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Information for Patients and the Public
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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).

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] 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

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)

Khwankeaw J, Bhurayanontachai R
Mortality correlation factors in patients with lymphoma and acute myeloid leukemia admitted into the intensive care unit at a referral center in the south of Thailand.
J Med Assoc Thai. 2014; 97 Suppl 1:S77-83 [PubMed] Related Publications
BACKGROUND: Recent treatments in hematological malignancies have substantially improved. Unfortunately, once a patient with a hematological malignancy has complications, the prognosis is poor and the in hospital and ICU mortality rates are high. Debates concerning the reluctance to admit patients into ICUs with poor prognoses often emerge. The aim of the present study is to identify the patients who are more likely to benefit from ICU admissions.
OBJECTIVES: To assess the outcomes and to identify early mortality risk factors in patients with lymphoma and acute myeloid leukemia admitted to the Intensive Care Unit (ICU) at Songklanagarind Hospital in the south of Thailand.
MATERIAL AND METHOD: This is a retrospective study of patients diagnosed with lymphoma and acute myeloid leukemia admitted to the ICU during the period of January 2004 through May 2008. Demographic factors, acute physiology, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and variables noted in the first 24-hours were collected. The risk factors for deaths in the ICU were studied by univariate and multivariate analysis. The risk factors taken from the best multivariate analysis model were calculated to predict the probability of lCU mortality.
RESULTS: A total of 145 patients were studied. The ICU mortality rate was 55.2%. The major cause of death was septic shock. Using univariate analysis, the significant mortality risk factors were neutropenia, mechanical ventilation, the use of vasopressors, abnormal serum creatinine (Cr) and APACHE II scores (p < 0.05). Using multivariate analysis, ICU mortality was best predicted on admission by mechanical ventilation, the use of vasopressors and the APACHE II scores. The presence of neutropenia, mechanical ventilation, vasopressors and an APACHE II score of greater than 27 predicts 80% sensitivity and a 75% specificity for an 82% ICU mortality.
CONCLUSION: Patients with lymphoma and acute myeloid leukemia admitted into the ICU referral center in the south of Thailand who had mechanical ventilation, use of vasopressors and APACHE II scores greater than 27 were associated with a higher ICU mortality rate. The authors suggest that early identification of the subgroup of patients whose probability of survival is so low that advanced ICU support should not be continued would be a more reasonable goal. This will allow more efficient care to potential survivors not in this group.

Related: Acute Myeloid Leukemia (AML) Thailand

He Y, Li XD, Wang DN, et al.
Acute pleural and pericardial effusion induced by chemotherapy in treating chronic myelocytic leukemia.
Clin Lab. 2014; 60(5):853-7 [PubMed] Related Publications
BACKGROUND: Report of a rare and serious complication of chemotherapy with daunorubicin and cytarabine (DA regimen).
METHODS: We report a special case of a patient diagnosed chronic myeloid leukemia (CML) with accelerated phase, who simultaneously suffered from acute pleural and pericardial effusion while receiving chemotherapeutic treatment with DA regimen.
RESULTS: Following treatment with DA regimen, the patient had the symptoms of chest distress and shortness of breath, followed by respiratory failure and pericardial tamponade. The patient's condition was improved when treated with the puncturation through the pericardium and pleural cavity, coupled with glucocorticosteroid treatment.
CONCLUSIONS: Physicians should be made aware of the potential for emergency pleural and pericardial effusion caused by daunorubicin and cytarabine in order to accurately diagnose and treat these conditions and thereby decrease mortality related to chemotherapy.

