The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines.

Posted by rob on April 27, 2006 under Uncategorized | Read the First Comment

Haematologica. 2006 Apr 3;

We evaluated the effect of the human immunodeficiency virus (HIV) protease inhibitor saquinavir on the imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia cell lines. Saquinavir, which is also a proteasome blocker, showed dose- and time-related anti-proliferative activity, particularly on the imatinib-resistant lines and a pro-apoptotic effect. Association with imatinib caused a significant increase of activity.

The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines.

BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia.

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J Immunol. 2006 Apr 15; 176(8): 5108-16

MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34+ cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL+ cell line K562, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels, but decreased MICA protein production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.

BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia.

Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples.

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Int J Oncol. 2006 May ; 28(5): 1099-103

Molecular monitoring of the BCR-ABL transcript in chronic myelogenous leukemia (CML) using quantitative RT-PCR provides clinicians with important diagnostic and prognostic information. To determine whether molecular detection and monitoring of CML is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples, we performed a prospective study using quantitative real-time RT-PCR (QRT-PCR) of paired PB and BM samples from 41 patients with CML entered onto a single Cancer and Leukemia Group B (CALGB) treatment study. QRT-PCR analysis of PB and BM samples was performed prior to initiation of, and during, treatment with homoharringtonine and cytarabine on a CALGB study for previously untreated CML. Statistical analyses demonstrated good agreement of PB and BM pre-treatment samples. However, using the Bland-Altman statistical method that measures true agreement between PB and BM values, we found that there was only modest agreement of BCR-ABL measurements in PB and BM for samples obtained during treatment. PB values obtained during treatment tended to be lower than the corresponding BM values [average difference = -0.37 (p
Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples.

Generation of the BCR/ABL fusion gene in a Philadelphia chromosome-negative chronic myeloid leukaemia: insertion of 5.6 Mb of 9q34 into the BCR region

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Hematol Oncol. 2006 Apr 6;

This report describes a chronic myelogenous leukaemia patient with an apparently normal bone marrow karyotype but BCR/ABL fusion-gene-positive. Commercial FISH probes showed an atypical pattern and the BCR/ABL fusion transcript was detected by RT-PCR, but not the reciprocal ABL/BCR. Consecutive FISH assays clarified the mechanism of the masked Ph. The ABL gene and the following 5.6-5.7 Mb of 9q are inserted into the BCR region of chromosome 22. There is no transference of 22q material to chromosome 9 or to any other chromosomes. Clinical features and evolution of the patient are similar to those cases with classic Ph chromosome. Copyright (c) 2006 John Wiley & Sons, Ltd.

Generation of the BCR/ABL fusion gene in a Philadelphia chromosome-negative chronic myeloid leukaemia: insertion of 5.6 Mb of 9q34 into the BCR region of chromosome 22.

Durable molecular complete remission induced by low-dose imatinib plus low-dose interferon alpha in a patient with chronic myelogenous leukaemia.

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J Int Med Res. 2006 Jan-Feb ; 34(1): 103-8

A 50-year-old male was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase in March 2000. He was treated initially with hydroxyurea, administered orally. This was changed to interferon alpha (IFN) 5 million units (5 MIU) subcutaneously daily in May 2000; complete cytogenetic response was achieved 11 months later. IFN dosage was reduced to 5 MIU, alternate days, in June 2001 and a cytogenetic relapse occurred 3 months later. Since April 2002, he has received IFN 5 MIU three times weekly in combination with imatinib 200 mg/day. The Philadelphia chromosome disappeared from his peripheral blood cells in July 2002 and a complete molecular response was achieved in January 2003. Serial molecular studies between January 2004 and January 2005 showed no detectable major BCR/ABL chimeric transcript. Grade 2 neutropenia and grade 1 non-haematological adverse effects have been observed. This case report suggests the combination of low-dose imatinib and IFN would be tolerable and effective for CML patients in chronic phase.
Durable molecular complete remission induced by low-dose imatinib plus low-dose interferon alpha in a patient with chronic myelogenous leukaemia.

