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Latest Research Publications
Childhood Leukaemia
Acute Lymphocytic Leukemia: (ALL)
Acute Myeloid Leukemia: (AML)
Chronic Lymphocytic Leukemia: (CLL)
Chronic Myeloid Leukemia: (CML)
Hairy Cell Leukemia

Information Patients and the Public (13 links)

Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Maharath A, Fucharoen S, Tanyong DI
p53 and nitric oxide are involved in cytokine-induced apoptosis in Kasumi-1 and Molt-4 Leukemics cells.
Asian Pac J Allergy Immunol. 2014; 32(2):133-9 [PubMed] Related Publications
BACKGROUND: Immunotherapy has been developed to treat cancers. There are many signaling pathways involved in cytokine induced apoptosis of many cancers but their role remains unclear in some cancers such as leukemia.
OBJECTIVE: To investigate the involvement of the nitric oxide (NO) and p53 tumor suppressor gene in apoptotic pathways induced by cytokines in leukemic cell lines.
METHODS: Leukemic cell lines, Kasumi-1 (AML-M2) and Molt- 4 (ALL) were treated with cytokines, interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ). The effect of cytokines on the induction cell apoptosis was analysed by flow cytometry. In addition, nitric oxide production and p53 protein levels were measured by using the Griess method and Western blot, respectively.
RESULTS: Upon cytokine treatment, there was a significant increase in the percentage of cell apoptosis in both leukemic cell lines. The highest apoptosis was shown in 40 U/ml IFN-γ treated cells. In addition, nitric oxide and p53 protein increased in IFN-γ treated cells. There was a reduction of apoptosis and p53 level after adding the inducible nitric oxide synthase inhibitor, SMT.
CONCLUSION: p53 and nitric oxide are involved in the mediation of apoptosis induced by cytokines in Kasumi-1 and Molt-4 leukemic cell lines.

Related: Apoptosis Cytokines TP53

Müller T, Schlahsa L, Zhang HJ, et al.
Allogeneic and xenogeneic anti-tumor effect of callithrix jacchus natural killer cells is dependent on NKp30 and B7-H6 interaction.
J Biol Regul Homeost Agents. 2014 Apr-Jun; 28(2):183-93 [PubMed] Related Publications
Natural Killer (NK) cells mount a fast and efficient immune response against tumor cells and are currently a major focus in the development of anti-cancer cell-based therapies. Due to major differences between the murine and human NK cell receptor system, a non-human primate model would be helpful to evaluate the efficiency of NK-cell based therapies prior to clinical applications. In humans, B7-H6 has been shown to facilitate the elimination of lymphoma cells through the interaction with its receptor NKp30. The common marmoset (Callithrix jacchus) is a new world monkey readily used in biomedical research due to its easy management and proximity to humans. In this study, we demonstrated the expression of B7-H6 antigen in marmoset B-lymphoblastoid cell lines. In addition, a method was established to isolate B- or NK-cells from peripheral blood of marmosets with purities of up to 97%We detected the expression of B7-H6 in lymphoma cells and for the first time in leukemic blasts of human acute myeloid leukemia (AML). Marmoset NK cells were shown to lyse marmoset B lymphoblastoid cell line (B-LCL) cells by up to 28.4% and human B-LCL cells by up to 20%. This effect was abrogated when the NK cells were pre-treated with an anti-NKp30 specific antibody. Also, marmoset NK cells were able to lyse primary leukemic AML cells and lymphoma cells by up to 8.3 and 20.3%respectively. Stimulation of marmoset NK cells with recombinant B7-H6 induced phosphorylation of ERK1/2 and proliferation rates. Furthermore, the secretion of IL-1β, IL-8, IFN-γ and TNF-α was significantly increased upon B7-H6 stimulation. In conclusion, we demonstrated that non-human primate NK cells have similar mechanisms for the lysis of tumor cells as human NK cells. Thus, this animal model constitutes a very promising tool for the development and evaluation of novel NK-cell based therapies.

Related: Acute Myeloid Leukemia (AML)

Antony-Debré I, Steidl U
CDK6, a new target in MLL-driven leukemia.
Blood. 2014; 124(1):5-6 [PubMed] Related Publications
In this issue of Blood, Placke et al identify the cell-cycle regulator CDK6 as a promising new target in mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) and show that its downregulation or pharmacological inhibition leads to growth inhibition and differentiation of MLL-driven leukemic cells.

