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[Title] Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia.

BACKGROUND: Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML).

A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP).

The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%).

CONCLUSIONS: Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.

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(PMID = 17236224.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] eng

[Grant] United States / NCI NIH HHS / CM / N01-CM-62202; United States / NCI NIH HHS / CA / P50CA100632

[Publication-type] Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

[Publication-country] United States

[Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 776B62CQ27 / decitabine; 8A1O1M485B / Imatinib Mesylate; M801H13NRU / Azacitidine

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval.

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN-alpha therapy, (b) accelerated phase, and (c) blast crisis.

The accelerated approval was accompanied by a postmarketing commitment by Novartis Pharmaceuticals to continue patient follow-up to determine duration of treatment response and survival.

The present review, based on a safety and efficacy report submitted on December 20, 2002, summarizes data applicable to the conversion of these three CML indications to full approval status.

RESULTS: Chronic phase CML: Five hundred thirty-two chronic phase CML patients who had not benefited from prior IFN therapy were treated at a starting imatinib mesylate dose of 400 mg p.o. qd; dose escalation to 800 mg p.o. qd was allowed.

Patients had received a median of 14 months of IFN therapy at doses > or =25 million IU/wk and were all in late chronic phase, with a median time from diagnosis of 32 months.

After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and the estimated overall survival was 90.8% (95% confidence interval, 88.3-93.2).

Accelerated phase CML: Patients enrolled totaled 293: 235 with CML accelerated phase, 48 with relapsed/refractory acute lymphocytic leukemia, 2 with relapsed/refractory acute myelocytic leukemia, and 8 with relapsed/refractory CML in lymphoid blast crisis.

The median survival in the advanced leukemia population (acute lymphocytic leukemia, acute myelocytic leukemia, and lymphoid blast crisis) was only 5 months, and only two patients are still on treatment.

Blast crisis CML: A total of 260 patients were recruited.

CONCLUSIONS: The results confirm those of the interim analysis and suggest that imatinib mesylate represents an effective therapeutic agent for the treatment of patients with CML in chronic phase after failure of IFN-alpha therapy, in blast crisis, and in accelerated phase.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / pharmacology. Pyrimidines / pharmacology

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(PMID = 15671523.001).

[ISSN] 1078-0432

[Journal-full-title] Clinical cancer research : an official journal of the American Association for Cancer Research

[ISO-abbreviation] Clin. Cancer Res.

[Language] eng

[Publication-type] Clinical Trial; Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.

Treatment options are limited for patients with imatinib-resistant or -intolerant accelerated phase chronic myeloid leukemia (CML-AP).

Dasatinib is a novel, potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC-family kinases that showed marked efficacy in a phase 1 trial of patients with imatinib-resistant CML.

Results are presented for 107 patients with CML-AP with imatinib-resistance or -intolerance from a phase 2, open-label study further evaluating dasatinib efficacy and safety.

Response rates for the 60% of patients with baseline BCR-ABL mutations did not differ from the total population.

In summary, dasatinib induced significant hematologic and cytogenetic responses in patients with imatinib resistance or intolerance, was well tolerated, and may represent a potent new therapeutic option for CML-AP.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology. Piperazines / therapeutic use. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

[MeSH-minor] Adult. Aged. Aged, 80 and over. Antineoplastic Agents / adverse effects. Antineoplastic Agents / therapeutic use. Benzamides. Blood Cell Count. Cytogenetic Analysis. Dasatinib. Disease Progression. Drug Resistance, Neoplasm / drug effects. Drug Resistance, Neoplasm / genetics. Female. Fusion Proteins, bcr-abl. Humans. Imatinib Mesylate. Male. Middle Aged. Point Mutation. Protein-Tyrosine Kinases / genetics. Treatment Outcome

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(PMID = 17264298.001).

[ISSN] 0006-4971

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] eng

[Publication-type] Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl; RBZ1571X5H / Dasatinib

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [The prognostic implications of secondary chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia patients after imatinib mesylate treatment].

OBJECTIVE: To investigate the change of Philadelphia chromosome-positive clone with secondary chromosomal aberrations after imatinib mesylate (IM) treatment in patients with chronic myeloid leukemia (CML) and its relation with prognosis.

METHODS: 37 cases of CML in accelerated phase and blastic phase were collected and chromosome specimens of bone marrow cells were prepared by with 24-hour culture.

The percentage of Philadelphia chromosome-positive clone with secondary chromosomal aberrations showed the following 4 types of change; amplification, no change, decrease and complete remission after treatment with IM.

2 of the 24 cases in CML in accelerated phase gained complete cytogenetic response (CCyR) and 2 of the 13 in blastic phase did so.

CONCLUSION: The percentage of Philadelphia chromosome-positive clone with secondary chromosomal aberrations may drop in some CML patients after IM treatment and the patients may gain CCyR with accompanied prolonged survival.

[MeSH-major] Chromosome Aberrations. Leukemia, Myeloid, Chronic-Phase / drug therapy. Leukemia, Myeloid, Chronic-Phase / genetics. Piperazines / therapeutic use. Pyrimidines / therapeutic use

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(PMID = 17967235.001).

[ISSN] 0578-1426

[Journal-full-title] Zhonghua nei ke za zhi

[ISO-abbreviation] Zhonghua Nei Ke Za Zhi

[Language] chi

[Publication-type] English Abstract; Journal Article

[Publication-country] China

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Central nervous system blastic crisis in chronic myeloid leukemia on imatinib mesylate therapy: a case report.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22.

Imatinib mesylate is a potent and selective inhibitory of the BCR/ABL tyrosine kinase.

Imatinib is a first choice of treatment of chronic phase CML.

It has also shown activity in patients with CML in accelerated or blastic phases.

Herein, we report a patient with CML in accelerated phase that developed central nervous system disease while on imatinib mesylate therapy.

[MeSH-major] Antineoplastic Agents / therapeutic use. Blast Crisis / drug therapy. Central Nervous System Neoplasms / secondary. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use. Sarcoma, Myeloid / drug therapy

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[Cites] Leuk Lymphoma. 2004 Aug;45(8):1623-6 [15370215.001]

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[Cites] J Pharmacol Exp Ther. 2003 Mar;304(3):1085-92 [12604685.001]

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(PMID = 17318411.001).

[ISSN] 0167-594X

[Journal-full-title] Journal of neuro-oncology

[ISO-abbreviation] J. Neurooncol.

[Language] eng

[Publication-type] Case Reports; Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 04079A1RDZ / Cytarabine; 7S5I7G3JQL / Dexamethasone; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; YL5FZ2Y5U1 / Methotrexate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): Data from an ongoing phase II trial.

: 7027 Background: Omacetaxine (OM), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism of action independent to tyrosine kinase inhibition.

Patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML.

METHODS: Pts include adult CML following resistance or intolerance to at least 2 TKIs.

T315I+ Pts are enrolled in a separate trial.

RESULTS: 60 pts (30 chronic phase [CP], 14 accelerated phase [AP], and 16 blast phase [BP] have been enrolled with 51% having failed at least 3 prior TKIs.

Median disease duration: 74 months.