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

El-Ghany HM, El-Saadany ZA, Bahaa NM, et al.
Stromal cell derived factor-1 (CXCL12) chemokine gene variant in myeloid leukemias.
Clin Lab. 2014; 60(5):735-41 [PubMed] Related Publications
BACKGROUND: Acute and chronic myeloid leukemia are initiated and sustained by a small, self-renewing population of leukemic stem cells, which produce progeny of a heterogeneous population of progenitor cells. CXCL12, a chemokine abundantly produced by the bone marrow microenvironment, and its receptor CXCR4 have crucial roles in malignant cell trafficking. We set out to determine the CXCL12 gene polymorphism at codon G801A and evaluate its influence on malignant cell dissemination and tissue infiltration in myeloid leukemias.
METHODS: Genotyping for CXCL12 was done by restriction PCR-RFLP for 48 myeloid leukemia patients: 38 de novo AML and 10 CML. Fifty age and gender matched volunteers were evaluated as controls.
RESULTS: Regarding AML patients, the frequency of wild genotype was 50% and the heterozygous genotype was 50%. In CML patients, the frequency of wild genotype was 30% while the heterozygous genotype was 70%. In the control group, 57.2% had wild genotype while 42.8% had heterozygous genotype with no significant difference detected between myeloid leukemia patients and the control group. There was a statistically insignificant association between wild and heterozygous genotypes regarding clinical, laboratory data and extramedullary dissemination.
CONCLUSIONS: CXCL12 polymorphism is not associated with either increased myeloid leukemia risk or extramedullary blast dissemination.

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

Apel A, Kedmi M, Levi E, et al.
Outcome differences in patients with precursor B cell acute lymphocytic leukemia over time: a retrospective analysis.
Isr Med Assoc J. 2014; 16(4):224-8 [PubMed] Related Publications
BACKGROUND: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989-93 and 1999-2003.
OBJECTIVES: To investigate whether the change in protocols over the years resulted in an outcome difference at two hospitals in Israel.
METHODS: We thoroughly reviewed the records of 153 patients from Sheba Medical Center and Soroka Medical Center, of whom 106 comprised the study group. The patients were divided into two groups according to the treatment protocol used: 40 patients with the 1989/93 protocol and 66 with the 1999/2003 protocol. Outcome was analyzed for the two groups.
RESULTS: We found a significant difference in disease-free survival (DFS) between the two groups for B cell-ALL (B-ALL) patients who achieved complete remission after induction. There was no difference in overall survival. We did not find any difference in outcome for T cell-ALL patients or for CD20-positive patients.
CONCLUSIONS: In our retrospective analysis, GMALL 99/2003 led to a better DFS for B-ALL patients who were in complete remission after induction. This is possibly related to the differences in medications between the protocols but may also be due to better supportive care. Despite the proven advantage of the newer protocols regarding overall survival, in our experience there was no other significant difference between the two regimens.

Martins VC, Busch K, Juraeva D, et al.
Cell competition is a tumour suppressor mechanism in the thymus.
Nature. 2014; 509(7501):465-70 [PubMed] Related Publications
Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

Molica S
FDG/PET in CLL today.
Blood. 2014; 123(18):2749-50 [PubMed] Related Publications
In this issue of Blood, Falchi et al present their experience with 2-deoxy-2-[18F] fluoroglucose/positron emission tomography (FDG/PET) in the management of patients with chronic lymphocytic leukemia (CLL) or Richter syndrome (RS) over a 10-year period at a referral center. The results of this study shed light on the potential role of FDG/PET in CLL.

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

Davis AS, Viera AJ, Mead MD
Leukemia: an overview for primary care.
Am Fam Physician. 2014; 89(9):731-8 [PubMed] Related Publications
Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia occurs more often in children, whereas the other subtypes are more common in adults. Risk factors include a genetic predisposition as well as environmental factors, such as exposure to ionizing radiation. Symptoms are nonspecific and include fever, fatigue, weight loss, bone pain, bruising, or bleeding. A complete blood count usually reveals leukocytosis and other abnormally elevated or depressed cell lines. Patients with suspected leukemia should be referred promptly to a hematologist-oncologist. The diagnosis is confirmed by further examination of the bone marrow or peripheral blood. Treatment may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. Complications of treatment include tumor lysis syndrome and serious infections from immunosuppression. Leukemia survivors should be monitored closely for secondary malignancies, cardiac complications, and endocrine disturbances such as metabolic syndrome, hypothyroidism, and hypogonadism. Five-year survival rates are highest in younger patients and in patients with chronic myelogenous leukemia or chronic lymphocytic leukemia.

