MDS on chromosome 7 and 8 and on the 5q, 12p, 17p and 20q regions.

Establishment and characterization of a new human acute myelomonocytic leukemia cell line JIH-3 - Corrected Proof

2012-02-16

Abstract: Here, a new acute myelomonocytic leukemia (AMML) cell line, JIH-3, is reported, and its biological characteristics are described. JIH-3 cells were maintained without any cytokines for 27 months. The JIH-3 cell line showed typical myelomonocytic morphological features. Additionally, it mainly expressed myeloid and monocytic markers (CD13, CD14, CD11b, CD15 and CD33), although it also expressed other antigens such as the markers of T and B lymphocytic lineage as well as stem cell, progenitor cell, and natural killer cell-related antigens (CD4, CD5, CD7, CD10, CD22, CD34, CD38, HLADR, CD16/CD56 and CD56); the expression of these markers, suggested that this cell line was in the early stage of myelomonocytic differentiation. Cytogenetic analysis initially showed a karyotype of 46, XY, del(7) (p1?3p2?2). During the passage period, the cells with this karyotype gradually decreased and were replaced by cells with a 45,XY,dic(4;7)(p11;p11),del(15)(q2?2) karyotype. Chromosome painting showed a deletion in the short arm of chromosome 7 for del(7)(p1?3p2?2) and der(4;7)(p11;p11). The latter had larger deleted segment than the former. Fluorescence in situ hybridization (FISH) revealed the dicentric nature of der(4;7), and Multiplex FISH (M-FISH) confirmed that der(4;7) was an unbalanced translocation. A deletion involving the 7p region on dic(4;7)(p11;p11) harbors many genes, including CDC2L5, C7ORF11, C7ORF10 and INHBA. Haploinsufficiency of the genes on 4p, 7p and 15q caused by deletions of 4p, 7p and 15q2?2 that resulted from dic(4;7)(p11;p11) and del(15)(q2?2) may play important roles in leukemogenesis and in the establishment of the JIH-3 cell line. JIH-3 cells did not express multidrug resistance (MDR)-related genes and apoptosis-related genes such as MDR1, multidrug resistance-related protein, lung resistance protein, BCL-2, Bax, GS-π or Fax, only P21 expression was detected, which probably leads the MDR indirectly through inhibition of the activities of cyclin-dependent kinase (CDK). JIH-3 cells had tumorigenic capacity in nude mice. In conclusion, JIH-3 is a new acute myelomonocytic leukemia cell line. It is from a well-characterized background and provides a new useful tool for the study of leukemia patients with a 7p deletion.

Transfusions at home in patients with myelodysplastic syndromes - Corrected Proof

2012-02-15

Abstract: We report descriptive data of a home care (HC) program, throughout a 5-years period (2006–2010), focusing on the reliability and the safety of transfusions at home in 211 patients affected by myelodysplastic syndromes (MDS). Our results outline the potentially relevant role of a specifically dedicated HC service in the global management of frail MDS patients for which transfusions at home may represent a valuable option to maintain a good quality of life and avoid the possible discomfort due to hospital admissions and outpatient visits.

Corrected Proof

Paul G. Rothberg — 2012-02-15

This multiauthored extensive review of molecular hematopathology is the first volume in a series on Molecular and Translational Medicine edited by William Coleman and Gregory Tsongalis. The book is an ambitious attempt to provide an overview of the molecular pathology and molecular diagnosis of leukemia and lymphoma. The first two chapters introduce the methods used in molecular and cytogenetic investigations of neoplasia. The third chapter is a disease by disease guide to the cytogenetic and molecular aspects of the World Health Organization classification of hematopoietic tumors . Chapters four through eight expound on these issues with each chapter focusing on a particular group of diseases, all using the WHO monograph as a starting point. Most of these five chapters go beyond the practical diagnostic aspects and include background information on the molecular pathology of the neoplasm. The final two chapters survey the areas of targeted therapy and microRNAs in hematologic malignancies.

RBC-transfusion guidelines update - Corrected Proof

2012-02-15

Results of our RAND Delphi consensus-panel report: What are RBC-transfusion-dependence and -independence? (Leuk Res 2011;35:8–11) have been well-received and widely adopted in clinical trials of anemia-response. Several colleagues since asked us how these guidelines, developed for Western adults treated in Western countries, can be applied to other settings including persons smaller than the average Western adult and in countries where the volume of 1U RBC is different than in Western countries. For example, the average 50 year-old US male weighs 90kg (gadzooks!) whereas the average 50 year-old Chinese male weighs 60kg. A similar weight-related issue obviously arises in children. Moreover, the average volume of 1U PRBC in Western countries is 240ml whereas the average volume of 1U PRBC in Japan and China is 125ml.

High expression of hematopoietic cell specific Lyn substrate-1 (HS1) predicts poor survival of B-cell chronic lymphocytic leukemia patients - Corrected Proof

2012-02-14

Abstract: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults in western countries. HS1 protein regulates leukemic cell migration and homing, and can indirectly promote disease progression and influence patient survival.The aim of this study was to evaluate HS1 expression in CLL patients in connection with other known prognostic factors and patients’ survival.Methods: 90 untreated CLL patients were included into the study. The control group consisted of 28 healthy matched people. HS1 detection was performed by western-blotting. Mutational status of IgVH, as well as CD38 and ZAP70 expression was also analyzed.Results: HS1 expression was significantly higher in CLL patients comparing to controls. Positive correlation was shown between HS1 and: age (p=0.0454), Rai stage (p=0.0412), leukocytosis (p=0.0129) and beta-2-microglobulin (p=0.0342). Patients with lymphocyte doubling time shorter or equal to 6 months had higher expression of HS1. Patients with higher HS1 expression had shorter survival than those with lower HS1 expression (p=0.0329).Conclusions: We showed, that high HS1 expression predicts poor survival of chronic lymphocytic leukemia patients.

