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Chronic myelogenous leukemia (CML) is a slowly progressing disease in which too many white blood cells (not lymphocytes) are made in the bone marrow. Learn about chronic myelogenous leukemia and find information on how we support and care for people with CML before, during, and after treatment.
The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström's macroglobulinemia.
The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.
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In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.
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Chronic myelogenous leukemia (also called CML or chronic granulocytic leukemia) is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age, and rarely occurs in children.
Normally, the bone marrow makes bloodstem cells (immature cells) that develop into mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. The lymphoid stem cell develops into a white blood cell. The myeloid stem cell develops into one of three types of mature blood cells:
In CML, too many blood stem cells develop into a type of white blood cell called granulocytes. These granulocytes are abnormal and do not become healthy white blood cells. They may also be called leukemic cells. The leukemic cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or easy bleeding may occur.
This summary is about chronic myelogenous leukemia. See the following PDQ summaries for more information about leukemia:
These and other symptoms may be caused by CML. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:
Sometimes CML does not cause any symptoms at all.
Every cell in the body contains DNA (genetic material) that determines how the cell looks and acts. DNA is contained inside chromosomes. In CML, part of the DNA from one chromosome moves to another chromosome. This change is called the "Philadelphia chromosome." It results in the bone marrow making an enzyme, called tyrosine kinase, that causes too many stem cells to develop into white blood cells (granulocytes or blasts).
The Philadelphia chromosome is not passed from parent to child.
The following tests and procedures may be used:
The prognosis (chance of recovery) and treatment options depend on the following:
Staging is the process used to find out how far the cancer has spread. There is no standard staging system for chronic myelogenous leukemia (CML). Instead, the disease is classified by phase: chronic phase, accelerated phase, or blastic phase. It is important to know the phase in order to plan treatment. The following tests and procedures may be used to find out the phase:
When cancer cells spread outside the blood, a solid tumor may form. This process is called metastasis. The three ways that cancer cells spread in the body are:
The new (metastatic) tumor is the same type of cancer as the primary cancer. For example, if leukemia cells spread to the brain, the cancer cells in the brain are actually leukemia cells. The disease is metastatic leukemia, not brain cancer.
As the amount of blast cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may result in infections, anemia, and easy bleeding, as well as bone pain and pain or a feeling of fullness below the ribs on the left side. The number of blast cells in the blood and bone marrow and the severity of symptoms determine the phase of the disease.
In chronic phase CML, fewer than 10% of the cells in the blood and bone marrow are blast cells.
In accelerated phase CML, 10% to 19% of the cells in the blood and bone marrow are blast cells.
In blastic phase CML, 20% or more of the cells in the blood or bone marrow are blast cells. When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis.
In relapsedCML, the number of blast cells increases after a remission.
Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.
A tyrosine kinase inhibitor called imatinib mesylate is used as initial treatment for certain types of chronic myelogenous leukemia in newly diagnosed patients. It blocks an enzyme called tyrosine kinase that causes stem cells to develop into more white blood cells (granulocytes or blasts) than the body needs. Another tyrosine kinase inhibitor called dasatinib is used to treat patients with certain types of CML that have progressed, and is being studied as an initial treatment.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant. Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor's blood and may be frozen for storage. The donor's lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient's cancer cells as not belonging to the body and attack them.
Splenectomy is surgery to remove the spleen.
Information about clinical trials is available from the NCI Web site.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's clinical trials database.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.
Treatment of chronic phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with chronic phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Treatment of accelerated phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with accelerated phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Treatment of blastic phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with blastic phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Treatment of relapsedchronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with relapsing chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about chronic myelogenous leukemia, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on October 30, 2009.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Note: Estimated new cases and deaths from chronic myelogenous leukemia (CML) in the United States in 2009:[1]
CML is one of a group of diseases called the myeloproliferative disorders. Other related entities include polycythemia vera, myelofibrosis, and essential thrombocythemia. (Refer to the PDQ summary on Chronic Myeloproliferative Disorders Treatment for more information.)
CML is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph1).[2][3] The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.[4] This translocation results in the transfer of the Abelson (ABL) on chromosome 9 oncogene to an area of chromosome 22 termed the breakpoint cluster region (BCR).[4] This in turn results in a fused BCR/ABL gene and in the production of an abnormal tyrosine kinase protein that causes the disordered myelopoiesis found in CML. Furthermore, these molecular techniques can now be used to supplement cytogenetic studies to detect the presence of the 9;22 translocation in patients without a visible Ph1 (Ph1-negative).
Ph1-negative CML is a poorly defined entity that is less clearly distinguished from other myeloproliferative syndromes. Patients with Ph1-negative CML generally have a poorer response to treatment and shorter survival than Ph1-positive patients.[5] Ph1-negative patients who have BCR/ABL gene rearrangement detectable by Southern blot analysis, however, have prognoses equivalent to Ph1-positive patients.[6][7] A small subset of patients have BCR/ABL detectable only by reverse transcriptase–polymerase chain reaction (RT–PCR), which is the most sensitive technique currently available. Patients with RT–PCR evidence of the BCR/ABL fusion gene appear clinically and prognostically identical to patients with a classic Ph1; however, patients who are BCR/ABL-negative by RT–PCR have a clinical course more consistent with chronic myelomonocytic leukemia, which is a distinct clinical entity related to myelodysplastic syndrome.[6][8][9] Fluorescent in situ hybridization of the BCR/ABL translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.[10]
The median age of patients with Ph1-positive CML is 67 years.[11] The median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years. Survival after development of an accelerated phase is usually less than 1 year and after blastic transformation is only a few months.[10]
American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
Kurzrock R, Kantarjian HM, Druker BJ, et al.: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138 (10): 819-30, 2003.
Goldman JM, Melo JV: Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med 349 (15): 1451-64, 2003.
Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.
Onida F, Ball G, Kantarjian HM, et al.: Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 95 (8): 1673-84, 2002.
Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991.
Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 75 (2): 464-70, 1995.
Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996.
Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.
Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.
Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.
Bone marrow sampling is done to assess cellularity, fibrosis, and cytogenetics. The Philadelphia chromosome (Ph1) is usually more readily apparent in marrow metaphases than in peripheral blood metaphases; in some cases, it may be mashed and reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescent in situ hybridization (FISH) analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22 translocation.
The most common finding on physical examination at diagnosis is splenomegaly.[1] The spleen may be enormous, filling most of the abdomen and presenting a significant clinical problem, or the spleen may be only minimally enlarged. In about 10% of patients, the spleen is neither palpable nor enlarged on splenic scan.