Gogia A, Sharma A, Chopra A, Kumar R
Mediastinal granulocytic sarcoma: poor risk AML?
J Indian Med Assoc. 2013; 111(8):562 [PubMed] Related Publications
Granulocytic sarcoma (GS), a rare extramedullary manifestation of acute myeloid leukaemia (AML) has been frequently reported in the skin, orbits, gingiva, maxilla and lymph nodes. GS in the mediastinum is often mistaken as lymphoblastic lymphoma or mediastinal germ cell tumour. We presented here three cases of AML with normal cytogenetics who presented with mediastinal masses with superior vena caval (SVC) syndrome. All the three cases summarised in this write-up, received standard AML therapy but had, poor outcome.

Related: Acute Myeloid Leukemia (AML)

Mousa S, Mostafa S, Shaheen I, Elnoshokaty E
Detection of trisomy 4 and 10 in Egyptian pediatric patients with acute lymphoblastic leukemia.
Clin Lab. 2014; 60(4):609-14 [PubMed] Related Publications
BACKGROUND: Improvement in cure rates for children with acute lymphoblastic leukemia (ALL) has focused attention on better methods of identifying patients with increased or decreased risk of treatment failure. Chromosome aberrations have a major role in pediatric ALL risk assessment. The aim of this work is to detect the frequency of trisomy 4 and 10 in Egyptian pediatric ALL patients and to analyze their possible prognostic significance.
METHODS: Forty newly diagnosed pediatric ALL patients were subjected to bone marrow aspirate morphological examination and immunophenotyping. Detection of copy number of chromosome 4 and 10 was done using Fluorescence In Situ Hybridization (FISH) technique using whole chromosome painting probes.
RESULTS: Combined trisomy 4 and 10 was detected in 7 cases (17.5%), all of them were of B-ALL type. Single trisomy 4 or 10 was not detected in any case. Trisomy positive patients had a statistically significant lower total leucocytic count (p = 0.041), higher platelet count (p = 0.018), and lower blast percentage in peripheral blood (p = 0.016) at diagnosis.
CONCLUSIONS: Combined trisomy 4 and 10 identifies a group of ALL patients that have good prognostic indicators. Screening of Egyptian pediatric ALL patients for trisomy 4 and 10 may help in "patients' stratification" aiming to develop a risk-adapted therapy in order to minimize therapy related morbidities particularly in children.

Related: Chromosome 10 Chromosome 4 Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Chandia M, Sayagués JM, Gutiérrez ML, et al.
Involvement of primary mesenchymal precursors and hematopoietic bone marrow cells from chronic myeloid leukemia patients by BCR-ABL1 fusion gene.
Am J Hematol. 2014; 89(3):288-94 [PubMed] Related Publications
For decades now, it is well established that chronic myeloid leukemia (CML) is a hematopoietic stem cell(HPC) disorder. However, it remains to be determined whether BCR-ABL1 gene rearrangement occurs in a HPC or at an earlier stem cell and whether the degree of involvement of hematopoiesis by the BCR-ABL1 fusion gene relates to the response to therapy. Here, we have investigated by interphase fluorescence in situ hybridization (iFISH) the distribution of BCR-ABL1 fusion gene in FACS-sorted bone marrow (BM) populations of mesenchymal precursor cells (MPC) and other hematopoietic cell populations from 18 newly diagnosed CML patients. Overall, our results showed systematic involvement at relatively high percentages of BM maturing neutrophils (97%615%), basophils (95%612%), eosinophils (90%68%), CD341 precursors cells (90%67%),monocytes (84%630%), nucleated red blood cells (87%624%), and mast cells (77%633%). By contrast, MPC(30%634%), B-cells (15%627%), T-lymphocytes (50%626%), and NK-cells (35%634%) were involved at lower percentages. In 8/18 CML patients, 2 tumor BCR-ABL11 subclones were detected by iFISH. Of note, all tumor cell subclones were systematically detected in CD341 cells, whereas MPC were only involved by the ancestral tumor cell subclone. In summary, here we confirm the presence at diagnosis of the BCR-ABL1 fusion gene inMPC, CD341 precursors, and other different BM hematopoietic myeloid cell lineages from CML patients,including also in a significant fraction of cases, a smaller percentage of T, B, and NK lymphocytes.Interestingly, involvement of MPC was restricted to the ancestral BCR-ABL11 subclone.