At baseline, 38.5% of pts had Bcr-Abl mutations including 9.6% with compound mutations.

Efficacy data are available for 30 Pts: Conclusions: Omacetaxine in multi-TKI resistant or intolerant CML is well tolerated and has achieved hematologic and cytogenetic responses in these heavily pre-treated Pts.

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(PMID = 27961400.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study.

: 7029 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM.

This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM.

RESULTS: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of 19 months (mos) were evaluated; 72% were treated with ≥600 mg/day IM prior to enrollment.

CONCLUSIONS: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in CML-CP pts failing prior therapy due to resistance or intolerance.

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(PMID = 27961402.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study.

: 7057 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in chronic phase or AP who are resistant or intolerant to prior therapy including IM.

This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-AP pts resistant or intolerant to IM.

RESULTS: 137 CML-AP pts (80% IM-resistant; 20% IM-intolerant with resistance) with minimum follow-up of 11 months (mos) (median age, 57 years; median duration of prior IM treatment, 28 mos) were included.

CONCLUSIONS: These long-term follow-up results confirm that nilotinib induces rapid and durable responses in CML-AP pts who failed prior IM due to intolerance or resistance, with a favorable risk/benefit.

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(PMID = 27961447.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance.

: 7030 Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2).

Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2.

METHODS: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008.

RESULTS: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP).

Median age at diagnosis was 60 (range 28-86) years, median follow-up 39.5 (range 2-109) months.

5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4-92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT.

Six patients (5 CP, 1 AP) were alive at a median 39 (range 2-85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT.

CONCLUSIONS: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived.

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(PMID = 27961392.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Molecular responses with nilotinib 800 mg daily as first-line treatment of chronic myeloid leukemia in chronic phase: Results of a phase II trial of the GIMEMA CML WP.

To investigate the efficacy and the safety of nilotinib 400 mg BID in untreated, early chronic phase (ECP) CML patients (pts), the GIMEMA CML WP is conducting a multicentric, phase II study trial (ClinicalTrials.gov NCT00481052 ).

One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation.

CONCLUSIONS: In ECP Ph-pos CML pts both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM.

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(PMID = 27961457.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial.

: 7008 Background: Omacetaxine (OM), a first-in-class cetaxine shows clinical activity against Ph+ CML with a mechanism independent of tyrosine kinase inhibition.

METHODS: Adult Pts with T315I+ CML following TKI failure received OM induction at 1.25 mg/m² subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25 mg/m² SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response).

RESULTS: 66 pts (39 chronic [CP], 16 accelerated [AP] and 11 blast phase [BP]) have been enrolled.

Median disease duration is 58 mos.

CONCLUSIONS: Omacetaxine in T315I+ CML Pts results in de-selection of the T315I clone and induces hematologic and cytogenetic responses.

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(PMID = 27961380.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?

: 7064 Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML.

METHODS: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML.

13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts.

Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies.

CONCLUSIONS: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete.

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(PMID = 27961440.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Does pre-imatinib (IM) fluorescence in situ hybridization (FISH) predict myelosuppression and outcomes in chronic myeloid leukemia (CML)?

: 7071 Background: IM-associated myelosuppression occurs in 4-40% of CML patients (pts) vs. 1-16% in GIST.

In the absence of clinically applicable methods to quantitate Ph+/Ph- progenitor ratio, we hypothesized that the pre-IM percentage of BCR-ABL+ cells measured by FISH predicts myelosuppression.

METHODS: FISH pre-IM was available in 58 CML pts with chronic phase (CP, n=52), or advanced phase (AP, accelerated =3, blast =3) at 2 institutions.

Myelosuppression AP pts expired (CML=2, GVHD=1); 1 after complete hematologic (CHR) and minor cytogenetic response (CTGR), 1 after partial HR, and 1 resistant disease.

CONCLUSIONS: Higher FISH pre-IM identifies a group of CML pts who develop myelosuppression and are less likely to respond to IM.

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(PMID = 27961454.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral center in India.

: 10047 Background: Chronic myeloid leukemia (CML) is a rare disease in children and there is limited data of safety and efficacy of imatinib mesylate (IM) in this age group.

METHODS: We analyzed the outcomes of 48 consecutive children (September 1998 to December 2008) in chronic phase (CP) or accelerated phase (AP) CML not eligible for Allo-SCT and were treated with IM [Glivec (Novartis), through patient assistance programme GIPAP or Veenat (NATCO), generic brand for GIPAP ineligible patients] within 12 months of diagnosis.

RESULTS: The median age at the time of diagnosis was 12 years (range 3-18 years).

One patient had secondary IM resistance and had progressive disease even on dose escalation.

Two patients in AP at diagnosis achieved CCR at 5 and 7 months and continue to be in CCR.

CONCLUSIONS: Results from this largest single center study indicate that outcome of children with CML receiving IM is similar to adults.

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(PMID = 27962473.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Patterns of imatinib resistance mutation analysis in chronic myeloid leukemia (CML) patients on imatinib at the time of loss of response to the drug in Asian Indian subjects.

: 7079 Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI).

METHODS: We identified 17 males and 8 female patients with median age 40 yrs (range 9-55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis.

RESULTS: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC).

Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available.

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(PMID = 27961486.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial.

PURPOSE Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options.

Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib.

We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population.

PATIENTS AND METHODS Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily.

Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation.

CONCLUSION Dasatinib is effective in patients with CML-AP after imatinib treatment failure.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Pyrimidines / therapeutic use. Thiazoles / therapeutic use. Treatment Failure

[MeSH-minor] Adult. Aged. Aged, 80 and over. Benzamides. Dasatinib. Disease-Free Survival. Female. Humans. Imatinib Mesylate. Male. Middle Aged. Treatment Outcome. Young Adult

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[Cites] Haematologica. 2006 Apr;91(4):513-21 [16533723.001]

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(PMID = 19487385.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; RBZ1571X5H / Dasatinib

[Other-IDs] NLM/ PMC4979080

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Current role of stem cell transplantation in chronic myeloid leukaemia.

Haematopoietic stem cell transplantation (HSCT) has seen considerable ups and downs in its role for patients with chronic myeloid leukaemia (CML).

It has provided the first proof of the principle for cure and has confirmed the concept of successful immunotherapy of leukaemia.

CML became the most frequent indication for an allogeneic HSCT worldwide.

The frequency of HSCT declined rapidly when the specific BCR/ABL tyrosine kinase inhibitor (TKI) imatinib appeared.

Risk assessment of both, disease risk and transplant risk, has become standard.

Allogeneic HSCT remains the first-line approach for patients with CML in accelerated phase or blast crisis.

It is the best option for all patients with failed second-line TKIs, with mutations T315I or with progressive disease.

[MeSH-major] Hematopoietic Stem Cell Transplantation / methods. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy. Protein Kinase Inhibitors / therapeutic use

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(PMID = 19959092.001).

[ISSN] 1532-1924

[Journal-full-title] Best practice & research. Clinical haematology

[ISO-abbreviation] Best Pract Res Clin Haematol

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] Netherlands

[Chemical-registry-number] 0 / Protein Kinase Inhibitors

[Number-of-references] 74

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Complex cytogenetic aberrations in a patient with chronic myeloid leukemia: a case report].