The Smac mimetic RMT5265.2HCL induces apoptosis in EBV and HTLV-I associated lymphoma cells by inhibiting XIAP and promoting the mitochondrial release of cytochrome C and Smac - Corrected Proof

2012-02-13

Abstract: The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

The clinical impact of DNA methylation frequencies of JAK2 negative regulators in patients with essential Thrombocythemia - Corrected Proof

2012-02-13

Abstract: Suppressors of cytokine signalling (SOCS) and protein tyrosine phosphatase (PTPN) proteins are negative regulators of Janus Kinase 2 (JAK2). They are thought to be involved in the molecular pathogenesis of essential thrombocythaemia (ET) particularly in patients with unmutated JAK2. In this study we compared DNA methylation of SOCS1, SOCS3 and PTPN6 in peripheral blood cells between 39 ET patients (24 JAK2 V617F mutated) and 22 healthy controls by methylation specific PCR (MSP) and analysed the clinical outcome of patients with respect to DNA methylation. In SOCS1, ET patients showed significantly less methylation (P<0.05) than healthy controls, and in SOCS3 and PTPN6 such a tendency was shown. However, there were no significant differences in the methylation frequencies between JAK2 wildtype and mutated ET patients. In addition, no correlation was detected between methylation of SOCS and PTPN and any clinical outcome parameters. Taken together, regarding the genomic regions investigated our data indicate a minor role of methylation of JAK2 negative regulators for the clinical course of ET.

Are low-intensity induction strategies better for older patients with acute myeloid leukemia? - Corrected Proof

2012-02-10

Abstract: This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups.

Sequential array comparative genomic hybridization analysis identifies copy number changes during blastic transformation of chronic myeloid leukemia - Corrected Proof

2012-02-10

Abstract: The present study was performed to provide direct evidence on copy number changes during progression from chronic phase (CP) to blastic phase (BP) in chronic myeloid leukemia (CML) through a longitudinal follow-up study. Matched CP and BP samples in three patients were analyzed using high-resolution array comparative genomic hybridization (aCGH) chips. During blastic transformation, loss of large genomic segments including 6q14.1-q22.31, chromosome 7 and 9p13.2-p21.3 were noted. Furthermore, small-sized copy number changes involving cancer-associated genes were observed. In addition, we identified a novel fusion gene consisted of PAX5 and MLLT3 (AF9). It is likely that blastic transformation of CML is a multi-step process associated accumulation of several genomic events which may largely overlap with those found in acute leukemias.

AZA-ESA combo: A new standard for higher risk MDS? - Corrected Proof

Moshe Mittelman — 2012-02-10

The cloning of the erythropoietin (EPO) gene, more than two decades ago , followed by the production of recombinant human erythropoietin (rHuEPO), allowed millions of patients with anemia to benefit from a novel effective treatment. The patient populations that were candidates for the hormone therapy were patients with anemia of end-stage renal disease , and with cancer-related anemia .

Neutropenia at baseline could indicate poor prognosis in low/intermediate risk myelodysplastic syndrome patients - Corrected Proof

2012-02-10

We read with interest the article by Cordoba et al. , which reported that the degree of neutropenia at baseline has a prognostic impact in low risk myelodysplastic syndromes (MDS). They referred that a neutrophil count less than 0.5×109/l at diagnosis was present in 48/1109 (4%) of patients at diagnosis and this mostly consisted of refractory cytopenia with multilineage dysplasia (RCMD, 40%) and refractory anemia with excess of blast type 1 (RAEB-1, 29%). A significant overall survival difference was reported between patients with neutrophil count less than 0.5×109/l (28 months) and those with values >0.5×109/l (66 months). Moreover, the severe degree of neutropenia has also a role in leukemia progression (30% at 2-year vs. 6% in patients with neutrophil count >0.5×109/l). Contrasting results were reported until now on the neutropenia value in low risk MDS: the observation by Cordoba et al. is in line with that reported by Pomeroy et al. , but is in contrast with that reported by Kao et al. . We tested the degree of neutropenia in our series of 670 MDS patients consecutively collected in a single institution, between January 1992 and December 2006. Statistical analysis was carried out using SPSS software; survival was defined as the interval from the time of diagnosis to last contact or death for any cause. IPSS application was possible in 460 out of the 670 patients who entered this analysis due to availability of all data. Median age of the whole population was 70 years (range 21–88), with a prevalence of male sex (ratio m/f 1.62). According to IPSS stratification, we identified 242 patients as low/intermediate-1 risk: of these 35 patients (14.4%) had a neutrophil count at baseline less than 0.5×109/l, whereas 207 patients (85.5%) had a neutrophil count >0.5×109/l. Median overall survival in patients with severe neutropenia at baseline was 21 months compared to 42 months for patients with neutrophil count >0.5×109/l (p=0.002). Nine out of 35 patients (25.7%) with severe neutropenia transformed to acute leukemia compared to 17 out of 207 patients (8%) with neutrophil count >0.5×109/l at baseline (p=0.001). Sixty three percentage of patients with severe neutropenia were classified as RCMD: we recorded 11 deaths, of which 9 were caused by progression of disease and only two by severe infections. We tested the degree of neutropenia also in intermediate-2/high risk patient category and we found that 25 out of 218 patients (11.4%) presented with neutrophil count less than 0.5×109/l. In this group, median overall survival was 18 months and rate of leukemic evolution was 36% compared to 19.8 months and 36%, respectively (p=ns) for the 192/218 patients (88%) without severe neutropenia. Thus, our results strongly support the findings reported by Cordoba and colleagues also because they derive from the evaluation of a consecutive series of patients diagnosed and followed in a single institution. Recently published score for the identification of poor prognostic features in low risk MDS did not consider the degree of neutropenia . Indeed, we agree with Cordoba et al., that severe neutropenia may have an important relevance in low risk MDS patients and should be taken into account to better identify patients at risk of leukemic progression and of short overall survival. Severe neutropenia, even if isolated, should be considered as a negative feature and patients with this characteristics should be candidate to investigational treatments.