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

Benjamini O, Dumlao TL, Kantarjian H, et al.
Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia.
Am J Hematol. 2014; 89(3):282-7 [PubMed] Related Publications
Dasatinib is a second generation tyrosine kinase inhibitor, with activity in imatinib resistant Ph-positive ALL.We have treated 34 patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia(ALL) (n519) or lymphoid blast phase of chronic myelogenous leukemia (CML-LB) (n515) with the combination of dasatinib and the hyper CVAD regimen. Prior regimens included hyper CVAD plus imatinib(n511, 4 had transplant in first CR), other combination chemotherapy (n512), monotherapy with kinase inhibitors other than dasatinib (n59), and investigational agents (n52). Pretreatment ABL mutations were noted in 10 patients. The overall response rate was 91%, with 24 patients (71%) achieving complete response(CR), and 7(21%) CR with incomplete platelet recovery (CRp). Two patients died during induction and one had progressive disease. Twenty-six patients (84%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (42%) achieved complete molecular response, and 11 patients (35%) had major molecular response (BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation.Grades 3 and 4 toxicities included hemorrhage, pleural and pericardial effusions and infections. The median follow-up for patients with CML-LB is 37.5 months (range, 7–70 months) with a 3-year overall survival of 70%;68% remained in CR at 3 years. For ALL patients, the median follow-up is 52 months (range, 45–59 months)with a 3-year survival of 26%; 30% remain in CR at 3 years. The combination of Hyper CVAD regimen with dasatinib is effective in patients with relapsed Ph-positive ALL and CML-LB.

Related: Cyclophosphamide Doxorubicin Chronic Myeloid Leukemia (CML) CML - Molecular Biology Acute Lymphocytic Leukemia (ALL) Vincristine Dasatinib (Sprycel)

Kissova J, Ovesna P, Penka M, et al.
Second malignancies in philadelphia-negative myeloproliferative neoplasms-single-center experience.
Anticancer Res. 2014; 34(5):2489-96 [PubMed] Related Publications
AIM: The aim of this work was to retrospectively analyze patients with Philadelphia-negative myeloproliferative neoplasms through evaluation of frequency and characteristics of second malignancies (other than acute leukaemia and myelodysplastic syndrome).
PATIENTS AND METHODS: Records of 172 patients were reviewed; an analysis was performed on data from 66 patients treated with hydroxyurea, 105 patients treated with other cytoreductive therapy, and 25 patients without treatment.
RESULTS: A higher occurrence of second malignancies was found in the group treated with hydroxyurea (7.6%; other cytoreduction: 1.2%; without therapy: 0). After a median follow-up of 89 months in the hydroxyurea group, 13 patients developed second cancer during hydroxyurea therapy, located on the skin (68.75%) and other sites (31.25%).
CONCLUSION: The incidence of second malignancies during hydroxyurea therapy in our cohort patient was significantly higher than the incidence of malignancies in the Czech population of corresponding age.