Histopathologic examination of bone marrow aspirate demonstrates a shift in the myeloid series to immature forms that increase in number as patients progress to the blastic phase of the disease. The marrow is hypercellular, and differential counts of both marrow and blood show a spectrum of mature and immature granulocytes similar to that found in normal marrow. Increased numbers of eosinophils or basophils are often present, and sometimes monocytosis is seen. Increased megakaryocytes are often found in the marrow, and sometimes fragments of megakaryocytic nuclei are present in the blood, especially when the platelet count is very high. The percentage of lymphocytes is reduced in both the marrow and blood in comparison with normal subjects, and the myeloid/erythroid ratio in the marrow is usually greatly elevated. The leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in the neutrophils of patients with chronic myelogenous leukemia (CML).[1]
Transition from the chronic phase to the accelerated phase and later the blastic phase may occur gradually over a period of 1 year or more, or it may appear abruptly (blast crisis). The annual rate of progression from chronic phase to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent years.[2][3] Signs and symptoms commonly heralding such a change include the following:
In the accelerated phase, differentiated cells persist, though they often show increasing morphologic abnormalities, and increasing anemia and thrombocytopenia and marrow fibrosis are apparent.[1]
Studies have suggested that certain presenting features have prognostic significance. The following are predictive of a shorter chronic phase:
Predictive models using multivariate analysis have been derived.[2][3][4][5][6][7]
Chronic-phase CML
Chronic-phase CML is characterized by bone marrow and cytogenetic findings as described above with less than 10% blasts and promyelocytes in the peripheral blood and bone marrow.[8]
Accelerated-phase CML
Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.[8]
Blastic-phase CML
Blastic-phase CML is characterized by 20% or more blasts in the peripheral blood or bone marrow.
When 20% or more blasts are present in the face of fever, malaise, and progressive splenomegaly, the patient has entered blast crisis.[8]
Relapsing CML
Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:
Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.[9]
Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63 (4): 789-99, 1984.
Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988.
Kantarjian HM, Smith TL, McCredie KB, et al.: Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 66 (6): 1326-35, 1985.
Sacchi S, Kantarjian HM, Smith TL, et al.: Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 16 (3): 882-9, 1998.
Hasford J, Pfirrmann M, Hehlmann R, et al.: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90 (11): 850-8, 1998.
Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al.: Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 19 (12): 2994-3009, 2001.
Cortes JE, Talpaz M, O'Brien S, et al.: Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106 (6): 1306-15, 2006.
Martinelli G, Iacobucci I, Rosti G, et al.: Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol 17 (3): 495-502, 2006.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Treatment of patients with chronic myelogenous leukemia (CML) is usually initiated when the diagnosis is established, which is done by the presence of an elevated white blood cell (WBC) count, splenomegaly, thrombocytosis, and identification of the BCR/ABL (breakpoint cluster region/Abelson) translocation.[1] The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the BCR/ABL tyrosine kinase. In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[2][Level of evidence: 1iiDiii] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR).[3][4][5] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival benefits are unavailable because of crossover in randomized trials, the preferred initial treatment for newly diagnosed patients in chronic phase involves imatinib mesylate.[6][7] In addition, the overall survival rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. Higher doses of imatinib, alternative tyrosine kinase inhibitors such as dasatinib or nilotinib, and allogeneic stem cell transplantation (SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[8][9][10][11][12][13][14][15]
The only consistently successful curative treatment of CML beyond 10 years' follow-up has been allogeneic bone marrow transplantation (BMT) or SCT.[16] Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the BCR/ABL translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent in situ hybridization [FISH]). Many patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 15% to 30% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.[16]
Long-term data are also available for patients treated with interferon-alpha.[17][18][19] Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of BCR/ABL translocation by any available test, and the majority of these patients are disease-free beyond 10 years.[16] Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
Newly diagnosed patients with very high levels of circulating leukocytes (WBC >100,000/mm3) require immediate therapy with imatinib mesylate to avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.
Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006.
Bhatia R, Holtz M, Niu N, et al.: Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101 (12): 4701-7, 2003.
Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349 (15): 1423-32, 2003.
Rosti G, Martinelli G, Bassi S, et al.: Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103 (6): 2284-90, 2004.
Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006.
Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006.
Jabbour E, Cortes J, Kantarjian HM, et al.: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 108 (4): 1421-3, 2006.
le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008.
Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.
Hochhaus A, Kantarjian HM, Baccarani M, et al.: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109 (6): 2303-9, 2007.
Quintas-Cardama A, Kantarjian H, Jones D, et al.: Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 109 (2): 497-9, 2007.
Cortes J, Rousselot P, Kim DW, et al.: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109 (8): 3207-13, 2007.
Kantarjian H, Pasquini R, Hamerschlak N, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109 (12): 5143-50, 2007.
Guilhot F, Apperley J, Kim DW, et al.: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109 (10): 4143-50, 2007.
Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993.
Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 122 (4): 254-61, 1995.
Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92 (5): 1541-8, 1998.
Treatment options:
A trial randomizing 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 76% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 19 months.[7][8][Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase or blast crisis compared with 91.5% of the interferon plus cytarabine group (P < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. By the 5-year median follow-up of this trial, imatinib mesylate induced complete cytogenetic response in more than 80% of the participants, with the annual rate of progression to accelerated phase or blast crisis dropping from 2% in the first year to less than 1% in the fourth year.[8] In addition, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. More than 90% of completely responding patients still show detectable evidence of the BCR/ABL translocation, usually by RT–PCR or by fluorescence in situ hybridization of progenitor cell cultures.[9][10][11] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival benefits are unavailable because of crossover in randomized trials, the preferred initial treatment for newly diagnosed patients in chronic phase involves imatinib mesylate.[12][13]
Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors such as dasatinib or nilotinib, and allogeneic stem cell transplantation are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[14][15][16][17][18][19] In a trial of 114 previously untreated patients given twice the usual dose of imatinib mesylate (400 mg twice daily), with 15 months' median follow-up, no patient had progressed to accelerated or blast phase, and 63% showed no detectable evidence of the BCR/ABL translocation by RT–PCR.[20][Level of evidence: 3iiiDiv] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.
Newly diagnosed patients with chronic phase CML should be offered clinical trials.
Among the many unanswered questions are the following:
All of these issues have led to an active reappraisal of recommendations for optimal frontline therapy for chronic phase CML.[24]
In patients with blast crisis who have relapsed following treatment with imatinib mesylate, imatinib resistance was associated with reactivation of BCR/ABL signal transduction, either by point mutation or gene amplification of the BCR/ABL kinase domain.[25]
About 20% of otherwise eligible CML patients lack a suitably matched sibling donor.[34] HLA-matched unrelated donors or donors mismatched at one-HLA antigen can be found for about 50% of eligible participants through the National Marrow Donor Program.[34] Major obstacles still exist to using unrelated donors, especially in older patients. Two retrospective series following allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate of 3% to 10% and a 5-year OS rate of 31% to 57%, and most of the deaths were treatment related.[28][Level of evidence: 3iiiA][31] Patients with unrelated donor transplants were generally younger and had a longer interval from diagnosis to transplant. Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years following BMT.[35] In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable BCR/ABL transcript by PCR analysis.[36] The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.[28][37] BMT from an unrelated donor is associated with a higher risk of posttransplant graft failure and infection (viral and fungal). The incidence of relapse is lower with BMT from unrelated donors than it is from sibling donors.