Related: Acute Myeloid Leukemia (AML)

Durum SK
IL-7 and TSLP receptors: twisted sisters.
Blood. 2014; 124(1):4-5 [PubMed] Related Publications
In this issue of Blood, Shochat et al report mutations in receptors for interleukin-7 (IL-7) and thymic stromal lymphopoietin (TSLP), resulting in a novel dimerization mechanism that drives acute lymphoblastic leukemias.

Related: Acute Lymphocytic Leukemia (ALL)

Kater AP, Eldering E
miR in CLL: more than mere markers of prognosis?
Blood. 2014; 124(1):2-4 [PubMed] Related Publications
In this issue of Blood, Mraz et al show that microRNA-150 (miR-150) is the most abundantly expressed miR in chronic lymphocytic leukemia (CLL) and affects the threshold for B-cell receptor (BCR) signaling by repressing expression levels of GAB1 and FOXP1. This functional link might explain the described association between expression levels of miR-150 and prognosis.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Signal Transduction FOXP1 gene

Tam CS, Seymour JF
A new prognostic score for CLL.
Blood. 2014; 124(1):1-2 [PubMed] Related Publications
In this issue of Blood, Pflug et al describe the new prognostic score published by the German Chronic Lymphocytic Leukemia Study Group (GCLLSG).

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Ghimire KB, Shah BK
Second primary malignancies in adult acute myeloid leukemia--A US population-based study.
Anticancer Res. 2014; 34(7):3855-9 [PubMed] Related Publications
BACKGROUND: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Long-term survivors from AML may be at higher risk of second primary malignancies.
PATIENTS AND METHODS: We selected adult patients with AML aged≥18 years from the National Cancer Institute's Surveillance, Epidemiology and End RESULTS (SEER 13) database. We used the multiple primary standardized incidence ratio session of SEER*stat software to calculate the risk of second primary malignancies in patients with AML.
RESULTS: Among 5,091 patients, 148 patients developed a total of 160 second primary malignancies, with an observed/expected (O/E) ratio of 1.17, (95% confidence interval=0.99-1.36), and an excess risk of 15.47 per 10,000 population. The risk of all-site cancer, cancer of gastrointestinal system, and oral and pharyngeal cancer in different age groups was found to be significantly higher among patients with AML compared to that of general US population.
CONCLUSION: Adult patients with AML have a significantly higher risk of second primary malignancies compared to the general population.

Related: Acute Myeloid Leukemia (AML) USA

Lowe HI, Toyang NJ, Watson CT, et al.
Antileukemic activity of Tillandsia recurvata and some of its cycloartanes.
Anticancer Res. 2014; 34(7):3505-9 [PubMed] Related Publications
BACKGROUND: Approximately 250,000 deaths were caused by leukemia globally in 2012 and about 40%-50% of all leukemia diagnoses end-up in death. Medicinal plants are a rich source for the discovery of new drugs against leukemia and other types of cancers. To this end, we subjected the Jamaican ball moss (Tillandsia recurvata) and its cycloartanes, as well as some analogs, to in vitro screening against a number of leukemia cell lines. The WST-1 anti-proliferation assay was used to determine the anticancer activity of ball moss and two cycloartanes isolated from ball moss and four of their analogs against four leukemia cell lines (HL-60, K562, MOLM-14, monoMac6). Ball moss crude methanolic extract showed activity with a 50% inhibition concentration (IC50) value of 3.028 μg/ml against the Molm-14 cell line but was ineffective against HL-60 cells. The six cycloartanes tested demonstrated varying activity against the four leukemia cancer cell lines with IC50 values ranging from 1.83 μM to 18.3 μM. Five out of the six cycloartanes demonstrated activity, while one was inactive against all four cell lines. The preliminary activity demonstrated by the Jamaican ball moss and its cycloartanes against selected leukemia cell lines continues to throw light on the broad anticancer activity of ball moss. Further studies to evaluate the efficacy of these molecules in other leukemia cell lines are required in order to validate the activity of these molecules, as well as to determine their mechanisms of action and ascertain the activity in vivo in order to establish efficacy and safety profiles.