Related: Hydroxycarbamide

Check JH, Check D, Cohen R, Sarumi M
Mifepristone causing complete remission of rapidly advancing leukemia with measurement of progesterone-induced blocking factor.
Anticancer Res. 2014; 34(5):2413-6 [PubMed] Related Publications
BACKGROUND: Mifepristone has been demonstrated to cause palliation from murine and human cancer, even in cancers not known to be positive for expression of progesterone receptors. The aim of the present study was to determine if rapidly advancing chronic lymphocytic leukemia responds to mifepristone therapy, and if so, is this effect related to increased expression of the progesterone-induced blocking factor? Case Report: An 81-year-old woman with chronic lymphocytic leukemia whose condition progressed to the acute rapidly progressing stage agreed to be exclusively treated orally with 200 mg mifepristone daily.
RESULTS: The patient showed a dramatic improvement after a short exposure time to mifepristone. Complete remission has persisted so far for 12 months on exclusive mifepristone therapy. Her PIBF levels were normal before mifepristone therapy and did not change after treatment.
CONCLUSION: Mifepristone can provide marked improvement of human leukemia even in the absence of increased serum PIBF levels.

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

Bernués M, Durán MA, Puget G, et al.
Genetics of lymphocytes influences the emergence of second cancer in chronic lymphocytic leukemia.
Anticancer Res. 2014; 34(5):2311-4 [PubMed] Related Publications
BACKGROUND: Patients affected by chronic lymphocytic leukemia (CLL) have an increased risk of developing a second cancer. There is not a definitive explanation for this phenomenon, although some hypotheses have been postulated. The aim of the present work was to assess the presence of second cancer in untreated patients with CLL who were cytogenetically characterized, and secondly to investigate if there is a correlation between the genetics of CLL and the emergence of second cancer.
PATIENTS AND METHODS: We performed conventional cytogenetics and Fluorescent in situ hybridization analyses in a series of 106 patients.
RESULTS: We observed that nearly 8% of cases developed second cancer, mostly epithelial tumors. The majority of them presented two common features, del(13)(q14.3) and the presence of at least two genetic alterations.
CONCLUSION: We suggest that the genetic background of CLL, particularly the presence of several genetic alterations, influences the emergence of second cancer in patients affected by CLL.

Related: Cancer Cytogenetics FISH Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Trendowski M, Yu G, Wong V, et al.
The real deal: using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells.
Anticancer Res. 2014; 34(5):2195-202 [PubMed] Related Publications
BACKGROUND/AIM: Sonodynamic therapy (SDT) is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the efficacy of ultrasound's preferential damage to neoplastic cells. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Cytochalasin B is a cytokinesis inhibitor that preferentially enlarges and multinucleates malignant cells, making them much more sensitive to ultrasonic irradiation.
MATERIALS AND METHODS: The present study investigated the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood cell populations. Cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm(2)).
RESULTS: Cytochalasin B preferentially damages U937 cells both before and after sonication. This agent also reduces rapid proliferation as the clonogenicity of U937 cells was considerably reduced following treatment.
CONCLUSION: Cytochalasin B may have profound therapeutic applications when combined with SDT.

Mutneja R, Shah M, Vyas D, et al.
Respiratory failure due to lung involvement with adult T-cell leukemia/lymphoma: case report and review of literature.
Conn Med. 2014; 78(3):139-42 [PubMed] Related Publications
Acute adult T-cellleukemia/lymphoma (ATLL) is a hematologic malignancy that usually entails a poor prognosis; median survival is only six months. Significant immunosuppression is commonly seen in these patients. Lung involvement in ATLL is usually documented either radiographically or as an autopsy finding. Few proven cases of ante mortem extensive lung infiltration have been described in the scientific literature. We present a fatal case of acute respiratory failure as a result of histologically proven lung infiltration by malignant lymphocytes in a patientwith acuteATLL. Although the most common cause of death i n patients with ATLL is respiratory failure in the setting of an infectious process, it should be kept in mind that patients with ATLL with acute respiratory failure may have malignant lung infiltration as a potential cause.