A novel three-way variant t(4;17;5)(p16;q23;q31) in a case of secondary plasma cell leukemia - Corrected Proof

Yoonjung Kim, Juwon Kim, Seo-Jin Park, Jong Rak Choi, Kyung-A Lee, Yu Ri Kim — 2012-02-10

Plasma cell leukemia (PCL) is a rare and aggressive variant of plasma cell myeloma that is classically divided into primary and secondary subtypes. The incidence of sPCL (40% of all PCL cases) which arises in the context of preexisting plasma cell myeloma is comparable to that of pPCL . Cytogenetic abnormalities of plasma cell myeloma with abnormal karyotypes observed in 70% and 100% of patients with pPCL and sPCL, respectively . Here, we report a new case of sPCL with a new three-way variant, t(4;17;5)(p16;q23;q31). A 63-year-old man was admitted to the neurosurgery department in May 2008 for a 3 day history of persistent, localized lower back pain associated with numbness and a tingling sensation in both legs. On admission, a peripheral blood count revealed a hemoglobin of 7.6g/dL, white blood cell (WBC) count of 4.56×103/μL, and platelet count of 123×103/μL. Rouleaux formation and leukoerythroblastosis (nucleated RBC: 13/100 WBCs) were also noted in the peripheral blood smear. Additional protein electrophoresis and immunofixation studies of the serum and urine were also positive for the M-protein (λ-light chains paraprotein). No evidence of hypercalcemia or renal insufficiency was observed. A subsequent bone marrow biopsy showed a diffuse infiltration of plasma cells (54% of ANC). The conventional chromosomal study revealed normal karyotype. Based on the diagnostic criteria for myeloma established by the International Myeloma Working Group, the patient was diagnosed with plasma cell myeloma, and subsequently underwent 12 cycles of melphalan/prednisolone chemotherapy between June 2008 and May 2009. However, the patient was readmitted to the hospital after this interval complaining of severe dizziness and general weakness after 5 month. A complete blood count obtained at this time showed a general pancytopenia (a hemoglobin of 5.4g/dL, a WBC count of 2.84×103/μL, a platelet count of 34×103/μL) and λ-light chains paraprotein was above the reportable range (>812.0mg/L). The follow-up bone marrow biopsy, performed 22 months after the initial diagnosis revealed marrow nearly packed with plasma cells (90.8% of ANCs). The peripheral smear demonstrated moderate rouleaux formation, and numerous circulating plasma cells accounting for about 29% of all white blood cells. A standard culture technique for bone marrow cells was applied and chromosomes were analyzed using Giemsa banding of a synchronized high-resolution culture of bone marrow cells. FISH analysis was performed according to the manufacturer's instructions with commercially available FGFR3/IGH probes (Abbott Molecular/Vysis, Des Plains, IL). Images were captured and analyzed using the Isis image analysis system (MetaSystems, Germany). The mFISH analyses was performed using the human 24XCyte (MetaSystems, Altlussheim, Germany), with hybridization, post-hybridization washes and signal detection carried out according to the manufacturer's instructions. All image analyses were performed using the Isis/mFISH imaging system (MetaSystems, Germany). A conventional chromosome study from bone marrow biopsy in March 2011 showed a 47–48, XY, t(11;14)(q13;q32), t(4;17;5)(p16;q23;q31), −16, +2–4mar[cp7]/46–47, idem, −Y[13] in all 20 cells analyzed (). As in most of the previously reported cases, t(11;14)(q13;q32) was also identified in this patient, and was believed to represent the most common translocation in plasma cell myeloma (about 15% of patients). Furthermore, cases with the t(11;14)(q13;q32) are considered to have a better prognosis than those lacking this translocation . Interestingly, the t(4;17;5)(p16;q23;q31) translocation was also identified in our patient, which has, to our knowledge, never been reported elsewhere. Using mFISH analysis, this complex translocation involved three-derivative chromosomes: t(4;17;5)(p16;q23;q31) (). The t(4;14)(p16.3;q32) translocation had been reported in plasma cell myeloma patients. As the breakpoint at 4p16.3 was mapped as about 50kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene, this chromosomal translocation may be involved in the deregulation of FGFR3 . Although mFISH analysis complemented the G-banding by identifying derivative chromosomes, we could not clarify the der(5)t(4;5)(p16;q31) by mFISH. This is attributed to the resolution limit of mFISH which was reported to range from 500 to 1500kb . That is, the subtle proportion of chromosome 4 translocated to the chromosome 5 were below the resolving power of mFISH, and thus not observable. To confirm the involvement of FGFR3 gene at 4p16 in this new three-way variant, we performed interphase FISH using FGFR3/IGH probe (Dual fusion signal, Abbott Molecular/Vysis, IL). FISH signals from FGFR3/IGH probe confirmed nuc ish (FGFR3×3), (IGH)×2 [11/110] (data not shown). Currently, the patient has been showing poor response to the previous chemotherapy regimens and is now being treated with bortezomib (3.5mg) and dexamethasone (40mg). The chromosomal study done recently showed persistence of t(11;14)(q13;q32), t(4;17;5)(p16;q23;q31) and −16. Of these translocations, t(11;14)(q13;q32) and −16 have never been reported elsewhere as poor prognostic factors in plasma cell neoplasm, whereas 5q31 have been reported as a poor prognostic factor (http://atlasgeneticsoncology.org/Anomalies/del5qID1092.html, accessed 10 September 2011). Accordingly, t(4;17;5)(p16;q23;q31) could have contributed to the poor prognosis in our patient with sPCL. Nonetheless, further studies are necessary to better define the role of this novel three-way translocation in the molecular pathogenesis and prognostic implications in plasma cell myeloma or PCL.