Jiang X
Distinguishing CML LSCs from HSCs using CD26.
Blood. 2014; 123(25):3851-2 [PubMed] Related Publications
In this issue of Blood, Herrmann et al elegantly demonstrate that CD26 is a new, specific chronic myeloid leukemia (CML) stem cell biomarker that phenotypically distinguishes leukemic stem cells (LSCs) from normal hematopoietic stem cells (HSCs), and that it is a potential therapeutic target in CML.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Rooney CM
Can Treg elimination enhance NK cell therapy for AML?
Blood. 2014; 123(25):3848-9 [PubMed] Related Publications
In this issue of Blood, Bachanova et al describe how modulation of the inhibitory tumor environment may enhance natural killer (NK) cell clinical activity and produce encouraging results in the treatment of refractory acute myeloid leukemia (AML). NK cells are highly proliferative, early responders of the innate immune response that in preclinical models can exert potent activity against a wide range of malignancies, including AML, and across HLA barriers. Considerable efforts have been made to exploit this activity in clinical trials but with only modest success.

Related: Interleukin 2 (Aldesleukin)

Liu GJ, Cimmino L, Jude JG, et al.
Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.
Genes Dev. 2014; 28(12):1337-50 [PubMed] Article available free on PMC after 15/12/2014 Related Publications
Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.

Related: PAX5 gene (9p13) Acute Lymphocytic Leukemia (ALL) Signal Transduction

Davis SA, Krowchuk DP, Feldman SR
Prescriptions for a toxic combination: use of methotrexate plus trimethoprim-sulfamethoxazole in the United States.
South Med J. 2014; 107(5):292-3 [PubMed] Related Publications
OBJECTIVES: To determine the frequency of using the potentially toxic combination of methotrexate and trimethoprim-sulfamethoxazole (TMP-SMX) in outpatient practice in the United States.
METHODS: Data from the National Ambulatory Medical Care Survey for 1993-2010 were used to assess the frequency of using methotrexate with TMP-SMX and associated physician specialties and diagnoses.
RESULTS: TMP-SMX was coprescribed in 22,000 methotrexate visits per year (1.0% of methotrexate visits). Pediatricians prescribed the combination most frequently, and the most common diagnosis was acute lymphoblastic leukemia. There was no significant change over time in coprescription of TMP-SMX with methotrexate (P = 0.4).
CONCLUSIONS: Low-dose TMP-SMX with methotrexate chemotherapy appears to be standard for patients with acute lymphoblastic leukemia; however, other uses appear questionable, and clinicians should be cognizant of the risk for fatal interactions, especially when medications are prescribed by multiple providers.

Related: Methotrexate Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology USA

Rahman F, Kabir AL, Khan MR, et al.
Disseminated intravascular coagulation in acute promyelocytic leukaemia and its impact on the induction failure: a single centre study.
Bangladesh Med Res Counc Bull. 2013; 39(2):57-60 [PubMed] Related Publications
Life-threatening coagulopathy associated with acute promyelocytic leukemia (APL) has been the defining clinical characteristic and is an important risk factor for fatal haemorrhage and early death. Pathogenesis of coagulopathy in APL is complex and mainly includes disseminated intravascular coagulation (DIC). The study was done to see the status of DIC and its impact on the outcome of APL in our setting. Among the total 60 patients, induction mortality rate was 30% and remission rate was 70%. The main cause of induction mortality was bleeding that accounts for 66.7% of mortality. DIC was present among 32 out of 60 patients (53.33%). Induction mortality has significant relationship to DIC as the induction mortality rate is 47% in patients with DIC and 11% in patient without DIC (P value 0.0009). Induction motality rate in low, intermediate and high risk group is 6.70%, 24% and 58% respectively (p value < 0.0001). Finally, risk group subclassification revealed presence of DIC in high risk group has the highest early mortality rate.

