Dasatinib: from treatment of imatinib-resistant or -intolerant patients with chronic myeloid leukemia to treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia.

BACKGROUND: Imatinib is an effective treatment for patients with newly diagnosed chronic phase chronic myeloid leukemia (CML-CP), but resistance to imatinib can occur. Second-generation BCR-ABL inhibitors have shorter onset times and higher rates of complete cytogenetic response (CCyR) than imatinib. Dasatinib has a half-maximal inhibitory concentration 325 times lower than imatinib for BCR-ABL substrate phosphorylation in vitro and is less susceptible to most known molecular mechanisms of BCR-ABL imatinib resistance. OBJECTIVES: This study summarized published data on the use of dasatinib in CML-CP, reviewed the importance of early response to therapy, and discussed additional therapies for patients with newly diagnosed disease. METHODS: PubMed was searched through June 2011 for English-language publications with the following search terms: imatinib, dasatinib, nilotinib, chronic myeloid/myelogenous leukemia or CML, and clinical trial. To identify follow-up data from published trials and data on trials in progress and products in development, similar searches were conducted for abstract and clinical trial databases. Relevant articles and abstracts were identified as those reporting results of Phase II and III clinical trials, predictors of treatment response, and treatment guidelines. No prespecified inclusion or exclusion criteria were used. RESULTS: Dasatinib was effective in patients resistant to imatinib and more effective than high-dose imatinib in patients with newly diagnosed CML who were resistant to standard dose imatinib. Compared with imatinib, dasatinib induced superior response rates and patient outcomes earlier in the disease. In a Phase III trial in patients with newly diagnosed CML-CP, dasatinib 100 mg once daily induced significantly higher and faster rates of confirmed CCyR and major molecular response by 12 months versus imatinib and was generally well tolerated. Early achievement of CCyR was associated with better long-term progression-free survival. Dasatinib was approved by the U.S. Food and Drug Administration and the European Medicines Agency for initial treatment of CML-CP. CONCLUSIONS: Dasatinib was an effective treatment with the potential to improve long-term outcomes for patients with newly diagnosed CML-CP.

Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway.

Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as beta1-integrin, paxillin and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of the phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function.

Diagnosis and management of lymphoma.

The 42nd Annual Meeting of the American Society of Clinical Oncology was held in Atlanta, GA, June 2-6, 2006. Some of the presentations pertaining to the diagnosis and management of non-Hodgkin's lymphoma are summarized in this review. Principal issues in indolent lymphoma included the role of maintenance therapy, novel agents such as bendamustine and pixantrone, and updates of predictive factors. Studies in aggressive lymphomas included standard regimens, such as rituximab-based chemotherapy and radioimmunotherapy, as well as novel salvage regimens. Advances in the management of mantle cell lymphoma with radioimmunotherapy, hyper-CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) and emerging agents, such as bortezomib and temsirolimus, were presented.

Recent advances in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is a low-grade B-lineage lymphoid malignancy. Based on recent findings, the disease appears to be more heterogeneous than previously thought. Many cases may require no treatment at all unless patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is noncurative and is directed at reducing the symptoms. Recently described molecular risk features may help delineate at initial diagnosis which patients will have a more aggressive course. Newer treatment regimens incorporating purine nucleoside analogs and monoclonal antibodies have increased the rate of molecular complete remissions, which may lead to increased survival. Reduced intensity conditioning regimens have made the potentially curative modality of allogeneic transplantation more widely available. All of these recent treatments have significant risks of infectious complications, which must be carefully weighed against the risks posed by the underlying disease, and many low-risk asymptomatic patients do not require any treatment. A proposed risk-based treatment algorithm will be discussed.

ABCG2 (BCRP): a cytoprotectant in normal and malignant stem cells.

ABCG2 is a member of the adenosine triphosphate-binding cassette (ABC) family of cell surface transport proteins. ABCG2 is expressed in many types of primitive repopulating cells, and may be a marker of tumor stem cells. The physiologic role of ABCG2 seems to be excretion of genotoxic substances from the body and from primitive repopulating cell populations. A unifying hypothesis is presented, linking the expression of ABCG2 in normal and malignant stem cells with a physiologic role for protection of stem cells. Future studies will explore the possible role of ABCG2 in tumor stem cells and how this may influence the selection of new cancer therapeutic strategies.