A tribute to Professor Terence “Terry” John Hamblin - Corrected Proof

John M. Bennett, Daniel Catovsky, David Bowen — 2012-02-06

With great sorrow we report the death of Professor Terry Hamblin on Sunday, 8 January 2012 from complications of a metastatic bowel carcinoma.

Abl-interactor 2 (ABI2): A novel MLL translocation partner in acute myeloid leukemia - Corrected Proof

2012-02-03

Mixed-Lineage Leukemia (MLL)-rearrangements are frequently involved in both adult and childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In childhood they are especially frequent in infant leukemia . The MLL-gene exhibits an 8-kb breakpoint cluster region in which virtually all rearrangements occur. So far more than 60 different fusion partners have been identified, some of them being observed in single cases only. In contrast, in 75% of the MLL-rearranged pediatric AML cases, 4 partners are involved: AF9/MLLT3 on chromosome 9p21, AF10/MLLT10 on 10p12, ELL on 19p13.1, and AF6/MLLT4 on 6q27 . In infant AML, AF9 and AF10 are among the most frequent MLL fusion partners . New translocation partners are still being reported to add to the diversity of MLL-rearranged leukemia . Here we describe a new translocation partner, Abl-interactor 2 (ABI2), which was identified in a 5-months old female with AML.

The clinical, quality of life, and economic consequences of chronic anemia and transfusion support in patients with myelodysplastic syndromes - Corrected Proof

Uwe Platzbecker, Lorenz C. Hofbauer, Gerhard Ehninger, Kristina Hölig — 2012-02-02

Abstract: Most patients with myelodysplastic syndromes (MDS) require transfusions due to chronic anemia. Apart from the acute risks associated with transfusions, chronic anemia and red blood cell (RBC) transfusion dependence impact negatively on survival and quality of life (QoL), and are associated with iron overload, potentially leading to organ damage. QoL studies demonstrate that regular transfusions do not correct the impact of chronic anemia. Furthermore, chronic transfusion support requires substantial resources. Therefore, major goals are to prevent or effectively treat anemia. Indeed, innovative drugs have been shown to be effective in achieving transfusion independence by altering the natural course of MDS.

Cytarabine in relapsed acute myeloid leukemia - Corrected Proof

Brandon M. Hardesty, Larry D. Cripe — 2012-01-30

The majority of adults with acute myeloid leukemia (AML) in remission will experience a relapse of their disease. Dose-escalated cytarabine has been the mainstay in the treatment of adults with relapsed AML since the demonstration that the administration of cytarabine at doses of 3000mg/m2 twice daily for up to 6 days, commonly referred to as high dose Ara-C (HiDAC) was feasible and produced complete remissions in 51% of subjects (CR) . However, clinical resistance, i.e., the failure to achieve or maintain a second or subsequent CR, is common and toxicity is appreciable especially in older adults. Since that time, a variety of doses and schedules of cytarabine in combination with other drugs have been studied but no preferred regimen has emerged. In a randomized trial, Kern et al. were able to demonstrate that giving cytarabine at a dose of 3000mg/m2 was superior to cytarabine given at 1000mg/m2 in combination with sequential mitoxantrone produced a marginally superior CR rate of 52% vs. 45% (P=0.045) in adults less than 60 years of age at the expense of a higher early death rate 32% vs. 17% . Karanes et al. demonstrated the addition of mitoxantrone to HiDAC produced an incremental improvement in the CR rate (44% vs. 32%) which was statistically significant only when presenting white blood cell count and neutrophil percentage were included in multivariate analysis .

The study of resistant mechanisms and reversal in an imatinib resistant Ph+ acute lymphoblastic leukemia cell line - Corrected Proof

Hongyun Xing, Xi Yang, Ting Liu, Juan Lin, Xiaoyi Chen, Yuping Gong — 2012-01-30

Abstract: In this study, we established an imatinib resistant Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15/RI in vitro and studied the mechanism of imatinib resistance. Our results showed that the BCR-ABL1 fusion gene and the mdr1 gene were 6.1 times and 1.7 times, respectively, as high as that of parental SUP-B15 cell line. We found no mutation in the Abl kinase domain of SUP-B15/RI. Furthermore, the detection of cell signaling pathway of PI3K/AKT/mTOR, RAS/RAF, NF-κB, JNK and STAT showed the up-regulation of phosphorylation of AKT, mTOR, P70S6K, and RAF, ERK, and MEK, down-regulation of PTEN and 4EBP-1, and no change in other cell signaling pathways in SUP-B15/RI. However, dasatinib and nilotinib showed partial resistance. Interestingly, bortezomib had no resistance. Imatinib combination with rapamycin had synergistic effect on overcoming the resistance. Altogether, over-expression of BCR-ABL1 and mdr1 gene were involved in the resistance mechanisms, and up-regulation of the cell signaling pathways of PI3K/AKT/mTOR, RAS/RAF in SUP-B15/RI cell line may be correlated with them. The SUP-B15/RI cell line was also resistant to the second generation tyrosine kinase, dasatinib, and nilotinib, not bortezomib. The combination of imatinib with rapamycin can partially overcome the resistance and blockade of the ubiquitin–proteasome can be also a promising pathway to overcome imatinib resistance.

Obesity but not overweight increases the incidence and mortality of leukemia in adults: A meta-analysis of prospective cohort studies - Corrected Proof

2012-01-30

Abstract: The main objectives of the present meta-analysis of prospective cohort studies were to evaluate the role of obesity on the incidence and mortality of leukemia in adults. Obesity was associated with a relative risk (RR) of 1.26 (95% CI 1.17–1.37; p<0.001) for leukemia incidence and 1.29 (95% CI 1.11–1.49; p=0.001) for mortality. Obesity was also associated with an increased incidence of acute myeloid leukemia (RR 1.53, 95% CI 1.26–1.85; p<0.001), chronic lymphocytic leukemia (RR 1.17, 95% CI 1.08–1.27; p<0.001), chronic myeloid leukemia (RR 1.16, 95% CI 1.04–1.30; p=0.007) and acute lymphoblastic leukemia (RR 1.62, 95% CI 1.12–2.32; p=0.009). The risk of incidence and mortality of leukemia in adults was consistently higher in obese men.