With the advent of imatinib mesylate, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched related donor underwent early allogeneic stem cell transplantation while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched unrelated donor transplant in remission.[38] With a 9-year median follow-up, survival still favored the nonmatched donor arm (P = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[38][Level of evidence: 2A] Among the many unanswered questions are the following:
Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.
Long-term follow-up of the interferon-treated patients from a randomized trial comparing interferon with chemotherapy showed that the median survival had not been reached at 10 years for patients who had complete or major cytogenetic responses to interferon.[43] Seventy-four percent of patients with complete cytogenetic responses and 55% of patients with major cytogenetic responses were alive and had shown no disease progression at date of publication (median follow-up time was not provided). Using molecular methods of analysis, however, small numbers of Ph1-positive cells can still be detected in the majority of patients having long-term cytogenetic remissions, and longer follow-up will be required to ascertain whether the disease will recur.
Patients older than 60 years with chronic phase CML have a hematologic and cytogenetic response rate and duration of cytogenetic response similar to that in younger patients; however, the incidence of complications is greater in elderly patients.[44] Interferon-alpha has significant toxic effects that can result in dosage modification or discontinuation of therapy in many cases. A randomized prospective trial of 407 patients compared two doses of interferon, 5 million units/m² daily versus 3 million units/m² daily; at a median follow-up of 53 months, no difference was seen in OS, progression-free survival, or number of major cytogenetic responses.[45][Level of evidence: 1iiA] As evidenced in the CALGB-9013 study, common side effects include influenza-like syndrome, nausea, anorexia, weight loss, and neuropsychiatric symptoms, all of which are completely reversible with cessation of therapy.[46] Immune-mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment.[47] Interferon-alpha is quite costly, and daily subcutaneous injections can be troublesome. Pegylated interferon-alpha is administered weekly; a randomized noninferiority trial of 344 newly diagnosed CML patients could not rule out the possibility that pegylated interferon-alpha may be slightly inferior to daily interferon-alpha.[48][Level of evidence: 1iiDiv]
Patients whose disease is in cytogenetic remission should continue therapy for at least 2 to 3 years beyond remission, and perhaps indefinitely, as suggested by some investigators. After 1 year, patients with only a partial cytogenetic response should consider alternative therapy with imatinib mesylate or allogeneic BMT or SCT (if eligible). The French Chronic Myeloid Leukemia Study Group randomized 721 patients to interferon and cytarabine versus interferon alone.[49][Level of evidence: 1iiA] Patients who received the combination had significantly more major cytogenetic responses (41% vs. 24%, P < .001) and improved 3-year survival (86% vs. 80%). Another trial by the Italian Cooperative Study Group on CML did not show a survival benefit for interferon plus cytarabine versus interferon alone.[50][Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone.[49][50] Interferon-alpha is also effective for patients who have relapsed after allogeneic BMT.[51][52]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with chronic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Hochhaus A, Druker B, Sawyers C, et al.: Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 111 (3): 1039-43, 2008.
Kantarjian HM, Cortes JE, O'Brien S, et al.: Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 104 (7): 1979-88, 2004.
Iacobucci I, Rosti G, Amabile M, et al.: Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment. J Clin Oncol 24 (3): 454-9, 2006.
Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.
O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003.
Shah NP, Kantarjian HM, Kim DW, et al.: Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26 (19): 3204-12, 2008.
Kantarjian H, Talpaz M, O'Brien S, et al.: High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103 (8): 2873-8, 2004.
Deenik W, van der Holt B, Verhoef GE, et al.: Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood 111 (5): 2581-8, 2008.
Peggs K, Mackinnon S: Imatinib mesylate--the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 348 (11): 1048-50, 2003.
Rousselot P, Huguet F, Rea D, et al.: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109 (1): 58-60, 2007.
Cortes JE: Imatinib therapy for chronic myeloid leukemia: where do we go now? J Clin Oncol 26 (20): 3308-9, 2008.
Branford S, Rudzki Z, Walsh S, et al.: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102 (1): 276-83, 2003.
Gratwohl A, Hermans J: Allogeneic bone marrow transplantation for chronic myeloid leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 17 (Suppl 3): S7-9, 1996.
Wagner JE, Zahurak M, Piantadosi S, et al.: Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits. J Clin Oncol 10 (5): 779-89, 1992.
Enright H, Davies SM, DeFor T, et al.: Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective. Blood 88 (2): 714-20, 1996.
Goldman JM, Szydlo R, Horowitz MM, et al.: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82 (7): 2235-8, 1993.
Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.
Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338 (14): 962-8, 1998.
Clift RA, Buckner CD, Thomas ED, et al.: Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84 (6): 2036-43, 1994.
Crawley C, Szydlo R, Lalancette M, et al.: Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 106 (9): 2969-76, 2005.
Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006.
Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006.
Pichert G, Roy DC, Gonin R, et al.: Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 13 (7): 1704-13, 1995.
Hehlmann R, Berger U, Pfirrmann M, et al.: Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109 (11): 4686-92, 2007.
Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. J Natl Cancer Inst 89 (21): 1616-20, 1997.
Kantarjian HM, Deisseroth A, Kurzrock R, et al.: Chronic myelogenous leukemia: a concise update. Blood 82 (3): 691-703, 1993.
Cortes J, Kantarjian H, O'Brien S, et al.: Result of interferon-alpha therapy in patients with chronic myelogenous leukemia 60 years of age and older. Am J Med 100 (4): 452-5, 1996.
Kluin-Nelemans HC, Buck G, le Cessie S, et al.: Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 103 (12): 4408-15, 2004.
Hensley ML, Peterson B, Silver RT, et al.: Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J Clin Oncol 18 (6): 1301-8, 2000.
Sacchi S, Kantarjian H, O'Brien S, et al.: Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia. J Clin Oncol 13 (9): 2401-7, 1995.
Michallet M, Maloisel F, Delain M, et al.: Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia 18 (2): 309-15, 2004.
Guilhot F, Chastang C, Michallet M, et al.: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med 337 (4): 223-9, 1997.
Baccarani M, Rosti G, de Vivo A, et al.: A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood 99 (5): 1527-35, 2002.