Blastic phase of chronic myelogenous leukemia.

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Curr Treat Options Oncol. 2006 May ; 7(3): 189-99

Chronic myelogenous leukemia (CML), also known as chronic myelocytic or chronic myeloid leukemia, is a clonal disorder of hematopoiesis that arises in a hematopoietic stem cell or early progenitor cell. This is characterized by the dysregulated production of mature nonlymphoid cells with normal differentiation. Eventually, in spite of the term chronic, there is progression to acute leukemia, usually of the myeloid variety, which is highly resistant to current therapies. Despite recent improvements in the treatment of early-stage disease, CML blast crisis (CMLBC) remains a therapeutic challenge. CMLBC is highly refractory to standard induction chemotherapy, with a response rate in myeloid blast crisis of less than 30%. Conventional chemotherapy has been much less successful in this disease compared with de novo acute leukemia, with a mean survival after diagnosis of blast crisis of only 2 to 4 months for nonresponders. Many regimens of chemotherapies have been tried in CMLBC, with minor success. Although imatinib was evaluated in patients with CMLBC, most CMLBC cases today arise in patients already on imatinib-based therapy and developing blastic phase on that therapy; thus there is no standard therapy for patients with CMLBC. Further studies of the mechanisms of transformation of chronic-phase CMLBC at a molecular level, and methods to target these molecular abnormalities, will determine the future direction of new treatment modalities. The prognosis of CML in blast crisis remains disappointing, despite great efforts. Currently, the most successful strategy for improving survival in CML is by prolonging the chronic phase and delaying the onset of blast crisis.

Blastic phase of chronic myelogenous leukemia.

Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

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Cancer Genet Cytogenet. 2006 Apr ; 166(1): 65-73

To evaluate the prognostic significance of submicroscopic deletions of the ABL or BCR gene associated with t(9;22) in chronic myelogenous leukemia (CML), we investigated the incidence of an ABL or BCR deletion on derivative chromosome 9 using fluorescence in situ hybridization (FISH). FISH was performed using the LSI BCR/ABL dual-fusion translocation probe on bone marrow cells of 86 patients with CML. Of 86 patients, ABL deletion was detected in 13 (15.1%) patients and BCR deletion in 8 patients (9.3%). Patients with ABL deletion showed shorter event-free survival time (EFS) than those without ABL deletion (P = 0.020). Patients with BCR deletion showed significantly short overall survival time (OS; P = 0.039). Patients with ABL and/or BCR deletion (14/86 patients, 16.3%) showed significantly short OS and EFS (median OS, 43.0 months; median EFS, 40.0 months), compared to the patients without any BCR or ABL gene deletions (median OS, 94.0 months; median EFS, 90.0 months; P = 0.041 for OS, P = 0.008 for EFS). All the patients with BCR deletion, except for one, had a concomitant ABL deletion, suggesting that BCR deletion occurs in conjunction with ABL deletion. In patients with ABL deletion only, BCR/ABL rearrangement with b2a2 mRNA type tended to be more frequent than in patients without any deletion of the two genes (P = 0.073). Deletion of any of the BCR or ABL genes on derivative chromosome 9 was associated with both short OS and EFS. We conclude that deletion of not only the ABL gene, but also of the BCR gene, is a poor prognostic marker that indicates rapid disease progression in CML.
Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem

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Haematologica. 2006 Apr 19;

Imatinib mesylate is highly effective in relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoetic stem cell transplantation (HSCT). However, it is unknown whether imatinib produces durable molecular remissions. The outcome of CML patients transplanted at our center who had received only imatinib for relapse after HSCT was compared with that of patients treated with donor lymphocyte infusions (DLI). Imatinib therapy resulted in a higher incidence of relapse and inferior leukemiafree survival (p=0.006 and p=0.016, respectively). These data suggest that imatinib alone probably does not cure relapse after HSCT.

A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation.