In this article is presented a case of multiple chromosomal aberrations in a patient with CML accelerated phase.

Our data suggested that detected changes can be correlated with previous treatment regimens and the influence of these changes on progression of disease is discussed.

[MeSH-major] Chromosome Aberrations. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics

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(PMID = 19938637.001).

[ISSN] 0564-3783

[Journal-full-title] T︠S︡itologii︠a︡ i genetika

[ISO-abbreviation] Tsitol. Genet.

[Language] ukr

[Publication-type] Case Reports; English Abstract; Journal Article

[Publication-country] Ukraine

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience.

BACKGROUND: The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown.

The objectives of this study were to update the long-term experience with imatinib in patients who had accelerated-phase CML and to compare outcomes with historic experience.

METHODS: The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated-phase CML who received treatment with interferon-alpha or with other modalities.

This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5-year survival were 25-30%.

CONCLUSIONS: The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated-phase CML.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myeloid, Accelerated Phase / drug therapy. Piperazines / therapeutic use. Protein Kinase Inhibitors / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Pyrimidines / therapeutic use

[MeSH-minor] Adult. Anemia / chemically induced. Benzamides. Bone Marrow Transplantation. Cohort Studies. Cytogenetic Analysis. Female. Follow-Up Studies. Fusion Proteins, bcr-abl / analysis. Hemoglobins / analysis. Humans. Imatinib Mesylate. Interferon-alpha / therapeutic use. Longitudinal Studies. Male. Middle Aged. Remission Induction. Survival Rate. Treatment Outcome

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(PMID = 15830345.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] eng

[Publication-type] Comparative Study; Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Hemoglobins; 0 / Interferon-alpha; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase II study of all-trans retinoic acid in the accelerated phase or early blastic phase of chronic myeloid leukemia: a study of the Eastern Cooperative Oncology Group (E1993).

The aims of this study were to evaluate the safety and efficacy of all-trans retinoic acid (ATRA) in the treatment of the accelerated and blastic phase of chronic myeloid leukemia (CML) and to evaluate in vitro correlates of biological activity.

ATRA was administered in an intermittent schedule to patients with CML in the accelerated or blastic phases for a 6 week induction period, which was continued if there was evidence of clinical response or stable disease.

Laboratory correlative studies were performed prior to treatment and at intervals during treatment to evaluate effects on maturation and differentiation, and on CML progenitor cell growth by assessment of colony-forming cells (CFC).

ATRA demonstrated clinical and hematological activity in 5 of 18 patients with the accelerated phase of CML, and there was evidence of a biological effect in laboratory studies of 3 of the 5 patients' progenitor cells.

Combination therapy with other differentiating agents may be useful in this disease.

[MeSH-major] Antineoplastic Combined Chemotherapy Protocols / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Tretinoin / administration & dosage

[MeSH-minor] Adult. Aged. Blast Crisis. Combined Modality Therapy. Cytogenetic Analysis. Disease-Free Survival. Dose-Response Relationship, Drug. Drug Administration Schedule. Female. Humans. Interferon-alpha / administration & dosage. Interferon-alpha / adverse effects. Male. Middle Aged. Recombinant Proteins. Survival Analysis. Time Factors

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(PMID = 15621827.001).

[ISSN] 1042-8194

[Journal-full-title] Leukemia & lymphoma

[ISO-abbreviation] Leuk. Lymphoma

[Language] eng

[Grant] United States / NCI NIH HHS / CA / CA 11083; United States / NCI NIH HHS / CA / CA 14548; United States / NCI NIH HHS / CA / CA 14958; United States / NCI NIH HHS / CA / CA 23318; United States / NCI NIH HHS / CA / CA 66636; United States / NCI NIH HHS / CA / CA21115

[Publication-type] Clinical Trial; Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.

[Publication-country] England

[Chemical-registry-number] 0 / Interferon-alpha; 0 / Recombinant Proteins; 5688UTC01R / Tretinoin; 76543-88-9 / interferon alfa-2a

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.

BACKGROUND: Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.

METHODS: In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib.

Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily.

The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs).

One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months.

Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months.

CONCLUSIONS: Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib.

[MeSH-major] Farnesyltranstransferase / antagonists & inhibitors. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperidines / therapeutic use. Pyridines / therapeutic use

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(PMID = 16342165.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] eng

[Publication-type] Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Piperidines; 0 / Pyridines; 0 / Pyrimidines; 193275-84-2 / lonafarnib; 8A1O1M485B / Imatinib Mesylate; EC 2.5.1.29 / Farnesyltranstransferase

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A report of early cytogenetic response to imatinib in two patients with chronic myeloid leukemia at accelerated phase and carrying the e19a2 BCR-ABL transcript.

The development of imatinib is a milestone in the treatment of chronic myeloid leukemia (CML), and its therapeutic effect has been extensively investigated in CML patients carrying M-bcr and m-bcr BCR/ABL fusion transcripts.

However, our knowledge about its therapeutic effect on CML patients with rare BCR/ABL fusion transcripts e19a2(u-bcr) remains sparse.

Here, we report on two CML patients with e19a2 transcripts who rapidly progressed into the accelerated phase, further confirming the possibility that 19a2 might be associated with an unfavorable prognosis in CML.

[MeSH-major] Gene Expression Regulation, Leukemic / drug effects. Genes, abl / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use

[MeSH-minor] Adult. Antineoplastic Agents / therapeutic use. Benzamides. Chromosomes, Human, Pair 22. Chromosomes, Human, Pair 9. Cytogenetic Analysis. Disease Progression. Exons. Female. Humans. Imatinib Mesylate. Male. Middle Aged. RNA, Messenger / drug effects. RNA, Messenger / metabolism. Time Factors. Translocation, Genetic. Treatment Outcome

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(PMID = 17656262.001).

[ISSN] 1873-4456

[Journal-full-title] Cancer genetics and cytogenetics

[ISO-abbreviation] Cancer Genet. Cytogenet.

[Language] eng

[Publication-type] Case Reports; Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 0 / RNA, Messenger; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [The efficacy of imatinib mesylate for 124 patients with chronic myeloid leukemia in accelerated and blastic phase].

OBJECTIVES: To evaluate the efficacy and safety of imatinib mesylate (imatinib) for patients with Philadelphia chromosome-positive (Ph+ ) chronic myeloid leukemia (CML) in accelerated and blastic phase.

METHODS: Seventy-five Ph+ CML patients in accelerated phase and 49 in blastic phase were treated with 400 mg or 600 mg of imatinib once daily.

RESULTS: For patients in accelerated phase, the cumulative hematological response (HR) rate was 93.3%, including complete HR (CHR) rate 85.3%, and returning to chronic phase (RCP) rate 8% in a median follow-up of 23.0 (1.0 -64.0 ) months.

For patients in blastic phase, the cumulative HR rate was 63.3%, including CHR rate 44.9%, and RCP rate 18.4% in a median follow-up of 4.5 (0.3 -63.0) months.