Chronic lymphocytic leukemia: recent advances in diagnosis and treatment.

Chronic lymphocytic leukemia (CLL) is a low-grade B-lineage lymphoid malignancy but may have more heterogeneity than previously thought. Many cases require no treatment at all because of an indolent course, while other patients become symptomatic or develop signs of rapid progression. Treatment is usually noncurative and is directed at reducing the symptoms. Some molecular risk features may help delineate, at initial diagnosis, which patients will have a more aggressive course. Newer CLL treatment regimens incorporating purine nucleoside analogues and monoclonal antibodies have increased the rate of molecular complete remissions, which may lead to better survival times. Reduced intensity allogeneic transplant conditioning regimens have made the potentially curative modality more widely available. All these treatments have significant risks for infectious complications, which must be carefully weighed against the risks posed by the underlying disease. A proposed risk-based treatment algorithm is discussed.

Advances in the diagnosis and treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a low-grade B-lineage lymphoid malignancy, which is often not treated until patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is non-curative and is directed at reducing the symptoms from an increasing disease burden. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in CLL patients. Recent combination chemoimmunotherapy regimens have produced frequent complete molecular remissions, and early evidence suggests this may result in an improved long-term survival. Allogeneic hematopoietic cell transplantation is the only curative therapy for CLL but is infrequently used due to the older age of most patients, although reduced intensity conditioning regimens have reduced the toxicity of allogeneic transplantation. This review will summarize recent advances in the management of CLL, including prognostic factors, combination chemotherapy including nucleoside analogs and monoclonal antibodies, and reduced intensity allogeneic transplant conditioning regimens.

Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.

We evaluated the safety and toxicity through a 5-cohort dose-modification model of once-daily administration of IV busulfan (Bu) in combination with high-dose cyclophosphamide (Cy) as preparative therapy for stem cell transplantation. Twenty-one adult patients with hematologic malignancies were evaluated. Eleven patients underwent autologous and 10 patients underwent HLA-matched sibling allogeneic transplantation. Patients were sequentially enrolled into 5 cohorts. Cohort 1 received intravenous (IV) Bu 1.6 mg/kg every 12 hours for 2 doses and then 0.8 mg/kg every 6 hours for 12 doses; cohort 2 received IV Bu 1.6 mg/kg every 12 hours for 4 doses and then 0.8 mg/kg every 6 hours for 8 doses; cohort 3 received IV Bu 3.2 mg/kg for 1 dose and then 1.6 mg/kg every 12 hours for 2 doses and 0.8 mg/kg every 6 hours for 8 doses; cohort 4 received IV Bu 3.2 mg/kg every 24 hours for 2 doses and then 0.8 mg/kg every 6 hours for 8 doses; and cohort 5 received IV Bu 3.2 mg/kg every 24 hours for 4 doses. In all groups, Bu was administered on day -7 through day -4 and was followed at least 6 hours after the last Bu dose by Cy 60 mg/kg daily for 2 doses on days -3 and -2. Blood samples were collected for pharmacokinetic analysis on the first and last day of IV Bu administration. All patients were alive and had engrafted at day 30. Five patients developed grade 3 or 4 toxicities. Four patients developed hepatic abnormalities, and 3 exhibited evidence of veno-occlusive disease. Two of 3 patients in cohort 5 with a Bu area under the curve >6000 micromol/min developed autopsy-confirmed veno-occlusive disease. Interpatient variability in AUCs was observed in patients within and between cohorts, but no statistically significant interpatient differences were observed in Bu half-life, volume of distribution, clearance, or dose-adjusted area under the curve. Further, minimal variability in Bu pharmacokinetics was observed between the 2 evaluations performed in each patient, thus reflecting the stability of Bu disposition within individual patients. On the basis of the dosing guidelines and schedule outlined in this study, our data suggest that administration of IV Bu 3.2 mg/kg IV every 24 hours for 4 doses in combination with Cy may result in excessive toxicity.