Related: Methotrexate

Smith NA, Byl JA, Mercer SL, et al.
Etoposide quinone is a covalent poison of human topoisomerase IIβ.
Biochemistry. 2014; 53(19):3229-36 [PubMed] Article available free on PMC after 28/04/2015 Related Publications
Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2-3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIβ in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIα have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIβ have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIβ. The quinone induced ~4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ~2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ~2-4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ.

Related: Etoposide TOP2B

Xiong Q, Yang Y, Wang H, et al.
Characterization of miRNomes in acute and chronic myeloid leukemia cell lines.
Genomics Proteomics Bioinformatics. 2014; 12(2):79-91 [PubMed] Related Publications
Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA) expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML) cell line, K562, via massively parallel signature sequencing. mRNA expression profiles of these cell lines that were established previously in our lab facilitated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppressors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expression patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phagocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress differentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias.

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

Ribera JM, Oriol A, Morgades M, et al.
Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.
J Clin Oncol. 2014; 32(15):1595-604 [PubMed] Related Publications
PURPOSE: Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation.
PATIENTS AND METHODS: Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10(-4) at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10(-4).
RESULTS: Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10(-3) after induction and ≥ 5 × 10(-4) after early consolidation) as the only prognostic factor for DFS and OS.
CONCLUSION: Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

Related: Acute Lymphocytic Leukemia (ALL)

Cooley S, Weisdorf DJ, Guethlein LA, et al.
Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia.
J Immunol. 2014; 192(10):4592-600 [PubMed] Article available free on PMC after 15/05/2015 Related Publications
Killer cell Ig-like receptors (KIRs) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor hematopoietic cell transplantation (HCT). We have shown previously that donors with KIR B versus KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia by reducing the incidence of leukemic relapse and improving leukemia-free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIRs that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T cell-replete transplants to examine the interaction between donor KIR B genes and recipient class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared with C2 homozygous recipients, with no effect due to donor HLA. The protective interaction between donors with two or more, versus none or one, KIR B motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of leukemia-free survival, 0.57 [0.40-0.79]; p = 0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared with C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of unrelated donor hematopoietic cell transplantation for acute myelogenous leukemia.

Related: Acute Myeloid Leukemia (AML)

Meulepas JM, Ronckers CM, Smets AM, et al.
Leukemia and brain tumors among children after radiation exposure from CT scans: design and methodological opportunities of the Dutch Pediatric CT Study.
Eur J Epidemiol. 2014; 29(4):293-301 [PubMed] Related Publications
Computed tomography (CT) scans are indispensable in modern medicine; however, the spectacular rise in global use coupled with relatively high doses of ionizing radiation per examination have raised radiation protection concerns. Children are of particular concern because they are more sensitive to radiation-induced cancer compared with adults and have a long lifespan to express harmful effects which may offset clinical benefits of performing a scan. This paper describes the design and methodology of a nationwide study, the Dutch Pediatric CT Study, regarding risk of leukemia and brain tumors in children after radiation exposure from CT scans. It is a retrospective record-linkage cohort study with an expected number of 100,000 children who received at least one electronically archived CT scan covering the calendar period since the introduction of digital archiving until 2012. Information on all archived CT scans of these children will be obtained, including date of examination, scanned body part and radiologist's report, as well as the machine settings required for organ dose estimation. We will obtain cancer incidence by record linkage with external databases. In this article, we describe several approaches to the collection of data on archived CT scans, the estimation of radiation doses and the assessment of confounding. The proposed approaches provide useful strategies for data collection and confounder assessment for general retrospective record-linkage studies, particular those using hospital databases on radiological procedures for the assessment of exposure to ionizing or non-ionizing radiation.