Differential diagnosis of paediatric bone pain: Acute lymphoblastic leukemia - Corrected Proof

2012-01-30

Acute lymphoblastic leukemia (ALL) is the commonest malignancy in childhood. While most patients with ALL present with pallor or bleeding signs, some present with localized or diffuse bone pains and these patients often have relatively normal full blood counts (FBC) and a lower incidence of organomegaly . It is presumed that the bone pain is caused by leukemic cells infiltrating the intramedullary bone marrow space . This form of presentation can lead to delays in the diagnosis of ALL.

The Hans algorithm is not prognostic in patients with diffuse large B-cell lymphoma treated with R-CHOP - Corrected Proof

2012-01-27

Abstract: Our objective was to evaluate the non-germinal center (GC) profile as a marker for response and survival in DLBCL and to compare the characteristics of patients with GC and non-GC DLBCL treated with rituximab-containing regimens. In this patient-level meta-analysis, retrospective data from 712 newly diagnosed DLBCL patients treated with chemoimmunotherapy from 7 centers were analyzed. GC and non-GC profiles were defined according to the Hans algorithm. Although the non-GC profile showed a trend towards worse overall survival (HR 1.24, 95% CI 0.92–1.66; p=0.15) and progression-free survival (HR 1.29, 95% CI 0.96–1.73; p=0.09), it did not retain its value in the multivariate survival analysis. Additionally, the non-GC profile was independently associated with worse complete response rates (OR 0.55, 95% CI 0.37–0.83; p<0.01) in the multivariate logistic regression analysis. Interestingly, Asian patients had higher proportion of GC DLBCL (p=0.01).

Rare tetraploidy with large 5q deletion in acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) - Corrected Proof

2012-01-27

In 2008, the World Health Organization (WHO) revised its classification of hematopoietic neoplasms and new “acute myeloid leukemia with myelodysplasia-related changes (AML-MRC)” was defined as “AML arising from a previous MDS or MDS/MPN, AML with an MDS-related cytogenetic abnormality, and/or AML-MLD changes, mainly with a complex karyotype” . Myelodysplastic syndrome (MDS)-related chromosomal changes involve mainly aberrations of chromosomes 5, 7, and a complex karyotype. The change from ploidy to tetraploidy (4n) is a rare chromosomal abnormality in AML, and only a few cases have been described in the literature . Despite its rarity in AML, tetraploidization can initiate chromosomal instability (CIN) and promote cell transformation . Presented here is a case of a 52-year-old male with an initial diagnosis of AML-MRC with tetraploid clones detected in his bone marrow. FISH analysis revealed a large deleted derivative chromosome 5 within a complex karyotype. To the best of our knowledge, such findings in AML-MRC have not yet been reported in the literature.

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes - Corrected Proof

Wei Wei, Fan Zhou, Yizi Zhang, Lieping Guo, Haotian Shi, Jian Hou — 2012-01-27

Abstract: Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.

Isolation of siRNA target by biotinylated siRNA reveals that human CCDC12 promotes early erythroid differentiation - Corrected Proof

2012-01-24

Abstract: Erythroid differentiation is a tightly regulated multi-step process that has not been fully elucidated. We previously reported that a siRNA screened from random siRNA library, siRNA clone-67, induced erythroid differentiation in human erythroleukemia K-562cell line. Here we identified that human CCDC12 (coiled-coil domain containing 12) is a target of siRNA clone-67, by target capture with biotinylated siRNA. Over-expression of CCDC12 in K-562cell up-regulated the expression of CD235, ɛ-globin and γ-globin, accelerated cell growth, and slightly down-regulated the expression of GATA-2. Knockdown of CCDC12 slowed down the cell growth. These data indicate that CCDC12 is a new participant that promotes early erythroid differentiation.

A comprehensive cytogenetic classification of 1466 Chinese patients with de novo acute lymphoblastic leukemia - Corrected Proof

2012-01-20

Abstract: Cytogenetics and molecular cytogenetics of 1466 Chinese patients with de novo acute lymphoblastic leukemia (ALL) were studied. Cytogenetic results were available in 1175 patients. Cross-correlations of 23 subclasses of cytogenetic abnormalities were described. Childhood cases had higher incidences of normal karyotype, t(1;19), +8, 12q−, +21, +22 and high hyperdiploidy with 51–65 chromosomes, and lower incidences of t(9;22) and −5/5q− than adult ones (all p<0.05). Relationships of cytogenetic subclasses with immunophenotyping subgroups of ALL were studied. Our study presents the cytogenetic characteristics of a large series of Chinese ALL patients.

The minimal residual disease concept coming of age – Now for the direct comparison of methodologies - Corrected Proof

Hans Beier Ommen, Anne Stidsholt Roug, Peter Hokland — 2012-01-20

The concept of minimal residual disease (MRD) and its translational and clinical implications is rapidly gaining recognition as one of the novel paradigms in the follow-up of cancer patients . Thus, the remission state achieved in a sizeable part of our leukemia and lymphoma patients, is in fact only a temporary respite from a relentless course of a disease, which – on standard cytoreduction – will return with vengeance. Intuitively, therefore, the better knowledge about the disease state in these patients at the time of classical remission, the better we can assess these patients and, by inference, intervene in those in whom treatment response is insufficient to sustain the remission state .

A rare cryptic and complex rearrangement leading to MLL-MLLT10 gene fusion masked by del(10)(p12) in a child with acute monoblastic leukemia (AML-M5) - Corrected Proof

2012-01-19

Acute myeloid leukemia (AML) in young children, defined as those younger than 24 months of age, occurs in 3–5% of all pediatric leukemias. Rearrangements involving the MLL gene, located on the 11q23 region, are between the most common cytogenetic aberrations found in M4 or M5 AML subtypes. MLL rearrangement is highly heterogeneous with more than 60 different fusion partners described to date. An association between the type of MLL rearrangement and prognosis has been reported .

