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Wednesday, August 27, 2008
 Latest
Chronic Leukemia News Headlines
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Chronic Leukemia News Headlines
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All Recent Chronic Leukemia News Headlines |
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Genmab announces four studies of ofatumumab in chronic lymphocytic leukemia
Genmab A/S announced today plans to begin four studies of ofatumumab in chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (NHL) this year. (Source: News-Medical News Feed)...
POSTED 08/25/2008 at 06:35 AM --
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Pentostatin in chronic lymphocytic leukemia
Expert Opinion on Drug Metabolism & Toxicology , September 2008, Vol. 4, No. 9, Pages 1217-1222.
Background: Chronic lymphocytic leukemia (CLL) is a disease that typically afflicts older individuals with a median age of diagnosis in the eighth decade of life for which treatments available now are not curative. Although purine analogue based ... (Source: Expert Opinion: Expert Opinion on Drug Metabolism & Toxicology: Table of Contents)...
POSTED 08/25/2008 at 12:34 AM --
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Genomic complexity in chronic lymphocytic leukemia
(Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Cytotoxic t lymphocytes directed to the preferentially expressed antigen of melanoma (prame) target chronic myeloid leukemia
The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02–restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFN in response to PRAME peptides (between 113 ± 8 and 795 ± 23 spot forming cells/105 T cells) and lysed PRAME peptide–loaded cells (45 ± 19% at an effector:target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02+/PRAME+ tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high βTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Effective elimination of fludarabine-resistant cll cells by peitc through a redox-mediated mechanism
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n = 58) and healthy subjects (n = 12), we showed that both fludarabine-resistant and -sensitive CLL cells were highly sensitive to β-phenylethyl isothiocyanate (PEITC) with mean IC50 values of 5.4 µM and 5.1 µM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50 = 27 µM, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Relative value of zap-70, cd38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia
Leukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70–negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70–positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Transcriptional repression of c-myb and gata-2 is involved in the biologic effects of c/ebp{alpha} in p210bcr/abl-expressing cells
Ectopic C/EBP expression in p210BCR/ABL-expressing hematopoietic cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To assess the underlying mechanisms, C/EBP targets were identified by microarray analyses. Upon C/EBP activation, expression of c-Myb and GATA-2 was repressed in 32D-BCR/ABL, K562, and chronic myelogenous leukemia (CML) blast crisis (BC) primary cells but only c-Myb levels decreased slightly in CD34+ normal progenitors. The role of these 2 genes for the effects of C/EBP was assessed by perturbing their expression in K562 cells. Ectopic c-Myb expression blocked the proliferation inhibition– and differentiation-inducing effects of C/EBP, whereas c-Myb siRNA treatment enhanced C/EBP-mediated proliferation inhibition and induced changes in gene expression indicative of monocytic differentiation. Ectopic GATA-2 expression suppressed the proliferation inhibitory effect of C/EBP but blocked in part the effect on differentiation; GATA-2 siRNA treatment had no effects on C/EBP induction of differentiation but inhibited proliferation of K562 cells, alone or upon C/EBP activation. In summary, the effects of C/EBP in p210BCR/ABL-expressing cells depend, in part, on transcriptional repression of c-Myb and GATA-2. Since perturbation of c-Myb and GATA-2 expression has nonidentical consequences for proliferation and differentiation of K562 cells, the effects of C/EBP appear to involve dif-ferent transcription-regulated targets. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Gossypol, a bh3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells
Gossypol, a cottonseed extract derivative, acts as a BH3-mimetic, binding to the BH3 pocket of antiapoptotic proteins and displacing pro-death partners to induce apoptosis. However, knowledge on the molecular underpinnings of its downstream effects is limited. Since chronic lymphocytic leukemia (CLL) cells express high levels of antiapoptotic proteins that act as a survival mechanism for these replicationally quiescent lymphocytes, we investigated whether gossypol induces apoptosis in these cells and what mechanism underlies gossypol-mediated cytotoxicity. Gossypol induced cell death in a concentration- and time-dependent manner; 24-hour incubation with 30 µM gossypol resulted in 50% cell death (median; range, 10%-80%; n = 47) that was not abrogated by pan-specific caspase inhibitor. Starting at 4 hours, the mitochondrial outer membrane was significantly permeabilized (median, 77%; range, 54%-93%; n = 15). Mitochondrial outer membrane permeabiliztaion (MOMP) was concurrent with increased production of reactive oxygen species (ROS); however, antioxidants did not abrogate gossypol-induced cell death. Mitochondrial membrane permeabilization was also associated with loss of intracellular adenosine triphosphate (ATP), activation of BAX, and release of cytochrome c and apoptosis-inducing factor (AIF), which was translocated to the nucleus. Blocking AIF translocation resulted in a decreased apoptosis, suggesting that AIF contributes to gossypol-mediated cytotoxicity in CLL lymphocytes. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Multidrug resistance gene (mdr1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia
Despite the excellent efficacy of imatinib in chronic myeloid leukemia (CML), the response in patients is heterogeneous, which may in part be caused by pharmacogenetic variability. Imatinib has been reported to be a substrate of the P-glycoprotein pump. In the current study, we focused on the ABCB1 (MDR1) genotype. We analyzed the 3 most relevant single nucleotide polymorphisms of MDR1 in 90 CML patients treated with imatinib. Among the patients homozygous for allele 1236T, 85% achieved a major molecular response versus 47.7% for the other genotypes (P = .003). For the 2677G>T/A polymorphism, the presence of G allele was associated with worse response (77.8%, TT/TA; vs 47.1%, GG/GA/GT; P = .018). Patients with 1236TT genotype had higher imatinib concentrations. One of the haplotypes (1236C-2677G-3435C) was statistically linked to less frequent major molecular response (70% vs 44.6%; P = .021). Hence, we demonstrated the usefulness of these single nucleotide polymorphisms in the identification of CML who may or may not respond optimally to imatinib. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Association between bmi-1 expression, acute graft-versus-host disease, and outcome following allogeneic stem cell transplantation from hla-identical siblings in chronic myeloid leukemia
Expression of CD7, ELA-2, PR-3, and the polycomb group gene BMI-1 reflects the intrinsic heterogeneity and predicts prognosis of patients with chronic myeloid leukemia (CML) who were not treated with allogeneic stem cell transplantation (allo-SCT). This study investigated whether expression of these genes determined outcome following allo-SCT in a cohort of 84 patients with chronic-phase (CP) CML. We found that patients expressing BMI-1 at a "high" level before allo-SCT had an improved overall survival (P = .005) related to a reduced transplantation-related mortality. In multivariate analysis, when adjusted for the European Group for Blood and Marrow Transplantation (EBMT)–Gratwohl score and other prog-nostic factors, there was an independent association between BMI-1 expression and grades 2 to 4 acute graft-versus-host disease (relative risk [RR] = 2.85; 95% confidence interval [CI], 1.3-6.4; P = .011), suggesting that BMI-1 measured prior to allo-SCT can serve as a biomarker for predicting outcome in patients with CP-CML receiving allo-SCT, and may thus contribute to better therapeutic decisions. (Source: Blood)...
POSTED 08/24/2008 at 11:00 PM --
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Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for gist.
Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST.
Dermatol Online J. 2008;14(7):7
Authors: Alexandrescu DT, Dasanu CA, Farzanmehr H, Kauffman L
Imatinib mesylate, a tyrosine kinase inhibitor targeting the Bcr-Abl protein, c-kit (KIT) and the platelet-derived growth factor receptors (PDGFR), is an important part of the therapeutic armamentarium used in chronic myelogenous leukemia and gastrointestinal stromal tumors. A multitude of dermatological toxicities occur with the clinical use of this drug, ranging from various acute rashes to Steven-Johnson syndrome. Hyperpigmentation of the skin is a less frequent side effect. This phenomenon may be linked to alterations in the c-kit signaling pathway, which plays an important role in melanogenesis. A similar cutaneous phenotypic expression is manifested in families carrying congenital tyrosine II domanin mutations of c-kit. We present a unique case of long-term persistent hyperpigmentation that occured after the treatment with imatinib and describe the possible pathogenetic mechanisms involved. Elucidation of the mechanisms of action of imatinib in the skin may open future directions for the treatment of pigmentary disorders.
PMID: 18718191 [PubMed - in process] (Source: Dermatol Online J)...
POSTED 08/24/2008 at 03:08 AM --
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50 years ago in the journal of pediatrics chronic monocytic leukemia in childhood.
50 years ago in The Journal of Pediatrics Chronic monocytic leukemia in childhood.
J Pediatr. 2008 Sep;153(3):390
Authors: Loh M
PMID: 18718261 [PubMed - as supplied by publisher] (Source: The Journal of Pediatrics)...