Higano CS, Raskind WH, Singer JW: Use of alpha interferon for the treatment of relapse of chronic myelogenous leukemia in chronic phase after allogeneic bone marrow transplantation. Blood 80 (6): 1437-42, 1992.
Arcese W, Goldman JM, D'Arcangelo E, et al.: Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group. Blood 82 (10): 3211-9, 1993.
Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 82 (2): 398-407, 1993.
Patients with accelerated-phase chronic myelogenous leukemia (CML) show signs of progression without meeting the criteria for blast crisis (acute leukemia). Symptoms and findings include:
Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, p53 mutations or deletions), and the combination of hematologic progression plus additional cytogenetic abnormalities predicts for lower response rates and a shorter time to treatment failure on imatinib mesylate.[1] At 1 year after the start of imatinib, the failure rate is 68% for patients with both hematologic progression and cytogenetic abnormalities, 31% for patients with only hematologic progression, and 0% for patients with cytogenetic abnormalities only. Before the availability of imatinib, the median survival time of accelerated-phase CML patients was less than 1 year.[1]
Standard treatment options:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with accelerated phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002.
Martin PJ, Clift RA, Fisher LD, et al.: HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood 72 (6): 1978-84, 1988.
Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 71 (4): 487-91, 1989.
Reiffers J, Trouette R, Marit G, et al.: Autologous blood stem cell transplantation for chronic granulocytic leukaemia in transformation: a report of 47 cases. Br J Haematol 77 (3): 339-45, 1991.
Kantarjian H, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience. Cancer 103 (10): 2099-108, 2005.
Cortes J, Talpaz M, O'Brien S, et al.: Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol 16 (10): 3279-85, 1998.
Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 10 (5): 772-8, 1992.
Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992.
Two larger trials involving a total of 304 patients in blastic-phase chronic myelogenous leukemia (CML) confirm a hematologic response rate of 52% to 55% and a major cytogenetic response rate of 16%, but the estimated 1-year survival is under 35%.[2][3][Level of evidence: 3iiiA] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic-phase CML.[4]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with blastic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Kantarjian HM, Cortes J, O'Brien S, et al.: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99 (10): 3547-53, 2002.
Sawyers CL, Hochhaus A, Feldman E, et al.: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99 (10): 3530-9, 2002.
Fruehauf S, Topaly J, Buss EC, et al.: Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109 (8): 1543-9, 2007.
Preti HA, O'Brien S, Giralt S, et al.: Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 97 (1): 60-5, 1994.
Walters RS, Kantarjian HM, Keating MJ, et al.: Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron. Cancer 60 (8): 1708-12, 1987.
Gratwohl A, Hermans J, Niederwieser D, et al.: Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant 12 (5): 509-16, 1993.
Overt failure is defined as a loss of hematologic remission or progression to accelerated phase or blast crisis phase as previously defined. Although presumed to represent relapsing disease, a rising quantitative reverse transcriptase–polymerase chain reaction signal is a controversial finding. Prospective studies comparing resumption of therapy versus continued observation have not been performed. Similarly, there has been no prospective validation for failure to achieve certain benchmarks during initial therapy. For initial use of imatinib mesylate, the designation of relative failure has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months.[1]
Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib or nilotinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) are being studied, as evidenced in the UCLA-0501047-01 trial, for example, in this setting.[2][3][4][5][6][7][8][9][10][11] Clinical trial participation should help establish the optimal sequence of these options.
Infusions of buffy coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant.[12][13] The efficacy of this treatment is thought to be the result of an immunologic graft-versus-leukemia effect. This treatment is most effective for patients whose relapse is detectable only by cytogenetics or molecular studies and is associated with significant graft-versus-host disease. After relapse from allogeneic SCT, some patients will also respond to interferon-alpha.[14] Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[15][16][17]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with relapsing chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008.
Kantarjian HM, Giles F, Gattermann N, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110 (10): 3540-6, 2007.
Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.
Pigneux A, Devergie A, Pochitaloff M, et al.: Recombinant alpha-interferon as treatment for chronic myelogenous leukemia in relapse after allogeneic bone marrow transplantation: a report from the Société Française de Greffe de Moelle. Bone Marrow Transplant 15 (6): 819-24, 1995.
Olavarria E, Ottmann OG, Deininger M, et al.: Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17 (9): 1707-12, 2003.
Kantarjian HM, O'Brien S, Cortes JE, et al.: Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100 (5): 1590-5, 2002.
Hess G, Bunjes D, Siegert W, et al.: Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 23 (30): 7583-93, 2005.
About PDQ
Additional PDQ Summaries
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
This information was last updated on July 2, 2009.
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Creative Arts program provides patients, family members and caregivers with a variety of options to support well-being during cancer treatment. From dance and drama to music and writing, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
Blood is made up of three basic types of cells:
Your body is constantly producing blood cells. Blood cells are made in the bone marrow, the spongy tissue inside your bones. They come from a type of cell called a stem cell. The stem cell divides in response to signals made by your body. It will either become a red blood cell, a white blood cell, or a platelet. These signals are called growth factors. Blood cells live for a specified time in your body. White blood cells live for a few hours to a few months. Red blood cells live for 120 days. Platelets live for five to nine days.
Chemotherapy affects rapidly growing cells more than slower growing cells. Some normal cells have a fast rate of growth. These include your blood cells. A side effect of chemotherapy may destroy young blood cells as they are growing. It can take anywhere from seven to 21 days for your blood cells to reach their lowest numbers.
Your nurse or doctor will tell you when your blood cells counts are expected to be low. This is called your nadir. You will have your blood tested periodically to see how many of each type of blood cell you have. This is called having your counts checked.
Rec blood cells are measured by values called hemoglobin (Hgb) and hematocrit (Hct). The normal value for hemoglobin is 14.0 to 18.0; hematocrit is 37 to 52. If your red blood cell count is low, you may feel more tired or short of breath than usual. This is called anemia. Your doctor may order a red blood cell transfusion for you. Sometimes your red blood cells may be low because of the disease itself. Your doctor may prescribe a growth factor called erythropoietin (EPO) to help increase your red blood cell counts.
One type of white blood cells are neutrophils. When neutrophils are low, this is called neutropenia. You may not see the usual signs of infection so review the signs of infection at the bottom of this page.
A normal white blood cell count is 4,000 to 10,000. Sometimes your doctor may order a growth factor called GM-CSF or G-CSF to help your white blood cells recover more rapidly. The neutrophils fight most common infections. For that reason, this portion of the white cell count is also monitored. This is called the Absolute Neutrophil Count (ANC).
A normal platelet count is 130,000 to 400,000. A platelet count below 50,000 may make you more at risk for bleeding. This is called thrombocytopenia. If your platelet count drops, your doctor may order a platelet transfusion for you.