CONCLUSIONS: The efficiency of imatinib was decreasing, and severer hematological toxicities increasing with the disease progressing in patients with Ph+ CML.

Imatinib improves progression-free survival significantly in most patients in accelerated phase, particularly in those with continuous CCyR or MMoR.

The response duration in majority of blastic phase patients is short, and the relapse rate is high.

[MeSH-major] Antineoplastic Agents / therapeutic use. Blast Crisis / drug therapy. Leukemia, Myeloid, Accelerated Phase / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use

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(PMID = 18457260.001).

[ISSN] 0253-2727

[Journal-full-title] Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi

[ISO-abbreviation] Zhonghua Xue Ye Xue Za Zhi

[Language] chi

[Publication-type] English Abstract; Journal Article

[Publication-country] China

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dasatinib and nilotinib in imatinib-resistant Philadelphia-positive chronic myelogenous leukemia: a 'head-to-head comparison'.

Imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML).

Dasatinib, approved in 2006 for the treatment of patients with CML in all phases who experience imatinib resistance or intolerance, has displayed significant efficacy, with a 2-year follow-up showing durable hematologic and cytogenetic responses, as well as prolonged progression-free and overall survival.

Nilotinib was approved in 2007 for the treatment of patients with CML in chronic phase or CML in accelerated phase, resistant or intolerant to prior therapy including imatinib, based on strong efficacy as well as a favorable safety profile.

[MeSH-major] Antineoplastic Agents / therapeutic use. Drug Resistance, Neoplasm / drug effects. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

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(PMID = 20302388.001).

[ISSN] 1029-2403

[Journal-full-title] Leukemia & lymphoma

[ISO-abbreviation] Leuk. Lymphoma

[Language] eng

[Publication-type] Comparative Study; Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't; Review

[Publication-country] England

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; RBZ1571X5H / Dasatinib

[Number-of-references] 30

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Chronic myeloid leukemia].

[Transliterated title] Krónikus myeloid leukaemia.

Chronic myeloid leukemia is still the most characteristic entity of the chronic myeloproliferative diseases.

The tumor promoter role of able-dependent tyrosine kinase activation, which is enhanced by bcr/abl rearrangement (due the classical translocation of Philadelphia chromosomal abnormality) has been quite well clarified.

The better understanding of the role of altered cell signalling pathways in the pathogenesis of chronic myeloid leukaemia opened new areas for extensive and fruitful pharmacological research.

The first, non-myelosuppressive agent, which was able to reduce the number of Philadelphia positive clonal cells was the interferon group, which drug could substantially prolong the chronic phase and mortality of chronic myeloid leukaemia.

Imatinib is also a powerful agent in the accelerated or blastic phased of chronic myeloid leukaemia.

With the advent of these new drugs the therapeutic algorithm of chronic myeloid leukaemia and allogenous bone marrow transplantation seems to be reconsidered, too.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive. Protein Kinase Inhibitors / therapeutic use. Protein-Tyrosine Kinases / metabolism

[MeSH-minor] Antineoplastic Combined Chemotherapy Protocols / therapeutic use. Benzamides. Diagnosis, Differential. Enzyme Activation / drug effects. Humans. Imatinib Mesylate. Interferons / therapeutic use. Piperazines / therapeutic use. Pyrimidines / therapeutic use. Signal Transduction / drug effects

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(PMID = 15779811.001).

[ISSN] 0030-6002

[Journal-full-title] Orvosi hetilap

[ISO-abbreviation] Orv Hetil

[Language] hun

[Publication-type] English Abstract; Journal Article; Review

[Publication-country] Hungary

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; 9008-11-1 / Interferons; EC 2.7.10.1 / Protein-Tyrosine Kinases

[Number-of-references] 19

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase].

[Transliterated title] Kombinace imatinibu s anagrelidem v lécbe blastického zvratu chronické myeloidní leukemie.

Chronic myeloid leukemia in blast phase (BP) is resistant to chemotherapy and majority of patients die within 6 months.

Inhibitor Bcr-Abl tyrosine kinase imatinib mesylate dramatically improved outcome of patients in chronic phase (CP) and is also effective in BP of CML.

High platelet counts are often observed at diagnosis or in the subsequent course of the CML in about 25% of patients.

Anagrelide selectively reduces circulating platelets and is used in treatment of thrombocythemia in chronic myeloproliferative disorders.

Efficacy and safety of combination imatinib mesylate with anagrelide was demonstrated in chronic and accelerated phase of CML.

51-year-old white man with CML presented in blast phase was followed for 4 years.

[MeSH-major] Antineoplastic Agents / administration & dosage. Blast Crisis / drug therapy. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / administration & dosage. Platelet Aggregation Inhibitors / administration & dosage. Protein Kinase Inhibitors / administration & dosage. Pyrimidines / administration & dosage. Quinazolines / administration & dosage. Thrombocytosis / drug therapy

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(PMID = 17091608.001).

[ISSN] 0042-773X

[Journal-full-title] Vnitr̆ní lékar̆ství

[ISO-abbreviation] Vnitr Lek

[Language] cze

[Publication-type] Case Reports; English Abstract; Journal Article

[Publication-country] Czech Republic

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Platelet Aggregation Inhibitors; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Quinazolines; 0 / anagrelide; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Tailoring tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

BACKGROUND: Research into chronic myeloid leukemia (CML) is increasingly focused on the problem of imatinib failure.

Dasatinib and nilotinib are both active in chronic- and accelerated-phase CML, including patients with imatinib-resistant or intolerant disease.

METHODS: This paper reviews advances in tailoring tyrosine kinase inhibition therapy according to patient risk profiles as well as hematologic, cytogenetic, and molecular responses, BCR-ABL mutation status, and emerging predictive factors.

CONCLUSIONS: Treatment for CML should be individualized and, when resistance to imatinib can be predicted, therapy should be modified so that patients do not progress beyond chronic phase and respond as promptly and deeply as required to maximally reduce risk.

[MeSH-major] Drug Resistance, Neoplasm / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics. Protein Kinase Inhibitors / therapeutic use. Protein-Tyrosine Kinases / genetics

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(PMID = 19337197.001).

[ISSN] 1526-2359

[Journal-full-title] Cancer control : journal of the Moffitt Cancer Center

[ISO-abbreviation] Cancer Control

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Review

[Publication-country] United States

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; RBZ1571X5H / Dasatinib

[Number-of-references] 118

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: a single- and multiple-dose, open-label pharmacokinetic study in Chinese patients.

BACKGROUND: Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib.

Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China.

OBJECTIVES: This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML.

METHODS: Chinese patients aged > or =18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible.

RESULTS: Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1).

Steady-state C(max), C(min), AUC(0-tau), and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose.

CONCLUSIONS: In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses.

The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.

[MeSH-minor] Administration, Oral. Adult. Aged. Area Under Curve. Asian Continental Ancestry Group. Benzamides. Blast Crisis / drug therapy. China. Chromatography, Liquid. Drug Administration Schedule. Drug Resistance, Neoplasm. European Continental Ancestry Group. Female. Humans. Imatinib Mesylate. Leukemia, Myeloid, Accelerated Phase / drug therapy. Leukemia, Myeloid, Chronic-Phase / drug therapy. Male. Middle Aged. Piperazines / administration & dosage. Tandem Mass Spectrometry. Young Adult

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(PMID = 19695406.001).