Takahashi Y, Itoh M, Nara N, Tohda S
Effect of EPH-ephrin signaling on the growth of human leukemia cells.
Anticancer Res. 2014; 34(6):2913-8 [PubMed] Related Publications
BACKGROUND: Signaling induced by binding of erythropoietin-producing hepatoma-amplified sequence (EPH) receptors to their cell-surface ephrin ligands is implicated in hematopoiesis and growth of various cancer cells. However, the roles of EPH-ephrin signaling in leukemia have not been elucidated. We investigated the effects of EPHB4 and ephrin B2 on the growth of leukemia cells.
MATERIALS AND METHODS: Seven human leukemia cell lines were used to examine the effects of recombinant ephrin B2 and EPHB4 on cell proliferation by colorimetric WST-1 assay and colony assays; on protein tyrosine phosphorylation; and on mRNA expression by reverse transcription-polymerase chain reaction and microarray analysis.
RESULTS: In an erythroid leukemia-derived cell line AA, exogenous ephrin B2 induced proliferation and colony formation; in addition, it up-regulated protein tyrosine phosphorylation and the expression of growth-related genes such as FBJ murine osteosarcoma viral oncogene homolog B and v-src avian sarcoma viral oncogene homolog.
CONCLUSION: Growth-promoting effects of ephrin B2 were observed in an erythroid leukemia cell line, suggesting that the EPH-ephrin signaling may be involved in the pathology of leukemia.

Related: Signal Transduction

Park J, Lai HC, Singh M, et al.
Development of a dihydroartemisinin-resistant Molt-4 leukemia cell line.
Anticancer Res. 2014; 34(6):2807-10 [PubMed] Related Publications
Artemisinin generates cytotoxic free radicals when it reacts with iron. Its toxicity is more selective toward cancer cells because cancer cells contain a higher level of intracellular-free iron. We previously reported that dihydroartemisinin (DHA), an active metabolite of artemisinin, has selective cytotoxicity toward Molt-4 human lymphoblastoid cells. A concern is whether cancer cells could develop resistance to DHA after repeated administration, thus limiting its therapeutic efficacy. In the present study, we developed a DHA-resistant Molt-4 cell line (RTN) by exposing Molt-4 cells to gradually increasing concentrations of DHA in vitro. The half-maximal inhibitory concentration (IC50) of DHA for RTN cells is 7.1-times higher than that of Molt-4 cells. RTN cells have a higher growth rate than Molt-4 cells. In addition, we investigated the toxicities of two more potent synthetic artemisinin compounds, artemisinin dimer-alcohol and artemisinin-tagged holotransferrin toward RTN cells; RTN cells showed no significant cross-resistance to these compounds.

McDermott J, Jimeno A
Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma.
Drugs Today (Barc). 2014; 50(4):291-300 [PubMed] Related Publications
Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin's lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Mantle Cell Lymphoma

Berenstein R, Blau IW, Kar A, et al.
Comparative examination of various PCR-based methods for DNMT3A and IDH1/2 mutations identification in acute myeloid leukemia.
J Exp Clin Cancer Res. 2014; 33:44 [PubMed] Article available free on PMC after 15/12/2014 Related Publications
BACKGROUND: Mutations in epigenetic modifiers were reported in patients with acute myeloid leukaemia (AML) including mutations in DNA methyltransferase 3A gene (DNMT3A) in 20%-30% patients and mutations in isocitrate dehydrogenase 1/2 gene (IDH1/2) in 5%-15% patients. Novel studies have shown that mutations in DNMT3A and IDH1/2 influence prognosis, indicating an increasing need to detect these mutations during routine laboratory analysis. DNA sequencing for the identification of these mutations is time-consuming and cost-intensive. This study aimed to establish rapid screening tests to identify mutations in DNMT3A and IDH1/2 that could be applied in routine laboratory procedures and that could influence initial patient management.
METHODS: In this study we developed an endonuclease restriction method to identify the most common DNMT3A mutation (R882H) and an amplification-refractory mutation system (ARMS) to analyse IDH2 R140Q mutations. Furthermore, we compared these methods with HRM analysis and evaluated the latter for the detection of IDH1 mutations.
RESULTS: Of 230 samples from patients with AML 30 (13%) samples had DNMT3A mutations, 16 (7%) samples had IDH2 R140Q mutations and 36 (16%) samples had IDH1 mutations. Sensitivity assays performed using serial dilutions of mutated DNA showed that ARMS analysis had a sensitivity of 4.5%, endonuclease restriction had a sensitivity of 0.05% and HRM analysis had a sensitivity of 5.9%-7.8% for detecting different mutations. HRM analysis was the best screening method to determine the heterogeneity of IDH1 mutations. Furthermore, for the identification of mutations in IDH2 and DNMT3A, endonuclease restriction and ARMS methods showed a perfect concordance (100%) with Sanger sequencing while HRM analysis showed a near-perfect concordance (approximately 98%).
CONCLUSION: Our study suggested that all the developed methods were rapid, specific and easy to use and interpret. HRM analysis is the most timesaving and cost-efficient method to rapidly screen all the 3 genes at diagnosis in samples obtained from patients with AML. Endonuclease restriction and ARMS assays can be used separately or in combination with HRM analysis to obtain more reliable results. We propose that early screening of mutations in patients with AML having normal karyotype could facilitate risk stratification and improve treatment options.

