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  • 1
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    A Gene Polymorphism within the Kinase Domain of BCR-ABL and Its Effects on Sensitivity to Tyrosine Kinase Inhibitors.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1530-1530
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1530-1530
    Abstract: Background: Point mutations that impair drug binding are the most important mechanism of acquired resistance to imatinib. Mutations within the ATP binding loop (P-loop) of BCR-ABL are associated with a poor prognosis in patients on imatinib. We have identified a single nucleotide polymorphism at position 247 (numbering according to ABL-B) that leads to the replacement of lysine by arginine. In CML patients, either the lysine or arginine allele of amino acid 247 becomes part of the BCR-ABL fusion gene. Due to its close proximity to the P-loop, we decided to investigate the allele frequency of K247R and whether the presence of the arginine allele affected sensitivity of Bcr-Abl to Abl kinase inhibitors. Patients and Methods: We investigated the frequency of the arginine allele of K247R in 157 patients with CML and 213 healthy blood donors by conventional sequencing, restriction enzyme digestion and single strand conformational polymorphism analysis. We used Abl autophosphorylation and substrate phosphorylation assays, immunoblotting and cellular proliferation assays to examine the influence of K247R upon imatinib and dasatinib sensitivity. Results: We found that frequency of the arginine allele of K247R was 1.6% in patients with CML and 0.2% in the controls (P = 0.11). In one patient analysis of CD3+ and CD33+ obtained at the time of complete cytogenetic response revealed the presence of K247R in both cell compartments, consistent with a polymorphism. Three out of 5 patients with the arginine allele of K247R expressed in BCR-ABL failed to achieve a major cytogenetic response to imatinib, suggesting reduced drug sensitivity. However, in vitro assays showed no alteration in sensitivity to imatinib or dasatinib compared to “wild type”. Conclusions: K247R is a rare polymorphism within the kinase domain of Abl. There is no evidence that K247R is more frequent in CML patients, and the presence of K247R does not affect drug sensitivity. It is important that clinicians are aware that K247R does not reflect a kinase domain mutation, and that its presence does not signal a need to change therapeutic strategy unless there are other signs of inadequate response to drug therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1530.1530
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 2
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    A Gene Expression Signature of CD34+ Cells to Predict Major Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib: Potential Involvement of Beta-Catenin in Drug Resistance.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 508-508
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 508-508
    Abstract: Abstract 508 In chronic phase chronic myeloid leukemia (CML) patients the lack of a major cytogenetic response (MCyR, 〈 36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure we performed gene expression array profiling of CD34+ cells from two independent cohorts of imatinib-naïve chronic phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response (CCyR) or 〉 65% Ph-positive metaphases within 12 months of imatinib therapy. Based on ANOVA p 〈 0.1 and fold difference 〉 I1.5I we identified 885 probe sets with differential expression between responders and non-responders, from which we extracted a 75-probe set minimal signature (classifier) that separated the two groups. Upon application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of non-responders. Bioinformatics analysis and comparison with published studies revealed highly significant overlap of the resistance signature with CML progression signatures. Consistent with this, differential expression of selected resistance genes was confirmed by qPCR on CD34+ cells from an independent set of patients with chronic phase vs. blast crisis. Furthermore, upon analysis of promoter sequences and comparison with a library of physical beta-catenin targets [generated by serial analysis of chromatin occupancy (SACO) in the HCC-116 colon cancer cell line] we find evidence that b-catenin may be a master regulator of resistance genes. Consistent with this, preliminary chromatin immunoprecipitation (ChIP) data on primary cells support physical beta-catenin binding to selected resistance genes, suggesting that Wnt/beta-catenin activation may be involved in primary cytogenetic resistance as well as disease progression. Conclusion: Our data suggest that chronic phase CML patients destined to fail imatinib have more advanced disease than evident by morphological criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit, while sparing good-risk patients from unnecessary toxicity. The potential role of beta-catenin in the regulation of resistance genes suggests that targeting Wnt/beta-catenin signaling may be useful to overcome resistance. Disclosures: Druker: MolecularMD: Equity Ownership; Novartis Pharmaceuticals: ; Bristol-Myers Squibb: . O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.508.508
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib
    American Society of Hematology ; 2010
    In:  Blood Vol. 115, No. 2 ( 2010-01-14), p. 315-325
    Details
    In: Blood, American Society of Hematology, Vol. 115, No. 2 ( 2010-01-14), p. 315-325
    Abstract: In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response ( 〈 36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34+ cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph+ metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated β-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2009-03-210732
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    RAPID siRNA Screen for Identification of Therapeutic Gene Targets in Patients with Hematologic Malignancies.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3978-3978
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3978-3978
    Abstract: Abstract 3978 Poster Board III-914 A large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of cancer, but identification of specific kinases as cancer targets has been a slow process. Inhibition of cancer-causing tyrosine kinases offers a promising avenue of therapy, however this strategy of targeted therapy will require a detailed understanding of the oncogenic targets in each cancer patient. Here, we present an RNAi-assisted protein target identification (RAPID) assay by which cells from leukemia patients are functionally screened with siRNA to determine tyrosine kinases that constitute amenable targets for therapeutic intervention. Combination of the RAPID screen with gene-specific therapeutic approaches promises to yield a powerful synthesis of methodologies by which cancer patients can be specifically treated on the basis of functionally diagnosed gene targets. Methods To detect gene targets necessary for viability of malignant cells, we screened primary cells from 150 patients with hematologic malignancies by electroporating siRNAs individually targeting each member of the tyrosine kinase gene family. Four days later, we measured cell viability and tabulated sensitivity to silencing of specific genes. Samples were also screened for sensitivity to small-molecule kinase inhibitors. The mechanism of oncogenesis was investigated for each positive result. Results In total, we have identified 40 patient-specific gene targets in primary leukemia samples. We demonstrate that siRNA screening can identify known oncogenic lesions such as K-RasG13D and JAK2V617F in primary cells from leukemia patients. The RAPID screen has also directed us towards a novel insertional mutation in the thrombopoietin receptor, MPL (1886InsGG). Additionally, we have detected FLT3 sensitivity in patients with FLT3-ITD and loss of heterozygosity, although not in FLT3-ITD heterozygous patients. Agreement between siRNA-sensitive gene targets and small-molecule inhibitor sensitivity profiles has been high. The mechanism of oncogenesis and its relation to the gene target has been established in select other samples with abnormalities including gene overexpression and patient-specific mis-splicing events. Conclusions We demonstrate that RNAi functional screening can determine sensitivity to individual genes in cells obtained directly from cancer patients. Thus, this technique offers the potential to match targeted therapies with patients in a personalized manner. Application of these technologies will enable efficient discovery of the genetic etiology of cancer as well as a means for gene-specific therapeutic intervention. Disclosures: Deininger: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3978.3978
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL
    American Society of Hematology ; 2022
    In:  Blood Advances Vol. 6, No. 21 ( 2022-11-08), p. 5737-5749
    Details
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 21 ( 2022-11-08), p. 5737-5749
    Abstract: T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021006293
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 6
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    RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. 20 ( 2018-11-15), p. 2154-2165
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. 20 ( 2018-11-15), p. 2154-2165
    Abstract: Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI] , 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-05-849893
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Online Resource
    RNAi Screening of the Tyrosine Kinome Identifies Therapeutic Targets in Leukemia Patients
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 758-758
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 758-758