[ISSN] 1879-114X

[Journal-full-title] Clinical therapeutics

[ISO-abbreviation] Clin Ther

[Language] eng

[Databank-accession-numbers] ClinicalTrials.gov/ NCT00302016

[Publication-type] Controlled Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dasatinib: in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC, c-KIT, ephrin A receptor and platelet-derived growth factor-beta receptor kinases, at nanomolar concentrations.

In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL.

The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials.

In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%).

Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up > or =9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up > or =12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up > or =12 months; START-L trial).

Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily).

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Protein Kinase Inhibitors / administration & dosage. Pyrimidines / administration & dosage. Thiazoles / administration & dosage

[MeSH-minor] Animals. Controlled Clinical Trials as Topic. Dasatinib. Humans. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy

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(PMID = 18215092.001).

[ISSN] 1173-8804

[Journal-full-title] BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

[ISO-abbreviation] BioDrugs

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] New Zealand

[Chemical-registry-number] 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; RBZ1571X5H / Dasatinib

[Number-of-references] 57

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Novel treatment strategies for chronic myeloid leukemia.

PURPOSE: Despite dramatic advances in the treatment of chronic myeloid leukemia (CML), resistance to therapeutic agents has emerged as a significant treatment dilemma.

Mutations of the BCR-ABL kinase domain, a common mechanism of resistance to imatinib in CML, are discussed.

SUMMARY: Several new targeted kinase inhibitors have reached clinical trials and have proved to be efficacious in halting the oncogenic activity of most BCR-ABL mutants.

Dasatinib is 300 times more potent than imatinib at BCR-ABL inhibition, has few side effects, and inhibits the SRC family kinases.

Nilotinib inhibits BCR-ABL at 20-50 times more potency than imatinib.

Both agents were highly effective in treating chronic phase CML but were less effective at treating accelerated phase CML in early phase clinical trials.

CONCLUSION: The new kinase inhibitors, dasatinib and nilotinib, are emerging as plausible therapeutic options for the treatment of imatinib-refractory CML.

[MeSH-major] Drug Therapy / methods. Immunotherapy, Active / methods. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy

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(PMID = 17106016.001).

[ISSN] 1079-2082

[Journal-full-title] American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists

[ISO-abbreviation] Am J Health Syst Pharm

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Review

[Publication-country] United States

[Chemical-registry-number] 0 / Protein Kinase Inhibitors

[Number-of-references] 23

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy.

Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon.

METHODS: A Phase I study was completed of subcutaneous (s.c.

) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration.

The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure.

The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable.

CONCLUSIONS: Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

[MeSH-major] Harringtonines / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy

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[ErratumIn] Cancer. 2007 Jun 15;109(12):2625. Dosage error in article text

(PMID = 17154172.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] eng

[Publication-type] Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents, Phytogenic; 0 / Benzamides; 0 / Harringtonines; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 6FG8041S5B / homoharringtonine; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.

BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase.

Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase.

For 5 years, we followed patients with CML who received imatinib as initial therapy.

METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events.

An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months.

Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001).

CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov]. )

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Pyrimidines / therapeutic use

[MeSH-minor] Antineoplastic Combined Chemotherapy Protocols / adverse effects. Antineoplastic Combined Chemotherapy Protocols / therapeutic use. Benzamides. Cytarabine / administration & dosage. Disease-Free Survival. Female. Follow-Up Studies. Fusion Proteins, bcr-abl / blood. Humans. Imatinib Mesylate. Interferon-alpha / administration & dosage. Kaplan-Meier Estimate. Male. Survival Analysis. Survival Rate. Treatment Outcome

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[Copyright] Copyright 2006 Massachusetts Medical Society.

[CommentIn] N Engl J Med. 2007 Apr 26;356(17):1780; author reply 1780 [17460235.001]

(PMID = 17151364.001).

[ISSN] 1533-4406

[Journal-full-title] The New England journal of medicine

[ISO-abbreviation] N. Engl. J. Med.

[Language] eng

[Databank-accession-numbers] ClinicalTrials.gov/ NCT00006343

[Publication-type] Journal Article; Multicenter Study; Randomized Controlled Trial

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Interferon-alpha; 0 / Piperazines; 0 / Pyrimidines; 04079A1RDZ / Cytarabine; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Secondary pulmonary alveolar proteinosis in a patient with chronic myeloid leukemia in the accelerated phase.

Pulmonary alveolar proteinosis (PAP) is a rare respiratory disease the character of which is accumulation of protein consisting of surfactant in alveolar spaces.

PAP sometimes complicates with hematological malignancies, especially myeloid leukemia.

We experienced a case of PAP with chronic myeloid leukemia (CML).

41 years old woman having CML for nine years developed PAP, and was treated by bronchoalveolar lavage and imatinib.

We consider that we should try to treat to improve respiratory status not only PAP but also hematological disease.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / complications. Pulmonary Alveolar Proteinosis / etiology

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(PMID = 21318986.001).

[ISSN] 2185-2243

[Journal-full-title] The Tokai journal of experimental and clinical medicine

[ISO-abbreviation] Tokai J. Exp. Clin. Med.

[Language] eng

[Publication-type] Case Reports; Journal Article

[Publication-country] Japan

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Successful induction of complete cytogenetic response with low-dose imatinib mesylate in an accelerated phase chronic myelogenous leukemia patient who developed severe bone marrow aplasia following standard-dose imatinib mesylate therapy].

Bone marrow appearance was consistent with CML-AP, and t (9;22) (q34;q11) was detected on karyotyping.

Bone marrow biopsy showed severe bone marrow aplasia with no morphological evidence of disease progression.

This case also suggests that low-dose imatinib would be tolerable and effective for some CML patients who are intolerant of a standard dose of imatinib.

[MeSH-major] Antineoplastic Agents / administration & dosage. Antineoplastic Agents / adverse effects. Bone Marrow / drug effects. Leukemia, Myeloid, Accelerated Phase / drug therapy. Piperazines / administration & dosage. Piperazines / adverse effects. Pyrimidines / administration & dosage. Pyrimidines / adverse effects

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(PMID = 20332700.001).

[ISSN] 0385-0684

[Journal-full-title] Gan to kagaku ryoho. Cancer & chemotherapy

[ISO-abbreviation] Gan To Kagaku Ryoho

[Language] jpn

[Publication-type] Case Reports; English Abstract; Journal Article

[Publication-country] Japan

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib.

The primary efficacy end point in chronic phase CML was major cytogenetic response.

The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response.

In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%.

Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively.

Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached.

The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL.

CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myeloid, Chronic-Phase / drug therapy. Piperazines / therapeutic use. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

[MeSH-minor] Benzamides. Clinical Trials, Phase I as Topic. Clinical Trials, Phase II as Topic. Dasatinib. Drug Approval. Drug Resistance, Neoplasm. Humans. Imatinib Mesylate. Multicenter Studies as Topic. Protein Kinase Inhibitors / adverse effects. Protein Kinase Inhibitors / chemistry. Protein Kinase Inhibitors / pharmacology. Protein Kinase Inhibitors / therapeutic use. United States. United States Food and Drug Administration

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(PMID = 18223208.001).