Related: Acute Myeloid Leukemia (AML) IDH2 gene IDH1 gene

Nishimoto M, Koh H, Bingo M, et al.
Posterior reversible encephalopathy syndrome following acute pancreatitis during chemotherapy for acute monocytic leukemia.
Rinsho Ketsueki. 2014; 55(5):552-7 [PubMed] Related Publications
We describe an 18-year-old man with acute leukemia who presented with posterior reversible encephalopathy syndrome (PRES) shortly after developing acute pancreatitis. On day 15 after the third consolidation course with high-dose cytarabine, treatment with broad-spectrum antibiotics was initiated for febrile neutropenia. On day 16, he developed septic shock, and subsequently, acute respiratory distress syndrome (ARDS). After adding vancomycin, micafungin and high-dose methylprednisolone (mPSL) to his treatment regimen, these manifestations subsided. On day 22, he received hemodialysis for drug-induced acute renal failure. On day 24, he developed acute pancreatitis possibly due to mPSL; the following day he had generalized seizures, and was intubated. Cerebrospinal fluid findings were normal. Brain MRI revealed hyperintense signals on FLAIR images and increased apparent diffusion coefficient values in the sub-cortical and deep white matter areas of the bilateral temporal and occipital lobes, indicative of vasogenic edema. Thus, we diagnosed PRES. Blood pressure, seizures and volume status were controlled, with MRI findings showing improvement by day 42. He was extubated on day 32 and discharged on day 49 without complications. Although little is known about PRES following acute pancreatitis, clinicians should be aware that this condition may develop.

Related: Cytarabine

Kirihara T, Fujikawa Y, Takeda W, et al.
Congenital dysfibrinogenemia coincidentally diagnosed at the onset of chronic myelogenous leukemia.
Rinsho Ketsueki. 2014; 55(5):541-5 [PubMed] Related Publications
A 34-year-old man was referred to our hospital for leukocytosis and fundal hemorrhage. Peripheral blood and coagulation tests showed increases in cells at all stages of the neutrophilic series and a low level of fibrinogen (Fbg). Chronic myelogenous leukemia (CML) was diagnosed, and nilotinib was administered. During the clinical course of CML treatment, plasma Fbg levels continued to be low, but the patient showed neither hemorrhagic nor thrombotic complications. Fbg analysis showed normal antigen levels and low activity levels, which indicated dysfibrinogenemia. Genetic analysis revealed a heterozygous gene mutation (γ308AAT→AAG), a mutation which was also found in the patient's mother. Asymptomatic patients with dysfibrinogenemia have a low risk of hemorrhage in daily life and do not require treatment. However, in those undergoing major surgery or in serious accidents, replacement therapy may be required. When the cause of low Fbg levels is unknown, dysfibrinogenemia or fibrinogen deficiency should be considered. Even asymptomatic patients may benefit from more detailed immunologic and genetic analyses.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Miyamura K, Okamoto S, Usui N, et al.
Evaluation of clinical performance of the major BCR-ABL mRNA detection kit which enables conversion to international standard scale using the reference material calibrator.
Rinsho Ketsueki. 2014; 55(5):534-40 [PubMed] Related Publications
In a multicenter study, we evaluated the Major BCR-ABL mRNA/ABL mRNA quantification kit (M135R), which uses reference material included in the kit designed to report results using the international scale (IS). In total, 127 samples were studied. A good correlation was observed between M135R results and home-brew RT-qPCR results, which are reported on the IS using a conversion factor (r=0.90; n=115). However, the correlation coefficient between M135R results and Amp-CML results was relatively low (r=0.56; n=108). A good correlation was observed between M135R results from the two assay sites (r=0.94; n=115). The subset analysis of samples from the two assay sites showed M135R to have a good correlation even in the low IS range (r=0.98; IS≤1%). M135R showed high sensitivity and accuracy for detecting minimal residual disease and is considered to be a useful tool for treatment response assessment and for early detection of recurrence in CML patients.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology Signal Transduction

