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Background: Imatinib has been found to substantially improve outcomes in patients with chronic myeloid leukemia (CML) compared with previously available therapies. However, its use is complicated by development of resistance or drug intolerance, prompting dose escalation or a trial of dasatinib or nilotinib, the secondgeneration tyrosine kinase inhibitors (TKIs). Objectives: This article reviews the mechanisms of TKI resistance; discusses the tolerability and efficacy of high-dose imatinib, dasatinib, and nilotinib; and provides background for the rational use of second-line treatment options. Methods: MEDLINE (1966–December 2009) and EMBASE (1993–December 2009) were searched for pertinent English-language publications using search terms that included, but were not limited to, chronic myeloid leukemia, imatinib, dasatinib, nilotinib, and clinical trial. Abstracts from American Society of Hematology annual meetings (2005–2009) were also reviewed. There were no prespecified inclusion or exclusion criteria. Results: Major and complete cytogenetic responses (MCyR and CCyR, respectively) to second-line treatment with high-dose (600–800 mg/d PO) imatinib were restricted to CML patients who had achieved a CyR to standard-dose imatinib: >90% of patients without a previous CyR failed to respond. The expected durability of the response to this approach remains unclear. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 14%, 39%, and 8%, respectively, of patients receiving high-dose imatinib. In patients who failed first-line treatment with imatinib, dasatinib (70 mg BID PO) was associated with higher rates of CCyR at 2 years compared with imatinib (44% vs 18%, respectively; P = 0.003), as well as higher estimated rates of progression-free survival at 2 years (86% vs 65%; P = 0.001). Dasatinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 57% and 63% of patients, respectively, and pleural effusion in 5%. Nilotinib treatment was effective in patients who were resistant to or unable to tolerate imatinib, with 46% and 58% achieving a CCyR and MCyR, respectively, at 2 years. Nilotinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 28% and 40% of patients, respectively, and QTc-interval prolongation in 1% to 10% of patients. Neither agent was clinically effective in patients with the common T315I mutation. Conclusion: Dasatinib and nilotinib were effective and generally well tolerated as second-line treatments for CML patients with a suboptimal response to standard doses of imatinib or imatinib intolerance. [Copyright &y& Elsevier]

Abstract: Over the past two decades, major advances in our understanding of cancer have translated into only modest increments in survival for the majority of cancer patients. Recent data suggesting cancers arise from rare self-renewing stem cells that are biologically distinct from their more numerous differentiated progeny may explain this paradox. Current anticancer therapies have been developed to decrease the bulk of the tumour mass (i.e. the differentiated cancer cells). Although treatments directed against the bulk of the cancer may produce dramatic responses, they are unlikely to result in long-term remissions if the rare cancer stem cells are also not targeted. Conversely, treatments that selectively attack cancer stem cells will not immediately eliminate the differentiated cancer cells, and might therefore be prematurely abandoned if clinical activity is judged solely by traditional response criteria that reflect changes in the bulk of the tumour. Re-examining both our pre-clinical and clinical drug development paradigms to include the cancer stem cell concept has the potential to revolutionize the treatment of many cancers. [Copyright &y& Elsevier]

Although treatment with the protein kinase C (P1(C) activator phorbol 12-myristate 13-acetate (PMA) is known to protect a subset of cells from induction of apoptosis by death ligands such as Fas ligand and tumor necrosis factor-α-related apoptosis-inducing ligand, the mechanism of this protection is unknown. This study demonstrated that protection in short term apoptosis assays and long term proliferation assays was maximal when Jurkat or HL-60 human leukemia cells were treated with 2-5 flM PMA. Immunoblotting demonstrated that multiple PKC isoforms, including PKCα, PKCβ, PKCϵ, and PKCO, translocated from the cytosol to a membrane-bound fraction at these PMA concentrations. When the ability of short hairpin RNA (shRNA) constructs that specifically down-regulated each of these isoforms was examined, PKCβ shRNA uniquely reversed PMAinduced protection against cell death, The PKCβ-selective small molecule inhibitor enzastaurin had a similar effect. Although mass spectrometry suggested that Fas is phosphorylated on a number of serines and threonines, mutation of these sites individually or collectively had no effect on Fas-mediated death signaling or PMA protection. Further experiments demonstrated that PMA diminished ligand-induced cell surface accumulation of Fas and DR5, and PKCβ shRNA or enzastaurin reversed this effect. Moreover, enzastaurin sensitized a variety of human tumor cell lines and clinical acute myelogenous leukemia isolates, which express abundant PKCβ, to tumor necrosis factor-a related apoptosis-inducing ligand-induced death in the absence of PMA. Collectively, these results identify a specific PKC isoform that modulates death receptor-mediated cytotoxicity as well as a small molecule inhibitor that mitigates the inhibitory effects of PKC activation on ligand-induced death receptor trafficking and cell death. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic blood and marrow transplantation (alloBMT) remains the only curative treatment for patients with myelodysplastic syndromes (MDS), but its application has been limited by the older age range of patients with this disease. T cell depletion decreases transplant-related toxicity related to graft-versus-host disease (GVHD), but does not improve overall survival because of increased risk for relapse and graft failure. Myeloid growth factors have been used to speed engraftment following alloBMT, but data suggest that they may also have anti-tumor properties. We treated 43 patients (median age 56) with MDS/AML with high-risk features using a myeloablative T cell depleted alloBMT followed by prolonged systemic GM-CSF. The current event-free survival at 1 and 3 years was 47% and 34%, respectively with a median follow-up of 22.8 months in surviving patients. The toxicities compared favorably with those seen using reduced intensity conditioning regimens and included grade III/IV GVHD (10%), graft failure (9%), and cumulative treatment-related mortality (28%). The cumulative incidence of relapse remained high at 38%; however, 3/10 patients receiving donor lymphocyte infusions achieved durable complete remissions. These results suggest that it is possible to maintain treatment intensity while minimizing toxicity in older, high-risk MDS patients. [Copyright &y& Elsevier]