[ISSN] 1078-0432

[Journal-full-title] Clinical cancer research : an official journal of the American Association for Cancer Research

[ISO-abbreviation] Clin. Cancer Res.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; RBZ1571X5H / Dasatinib

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance.

BACKGROUND: : INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases.

Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively).

In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance.

Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%.

No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL.

CONCLUSIONS: : INNO-406 had anti-CML efficacy in a heavily pretreated study population.

On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily.

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[Copyright] (c) 2010 American Cancer Society.

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(PMID = 20310049.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] ENG

[Grant] United States / NCI NIH HHS / CA / P50 CA100632-070007; United States / NCI NIH HHS / CA / CA100632-070007; United States / NCI NIH HHS / CA / P01CA049639; United States / NCI NIH HHS / CA / P50 CA100632; United States / NCI NIH HHS / CA / P01 CA049639

[Publication-type] Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural

[Publication-country] United States

[Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 859212-16-1 / bafetinib; 8A1O1M485B / Imatinib Mesylate

[Other-IDs] NLM/ NIHMS189694; NLM/ PMC2876208

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice.

The BCR-ABL inhibitor imatinib revolutionized the treatment of chronic myeloid leukemia (CML).

The mechanisms underlying resistance are multifactorial and may include mutations in the kinase domain of BCR-ABL, increased production of BCR-ABL, or activation of BCR-ABL-independent pathways.

Two second-line BCR-ABL inhibitors are now approved for treatment of patients with resistance or intolerance to imatinib.

Dasatinib is a dual BCR-ABL/Src-family kinase (SFK) inhibitor approved for patients with imatinib-resistant and -intolerant CML in any phase and Ph+ ALL.

Nilotinib, an analogue of imatinib, is approved for the treatment of imatinib-resistant or -intolerant patients with chronic or accelerated phase CML.

Both agents have shown significant clinical activity in patients with imatinib-resistant or -intolerant CML, and their approval represents a major advancement in the treatment options available.

The presence of certain disease characteristics (e.g. specific BCR-ABL mutations) or patient comorbidities may facilitate more effective treatment.

[MeSH-major] Antineoplastic Agents / therapeutic use. Drug Resistance, Neoplasm. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Mutation. Piperazines / therapeutic use. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

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(PMID = 20038231.001).

[ISSN] 1029-2403

[Journal-full-title] Leukemia & lymphoma

[ISO-abbreviation] Leuk. Lymphoma

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] England

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / src-Family Kinases; RBZ1571X5H / Dasatinib

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Clinical outcomes and direct hospital costs of reduced-intensity allogeneic transplantation in chronic myeloid leukemia.

A reduced-intensity conditioning allogeneic stem cell transplantation was given to 19 patients (aged 15-59 years) in the first chronic phase and one patient in the accelerated phase with chronic myeloid leukemia (CML) after a regimen consisting of fludarabine (Flu), busulfan (Bu) and ATG Fresenius.

The incidence of acute and chronic graft-versus-host disease (GvHD) was 55 and 75%, respectively.

Flu+Bu+ATG is a low-toxicity regimen for patients with CML.

[MeSH-major] Antineoplastic Combined Chemotherapy Protocols / therapeutic use. Hematopoietic Stem Cell Transplantation / economics. Hospital Costs / statistics & numerical data. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy. Transplantation Conditioning

[MeSH-minor] Adolescent. Adult. Antilymphocyte Serum / administration & dosage. Busulfan / administration & dosage. Czech Republic. Female. Graft vs Host Disease / prevention & control. Humans. Male. Middle Aged. Myeloablative Agonists / administration & dosage. Philadelphia Chromosome. Retrospective Studies. Survival Analysis. Transplantation, Homologous / economics. Transplantation, Homologous / methods. Vidarabine / administration & dosage. Vidarabine / analogs & derivatives

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(PMID = 16980996.001).

[ISSN] 0268-3369

[Journal-full-title] Bone marrow transplantation

[ISO-abbreviation] Bone Marrow Transplant.

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] England

[Chemical-registry-number] 0 / Antilymphocyte Serum; 0 / Myeloablative Agonists; FA2DM6879K / Vidarabine; G1LN9045DK / Busulfan; P2K93U8740 / fludarabine

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Advanced CML: therapeutic options for patients in accelerated and blast phases.

Tyrosine kinase inhibitor (TKI) therapy has impacted the natural course of chronic myelogenous leukemia (CML), because patients diagnosed as having chronic-phase disease can experience long-lasting responses.

However, for patients with advanced CML (accelerated and blast phases), the efficacy of all current therapies is reduced.

For patients with accelerated-phase CML, imatinib, dasatinib, and nilotinib have been shown to produce meaningful rates of hematologic and cytogenetic response.

Imatinib and dasatinib are also approved for blast-phase CML.

Moreover, because fewer mechanisms appear to exist for secondary resistance to dasatinib and nilotinib, reducing the potential for disease to escape TKI therapy, these agents may result in improved longer-term outcomes.

However, BCR-ABL-independent pathways may also become more important, indicating that other therapeutic targets may also have a future role in managing patients with advanced CML.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology. Protein Kinase Inhibitors / therapeutic use

[MeSH-minor] Blast Crisis / pathology. Clinical Trials as Topic. Drug Resistance, Neoplasm. Fusion Proteins, bcr-abl / genetics. Humans

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(PMID = 18397679.001).

[ISSN] 1540-1405

[Journal-full-title] Journal of the National Comprehensive Cancer Network : JNCCN

[ISO-abbreviation] J Natl Compr Canc Netw

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] United States

[Chemical-registry-number] 0 / Protein Kinase Inhibitors; EC 2.7.10.2 / Fusion Proteins, bcr-abl

[Number-of-references] 33

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] e19a2 BCR-ABL fusion transcript in typical chronic myeloid leukaemia: a report of two cases.

This report describes two patients with chronic myeloid leukaemia (CML): one of them developed accelerated phase CML and died 8 years after diagnosis and the other is at the chronic phase.

Sequence analysis of reverse transcription-polymerase chain reaction products showed the presence of BCR-ABL fusion transcript e19a2.

This finding suggests that CML carrying mu-BCR breakpoint may exhibit a clinical course similar to typical CML.

[MeSH-major] Fusion Proteins, bcr-abl / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics

[MeSH-minor] Adult. Disease Progression. Fatal Outcome. Humans. Male. Reverse Transcriptase Polymerase Chain Reaction / methods. Transcription, Genetic

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[Cites] J Exp Med. 1999 May 3;189(9):1399-412 [10224280.001]

[Cites] Blood. 2000 May 1;95(9):2913-21 [10779439.001]

[Cites] Haematologica. 2001 Mar;86(3):320-1 [11255282.001]

[Cites] Haematologica. 2002 Aug;87(8):ELT35 [12161380.001]

[Cites] Br J Haematol. 1998 Dec;103(4):1104-8 [9886327.001]

[Cites] Blood. 1990 Nov 1;76(9):1819-24 [2224129.001]

[Cites] Blood. 1996 Oct 1;88(7):2410-4 [8839830.001]

[Cites] Blood. 1997 Jun 1;89(11):4239-41 [9166872.001]

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(PMID = 17021137.001).