Survival advantage from Imatinib compared to the combination Interferon-{alpha} plus Cytarabine in chronic phase CML: historical comparison between tw

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Blood. 2006 Apr 20;

In the multinational IRIS study comparing imatinib to interferon plus cytarabine (IFN/AraC) in patients with newly diagnosed chronic-phase chronic myelogenous leukaemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyR) and improved progression free survival (PFS). However, because of a high early cross over rate to imatinib, survival benefit was not assessable. Here we report the result of a study comparing long term outcome of patients included in two prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/AraC in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation and overall survival were significantly higher with imatinib compared with IFN/AraC (P

Survival advantage from Imatinib compared to the combination Interferon-{alpha} plus Cytarabine in chronic phase CML: historical comparison between two phase III trials.

A novel MHC-associated Proteinase 3 peptide isolated from primary chronic myeloid leukaemia cells further supports the significance of this antigen fo

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Leukemia. 2006 Apr 20;

Three of the most promising antigens for immunotherapy of chronic myelogenous leukaemia (CML) include the specific fusion-protein, Bcr/Abl, and the overexpressed proteins WT1 and Proteinase 3. The clinical significance of Proteinase 3 as a target in myelogenous leukaemias has been bolstered by detection of high frequencies of cytotoxic CD8+ lymphocytes specific for this antigen in patients undergoing immune therapies. Our investigation aimed to directly identify MHC-ligands derived from these antigens and presented on CML blasts by means of affinity-purification and mass spectrometric peptide-sequencing. Although no known or potential new epitopes were discovered for Bcr/Abl or WT1, a novel peptide from Proteinase 3 was detected among the more abundant MHC-ligands. Additionally, MHC-ligands derived from known immunogenic proteins overexpressed as a result of Bcr/Abl transformation were also identified. Our investigation is the second of only a small number of studies to identify a peptide from Proteinase 3 among the more abundant MHC-associated peptides and thus implies that peptides from this antigen are among the more abundantly presented of the known leukaemic antigens. Taken in conjunction with clinical observations of functional Proteinase 3 specific CTL in patients’, these data further support the application of this antigen as an immunotherapeutical target for myelogenous leukaemias.Leukemia advance online publication, 20 April 2006; doi:10.1038/sj.leu.2404234.

A novel MHC-associated Proteinase 3 peptide isolated from primary chronic myeloid leukaemia cells further supports the significance of this antigen for the immunotherapy of myeloid leukaemias.

St. Jude unlocks mystery of very aggressive leukemia

Posted by rob on April 19, 2006 under Uncategorized | Be the First to Comment

Contact: Kelly Perry
media@stjude.org
901-495-3306
St. Jude Children’s Research Hospital

St. Jude unlocks mystery of very aggressive leukemia

Investigators at St. Jude Children’s Research Hospital have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are extremely aggressive and resist a drug that is effective in treating a different type of leukemia.

The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of ALL. Inactivation of both Arf genes facilitated the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec?). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude study provided evidence that imatinib resistance in mouse models of ALL did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds inhibiting enzymes called JAK kinases restored the cells’ imatinib sensitivity.

The study’s findings suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation and point to a strategy for overcoming this resistance. A report on this work appears in the April 17 issue of Proceedings of the National Academy of Sciences.

The Bcr-Abl oncogene (a cancer-causing gene) is formed when parts of two chromosomes switch places, leading to fusion of a fragment of the Bcr gene from one chromosome to a portion of the Abl gene from the other. Bcr-Abl encodes a type of enzyme called a tyrosine kinase, which then drives the abnormal, uncontrolled multiplication of leukemic cells.

Other researchers had previously shown that inhibiting the Bcr-Abl kinase with imatinib causes durable remissions of cancer with minimal side effects in patients with CML–a finding that has revolutionized the treatment of this form of leukemia. However, imatinib has proven far less effective in treating ALL patients with the Bcr-Abl mutation, and the basis of drug resistance in this disease is unknown.