Byrd JC, Brown JR, O'Brien S, et al.
Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.
N Engl J Med. 2014; 371(3):213-23 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
BACKGROUND: In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
METHODS: In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.
RESULTS: At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
CONCLUSIONS: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Related: Monoclonal Antibodies Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Musialik E, Bujko M, Kober P, et al.
Comparison of promoter DNA methylation and expression levels of genes encoding CCAAT/enhancer binding proteins in AML patients.
Leuk Res. 2014; 38(7):850-6 [PubMed] Related Publications
CCAAT/enhancer binding proteins (CEBPs) are transcription factors regulating myeloid differentiation. Disturbances of their expression may contribute to leukemogenesis. In this study we compared promoter methylation and expression levels of selected CEBP genes in a group of 78 AML patients, normal bone marrow and hematopoietic precursor cells. CEBPA, CEBPD and CEBPE promoter methylation levels were elevated in 37%, 35.5% and 56.7% of patients. No CEBPZ(DDIT3) methylation was observed. An inverse relationship between CEBPA and CEBPD DNA methylation and expression levels was observed. AML cytogenetic risk groups and patients with particular translocation are characterized by distinct methylation/expression profile of CEBPs encoding genes.

Related: Acute Myeloid Leukemia (AML)

Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, et al.
The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation.
Nature. 2014; 511(7507):90-3 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor prognosis AML, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.

Related: Cytarabine Acute Myeloid Leukemia (AML) Signal Transduction GLI

Woyach JA, Furman RR, Liu TM, et al.
Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.
N Engl J Med. 2014; 370(24):2286-94 [PubMed] Article available free on PMC after 12/12/2014 Related Publications
BACKGROUND: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.
METHODS: We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis.
RESULTS: We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib.
CONCLUSIONS: Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Claus R, Lucas DM, Ruppert AS, et al.
Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia.
Blood. 2014; 124(1):42-8 [PubMed] Related Publications
ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation (<20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P < .0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR = 1.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (κ coefficient > 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

James DF, Werner L, Brown JR, et al.
Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium.
J Clin Oncol. 2014; 32(19):2067-73 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Lenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.
PATIENTS AND METHODS: Lenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis.
RESULTS: Sixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort.
CONCLUSION: Intrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Thalidomide Rituximab (Mabthera) Lenalidomide

Huan T, Wu X, Bai Z, Chen JY
Seed-weighted random walk ranking for cancer biomarker prioritisation: a case study in leukaemia.
Int J Data Min Bioinform. 2014; 9(2):135-48 [PubMed] Related Publications
A central focus of clinical proteomics for cancer is to identify protein biomarkers with diagnostic and therapeutic application potential. Network-based analyses have been used in computational disease-related gene prioritisation for several years. The Random Walk Ranking (RWR) algorithm has been successfully applied to prioritising disease-related gene candidates by exploiting global network topology in a Protein-Protein Interaction (PPI) network. Increasing the specificity and sensitivity ofbiomarkers may require consideration of similar or closely-related disease phenotypes and molecular pathological mechanisms shared across different disease phenotypes. In this paper, we propose a method called Seed-Weighted Random Walk Ranking (SW-RWR) for prioritizing cancer biomarker candidates. This method uses the information of cancer phenotype association to assign to each gene a disease-specific, weighted value to guide the RWR algorithm in a global human PPI network. In a case study of prioritizing leukaemia biomarkers, SW-RWR outperformed a typical local network-based analysis in coverage and also showed better accuracy and sensitivity than the original RWR method (global network-based analysis). Our results suggest that the tight correlation among different cancer phenotypes could play an important role in cancer biomarker discovery.