Advances in the diagnosis and treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, accounting for up to 25% of all newly diagnosed leukemia. Many cases of CLL have a non-aggressive course and often do not require treatment, while other cases exhibit rapid progression within several years. Recent advances in the diagnosis of CLL include the identification of several prognostic factors, such as ZAP70 expression and the absence of immunoglobulin gene rearrangements. These prognostic factors may identify subgroups of CLL patients who would benefit from earlier treatment rather than "watchful waiting." New combination treatment regimens that include nucleoside analogs (fludarabine, cladribine, and pentostatin) and monoclonal antibodies (rituximab and alemtuzumab) have resulted in improved rates of complete remissions in newly diagnosed and relapsed CLL patients; many of these are molecular complete remissions. The only known cure for CLL remains allogeneic hematopoietic cell transplantation. Newer conditioning strategies with lower, nonmyeloablative doses of chemotherapy and radiation therapy have made this option available to a broader group of patients, including older and sicker populations. These advances in prognostic factors, chemotherapy regimens, and allogeneic transplantation will likely enable increases in survival for CLL patients.

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells.

ABCG2 (BCRP) is a member of the ATP-binding cassette (ABC) family of cell surface transport proteins. ABCG2 expression occurs in a variety of normal tissues, and is relatively limited to primitive stem cells. ABCG2 expression is associated with the side population (SP) phenotype of Hoechst 33342 efflux. The substrate profile of ABCG2 includes the antineoplastic drugs primarily targeting topoisomerases, including anthracyclines and camptothecins. More recently, pheophorbide, a chlorophyll-breakdown product, and protoporhyrin IX have been described as ABCG2 substrates, perhaps indicating a physiologic role of cytoprotection of primitive cells. Also, mice lacking ABCG2 expression have no intrinsic stem cell defects, although there is a remarkable increase in toxicity with antineoplastic drugs that are ABCG2 substrates, and also a photosensitivity resembling protoporphyria. Like other members of the ABC family, such as MDR1 and MRP1, ABCG2 is expressed in a variety of malignancies. Despite numerous reports of ABCG2 expression in AML, there is little evidence that ABCG2 expression is correlated with an adverse clinical outcome. This review will focus on the potential usefulness of ABCG2 as a marker primitive stem cells and possible physiologic roles of ABCG2 in protection of primitive stem cell populations, and potential methods of overcoming ABCG2-associated drug resistance in anticancer therapy.

Low levels of ABCG2 expression in adult AML blast samples.

Previous reports have suggested that the adenosine triphosphate-binding cassette protein ABCG2 (breast cancer resistance protein [BCRP], mitoxantrone resistance [MXR]) is associated with drug resistance in acute myeloid leukemia (AML). The aims of this study were to determine the level of ABCG2 mRNA expression necessary to produce drug resistance and to define the ABCG2 levels in normal bone marrow (BM), peripheral blood (PB), cord blood (CB), and adult AML blast cell populations. First, using transduced clonal cell lines expressing varying levels of ABCG2, we found that ABCG2 expression conferred resistance to mitoxantrone and topotecan, but not to idarubicin. Next, we developed a real-time reverse transcription-polymerase chain reaction assay for measuring ABCG2 mRNA expression levels in clinical samples. Normal BM and PB contained low levels of ABCG2 mRNA, while higher levels were measured in CB mononuclear cells, CD34(+), and Ac133(+) populations, consistent with the known stem cell enrichment in these populations. Next, we studied the ABCG2 mRNA levels in 40 specimens from newly diagnosed adult AML patients. Only 7% of these samples contained ABCG2 mRNA levels within the range of our drug-resistant clone, although another 78% were higher than normal blood and bone marrow. Flow cytometry revealed very small subpopulations of ABCG2-expressing cells in the cases we examined. Our data suggest that high levels of ABCG2 mRNA expression in adult AML blast specimens are relatively uncommon and that ABCG2 expression may be limited to a small cell subpopulation in some cases.