POSTED 08/23/2008 at 03:07 PM --
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Current perspectives on the management of chronic myeloid leukemia
Review the molecular pathogenesis of chronic myeloid leukemia, and explore the latest advances in tyrosine kinase inhibitors for its treatment. (Source: Medscape Hematology-Oncology Headlines)...
POSTED 08/22/2008 at 01:55 PM --
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Promyelocytic blast crisis of chronic myeloid leukemia during imatinib treatment.
Promyelocytic blast crisis of chronic myeloid leukemia during imatinib treatment.
Ann Clin Lab Sci. 2008;38(3):283-6
Authors: Chung HJ, Chi HS, Cho YU, Park CJ, Seo EJ, Kim KH, Lee JH
A 32-yr-old man with the chronic phase of chronic myeloid leukemia (CML-CP) was treated with imatinib mesylate for 6 mo. The real-time quantitative reverse transcription PCR ratio for BCR/ABL in blood mRNA (BCR/ABL RT-QPCR) decreased from an initial value of 0.0159 to a low value of 0.0012 after 3 mo, indicating complete hematologic response. During the next 3 mo, the patient progressed to a promyelocytic blast crisis, displaying leukemic cells containing both BCR/ABL and PML/RARalpha chimeric mRNAs. Complete remission was achieved by therapy with all-trans retinoic acid (ATRA) and high-dose imatinib mesylate. Using retrospective PML/RARalpha RT-QPCR with a bone marrow specimen obtained at the initial diagnosis of CML-CP, we quantified the mRNA ratio as 0.000321, suggesting that the clonal evolution of PML/RARalpha translocation occurred early in the CML-CP.
PMID: 18715859 [PubMed - in process] (Source: Annals of Clinical and Laboratory Science)...
POSTED 08/22/2008 at 09:25 AM --
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Bilateral infiltrative disease of the extraocular muscles: a rare clinical presentation of early stage chronic lymphocytic leukemia.
Bilateral infiltrative disease of the extraocular muscles: a rare clinical presentation of early stage chronic lymphocytic leukemia.
Orbit. 2008;27(4):293-5
Authors: Ramkissoon YD, Lee RW, Malik R, Hsuan JD, Potts MJ
Orbital involvement in chronic lymphocytic leukemia (CLL) is highly unusual and most commonly involves hemorrhage or soft tissue infiltration in advanced disease. We report a case of rapid onset bilateral orbital muscle infiltration as the presenting feature of early stage CLL. In addition, we demonstrate clinico-pathological correlation with an identical chronic B-cell lymphocytic infiltrate in both orbit and bone marrow, with good response of the orbital disease to local radiotherapy.
PMID: 18716967 [PubMed - in process] (Source: Orbit)...
POSTED 08/22/2008 at 08:33 AM --
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Chronic lymphocytic leukemia cells bind and present the erythrocyte protein band 3: possible role as initiators of autoimmune hemolytic anemia.
Chronic lymphocytic leukemia cells bind and present the erythrocyte protein band 3: possible role as initiators of autoimmune hemolytic anemia.
J Immunol. 2008 Sep 1;181(5):3674-83
Authors: Galletti J, Cañones C, Morande P, Borge M, Oppezzo P, Geffner J, Bezares R, Gamberale R, Giordano M
The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4(+) T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.
PMID: 18714043 [PubMed - in process] (Source: Journal of Immunology)...
POSTED 08/22/2008 at 04:32 AM --
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Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders
Increasing evidence points to a heritable contribution in the development of lymphoma. The goal of this study was to determine the rate of familial lymphoproliferative malignancy among consecutive lymphoma patients presenting to a tertiary care center and to enrol families with multiple affected first-degree relatives on a data and tissue collection study. Beginning in 2004 all new patients presenting to the Dana-Farber Cancer Institute with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) or chronic lymphocytic leukaemia (CLL) were asked to complete a one-page self-administered family history questionnaire. 55·4% of 1948 evaluable patients reported a first-degree relative with a malignancy, with the highest rate among CLL probands. Lymphoid malignancies were particularly common, with 9·4% of all probands reporting a first-degree relative with a related lymphoproliferative disorder (LPD). This frequency was again highest for CLL, at 13·3% of CLL probands, compared to 8·8% of NHL probands and 5·9% of HL probands (P = 0·002). The prevalence of CLL was significantly increased in parents of CLL probands (P < 0·05), and a greater risk of NHL was seen in fathers of NHL probands than in mothers (P = 0·026). We conclude that familial aggregation of LPDs is common among newly diagnosed patients, varies significantly by diagnosis and contributes meaningfully to the population disease burden. (Source: British Journal of Haematology)...