Talk with your nurse or physician about avoiding crowds and public places such as shopping malls, airplanes, buses, trains, etc. You may need to wear a mask if your white blood count is very low.
Good hygiene is important. Shower or bathe daily and pat yourself dry. Wash hands often and well. Always wash them before eating and after using the bathroom.
Be sure to notify your nurse or doctor immediately if you have any abnormal bleeding. This includes nose bleeds, blood in urine or stool, dark tarry stools, bleeding gums or easy bruising.
Be sure to let your nurse or doctor know if you develop any of the following signs of an infection:


text:
Recycle all those old magazines you have lying around by making this cute waste basket.
All little boys love a treasure box for their treasures and memories...
great way to recycle what you have and give as gifts!
A tissue paper decorated vase that's easy and inexpensive to make.
Easily create your own bulletin board from an old frame and bed spring from a cot or baby bed

subset: commoncrawl


text:
KA-BAR 3076 Agama Folding Knife 3-5/8" Plain Blade, G10 Handles
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KA3076: 3076 Agama Folder
KA-BAR Knives
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Includes a pocket clip for easy accessibility and a more secure carry.
Formed in a sheet under high pressure by combining fiberglass and an epoxy resin binder. These handles are lightweight and shaped to ensure a solid grip.


text:
View the most popular tags overall?
The Passover seder is a wonderful chance to connect with certain relatives that you love, along with hearing again the inspiring account of moving out of enslavement and fear while moving toward freedom and compassion for all who are hungry or mistreated. But for the majority of Jewish families, it's also a stressful time when personality clashes and unresolved conflicts with a few particular relatives spring up once again.


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Posted Jan 8, 2013 10:50 UTC (Tue) by tialaramex (subscriber, #21167) [Link]
If you chose a fairly good password, and you weren't first on the list of targets the weak MoinMoin password hashing may have bought you enough time to go change it anywhere else that you used it - nothing more.
I don't know why that Wiki page is called "Secure Password Storage". A few minutes with Google would have told the MoinMoin developers that this fell short of the state of the art circa 1975 let alone today, but then they're competing with PHP software that still thinks MD5(password) is "uncrackable encryption"...
Posted Jan 8, 2013 10:58 UTC (Tue) by epa (subscriber, #39769) [Link]
- set the password for a given username
- check the password provided for a given username
The device could have some rate limiting to say one check per second for the same username, and 1000 checks per second in total. Surely it could be built using a Raspberry Pi or whatever and then it would just be normal when setting up a server to get one of these devices plugged in and use it for password storage. (To keep the passwords secure even if the device is stolen, it should use pessimized salted hashing for its internal storage, but this is not strictly necessary.)
Of course, many servers these days are virtualized, so Amazon S3 and other cloud providers would need to give you a virtual password-checker attached to your virtual server.
Posted Jan 8, 2013 13:19 UTC (Tue) by sbakker (subscriber, #58443) [Link]
Cheers, Steven
Posted Jan 8, 2013 14:03 UTC (Tue) by epa (subscriber, #39769) [Link]
Posted Jan 8, 2013 14:42 UTC (Tue) by sbakker (subscriber, #58443) [Link]
Regarding the LDAP server being compromised or not, that depends on how well you protect/harden your LDAP server(s). I just don't see USB devices on each host scale very well and single sign-on is pretty much out of the question... Unless you attach your USB device to your LDAP server.
Also, how do you synchronise passwords in a HA environment? Given that the storage on the USB device is not accessible, it means you cannot make backups either. If the USB device breaks, that's it. Game over.
And, of course, you are assuming that the USB device has faultless security, and cannot be compromised itself. You still need to talk to it; over USB rather than IP, but buffers being buffers and programmers being programmers, I'm far from convinced there wouldn't be exploitable holes. Holes that would be that much harder to plug, because the device wouldn't (shouldn't!) allow you to fiddle with the firmware. Compare that to an apt-get/yum update to patch slapd.
Posted Jan 8, 2013 15:54 UTC (Tue) by epa (subscriber, #39769) [Link]
Posted Jan 8, 2013 15:46 UTC (Tue) by tialaramex (subscriber, #21167) [Link]
Don't bolt password authentication into every single individual application.
There's no reason (other than laziness on the part of MoinMoin's developers) why it cares about passwords at all, either in the general case or in the specific case of this Debian wiki. We're not talking about a missile launch system, or even a financial institution, it's just a wiki, password authentication was used because it's the "easy" way out if you don't actually care about security.
Every time we sell a hosted version of our main revenue generating service, we walk the partner through the options for how their users can get access to the service. We work really hard to persuade them to pick a single sign-on approach, even if means more work for us, because it's not only a better experience for users, it's a far more secure option for everybody. We don't store any passwords, hashes or password equivalents, the user doesn't end up memorising another password (or more likely, re-using one) and Bad Guys™ can't steal a password because there isn't one.
Yet apparently we're the only ones, since every service _our_ company buys (e.g. video conferencing, travel booking, online training, expense claims) from a big enterprise vendor expects to have its own passwords and its own separate user management, even though that's both wasteful and less secure.
Posted Jan 8, 2013 18:05 UTC (Tue) by drag (subscriber, #31333) [Link]
You want to force everybody that wants to help update Debian wiki to subscribe to a third party web-based SSO system?
Seems rather big PITA for something that is a effort with international scope like Debian has.
Posted Jan 8, 2013 18:13 UTC (Tue) by pboddie (guest, #50784) [Link]
In fact, MoinMoin supports a variety of single sign-on technologies and alternative authentication mechanisms that don't involve having to be concerned about how you, as the person deploying the Web application, will store your user's passwords. That said, you then have to integrate applications with the authentication infrastructure which is sometimes easier said than done. And for a lot of sites, if you go for something like OpenID, you also have to tell your users to go and make identities with other services who will, of course, want you to provide credentials that they store in a hopefully secure fashion.
It also doesn't help that the various single sign-on technologies are a stew of continuously changing aspirations, features and the occasional nod in the direction of backwards compatibility. Coincidentally, I am currently investigating one of the favourite federated authentication technologies and the available Free Software client (relying party) and server (provider) solutions, and it's hardly surprising that most people would rather not even look at such things given the breadth of homework required to not only figure out what the solution is supposed to be doing but also to deploy it correctly with only minimal and vague documentation (and not to mention fight with bizarre Web framework behaviour).
So yes, we could encourage everyone to not write their own password storage code and instead delegate authentication to other services or, at the very least, to well-documented, portable, easily-deployed libraries that everyone knows about, uses and supports. However, until such time as the grunt work involved in delivering these usable libraries and services has been done - a prime candidate for paying people instead of having them or others paid to ruin the Linux desktop, or whatever it is that we like to complain about - one can't blame Web application developers for working within the constraints of their domain - presumably not getting paid to do everything in the absolute best way possible while also meeting demand for new features and the stuff people also want (because they saw Facebook do it, or whatever) - and providing the option for only moderately secure password storage.