Proteomic analysis identifies differentially expressed proteins in AML1/ETO acute myeloid leukemia cells treated with DNMT inhibitors azacitidine and decitabine - Corrected Proof

2012-01-10

Abstract: Azacitidine and decitabine are DNA methyltransferase inhibitors used to treat myelodysplastic syndromes and acute myeloid leukemias. To further characterize different mechanisms between these two agents, cellular extracts from leukemic cells untreated or treated with either drug were analyzed using 2D electrophoresis. Numerous differentially expressed proteins were identified with MALDI-TOF/TOF-MS. Cyclophilin A, Catalase, Nucleophosmin and PCNA were decreased exclusively by azacitidine, TCP1 and hnRNP A2/B1 by both drugs; alpha-Enolase and Peroxiredoxin-1 by decitabine. Interestingly, the expression of the proinflammatory protein Cyclophilin A, also suggested as marker of cell necrosis, was stimulated by decitabine. Finally, a comprehensive pathway analysis of data highlighted a relationship between the identified proteins and potential effectors.

PDS5A, a novel translocation partner of MLL in acute myeloid leukemia - Corrected Proof

2012-01-10

Mixed lineage leukemia (MLL)-rearranged leukemias represent about 10% of all acute lymphoblastic and myeloid leukemia cases. So far, 71 different MLL fusion partner genes have been characterized at the molecular level .

RT-PCR diagnosis of recurrent rearrangements in pediatric acute lymphoblastic leukemia in Argentina - Corrected Proof

2012-01-09

Abstract: The present study was performed to establish the prevalence of the recurrent fusion transcripts in Argentinean pediatric patients with acute lymphoblastic leukemia (ALL). A total of 380 newly diagnosed children (including 50 infants and 44 T-ALL) were screened by RT-PCR; the incidence of recurrent rearrangements was: ETV6-RUNX1, 12.9%; TCF3-PBX1, 5.0%; BCR-ABL1, 1.6%; and MLL rearrangements, 10.5%. STIL-TAL1 was detected in 22.7% of T-ALL cases. In B-ALL cases, the pEFS was significantly influenced by the presence of genetic alterations. RT-PCR studies improved patients’ stratification and also the overall outcome of children treated in a pediatric hospital from a developing country.

Fludarabine and a histone deacetylase inhibitor – Strange bedfellows - Corrected Proof

H. Miles Prince — 2012-01-09

Alas, the storm is come again! My best way is to creep under his gaberdine; there is no other shelter hereabout: misery acquaints a man with strange bedfellows. I will here shroud till the dregs of the storm be past. The Tempest, William Shakespeare

A novel recurrent translocation t(7;17)(q22;p13) and a late-appearing t(2;3)(p13;q26.2) with dysmegakaryopoiesis in acute myeloid leukemia - Corrected Proof

2012-01-09

Deletions of the long arm of chromosome 7 are commonly found in a variety of myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) . These abnormalities are detected as a part of more complex karyotypes, and are generally associated with very poor prognosis. Molecular cytogenetic analyses revealed that 7q22 could be one of the critical regions in the pathogenesis of MDS/AML with del(7q), and the presence of tumor suppressor genes at 7q22 has been suggested . On the other hand, less information is available for balanced translocations involving 7q22, and only limited cases have been analyzed in MDS/AML .

N-terminally truncated WT1 variant (sWT1) is expressed at very low levels in acute myeloid leukemia and advanced phases of chronic myeloid leukemia - Corrected Proof

2012-01-09

The Wilms’ tumour gene 1 (WT1) encodes a multifunctional protein important for regulation of cell growth and survival. It plays a role in many physiological developmental processes and also in cancers including leukemia. WT1 is overexpressed in most of leukemias and therefore it is sometimes even called a “panleukemic marker”. Total WT1 expression level is used in monitoring minimal residual disease in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients . Besides this, WT1 is being currently tested for vaccination. Although the oncogenic behaviour of WT1 in leukemia has been proved, the mechanism has not yet been clearly explained. Detailed understanding of the role of WT1 in leukemia will improve the utilization of WT1 in diagnostics, prognostics and also in therapy. WT1 has an enormous number of variants due to alternative splicing, alternative initiation of translation etc. In 2004, a novel N-terminally truncated WT1 variant (sWT1) has been described by Dalloso et al. . The sWT1 arises from alternative first exon E1a; it lacks the N-terminal transcriptional repression domain of full length WT1 (fWT1) and it activates expression of genes, which are repressed by fWT1. Hossain et al. reported overexpression of sWT1 in leukemias and assumed that sWT1 might be the oncogenic WT1 variant based on in vitro experiments. Recently, we have read with high interest a study of Ishikawa et al. which supplemented Hossain's and also our own data on sWT1 expression in myeloid leukemias.

Elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia - Corrected Proof

2012-01-09

Cytarabine (ara-C, [1-β-d-arabinofuranosylcytosine]), enters cells primarily as a false substrate through specialized nucleoside transporter proteins, predominantly hENT1 (the human equilibrative nucleoside transporter). Reduced hENT1 expression and activity is associated with adverse therapeutic outcomes and reduced cytotoxicity for patients treated with cytarabine . Patients with AML and low hENT1 expression have reduced disease-free survival . Elacytarabine (CP-4055) (), the lipophilic 5′-elaidic acid ester of cytarabine, enters cells independently of hENT1. Preclinical studies of elacytarabine demonstrate activity in cytarabine-resistant cell lines and in animal models with tumor xenografts . Elacytarabine may thus be active in patients with leukemia for whom cytarabine is ineffective . We conducted a study to determine DLT, establish the pharmacokinetics (PK) and toxicity profiles and to obtain a preliminary assessment of activity of elacytarabine CIV combined with idarubicin in adult patients with refractory AML.