    Abstract: A large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of cancer, but identification of specific tyrosine kinases as cancer targets has been a slow process. In the near future, whole-genome sequencing will enable vast amounts of sequence data to be collected, however clinical application of this information will require a detailed understanding of the functional consequences of each sequence change. Here, we present an RNAi-assisted protein target identification (RAPID) assay by which cells from leukemia patients are functionally screened with siRNA to determine tyrosine kinases that constitute amenable targets for therapeutic intervention. These data have led to identification of novel oncogenic anomalies in cancer patients. Combination of the RAPID screen with whole-genome sequencing promises to yield a powerful synthesis of methodologies by which both functional targets and genetic lesions can be rapidly determined. Methods: To detect targets necessary for viability of malignant cells, we screened primary cells from 75 patients with AML, ALL, CMML, and other MPD as well as white blood cells from healthy individuals by electroporating siRNAs individually targeting each member of the tyrosine kinase family. Four days later, we determined the cell viability and tabulated sensitivity of the cells to any individual tyrosine kinase. Where possible, results were confirmed by treating samples with small-molecule inhibitors with activity against the genes identified by the assay. In addition, the mechanism of oncogenesis was investigated for each positive result. Results: We demonstrate that siRNA screening can identify known oncogenic lesions such as K-RasG13D and JAK2V617F in primary cells from leukemia patients. The RAPID screen has also directed us towards a novel insertional mutation in the thrombopoietin receptor, MPL (1886InsGG). Additionally, we have detected FLT3 sensitivity in patients with FLT3-ITD and loss of heterozygosity, although not in FLT3-ITD heterozygous patients. In total, of 75 patients screened, this assay has yielded 25 cases that exhibit sensitivity to one or more tyrosine kinases. The mechanism of oncogenesis and its relation to the gene target has been established in select other samples with genetic abnormalities including evidence of chromosomal rearrangements as well as gene overexpression and mis-spicing events. Conclusions: We demonstrate that RNAi functional screening can determine sensitivity to individual tyrosine kinases in primary samples. Thus, this technique offers the potential to match specific therapies for targeted intervention with individual patients based on a functional assay. Additionally, in many cases, combination of the RAPID screen with whole-genome sequencing will enable efficient discovery of the genetic etiology of cancer.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.758.758
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Mutational Analysis of BCR-Abl From Subjects with Relapsed Ph+ALL Treated On the COG Protocol AALL0031: a Report From the Children's Oncology Group.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2634-2634
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2634-2634
    Abstract: Abstract 2634 Poster Board II-610 Background: Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph+ALL) occurs in 2–5% of pediatric ALL and is associated with a poor prognosis. COG AALL0031 treated children with an intensified chemotherapy backbone plus imatinib. All subjects received imatinib at 340mg/m^2 daily. Exposure to imatinib progressively increased in each of five cohorts. Patients had a total imatinib exposure (before maintenance) of 42 days in cohort 1, 63 days in cohort 2, 84 days in cohort 3, 126 days in cohort 4, and 280 days in cohort 5. All groups received an additional 336 days of imatinib exposure in maintenance cycles 1 through 12 for approximately 2 years (with imatinb given on 21 day cycles for maintenance cycles 1 – 4, and a two-week on/two-week off schedule for maintenance cycles 5 - 12). Early results of this trial show encouraging outcome with a 3-year event free survival of 80±11% (95% CI 64 – 90%) for patients in cohort 5. In studies of adults with Ph+ALL treated with imatinib many patients recurred with imatinib resistant BCR-Abl mutations. To date, there are no data on the occurrence of BCR-Abl mutations in pediatric Ph+ALL. Patients and Methods: We performed nested PCR to identify BCR-Abl point mutations in nine samples obtained at bone marrow (BM) relapse from Ph+ALL subjects on AALL0031. Results: (Table 1) Three samples from cohort 1 that had no exposure to imatinib prior to relapse showed wild-type sequence. There were 5 of 6 samples that also showed wild-type sequence. One sample was from cohort 2 and 3 samples were from cohort 3. Each subject relapsed 1 to 2 years after diagnosis while receiving varying amounts of imatinib with continued intensive therapy. One subject recurred after stem cell transplant in first remission. One sample from cohort 4 recurred after the completion of chemotherapy and imatinib. One subject from cohort 5 carried the histidine 396 to proline (H396P) mutation. This mutation, which increases the imatinib IC50 by 10-fold, has been previously described to occur in adults with CML and Ph+ALL treated with imatinib. The subject from cohort 5 recurred 1 year after diagnosis on therapy with imatinib. Conclusions: Only 1 resistant mutation in BCR-Abl has been identified among nine children with Ph+ALL treated on AALL0031. Therefore, unlike results in the adults, resistant mutations do not appear to drive early recurrence in Ph+ALL. Further studies will be needed to identify whether BCR-Abl mutations are identified in subjects who develop a late relapse after treatment with AALL0031 or subsequent treatment studies. Disclosures: Druker: OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Schultz:novartis: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2634.2634
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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    detail.hit.zdb_id: 80069-7
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