[ISSN] 0021-9746

[Journal-full-title] Journal of clinical pathology

[ISO-abbreviation] J. Clin. Pathol.

[Language] eng

[Publication-type] Case Reports; Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] England

[Chemical-registry-number] EC 2.7.10.2 / Fusion Proteins, bcr-abl

[Other-IDs] NLM/ PMC1861751

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules.

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology.

Dose-escalated imatinib (800 mg daily) has shown some limited activity in patients with imatinib-resistant CML, but the development of second-generation tyrosine kinase inhibitors has broadened the treatment options.

Dasatinib has demonstrated activity in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the treatment of adults in this setting.

Recent phase III data have demonstrated that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally effective, with improved tolerability, compared with the previously approved 70-mg twice-daily dose.

Nilotinib, which has been recently approved, has increased potency for Brc-Abl compared with imatinib and has demonstrated activity in patients with imatinib-resistant and -intolerant chronic- and accelerated-phase CML.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Philadelphia Chromosome. Protein Kinase Inhibitors / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

[MeSH-minor] Clinical Trials as Topic. Dasatinib. Fusion Proteins, bcr-abl. Humans

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(PMID = 19254884.001).

[ISSN] 1557-9190

[Journal-full-title] Clinical lymphoma & myeloma

[ISO-abbreviation] Clin Lymphoma Myeloma

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Review

[Publication-country] United States

[Chemical-registry-number] 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl; RBZ1571X5H / Dasatinib

[Number-of-references] 51

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [A clinical study of treating 120 cases of adult chronic myelocytic leukemia with imatinib mesylate].

OBJECTIVE: To analyze and evaluate the clinical efficacy and safety of imatinib mesylate (IM) as a tyrosine kinase inhibitor on Ph-positive or BCR/ABL positive chronic myelogenous leukemia (CML).

METHODS: 120 patients diagnosed as CML with positive Ph chromosome were treated with IM 400 mg/d for CML in chronic phase (CP) (n = 90) or 600 mg/d for CML in accelerated or blastic phase (AP or BP) (n = 30) once daily.

Hematological, cytogenetic and molecular effects of IM on the disease process of these patients were evaluated with blood and marrow cells morphology examination, G-band conventional cytogenetics analysis for Ph chromosome and PCR assay for BCR/ABL gene.

(1) In CML-CP patients, after a follow-up of 9 ( range 3-42) months, cumulative complete hematological response (CHR), complete cytogenetic response (CCyR) and complete molecular response (CMR) rates were 73.3%, 66.7% and 54.4%, which was not influenced by prior treatment of interferon.

CMR was better when time from diagnosis to treatment with IM was < or = 6 months (P < 0.05).

It is significant that the time to first CHR and time to first CCyR were related with the time to first CCyR and the time to first negative BCR/ ABL, respectively (both P < 0.05), while there was no relation between the time to first CHR and the time to first negative BCR/ABL (P > 0.05). (2) CHR, CCyR and CMR rates of the patients with progressive course (AP and BP) were 43.3%, 25.9% and 25.0%, respectively.

CONCLUSION: IM can lead to considerable hematological, cytogenetic and molecular response rates in CML, especially CML-CP patients, with minor tolerable side effects.

[MeSH-major] Leukemia, Myeloid, Chronic-Phase / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use

[MeSH-minor] Adolescent. Adult. Antineoplastic Agents / adverse effects. Antineoplastic Agents / therapeutic use. Benzamides. Female. Fusion Proteins, bcr-abl / genetics. Humans. Imatinib Mesylate. Male. Middle Aged. Philadelphia Chromosome. Retrospective Studies. Treatment Outcome

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(PMID = 18478917.001).

[ISSN] 0578-1426

[Journal-full-title] Zhonghua nei ke za zhi

[ISO-abbreviation] Zhonghua Nei Ke Za Zhi

[Language] chi

[Publication-type] English Abstract; Journal Article

[Publication-country] China

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Hematopoietic stem cell transplantation for T315I-mutated chronic myelogenous leukemia.

BACKGROUND: The T315I mutation of BCR/ABL gene is known to produce complete resistance of chronic myelogenous leukemia (CML) to all currently available BCR/ABL inhibitors.

However, evidence on efficiency of this treatment modality in CML with T315I mutation is lacking.

CASE REPORT: A 25-year-old patient was diagnosed with Philadelphia chromosome positive CML in accelerated phase.

Moreover, despite escalation of imatinib dosage, the disease relapsed after further 3 months of treatment.

Molecular studies revealed T315I mutation of BCR/ABL gene.

The course of transplantation was complicated by staphylococcal sepsis, grade I skin acute GvHD and limited chronic skin GVHD.

CONCLUSIONS: The clinical course of this case supports the idea that allogeneic hematopoietic transplantation is a viable treatment option for patients with CML bearing T315I mutation.

[MeSH-major] Genes, abl. Hematopoietic Stem Cell Transplantation. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy. Mutation, Missense

[MeSH-minor] Adult. Amino Acid Substitution. Drug Resistance, Neoplasm / genetics. Fusion Proteins, bcr-abl / antagonists & inhibitors. Fusion Proteins, bcr-abl / genetics. Humans. Leukemia, Myeloid, Accelerated Phase / drug therapy. Leukemia, Myeloid, Accelerated Phase / genetics. Leukemia, Myeloid, Accelerated Phase / therapy. Male. Protein Kinase Inhibitors / pharmacology. Remission Induction. Transplantation, Homologous

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(PMID = 20657522.001).

[ISSN] 2329-0358

[Journal-full-title] Annals of transplantation

[ISO-abbreviation] Ann. Transplant.

[Language] eng

[Publication-type] Case Reports; Journal Article

[Publication-country] Poland

[Chemical-registry-number] 0 / Protein Kinase Inhibitors; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] 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.

Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options.

Nilotinib is a highly selective BCR-ABL tyrosine kinase inhibitor.

This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint.

In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myeloid, Accelerated Phase / drug therapy. Piperazines / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Protein-Tyrosine Kinases / genetics. Pyrimidines / therapeutic use

[MeSH-minor] Adult. Aged. Benzamides. Blood Cell Count. Dose-Response Relationship, Drug. Drug Administration Schedule. Drug Resistance. Female. Fusion Proteins, bcr-abl. Humans. Imatinib Mesylate. Male. Middle Aged. Mutation. Safety

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(PMID = 18048643.001).

[ISSN] 0006-4971

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] eng

[Databank-accession-numbers] ClinicalTrials.gov/ NCT00384228

[Publication-type] Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.

Altered mRNA translation is one of the effects exerted by the BCR/ABL oncoprotein in the blast crisis phase of chronic myelogenous leukemia (CML).