Related: Childhood Brain Tumours Childhood Brain Tumors

Aref S, El-Ghonemy M, Abouzeid T, et al.
Prevalence and impact of colony stimulating factor 3 receptor (CSF3R) mutations among Egyptian acute myeloid leukemia patients.
Leuk Res. 2014; 38(6):722-5 [PubMed] Related Publications
Granulocyte-colony stimulating factor receptor (G-CSFR) mutations have been implicated in the progression of severe congenital neutropenia (SCN) to leukemia. This study aimed to investigate the prevalence of colony stimulating factor 3 receptor (CSF3R) mutations among Egyptian acute myeloid leukemia and their clinic-pathological impact. The study was conducted on 179 adult patients (156 de novo AML and 23 secondary AML on top of SCN). CSF3R mutations were analyzed by sequencing of the PCR products. CSF3R mutations were detected in 2 cases out of 156 de novo AML patients (1.2%) and eighteen cases out of 23 secondary AML patients (78.2%). It was noticed that most of the mutant cases are of younger age, have a high white blood cells count, high bone marrow blasts, bad performance status, and absence of extra medullary disease and with low rate induction remission. Also the overall survival of AML patient's secondary to CSF3R mutations was shorter as compared to those with wild type AML cases. In conclusion the frequency of CSF3R mutations is highly prevalent among AML patients secondary to SCN compared to de novo AML.

Related: Acute Myeloid Leukemia (AML)

Antohe I, Dascalescu A, Burcoveanu C, et al.
Pact with the devil: alemtuzumab therapy, immune suppression and infectious complications in chronic lymphocytic leukemia.
Rev Med Chir Soc Med Nat Iasi. 2014 Jan-Mar; 118(1):92-5 [PubMed] Related Publications
Infectious complications are an important cause of hospitalization in patients diagnosed with chronic lymphocytic leukemia. The pathogenesis of infection is complex, involving both disease-induced and treatment-related immune depression. During the last decade, the management of chronic lymphocytic leukemia (CLL) has been redefined by the approval of monoclonal antibody-based treatment, which resulted in improved therapeutic responses. Nonetheless, the profound lymphopenia induced by monoclonal agents was accompanied by increased incidence of infections caused by a new spectrum of opportunistic microorganisms. We report the case of a patient with hypercellular CLL who received Alemtuzumab as first line therapy and obtained a satisfactory therapeutic response, but developed subsequent atypical infectious complications.

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

Abulaban AA, Algahtani HA, Alharthi A
A child with leukemia and behavioral changes.
Neurosciences (Riyadh). 2014; 19(2):144-5 [PubMed] Related Publications
A 12-year-old Saudi girl, known case of T-cell leukemia with CNS relapse. She was diagnosed 2 years ago. Multiple cycles of chemotherapy had been used (Fludarabine, Cytarabine, Methotrexate, Cyclosporine, and Mercaptopurine). She was admitted electively for cord blood transplantation. Afterward, she developed visual, and behavioral change followed by seizure.

Zheng Y, Tan D, Chen Z, et al.
A non-genetic approach to labelling acute myeloid leukemia and bone marrow cells with quantum dots.
J Nanosci Nanotechnol. 2014; 14(6):4014-21 [PubMed] Related Publications
The difficulty in manipulation of leukemia cells has long hindered the dissection of leukemia pathogenesis. We have introduced a non-genetic approach of marking blood cells, using quantum dots. We compared quantum dots complexed with different vehicles, including a peptide Tat, cationic polymer Turbofect and liposome. Quantum dots-Tat showed the highest efficiency of marking hematopoietic cells among the three vehicles. Quantum dots-Tat could also label a panel of leukemia cell lines at varied efficiencies. More uniform intracellular distributions of quantum dots in mouse bone marrow and leukemia cells were obtained with quantum dots-Tat, compared with the granule-like formation obtained with quantum dots-liposome. Our results suggest that quantum dots have provided a photostable and non-genetic approach that labels normal and malignant hematopoietic cells, in a cell type-, vehicle-, and quantum dot concentration-dependent manner. We expect for potential applications of quantum dots as an easy and fast marking tool assisting investigations of various types of blood cells in the future.