POSTED 08/21/2008 at 11:00 PM --
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Octreotide therapy in asparaginase-associated pancreatitis in childhood acute lymphoblastic leukemia
Little is known about octreotide therapy in asparaginase-associated pancreatitis (AAP) in children. Of the 59 children with acute lymphoblastic leukemia (ALL) receiving E. coli L-asparaginase, 5 patients (8.5%) developed AAP. Octreotide was administered to four patients. Clinical and laboratory improvement were evident after octreotide therapy. There were no deaths and no severe adverse side effects were noted. No pseudocysts were detected; however, two of the four patients developed diabetes. One child without octreotide treatment developed chronic pancreatitis and pseudocyst. We conclude that octreotide therapy appears to be safe and potentially beneficial in the management of AAP in children. Pediatr Blood Cancer © 2008 Wiley-Liss, Inc. (Source: Pediatric Blood and Cancer)...
POSTED 08/21/2008 at 11:00 PM --
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Combination of 5-azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia
The treatment of myelodysplastic syndromes (MDS) remains a challenge to the clinician despite recent advances. Many patients will either not respond or will have only limited and/or brief responses to single-agent therapy. Eventually, 30% of patients with MDS will progress and develop acute myeloid leukemia (AML). New strategies are needed for these patients.5-Azacytidine (AZA) and thalidomide were administered to 40 patients with MDS or AML. AZA was given at a dose of 75 mg/m2 subcutaneously for 5 of 28 days together with thalidomide starting at a dose of 50 mg per day and increasing to 100 mg per. Six patients had refractory anemia (RA), 2 patients had RA with ringed sideroblasts, 10 patients had RA with excess blasts (RAEB), 1 patient had RAEB in transformation, 4 patients had chronic myelomonocytic leukemia, 1 patient had chronic idiopathic myelofibrosis, and 16 patients had AML. Thirty-six patients were evaluable for outcome.A hematologic improvement (HI) was observed in 15 of 36 patients (42%), stable disease was observed in 5 of 36 patients (14%), and 10 of 36 patients (28%) had disease progression. Six patients experienced complete remission (CR), 2 patients experienced an erythroid HI (HI-E), 1 patient experience an absolute neutrophil count HI (HI-ANC), 5 patients experienced a platelet HI (HI-P), and 7 patients had bilineage HI (HI-P and HI-ANC or an HI-E and HI-ANC). It was noteworthy that 9 of 14 patients with AML had a history of prior MDS, 2 of 9 patients achieved a CR, 4 of 9 patients had HI (HI-E and bilineage HI), and 1 patient had stable disease and was continuing treatment. DNA microarray analysis of 8 responders and 4 nonresponders revealed that the genes associated with cellular proliferation had higher expression levels in nonresponders.The current findings indicated that a combination of low-dose AZA and thalidomide was well tolerated and was effective therapy for the treatment of patients with MDS and AML arising from prior MDS. Cancer 2008. © 2008 American Cancer Society. (Source: Cancer)...
POSTED 08/19/2008 at 11:00 PM --
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Successful outcome of langerhans cell histiocytosis complicated by therapy-related myelodysplasia and acute myeloid leukemia: a case report
Background:
Various therapeutic options are available for the management of Langerhans cell histiocytosis. However, treatment administered to control this disease may be complicated by acute leukemia.Case presentationA 34 years old male was diagnosed to have Langerhans cell histiocytosis in March 1999. Unfortunately, the cytotoxic chemotherapy and radiotherapy given to control the repeated relapses and exacerbations of the primary disease predisposed him to therapy-induced myelodysplastic syndrome which transformed into acute myeloid leukemia. After achieving complete remission of his leukemia, the patient received an allogeneic hematopoietic stem cell transplant. The allograft was complicated by chronic graft versus host disease that was controlled by various immunosuppressive agents and extracorporal photophoresis.
Conclusion:
Management of complicated cases of histiocytosis requires various therapeutic modalities and a multidisciplinary approach. Having complications of therapy eg myelodysplasia or acute leukemia make the outcome more dismal and the management options limited to aggressive forms of treatment. High dose chemotherapy followed by an allograft may be a curative option not only for therapy-related myelodysplasia / acute leukemia, but also for frequently relapsing and poorly controlled Langerhans cell histiocytosis. (Source: Cases Journal)...
POSTED 08/17/2008 at 11:00 PM --
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