Phase 1 Study of sorafenib in patients with refractory or relapsed acute leukemias.
Haematologica. 2010 Oct 15;
Authors: Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ, Faderl S, Verstovsek S, Mathews S, Andreeff M, Cortes J
Background. Sorafenib is a multi- kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase 1 dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Design and Methods. Fifty patients received one of two different schedules: Schedule “A”: Once or twice daily, 5 days per week, every week for a 21 day cycle; and Schedule”B”: Once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase 2 dose in hematologic malignancies is 400 mg twice daily for both schedules. Results. Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions /complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. Conclusions. Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations.Clinical Trial Registration Information: ClinicalTrials.gov Identifier: NCT00217646.
PMID: 20952518 [PubMed - as supplied by publisher]
p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells.
Carcinogenesis. 2010 Oct 15;
Authors: Borriello A, Caldarelli I, Bencivenga D, Cucciolla V, Oliva A, Usala E, Danise P, Ronzoni L, Perrotta S, Della Ragione F
Chronic myelogenous leukemia (CML) is characterized by the expression of BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show that BCR-ABL positive CML cell lines treated with imatinib (STI571) undergo G1 cell cycle arrest associated with the accumulation of p57(Kip2), a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57(Kip2) increase precedes the reported STI571-dependent up-regulation of p27(Kip1). A number of complementary approaches allow the demonstration that p57(Kip2) build-up is due to the transcriptional activation of CDKN1C, the p57(Kip2)-encoding gene, while neither p57(Kip2) half-life elongation nor its cell relocalization were observed. We also identified a heretofore undescribed pattern of p57(Kip2) phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57(Kip2) up-regulation occurs only in STI571-responsive cells, while the CKI accumulation was not evidenced in an imatinib-resistant clone. Nilotinib and dasatinib (second-generation BCR-ABL inhibitors), at concentrations comparable to those used in therapy, increase the CKI but do not affect p27(Kip1) level. Finally, CD34(+) cells from CML patients display a clear imatinib-dependent p57(Kip2) up-regulation, which was not observed in CD34(+) cells from control subjects. In conclusion, our study points to p57(Kip2) as a novel and precocious effector of BCR-ABL targeting drugs.
PMID: 20952511 [PubMed - as supplied by publisher]
Can grapefruit juice decrease the cost of imatinib for the treatment of chronic myelogenous leukemia?
Leuk Res. 2010 Oct 15;
Authors: Kimura SI, Kako S, Wada H, Sakamoto K, Ashizawa M, Sato M, Terasako K, Kikuchi M, Nakasone H, Okuda S, Yamazaki R, Oshima K, Nishida J, Watanabe T, Kanda Y
PMID: 20952061 [PubMed - as supplied by publisher]
Chronic myelogenous leukemia cells convert to myofibroblasts in vitro: Effect of vascular endothelial growth factor on development of the microenvironment.
Leuk Res. 2010 Oct 15;
Authors: Shirasaki R, Tashiro H, Mizutani-Noguchi M, Kawasugi K, Shirafuji N
To elucidate the biological characteristics of chronic myelogenous leukemia (CML) cells, we observed morphological and functional changes of CML cells during primary long-term culture, in which their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental CML cells including BCR-ABL fusion gene, and produced cytokines such as granulocyte colony-stimulating factor, interleukin-6, and vascular endothelial growth factor (VEGF)-A. When cultured on the CML-derived myofibroblasts, parental non-adherent CML cells significantly proliferated. When anti-VEGF-A-neutralizing antibody was added to the cultures, non-adherent CML cell proliferation was significantly inhibited. These observations indicate that CML cells can convert their morphology and function to adherent myofibroblasts, and produce a significant amount of cytokine to give a growth-promotion activity to CML cells.
PMID: 20952060 [PubMed - as supplied by publisher]
The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or immunosuppressed patients.