Related: Acute Myeloid Leukemia (AML)

Reuter CW, Krauter J, Onono FO, et al.
Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia.
Ann Hematol. 2014; 93(6):977-82 [PubMed] Related Publications
Transforming mutations in RAS genes are commonly found in human malignancies, including myeloid leukemias. To investigate the incidence, spectrum, and distribution of activating K- and N-RAS mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients, 204 CN-AML patients were screened. Activating K- and N-RAS mutations were detected in 3 of 204 (1.5 %) and 22 of 204 (10.8 %) CN-AML samples, respectively. RAS mutated patients presented with a lower percentage of bone marrow blasts (65 vs 80 %, P = 0.022). RAS mutations tended to occur with nucleophosmin-1 (NPM1) mutations (P = 0.079), and all three samples containing K-RAS mutations had concomitant NPM1 mutations. There was no significant overlap between K-RAS mutations and N-RAS, FLT3, CEBPA, IDH1/2, WT1 or MLL mutations. RAS mutation status did not impact relapse-free or overall survival of CN-AML patients. In contrast to reports of noncanonical RAS mutations in other cancers, including some leukemia subtypes, we only observed K- and N-RAS mutations in codons 12, 13, or 61 in CN-AML samples. Our findings suggest that while K-RAS mutations are infrequent in CN-AML, activating K-RAS mutations may cooperate with mutated NPM1 to induce leukemia.

Related: Acute Myeloid Leukemia (AML) NPM1 gene

Niewerth D, Jansen G, Riethoff LF, et al.
Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor salinosporamide A (Marizomib).
Mol Pharmacol. 2014; 86(1):12-9 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Salinosporamide A (NPI-0052, marizomib) is a naturally occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to salinosporamide A by expressing redundant catalytically active mutants of the 20S proteasome β-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor bortezomib (BTZ). Here, we assessed the growth inhibitory potential of salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7) and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to salinosporamide A (IC50 = 5.1 nM), whereas their bortezomib-resistant sublines were 9- and 17-fold cross-resistant to salinosporamide A, respectively. Notably, combination experiments of salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (M45V) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Last, compared with parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. β-Subunit point mutations as a common feature of acquired resistance to salinosporamide A and bortezomib in hematologic cells and S. tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors.

Related: Bortezomib

Guo D, Zhao Y, Zhang Y, et al.
The cellular uptake and cytotoxic effect of silver nanoparticles on chronic myeloid leukemia cells.
J Biomed Nanotechnol. 2014; 10(4):669-78 [PubMed] Related Publications
Several studies have suggested that silver nanoparticles (AgNPs) have the potential to treat human cancers, including leukemia. However, the detailed cellular mechanisms for AgNPs to inhibit the growth of leukemic cells and their efficacy on clinical isolates of leukemic patients are not elucidated. In this study, the cellular uptake and cytotoxic mechanism of AgNPs in chronic myeloid leukemia (CML) cells were investigated. AgNPs were synthesized with a modified polyol method, which were stable under cell culture conditions with fetal bovine serum (FBS). AgNPs were demonstrated to be able to enter K562 cells (a CML cell line) in a dose-dependent manner and locate in endosomes. Reactive oxygen species (ROS) could be generated upon AgNPs exposure and cause cytotoxicity and apoptosis. It was also found that AgNPs treatment inhibited the viability of cells from CML patients (n = 4). The cell cycle status and several critical regulators were altered upon AgNPs treatment as well. All these cellular and molecular alterations caused by AgNPs exposure could be reversed by the addition of Vitamin C (an antioxidant). These results suggested that proper usage of AgNPs would be of great significance for CML treatment in future.

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

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