Hypomethylating therapy and autoimmunity in MDS: An enigmatic relationship - Corrected Proof

2012-01-09

MDS pathogenesis is multifactorial and involves a dynamic interplay of genetic, epigenetic and immune mechanisms. The contribution of the latter is supported by the relatively high percentage of MDS patients that exhibit autoimmune manifestations and the favorable clinical responses induced by immunomodulatory agents in selected patients. Recently, the hypomethylating agent 5-azacitidine has been reported to abrogate autoimmune manifestations in four responding MDS patients and to improve autoimmune interstitial lung disease (ILD) in one of them . The authors postulated that this resulted from either a direct immunomodulatory effect of azacitidine, or indirectly by acting on a multipotent hematopoietic stem cell, which in turn leads to the gradual repair of the abnormal immunologic response. In contrast to these reports, three cases of 5-azacitidine-induced ILD have been recorded so far . We now describe, for the first time, a case of a MDS patient who experienced 5-azacitidine-induced enhancement of Th1 and Th17 responses accompanied by a concomitant reactivation of sarcoidosis.

Incidence of the BRAF V600E mutation in chronic lymphocytic leukaemia and prolymphocytic leukaemia - Corrected Proof

2012-01-09

Abstract: The spectrum of underlying molecular abnormalities of clinically and biologically heterogeneous chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) has yet to be identified. While whole genome sequencing has identified several genes implicated in the pathogenesis and progression of CLL, the molecular lesions in a substantial proportion of patients remain to be elucidated. The incidence of the BRAF V600E mutation, widely implicated in solid tumours and other B-cell malignancies, was sought in a cohort of patients with CLL and related disorders. One CLL patient and one patient with B-prolymphocytic leukaemia (PLL) were found to harbour this mutation. Although present at a low frequency, the finding of BRAF V600E has biological and clinical implications for CLL and PLL.

Cardamonin exerts potent activity against multiple myeloma through blockade of NF-κB pathway in vitro - Corrected Proof

2012-01-06

Abstract: NF-κB plays a major role in the pathology of multiple myeloma. Here, we intended to investigate the regulating effect of cardamonin on NF-κB in myeloma cells. We found for the first time that cardamonin suppressed viability and induced apoptosis of myeloma cells. Cardamonin activated caspase-3 and PARP and suppressed the expression of various anti-apoptotic proteins. We discovered that NF-κB was repressed by cardamonin through suppression of IKK expression and IκBα phosphorylation. Furthermore, the expression of NF-κB-regulated gene products ICAM-1, COX-2 and VEGF was down-regulated by cardamonin. These results suggest that cardamonin blocks NF-κB pathway in human multiple myeloma cells.

Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML - Corrected Proof

2012-01-04

Abstract: In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR-ABL and JAK activity was a successful strategy to potentiate their elimination.

Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes and is likely correlated with increased body mass index - Corrected Proof

2012-01-04

In 2007, we reported for the first time that nilotinib, when used as second-line treatment in resistant/intolerant chronic myeloid leukaemia (CML) patients, induced hyperglycaemia as a side effect in 13 non-diabetic CML patients . Indeed, we also measured Hb1Ac levels during therapy, but the median level was within the normal range, and none of the patients developed diabetic alterations. In one patient, the discontinuation of treatment due to other side effects resulted in a return to normal fasting glucose levels, thus indicating the reversibility of the adverse event. Following our report, le Coutre et al. performed a large-scale analysis of the glycemic profiles of patients receiving nilotinib as a second-line therapy. The authors observed that 12.5% of chronic-phase and 6.7% of accelerated-phase patients developed grade 3/4 hyperglycaemia; none of the patients suffered from diabetic complications, such as ketoacidosis, hyperosmolar coma, hospitalisation due to these adverse events or increased weight. We reviewed our series of patients treated with nilotinib to identify features predisposing patients to this side effect or modifications of clinical outcomes pursuant to the emergence of hyperglycaemia. Overall, 62 patients at our institution received nilotinib as a second-line treatment (30 patients, 12 of whom were enrolled in phases II and IIIB sponsored Novartis trials, were all treated with 400mg BID) or as a first-line treatment (32 patients, 27 of whom were enrolled in a GIMEMA phase II trial and 5 of whom were enrolled in a phase III ENESTnd trial, were all treated with 400mg BID, except 2, who received 300mg BID). The median age was 52 years (range 22–77.7 years); 38 patients were males, and 24 patients were females. None of these patients was diagnosed as having diabetes at baseline. Clinical features at the initiation of nilotinib treatment differed between the groups with regard to median age (58 years in patients who received the second-line treatment vs. 46 years in patients who received the first-line treatment), sex (a male/female ratio of 1.1 for patients treated after imatinib resistance and 0.6 for patients without imatinib resistance). Regarding comorbidities at baseline, no difference was observed between the groups of patients with respect to hypertension, heart conditions or hypercholesterolemia. The calculation of body mass index revealed that 15% of patients treated with nilotinib as second-line treatment and 18% of patients treated with nilotinib as first-line treatment were overweight/obese (BMI>25). The median fasting glucose level at baseline in the whole cohort was 98mg/dl. After a median follow-up of 1.5 years (range 1–4 years), this value was 109mg/dl (p=0.34). No difference was apparent between the groups regarding changes in the median value of fasting glucose from baseline to 12 months after the treatment began. In patients treated with nilotinib as second-line therapy, the median changed from 102mg/dl at baseline to 110mg/dl at 12 months; in patients treated with nilotinib as first-line therapy, values rose from a median of 95mg/dl to 108mg/dl. We detected grade 3/4 hyperglycaemia in only 7 patients (11%) among the entire cohort: 4 patients treated with nilotinib as second-line treatment and 3 patients treated with nilotinib as first-line treatment. None of these patients developed severe diabetic consequences: all patients discontinued the drug for a median of 8 days (range 4–12), and none had recurrent episodes of hyperglycaemia. No clinical difference was detected between patients who experienced grade 3/4 hyperglycaemia and patients who did not, except for BMI, which had a median value of 28 in the former group compared with a median value of 20 in the latter category (p=0.02).