The Arf gene normally suppresses the proliferation of cells carrying cancer-causing mutations such as Bcr-Abl, according to Charles J. Sherr, M.D., Ph.D., a Howard Hughes Medical Institute investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology. Arf acts as a safeguard against the cancer-causing effects of Bcr-Abl, Sherr said. Sherr is senior author of the paper. The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine F. Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is also an author of the current paper.

The St. Jude team found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to ALL, in which Arf loss frequently occurs and imatinib treatment is far less effective. “This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage,” Sherr said. “And this advantage might contribute to imatinib resistance in some way.”

To investigate this hypothesis, the researchers used a virus-like piece of DNA to carry the Bcr-Abl oncogene into bone marrow-derived lymphocytes obtained from mice that either retained Arf or were previously engineered to lack this gene. These pre-B lymphocytes represent one type of white blood cell that can become cancerous and cause ALL.

The researchers then transplanted these “transformed” cells carrying Bcr-Abl back into normal mice. Animals that received transformed pre-B cells that had both copies of the Arf gene intact were highly resistant to disease development. However, mice injected with cells that carried Bcr-Abl and lacked Arf rapidly developed an aggressive form of ALL that could not be cured with high doses of imatinib.

“Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug,” noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr’s laboratory and the paper’s lead author. “This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival.”

Sherr’s team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib’s growth inhibitory effects.

IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the ALL cells’ sensitivity to imatinib.

“Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice–and potentially in humans–might contribute to imatinib resistance,” Williams said. “Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs.”

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This work was supported in part by the Howard Hughes Medical Institute, a National Institutes of Health Cancer Center Core Grant and ALSAC.

St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.

St. Jude unlocks mystery of very aggressive leukemia

A Broken Stress Response System Can Contribute to Gleevec Resistance

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New clues to why some kinds of leukemia are more aggressive and deadly than others are coming from research examining the types of genetic damage that allow some blood cells to grow out of control, scientists report.

According to Charles J. Sherr, a Howard Hughes Medical Institute researcher at the St. Jude Children’s Research Hospital in Memphis, Tennessee, his team’s new findings may help doctors understand why some cancers can be controlled with drugs, at least temporarily, while others somehow resist treatment.


“The combination of the two [genetic abnormalities] makes the tumors almost 1,000 times more aggressive.”
Charles J. Sherr

Sherr and colleagues Richard T. Williams, the lead author, and Martine F. Roussel reported their research findings on April 17, 2006, in an advance online publication in the Proceedings of the National Academy of Sciences.

The investigators studied two types of leukemia: CML—chronic myelogenous leukemia, which can now be alleviated to a large extent with a drug called Gleevec (imatinib), and a subtype of ALL—acute lymphoblastic leukemia, which does not respond well to this drug. The hallmark of both diseases is a genetic alteration in an enzyme (BCR-ABL) whose activity is specifically blocked by Gleevec treatment. The work reveals that loss of a gene known as Arf, which is frequently mutated in patients with ALL, but not CML, can cause some leukemias to resist Gleevec treatment.

Patients with CML who are taking Gleevec readily go into remission, and their cancer cells stop growing while they are maintained on drug therapy. Sherr explained that Gleevec’s impact has been truly revolutionary. “It’s a targeted therapy that works; the results have been miraculous.”

Unfortunately, there is still a small relapse rate—about five percent per year—that doctors would like to erase. Other researchers have found that “patients who fail while on therapy have developed subsequent mutations in the BCR-ABL enzyme” that alter Gleevec’s effectiveness,” Sherr said.

Further clinical trials are now under way, he said, with drugs that block these mutated forms of BCR-ABL, building upon the benefit that is offered by Gleevec and keeping CML under better control.

CML is caused by a genetic change that scientists call the Philadelphia chromosome. It results when chromosomes 9 and 22 break and reattach themselves to one another. At the point where the chromosomes meet, the joined DNA creates the BCR-ABL gene, which has the unfortunate property of causing abnormal growth of the white blood cells that leads to leukemia.