I think we'd all like to be able to do everything to the best of our ability all the time. Unfortunately, no-one ever seems to pay the rates required or permit the necessary working conditions, at least in my experience.
Posted Jan 9, 2013 11:26 UTC (Wed) by tialaramex (subscriber, #21167) [Link]
The wiki situation, like web forums, is not like that. The tired excuse is trotted out, "We don't want to inconvenience our users" which ignores the fact that the _only_ reason this doesn't inconvenience ordinary users is because they've learned to type "pa55word" into the box whenever prompted and as a result they have no security anyway (and so MoinMoin contributes to other break-ins all over the web and perhaps beyond). If you don't care about their security why waste their time with the login box at all?
The excuse that it's easier for the developers is stupid, it portrays the situation as "secure password handling is easy, everything else is hard" when in fact the situation is that MoinMoin never really offered secure password handling as we've seen above.
Posted Jan 9, 2013 13:59 UTC (Wed) by pboddie (guest, #50784) [Link]
As for integration with identity providers, apart from leaning heavily on Google and Facebook, for it to be commonplace the various solutions would have to be a lot easier to deploy - particularly under the conditions currently experienced by those deploying Web applications - than they currently are. Even the commercial solutions can be dreadful: on one project I was involved in, the large vendor concerned had to get consultants in from abroad because there was no-one in the entire country who could offer the necessary assistance.
With things as they are, I think it is somewhat optimistic to expect people - those deploying applications, of course - to enthusiastically abandon the simplest thing that works for them and somehow hook up their application to an inscrutable stack of authentication components with varying levels of documentation for a technology that, if not properly digested, will have people wagging their fingers once again that the resulting solution is insecure because some aspect of the configuration was not fully understood.
All this reminds me of people trying to fathom why organisations buy monolithic solutions (often not very nice and even rather maintenance-intensive) from vendors instead of piecing together freely available tools. No amount of pointing to "how to" documents and calling people stupid is going to change people's behaviour in situations like that.
Posted Jan 10, 2013 1:21 UTC (Thu) by dlang (✭ supporter ✭, #313) [Link]
Whatever SSO source you pick, you are going to run into some people who won't use it.
Posted Jan 11, 2013 15:59 UTC (Fri) by kleptog (subscriber, #1183) [Link]
So I think, yay, don't have to deal passwords, lost passwords, changing password, encrypting passwords, etc. And then I get people complaining that they don't want to use OpenID because it lets the provider know that you're logging in, and so they asked for username/password mechanism.
What's a developer to do in this situation? People can set up their own provider, but no. The set of people who don't trust OpenID providers and don't want to setup their own is apparently larger than I thought.
Posted Jan 11, 2013 16:49 UTC (Fri) by pboddie (guest, #50784) [Link]
Sadly, like everything else, the original simple idea has raced away leaving a lot of people to abandon the idea of running their own provider, and it also doesn't help that people who supposedly accept OpenID sometimes reject identities from providers other than the big names because, paraphrasing one explanation I heard at one point, "you can't trust providers you've never heard of before". Obviously, OpenID is just about the identity and not whether that identity can be trusted with anything - something a Google-minted identity isn't going to help you decide anyway. And let us not consider the expanding interoperability matrix and all its accompanying problems.
I think we're going to see a lot more discussion around trust and decentralisation - for example, whether it is prudent to delegate any control over one's identity either by using a big-name service or by running one's own Internet-resident service on someone else's server - as people begin to question the centralised nature of their Internet interactions.
Posted Jan 8, 2013 19:32 UTC (Tue) by corsac (subscriber, #49696) [Link]
Copyright © 2013, Eklektix, Inc. Comments and public postings are copyrighted by their creators. Linux is a registered trademark of Linus Torvalds


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Frances O'Connor (II)
Frances O'Connor was born on June 12, 1967 in Wantage, Oxfordshire, England. She is an actress, known for A.I. Artificial Intelligence (2001), Timeline (2003) and Bedazzled (2000).
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text:
Here are a couple photo's of a reed protected buffalo horn howler that I recently completed. A lanyard of parachute cord will be attached to this howler before I ship it to a customer. I am asking 60.00 for this one. A 7.50 shipping charge will be added to the asking price.THIS HOWLER IS SOLD.
Buffalo horn howler
Started by
Rich Cronk
, Aug 13 2010 08:23 AM
3 replies to this topic
Posted 13 August 2010 - 08:23 AM
Posted 13 August 2010 - 08:26 AM
Very nice Rich.
Handmade Calls by Braz
"Suppose you were an idiot. And suppose you were a member of Congress.. But I repeat myself."--Mark Twain
"Suppose you were an idiot. And suppose you were a member of Congress.. But I repeat myself."--Mark Twain
Posted 13 August 2010 - 10:55 PM
Real nice .
You can hop but you can't hide. Yahi Bowmen. Its not how far you can shoot but how close to the game you get when you shoot. Sights we don't need any sights. Why waist time reloading when I can be making arrows.
Posted 27 August 2010 - 02:44 PM
I sold the above howler today.
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Television favourites line up for races at Blenheim Palace (From Herald Series)
When It Happens Panel Get involved: send your photos, videos, news & views by texting 'OXFORD NEWS' to 80360 or email
Television favourites line up for races at Blenheim Palace
1:00pm Wednesday 2nd October 2013 in News By Emma Harrison, Reporter covering Rose Hill, Littlemore and Iffley. Contact me on 01865 425430
Celebrities back Heart Foundation run
TV FAVOURITES are limbering up for a tough race at Blenheim Palace.
X Factor celebrity Stacey Solomon and comedian Russell Howard, as well as Made In Chelsea's Spencer Matthews and Caggie Dunlop, will be running the Blenheim Palace 10k on Sunday for the British Heart Foundation.
And they will be joined by actress Gemma Atkinson, opera singer Natalie Coyle, Kidulthood actor Femi Oyeniran and Team GB athlete Louise Hazel – who will lead the team along with the warm-up.
More than 4,000 runners are expected to take part in the three races – a 2k family fun run, 10k and a half marathon – around the palace's grounds in Woodstock.
Ms Hazel said: "Heart disease can affect anyone and strike when you least expect it.
"I should know – I lost my father at just 50 years old.
"This is why I'm lending my support to the Blenheim Palace 10k Run. It is money raised from events such as this that is helping to find the vital treatments that are transforming the fight against heart disease and making a difference to the millions of adults and children affected by it."