Baran I, Ionescu D, Filippi A, et al.
Novel insights into the antiproliferative effects and synergism of quercetin and menadione in human leukemia Jurkat T cells.
Leuk Res. 2014; 38(7):836-49 [PubMed] Related Publications
The flavonoid quercetin and menadione (vitamin K3) are known as potent apoptogens in human leukemia Jurkat T cells. We explored some underlying mechanisms and the potential relevance of the combination quercetin-menadione for clinical applications. In acute treatments, quercetin manifested a strong antioxidant character, but induced a transient loss of Δψm, likely mediated by opening of the mitochondrial permeability transition pore. After removal of quercetin, persistent mitochondrial hyperpolarization was generated via stimulation of respiratory Complex I. In contrast, menadione-induced Δψm dissipation was only partially and transiently reversed after menadione removal. Results indicate that Ca(2+) release is a necessary event in quercetin-induced cell death and that the survival response to quercetin is delineated within 1h from exposure. Depending on dose, the two agents exhibited either antagonistic or synergistic effects in reducing clonogenicity of Jurkat cells. 24-h combinatorial regimens at equimolar concentrations of 10-15 μM, which are compatible with a clinically achievable (and safe) scheme, reduced cell viability at efficient rates. Altogether, these findings support the idea that the combination quercetin-menadione could improve the outcome of conventional leukemia therapies, and warrant the utility of additional studies to investigate the therapeutic effects of this combination in different cellular or animal models for leukemia.

Decitabine. Acute myeloid leukaemia: no progress.
Prescrire Int. 2014; 23(148):92-4 [PubMed] Related Publications
Acute myeloid leukaemia is a life-threatening disease. Its incidence increases with age. There is no consensus on treatment for patients over 60 years of age who cannot receive first-line high-dose chemotherapy. Options include low-dose cytarabine, other non-intensive chemotherapy regimens, or tailored supportive care. Decitabine, a cytotoxic drug related to cytarabine, has been authorised for patients aged 65 years or older who are not eligible for intensive chemotherapy. Clinical evaluation of decitabine in this setting is mainly based on an unblinded randomised controlled trial including 485 patients, who received either decitabine, or low-dose cytarabine or symptomatic treatment alone. There was no statistically significant difference in overall survival between the two active treatment groups (median about 6 months). Serious adverse events occurred in 80% of patients in the decitabine group, compared to 73% of those in the cytarabine group. They consisted mainly of haematological disorders (neutropenia, thrombocytopenia, anaemia), infections (pneumonia) and gastrointestinal disorders. In practice, for patients at least 65 years of age with acute myeloid leukaemia who are not candidates for intensive chemotherapy, decitabine has no advantages over existing treatments in terms of survival time or adverse effects. Low-dose cytarabine or tailored supportive care are better-assessed options.

Related: Azacitidine Cytarabine Acute Myeloid Leukemia (AML)

Islam N, Rahman MM, Aziz MA, et al.
Clinical and haemato-pathological characteristics of adult acute lymphoblastic leukaemia.
Mymensingh Med J. 2014; 23(2):281-5 [PubMed] Related Publications
Acute lymphoblastic leukaemia (ALL) is a heterogeneous group of disorders. It varies with respect to the morphologic, cytogenetic, molecular and immunologic features of the neoplastic cells reflecting the variable clinical-pathologic presentations and outcome of the patients. The aim of the study was to observe the clinical and haemato-pathological characteristics in newly diagnosed adult ALL patients. A total number of 61 patients morphologically diagnosed as acute lymphoblastic leukaemia aged 15 and above assigned for this observational study. The study was carried out in the Department of Haematology, BSMMU from January 2007 to December 2008. Among 61 patients, aged 15 to 80 years with median age 25 years, 79% were male and 21% were female. Most of the patients presented with anaemia (67%), fever (66%), lymphadenopathy (64%) and splenomegaly (57%). Other common clinical findings were hepatomegaly (39%), bone tenderness (44%) and bleeding manifestations (34%). Among haemato-pathological findings 67% patients had Hb level ≤10gm/dl, 46% patients had WBC count ≥30×10⁹/L, 67% patients had platelet count ≤100×10⁹/L, 93% patients had blast in peripheral blood and 61% patients had ≥90 % blasts in the bone marrow at the time of diagnosis. In this study adult ALL patients were analyzed only for their clinical and haemato-pathological characteristics. But their biologic characteristics were not analyzed due to lack of availability of facility. A progressive understanding of the biologic and genetic characteristics of ALL will allow us to identify different prognostic subgroups with specific molecular and cellular features. All the necessary measures have to be developed in our country in order to identify prognostically distinct subgroups of patients.

Related: Acute Lymphocytic Leukemia (ALL)

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