This misarranged chromosome is also seen in a subset of patients with ALL. Unfortunately, Gleevec is much less effective against this more aggressive form of the disease. Sherr’s team is studying why that is true, focusing especially on a way to “re-sensitize” the tumor cells to Gleevec treatments.

Chromosomes are the long, coiled molecules on which genes—life’s blueprints—reside. So when chromosomes and genes are disrupted, the damage can lead to diseases, including cancer. Nature has equipped cells with repair systems that recognize genetic damage and try to correct it. But if the damage cannot be fixed, one alternative is to kill the sickened cell by activating a built-in cell suicide system.

Trouble ensues when normal growth-control mechanisms go awry and normal repair and cell suicide mechanisms also fail. Thus cancer cells gain immortality—not dying when they should—and begin growing without restraint to form tumors. In leukemia, the problem is a severe over-supply of one type of white blood cell or another.

In their experiments with mice, Sherr and his colleagues found evidence that a mutation in one of the cell’s stress response systems can contribute to tumor growth even in the presence of Gleevec. The mutation disables or erases the function of a gene called Arf, which normally helps suppress the growth of cancer cells. Mutations in the Arf gene are found in the cells of more than 30 percent of patients with ALL, whereas they have not been observed in patients with CML.

The researchers found that when the Arf gene was inactivated, BCR-ABL induced a much more aggressive form of ALL in mice. These mice “do not achieve remission on high doses of oral imatinib (Gleevec), and succumb to leukemia,” Sherr said. In other words, the drug doesn’t work and the mice die soon. “The combination of the two [genetic abnormalities] makes the tumors almost 1,000 times more aggressive” in terms of their ability to induce disease, he explained.

Although the biological mechanism that underlies this form of drug resistance isn’t well understood, “tumor cells removed from the drug-resistant mice remained sensitive to Gleevec treatment in cell cultures,” Williams said, “so there must be a host signaling system in the mice that makes the cells drug resistant.” The investigators provide proof of principle that additional drugs might reverse this form of drug resistance, thereby restoring Gleevec’s power to control this type of leukemia.

HHMI News: A Broken Stress Response System Can Contribute to Gleevec Resistance

Researchers Seek Alternative for Leukemia Patients Resistant to Standard Therapies

Posted by rob on April 3, 2006 under Uncategorized | Be the First to Comment

A study led by researchers from the Howard Hughes Medical Institute has found that dasatinib provides significant benefit in chronic myeloid leukemia (CML) patients resistant to Gleevec® (imatinib), according to a study presented today during the 97th Annual Meeting of the American Association for Cancer Research.

In an update of a phase I study initiated in November 2003, researchers looked at the use of dasatinib in imatinib resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC/Ph+ ALL). Data are available for 84 patients (40 CP, 11 AP, 23 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.

Imatinib – which blocks the irregular protein that allows the overproduction of abnormal white blood cells – has become a standard therapy for CML patients not undergoing stem cell transplantation. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.

The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and complete cytogenetic response (CCyR) in 35 percent.

In advanced disease, 44 patients have been treated with dasatinib (50 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 80 percent in LBC/Ph+ ALL. The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL groups, often due to dasatinib-resistant BCR-ABL mutations.

CML is usually diagnosed by finding what is called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of a genetic abnormality among portions of chromosomes 9 and 22. In this, part of the BCR (breakpoint cluster region) gene from chromosome 22 is merged with part of the ABL (abelson leukemia virus) gene on chromosome 9. The irregularity takes place in a single bone marrow cell and – through the process of cell division and expansion – results in leukemia, including some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Imatinib resistance in CML and Ph chromosome positive ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to stop BCR-ABL overproduction. Dasatinib (BMS-354825), which targets BCR-ABL, is 325-fold stronger than imatinib in cells with normal BCR-ABL genes and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.

*Abstract No. CP-2: Development of the ABL Kinase Inhibitor, Dasatinib (BMS-354825), in Imatinib-Resistant Philadelphia Chromosome Positive Leukemias

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 60 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 16,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

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