Phase II study on combination therapy with CHOP-Zenapax for HTLV-I associated adult T-cell leukaemia/lymphoma (ATLL) - Corrected Proof

2012-01-03

Abstract: Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy caused by the human T-lymphotropic virus type-1 (HTLV-1) and is associated with a very poor prognosis. Combination chemotherapy has had little impact on the long term survival of these patients. ATLL cells are characterised by the expression of CD25 (IL-2Rα), which is not expressed in normal resting T-cells. Daclizumab (Zenapax®) is a humanised murine anti-CD25 monoclonal antibody, which contains 10% murine CDR sequences. In this prospective trial 15 patients with aggressive ATLL were treated with CHOP-Zenapax (CHOP-Z) to determine the tolerability and feasibility of this novel regimen as well as evaluate its efficacy. Eleven patients had acute ATLL and four had the lymphoma subtype. The main presenting features were elevated LDH (100%), lymphocytosis (73%), lymphadenopathy (67%), skin lesions (40%), hypercalcaemia (53%), and hepato-splenomegaly (27%). Ten (67%) patients received the six scheduled cycles. Complete response (CR) lasting for two months or more was seen in 5 (33%), partial response in 3 (20%), minor response in 1 (7%), and no response in 6 (40%) patients. The median overall survival was 10 months (95% CI: 0.05–20.88) but this was significantly longer among responders (18 months) compared to non responders (3months) (P=0.019). For patients who achieved CR the disease free survival (DFS) was 15 months while the event-free survival (EFS) was 5 months. In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival.

Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics: Outcomes of prolonged therapy - Corrected Proof

2011-12-28

Acute myeloid leukemia (AML) is predominantly a disease of the elderly, with over half of patients aged >60 years at diagnosis . Prognosis in this age group is typically poor, and use of intensive therapies is limited by factors such as comorbidities and poor performance status, often resulting in inferior response to treatment and pronounced toxicities compared with younger patients . Azacitidine (Vidaza®; Celgene) has recently been approved in the European Union for the treatment of patients with AML with 20–30% bone marrow (BM) blasts and multi-lineage dysplasia, according to World Health Organization (WHO) criteria. In a recent phase III study (AZA-001), azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCR) in patients with higher-risk myelodysplastic syndromes (MDS) (p=0.001) . In this trial, patients had intermediate-2- or high-risk MDS according to French–American–British (FAB) classification, including 113 patients with refractory anemia with excess blasts in transformation (RAEB-t; 20–30% BM blasts), who would now be considered as having AML according to revised WHO criteria . A subsequent analysis demonstrated a median OS of 24.5 months with azacitidine versus 16.0 months with CCR (p=0.005) in these patients . Here we report the case of an elderly patient with WHO AML, initially randomized to receive azacitidine in the AZA-001 trial in July 2006, and who has continued to receive azacitidine therapy to present day.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children - Corrected Proof

2011-12-26

Abstract: The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.

Prognostic implications of leg ulcers from hydroxycarbamide therapy in patients with essential thrombocythaemia - Corrected Proof

Sebastian Francis, David Bareford, Christina Baginott, Jecko Thachil — 2011-12-26

Abstract: Essential thrombocythemia (ET) is a clonal stem-cell disorder characterized by persistent thrombocytosis. Patients with ET and risk factors for thrombotic complications have been shown to benefit from cytoreductive therapy, the most common agent used being, hydroxycarbamide. Although this agent is usually well-tolerated, one of the recognized adverse effects is the development of leg ulcers. We undertook retrospective analysis of consecutive ET patients treated with hydroxcarbamide and identified several specific features for this complication including advanced age, female preponderance, reduced overall survival, tendency to develop future vascular events and intolerance to the second line agent, anagrelide.

Comparison between multiparameter flow cytometry and WT1-RNA quantification in monitoring minimal residual disease in acute myeloid leukemia without specific molecular targets - Corrected Proof

2011-12-26

Abstract: Despite a high remission rate, a significant number of patients with acute myeloid leukemia (AML) relapse. Thus, the evaluation of minimal residual disease (MRD) in AML is an important strategy to better identify high risk patients. Most sensitive methodology to detect MRD is molecular polymerase chain reaction (PCR) but its applicability is restricted to AML with leukemia-specific molecular targets (e.g. AML1-ETO, CBFB-MYH11, MLL, FLT-3). In our study, MRD was monitored at different time points with both MFC and WT1-RNA quantification in 23 AML patients who did not present specific molecular targets. As previously published, we considered values of 10−3 (0.1%) in MFC and 90 WT1-RNA ×104 ABL copies as optimal thresholds. Receiver operating characteristics (ROC) analysis was used to confirm these data. To realize the methodology that better identify high risk patients, an analysis of sensitivity, specificity, predictive values (PV) and likelihood ratio (LR) was provided and similar results were showed. MRD levels ≥10−3 in MFC as well MRD levels ≥90 WT1-RNA copies in RQ-PCR, identify risk groups of patients with poor prognosis. Therefore, MFC and WT1-RNA quantification showed a comparable capacity in terms of technical performance and clinical significance to identify high risk patients who eventually relapsed.

The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients - Corrected Proof

2011-12-22

Abstract: The hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of early death and survival in elderly patients with acute myeloid leukemia (AML). The aim of this study was to determine the prognostic role of the HCT-CI for early death and survival in adult AML patients. In the single-center retrospective study, we analyzed the outcome of 233 adult AML patients. The results indicated that the HCT-CI score is an independent predictor of early death in entire cohort of adult patients with AML. In subgroup analysis, HCT-CI is an independent predictor for early death in elderly patients but not in patients younger than 60 years. A high HCT-CI score predicts shorter survival in adult patients with AML.