The is the third year the British Heart Foundation has held the event at Blenheim Palace.
Money raised by the runners will fund vital research, much of which takes place in Oxford.
British Heart Foundation researcher Michael Dodd, who is based at the John Radcliffe Hospital in Oxford, is taking on the 13.1 mile route.
The 28-year-old said: "I regularly participate in British Heart Foundation events as it feels like the perfect way for me to give something back to the charity that has been so prominent in my life for several years.
"I was fortunate enough to be funded by the British Heart Foundation through my PhD and am now working on a British Heart Foundation-funded project at the John Radcliffe Hospital."
Mr Dodd's father, Ian, was diagnosed with hypertrophic cardiomyopathy, a genetic condition where the muscle wall of the heart becomes thickened.
Mr Dodd and his brother have since discovered they both have the gene.
Melanie Blackman, regional event organiser for the British Heart Foundation, said: "Heart and circulatory disease devastates too many lives, killing more than 159,000 people each year and accounting for more than a quarter of all deaths in the UK.
"It's vital that we all get behind the fight to find a breakthrough to eradicate this deadly disease and the misery it brings."
Entry ranges from £10 to £23 for adults and £5 for children for the Family Fun Run and 10k.
s The half-marathon is open to runners aged 17 and over. To register, visit bhf.org.uk/Blenheim To support the celebrities visit justgiving.com/ TeamHazel
Comments are closed on this article.


text:
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text:
Aphasia (cont.)In this ArticleHow is aphasia diagnosed?
Comment on this
Aphasia is usually first recognized by the physician who treats the person for his or her brain injury. Frequently this is a neurologist. The physician typically performs tests that require the person to follow commands, answer questions, name objects, and carry on a conversation. If the physician suspects aphasia, the patient is often referred to a speech-language pathologist, who performs a comprehensive examination of the person's communication abilities. The examination includes the person's ability to speak, express ideas, converse socially, understand language, read, and write, as well as the ability to swallow and to use alternative and argumentative communication. How is aphasia treated?
Comment on this
In some cases, a person will completely recover from aphasia without treatment. This type of spontaneous recovery usually occurs following a type of stroke in which blood flow to the brain is temporarily interrupted but quickly restored, called a transient ischemic attack. In these circumstances, language abilities may return in a few hours or a few days. For most cases, however, language recovery is not as quick or as complete. While many people with aphasia experience partial spontaneous recovery, in which some language abilities return a few days to a month after the brain injury, some amount of aphasia typically remains. In these instances, speech-language therapy is often helpful. Recovery usually continues over a two-year period. Many health professionals believe that the most effective treatment begins early in the recovery process. Some of the factors that influence the amount of improvement include the cause of the brain damage, the area of the brain that was damaged, the extent of the brain injury, and the age and health of the individual. Additional factors include motivation, handedness, and educational level. Aphasia therapy aims to improve a person's ability to communicate by helping him or her to use remaining language abilities, restore language abilities as much as possible, compensate for language problems, and learn other methods of communicating. Individual therapy focuses on the specific needs of the person, while group therapy offers the opportunity to use new communication skills in a small-group setting. Stroke clubs, regional support groups formed by people who have had a stroke, are available in most major cities. These clubs also offer the opportunity for people with aphasia to try new communication skills. In addition, stroke clubs can help a person and his or her family adjust to the life changes that accompany stroke and aphasia. Family involvement is often a crucial component of aphasia treatment so that family members can learn the best way to communicate with their loved one. Family members are encouraged to:
Other treatment approaches involve the use of computers to improve the language abilities of people with aphasia. Studies have shown that computer-assisted therapy can help people with aphasia retrieve certain parts of speech, such as the use of verbs. Computers can also provide an alternative system of communication for people with difficulty expressing language. Lastly, computers can help people who have problems perceiving the difference between phonemes (the sounds from which words are formed) by providing auditory discrimination exercises. Patient CommentsViewers share their comments
Aphasia - Types
Question: What type of aphasia were you or your loved one diagnosed with?
Aphasia - Treatment
Question: What kind of treatment have you or your loved one had for aphasia?
Aphasia - Diagnosis
Question: Describe the events that led to a diagnosis of aphasia.
Aphasia - Causes
Question: What was the cause of aphasia in you or someone you know? Please share your experience.


text: Man, I just spent a week playing almost nothing but bass to get my signature performance to be a bass song (just to change it up, if nothing else). I expected "Radar Love" since my score is in the top 20, and it's an on-disc song so top 20 actually means something (not to mention it's a 5-dot tier, ~1500 note FC), but instead it's "The Feeling." That's an all right song, but my score/placing is nowhere near as good. Plus, on my gameplay page, it shows five plain stars for that song, when I have most certainly GS'd and FC'd it.


text:
jmadonald Wrote:my fanart has a blue tint to them all. as well as thumbnails.
I had the same problem after enabling <useddsfanart>. All fanart and thumbs started to become blue tinted. My guess is that there is a problem with .dds generation in atv2 nightlies, so I changed <useddsfanart> to false in advanced settings.xml (it's the default, so I could just delete it) and then I deleted all .dds files in userdata/Thumbnails subdirectories.
After that, all thumbs and fanarts came back to normal.
ATV2 XBMC nightly build 20110825-bb4f856


text:
Latest Headlines
According to the Florida Highway Patrol four people, including ...
According to a release from the State Attorney's office, Christopher Leon ...
A video on YouTube is calling into question the actions of officers making an ...
Click here to vote for the best play from Sideline ...
The attorney for the woman who accused Florida State quarterback of raping her ...
The Ribault Trojans improved to 8-0 on the season after their 71-62 win over Ed ...
Victim, suspect both in their 50's involved in shooting on Radcliff Court
A funeral was held near Longwood Monday for University of North Florida student Dara Kusiv
Windy Hill Elementary School Principal demoted after alleged misconduct
Lake City skydiver Kurt Ruppert missing near Seattle thought to be dead
Assault rifles at heart of gun debate
FHP: Man killed in single-vehicle accident on Interstate 95
In foreclosure limbo, Middleburg woman hopes to settle nagging four-year loan issue
Flu season turning out to be harsh
Historic St. Augustine church facing foreclosure
FHP releases updated vehicle information in Timuquana fatal hit-and-run
DAYTONA BEACH, Fla. -- A Florida appellate court is being asked Tuesday to decide whether Casey Anthony was in police custody when she made statements that led to her being convicted of four counts of lying to law enforcement officers.
Anthony's attorneys are appealing the misdemeanor convictions on the grounds that her statements were inadmissible at her murder trial since she hadn't been read her Miranda rights, which warn suspects that they can remain silent and that their statements can be used against them in court. The three judges on the Fifth District Court of Appeals aren't expected to rule Tuesday.