Int J Antimicrob Agents. 2010 Oct 12;
Authors: Perkhofer S, Lass-Flörl C, Hell M, Russ G, Krause R, Hönigl M, Geltner C, Auberger J, Gastl G, Mitterbauer M, Willinger B, Knöbl P, Resch G, Waldner R, Makrai A, Hartmann G, Girschikofsky M, Greil R
A prospective, observational, multicentre study was performed to assess the incidence, diagnosis, epidemiology and outcome of invasive mould infections (IMIs) reported to the Nationwide Austrian Aspergillus Registry. In total, 186 cases were recorded, corresponding to an annual incidence of 42 cases/1000 patients at risk or 2.36 cases/100000 inhabitants. Patients with acute myelogenous leukaemia (34%) and lung transplant recipients (17%) are currently at highest risk for IMI, followed by a mixed population with impaired immunity (14%). In total, 34%, 30% and 36% were proven, probable and possible cases of IMI. Predominant pathogens were Aspergillus spp. (67%), followed by the zygomycetes (28%). Voriconazole was the most frequently administered agent (38%), followed by caspofungin (20%) and posaconazole (19%). Eighty patients (43%) received antifungal prophylaxis for ?7 days, 30% of whom (24 patients) suffered from a breakthrough infection. The overall crude 12-week mortality was 34%. Multivariate analysis showed that outcome and survival did not correlate with the status of fungal disease, breakthrough infection, fungal species or age (P>0.05). Aspergillosis remains the most commonly identified IMI amongst immunocompromised and/or immunosuppressed patients, but other moulds constitute a significant problem. Survival from IMIs appears to have improved and the main challenge is to overcome breakthrough fungal infections.
PMID: 20947312 [PubMed - as supplied by publisher]
Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily.
Cancer. 2010 Aug 15;116(16):3852-61
Authors: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H
BACKGROUND: In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome-positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow-up are reported. METHODS: Patients were stratified according to whether they had CML in myeloid blast phase (MBP-CML) or in lymphoid blast phase (LBP-CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily. RESULTS: In patients with MBP-CML, the major hematologic response rate was 28% for both regimens; and, in patients with LBP-CML, the major hematologic response rate was 42% for once-daily dasatinib and 32% for twice-daily dasatinib. The major cytogenetic response rates were 25% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective rates in patients with LBP-CML were 50% and 40%. The overall survival rate at 24 months was 24% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective values in patients with LBP-CML were 21% and 16%. Adverse events indicated a trend toward improved tolerability for the once-daily regimen. CONCLUSIONS: The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70-mg twice-daily regimen in patients with imatinib-resistant, blast phase CML.
PMID: 20564086 [PubMed - indexed for MEDLINE]
Delivery of therapeutic shRNA and siRNA by Tat fusion peptide targeting BCR-ABL fusion gene in Chronic Myeloid Leukemia cells.
J Control Release. 2010 Aug 3;145(3):272-80
Authors: Arthanari Y, Pluen A, Rajendran R, Aojula H, Demonacos C
Gene silencing by RNA interference (RNAi) is a promising therapeutic approach for a wide variety of diseases for which the biological cause is known. The main challenge remains the ineffective RNAi delivery inside the cells. Non-viral gene delivery vectors have low immunogenicity compared to viral vectors, but are constrained by their reduced transfection efficiency. Silencing of the bcr-abl gene expression by RNAi confers therapeutic potential in Chronic Myeloid Leukemia (CML), but is limited by the cytotoxicity of the existing delivery methods. Here, we present evidence that the fusion between the cell penetrating peptide (CPP) HIV-Tat (49-57) and the membrane lytic peptide (LK15), Tat-LK15, mediates high transfection efficiency in delivering short hairpin RNA (shRNA) and small interfering RNA (siRNA) targeting the BCR-ABL oncoprotein in K562 CML cells. Our results show that shRNA complexes induce a more stable gene silencing of bcr-abl when compared to silencing mediated by siRNA complexes. In addition, silencing of the BCR-ABL oncoprotein by both shRNA and siRNA delivered by Tat-LK15 is more efficient and longer lasting than that achieved using Lipofectamine and more importantly without considerable cytotoxicity. In these terms Tat-LK15 can be an alternative to DNA/siRNA delivery in difficult-to-transfect leukemic cells.
PMID: 20403398 [PubMed - indexed for MEDLINE]
Interferon regulatory factor 4 (IRF-4) plays important functions in B- and T-cell development and immune response regulation and was originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. Although IRF-4 is expressed in myeloid cells, its function in that lineage is not known. The closely related family member IRF-8 is a critical regulator of myelopoiesis, which when deleted in mice results in a syndrome highly similar to human chronic myelogenous leukemia. In early lymphoid development, we have shown previously that IRF-4 and IRF-8 can function redundantly. We therefore investigated the effects of a combined loss of IRF-4 and IRF-8 on hematologic tumorigenesis. We found that mice deficient in both IRF-4 and IRF-8 develop from a …