Anthony was acquitted in 2011 of murdering her 2-year-old daughter, Caylee.
After Caylee disappeared in the summer of 2008, Anthony told investigators that a babysitter named Zenaida Gonzalez had kidnapped her daughter, that she worked at Universal Studios, that she had told co-workers about Caylee's disappearance and that she had recently received a phone call from her daughter. All of the statements were lies and were the basis for her misdemeanor convictions.
Anthony's attorneys argued that because Anthony had been handcuffed and placed in a squad car, she was effectively under arrest and should have had her Miranda rights read to her. They also argue that her convictions on four similar charges stemming from a single encounter with police represents double jeopardy - a person's constitutional protection from being punished multiple times for one offense.
Attorneys for prosecutors argued that the trial judge was correct to allow the statements to be used. They said that Anthony only was handcuffed because her mother thought she would flee and not help them try to locate Caylee. They also noted that a supervisor ordered a detective to take the handcuffs off Anthony a few minutes later.
The appellate court's decision could affect how Anthony testifies in a civil lawsuit. A woman with the name Zenaida Gonzalez sued Anthony, claiming her reputation had been ruined. Anthony has used the pending appeal to delay questioning in the lawsuit. The trial over the lawsuit has been postponed indefinitely until the appellate court rules.
Associated Press


text:
Will this device work with the "lightning" connector on the iPhone 5?
I know there are adaptors for the lightning connector, but Apple say that some existing 30-pin connector devices won't work with the Lightning connector.
Will this device work with the iPhone 5? I ask because I'm thinking of upgrading my phone. If the answer is no, then that'll make the upgrade that more expensive for me.
- Asked by Ian E
- Sep 15, 2012
- Flag as inappropriate
2 Answers from the Community
You're right, it will require an adaptor. Only Apple make working adaptors. They have quite sophisticated circuitry inside, apparently including an authenticator. So they're hard to reproduce.
- Answered by Ian E
- Dec 3, 2012
- Flag as inappropriate
At the very least one needs to assume a $40 adapter which is not a very appealing prospect.I have had 3 Chinese knock offs, none of which work.
- Answered by Barry F from Los Gatos
- Nov 26, 2012
- Flag as inappropriate
Related Questions
will this work with iphone 5 or ipad mini if we use connector or converter? thanks.
- Asked by Lorenzo E from Manila
- Jun 16, 2013
- Flag as inappropriate
- Asked about: Apple 30-pin Digital AV Adapter
Is there an FM Trantsmitter available with the lightning connector?
- Asked by Alisdair G
- Aug 19, 2013
- Flag as inappropriate
- Asked about: iPhone
No answers yet
what does the bottom look like where the lightning connector is?
- Asked by Mark S from Seattle
- Sep 10, 2013
- Flag as inappropriate
- Asked about: iPhone 5s Case - (PRODUCT) RED


text:
After a general introduction, the book systematically describes law related to the medical profession, proceeding from training, licensing, and other aspects of access to the profession, through disciplinary and professional liability and medical ethics considerations and quality assurance, to such aspects of the physician-patient relationship as rights and duties of physicians and patients, consent, privacy, and access
Succinct and practical, this book will prove to be of great value to professional organizations of physicians, nurses, hospitals, and relevant government agencies. Lawyers representing parties with interests in Poland will welcome this very useful guide, and academics and researchers will appreciate its comparative value as a contribution to the study of medical law in the international context.
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text:
Posts Tagged 'stitch'
Bag Crochet Pattern
More attractive and impressive one hand, there is nothing now. Certainly many of our tactics is difficult, careful hand-made gifts were lucky enough to receive. Someone long ago not to forget those childhood crafts? Who knit something (usually by our grandmother) do not? All the girls there are not exceed. In many cases, it is a craft. Despite the advent of technology, he's really, you have not dated that many transactions are one of the hooks.
Crochet items are still above the table, curtain, blanket, sweater and gloves in a typical home in the enchanting shops can be found on many items. This is still a living art and a strong industry. Over the years, the hook is still very popular topic of socks in her home heart.Handbags can find a place. They come in many shapes and sizes. On the right side of his plain simple is beautiful. They need more time to complete, and more effort into the creation of a grant because they are unique and special, but the design will be considered separately.
It, along with drawings for the design of each bag before it is considered to be difficult to create a little bit from the first or the design must be modeled. In addition, special attention should be given to the design on paper, but as well as the canvas itself, is clearly visible. It well.Thanks time and with current technology, a loan can be used in many models to choose from an attentive and patient and the manufacturer is required for the activity.


text:
PHOENIX (AP) — St. Louis pitcher Chris Carpenter was removed with a strained left ribcage in the fourth inning of Tuesday night's game against the Arizona Diamondbacks.
Carpenter was injured when he grounded out to third base to end the top of the fourth, team spokesman Melody Yount said. Carpenter went to the mound to warm up before the bottom of the inning, then called for a trainer.
The Cardinals led 3-0 when Carpenter was removed.
The 2005 NL Cy Young Award winner allowed four hits in three innings, striking out two. He has not allowed a run in 10 innings this season.
The 33-year-old right-hander made only four appearances last season after reconstructive elbow surgery. He underwent another procedure in November to transpose an elbow nerve that was irritating the muscles in the back of his shoulder and around his neck.
Copyright 2009 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Barrington Broadcasting is a member of the AP Network.


text:
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Healthy, imaginative pizzas and salads in a space buzzing with a local and community vibe
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Old School
So my log says I'm at 1241.9 miles for the year as of yesterday and I haven't run yet today. I'm waiting for my car repairman to call so I can have my ride back, then I hope to go run 12 miles on the indoor track, since I'm a wuss and won't run outside in "this weather" if I don't have to.. I should easily pass the 2K mark, even if I don't get in all 12 miles. This is all a new lifetime mileage high for me...
Done, 13.17 miles on the indoor track today, pushing me past 2000k for the year .
Cecil - Congratulations on beating the bunny ahead of the deadline and also on your highest year ever! That's super!
Use your momentum...keep going. You know you can make it.
Thanks, HappyFeet! Looks like I'm on track to finish up the year around 1350-1400 miles. Maybe next year I can aim for 1500 or better, if my feet and knees hold up.
great effort, 1500 mi sounds like a good goal for next year.
"Training is like fighting with a gorilla. You don't stop when you're tired. You stop when the gorilla is tired."
Goals 2013
Length of the Lake Ultra 67 km 23 Feb Smashed it in 6:56
Tarawera Ultra 100 km - 16 Mar Brutal 16:46
Marton to Wanganui Ultra 66km September New PR 6:51
2013 km in 2013
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