Here, we report that in BCR/ABL+ cell lines and in patient-derived CML blast crisis mononuclear and CD34+ cells, p210(BCR/ABL) increases expression and activity of the transcriptional-inducer and translational-regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K or HNRPK) in a dose- and kinase-dependent manner through the activation of the MAPK(ERK1/2) pathway.

Furthermore, HNRPK down-regulation and interference with HNRPK translation-but not transcription-regulatory activity impairs cytokine-independent proliferation, clonogenic potential, and in vivo leukemogenic activity of BCR/ABL-expressing myeloid 32Dcl3 and/or primary CD34+ CML-BC patient cells.

Mechanistically, we demonstrate that decreased internal ribosome entry site (IRES)-dependent Myc mRNA translation accounts for the phenotypic changes induced by inhibition of the BCR/ABL-ERK-dependent HNRPK translation-regulatory function.

Accordingly, MYC protein but not mRNA levels are increased in the CD34+ fraction of patients with CML in accelerated and blastic phase but not in chronic phase CML patients and in the CD34+ fraction of marrow cells from healthy donors.

Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation.

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(PMID = 16293596.001).

[ISSN] 0006-4971

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] ENG

[Grant] United States / NCI NIH HHS / CA / R01 CA095512; United States / NCI NIH HHS / CA / CA095512; United States / NCI NIH HHS / CA / CA16058

[Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

[Publication-country] United States

[Chemical-registry-number] 0 / Antigens, CD34; 0 / MYC protein, human; 0 / Proto-Oncogene Proteins c-myc; 0 / RNA, Messenger; 0 / Ribonucleoproteins; 146410-60-8 / HNRNPK protein, human; EC 2.7.10.2 / Fusion Proteins, bcr-abl; EC 2.7.11.24 / Mitogen-Activated Protein Kinases

[Other-IDs] NLM/ PMC1895740

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines.

Despite progress in the treatment of early-stage chronic myeloid leukemia (CML), the accelerated and blastic phases of CML still remain a therapeutic challenge.

Persistence of BCR-ABL-positive (bcr-abl(+)) cells or secondary resistance during imatinib therapy frequently occurs.

In this study, we investigated the activity of a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) against CML blast crisis cell lines.

Exposure of these cell lines (K562, KU812 and KCL22) to TZD18 resulted in a growth inhibition in a dose- and time-dependent manner.

Overall, our findings strongly suggest that either TZD18, either alone or in combination with imatinib may be beneficial for the treatment of CML in myeloid blast crisis.

[MeSH-major] Antineoplastic Combined Chemotherapy Protocols / pharmacology. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Phenyl Ethers / pharmacology. Piperazines / pharmacology. Pyrimidines / pharmacology. Thiazolidinediones / pharmacology

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(PMID = 17102607.001).

[ISSN] 1551-4005

[Journal-full-title] Cell cycle (Georgetown, Tex.)

[ISO-abbreviation] Cell Cycle

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / 5-(3-(3-(4-phenoxy-2-propylphenoxy)propoxy)phenyl)-2,4-thiazolidinedione; 0 / Benzamides; 0 / PPAR alpha; 0 / PPAR gamma; 0 / Phenyl Ethers; 0 / Piperazines; 0 / Pyrimidines; 0 / Thiazolidinediones; 8A1O1M485B / Imatinib Mesylate

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Chronic myelogenous leukaemia (CML): an update.

The management of chronic myelogenous leukaemia (CML) has undergone a major change over the past 5 years.

All newly diagnosed patients of CML are candidates for imatinib mesylate therapy.

Almost 95% of patients with early chronic phase CML achieve complete haematological remission (CHR) and nearly 80% achieve complete cytogenetic response (CGR; 0% Philadelphia [Ph] chromosome-positive metaphases).

For patients with advanced CML (accelerated phase and blast crisis), achievement of CHR and major (complete and partial) CGR occurs in 25%-37% and 10%-30% of patients, respectively.

Most investigators agree that patients who fail to achieve CHR by 12 weeks, have partial cytogenetic response (< 35% Ph-positive metaphases) at 12 months, have CGR by 18 months, who relapse after initial response to imatinib, and those with a high Sokal score or in an advanced phase of CML should be considered for allogeneic stem cell transplantation (SCT).

Despite Ph negativity with imatinib treatment, most patients continue to remain BCR-ABL positive on molecular studies, and require treatment indefinitely.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use

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(PMID = 17203680.001).

[ISSN] 0970-258X

[Journal-full-title] The National medical journal of India

[ISO-abbreviation] Natl Med J India

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] India

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Interferon-alpha; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; X6Q56QN5QC / Hydroxyurea

[Number-of-references] 87

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Quantitative RT-PCR of Wilms tumor gene transcripts (WT1) for the molecular monitoring of patients with accelerated phase bcr/abl + CML.

The tyrosine kinase inhibitor imatinib inhibits the activity of the bcr/abl fusion protein present in patients with chronic myeloid leukemia.

Although in chronic phase patients response to therapy can be monitored by quantitative RT-PCR for bcr/abl mRNA transcripts, in advanced disease (accelerated phase or blast crisis) only few patients respond on a molecular level.

We investigated Wilms tumor gene (WT1) and bcr/abl mRNA transcripts in 16 accelerated phase CML patients by quantitative real time PCR.

In contrast to the bcr/abl mRNA levels the WT1 mRNA levels were indicative for hematologic relapse (n = 6) versus response (n = 10).

[MeSH-major] Biomarkers, Tumor / analysis. Fusion Proteins, bcr-abl / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics. WT1 Proteins / genetics

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(PMID = 15661271.001).

[ISSN] 0145-2126

[Journal-full-title] Leukemia research

[ISO-abbreviation] Leuk. Res.

[Language] eng

[Publication-type] Journal Article

[Publication-country] England

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Biomarkers, Tumor; 0 / Piperazines; 0 / Pyrimidines; 0 / RNA, Messenger; 0 / WT1 Proteins; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Fusion Proteins, bcr-abl

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Imatinib: a review of its use in chronic myeloid leukaemia.

Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML).

It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome.

CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes.

Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-alpha therapy.

It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-alpha therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT).

Imatinib is effective and generally well tolerated in patients with Ph+ CML.

In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-alpha plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses.

Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-alpha therapy also benefit from imatinib treatment.

The introduction of imatinib has had a marked impact on outcomes in patients with CML.

It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use

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(PMID = 17284091.001).

[ISSN] 0012-6667

[Journal-full-title] Drugs

[ISO-abbreviation] Drugs

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] New Zealand

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

[Number-of-references] 90

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Guidelines for the management of nilotinib (Tasigna)-induced side effects in chronic myelogenous leukemia: recommendations of French Intergroup of CML (Fi-LMC group)].

[Transliterated title] Recommandations du groupe Fi-LMC pour la gestion des effets indésirables du traitement par nilotinib (Tasigna) au cours de la leucémie myéloïde chronique.

Nilotinib (Tasigna) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib.

This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use.

[MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Protein Kinase Inhibitors / adverse effects. Pyrimidines / adverse effects

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(PMID = 20529767.001).

[ISSN] 1769-6917

[Journal-full-title] Bulletin du cancer

[ISO-abbreviation] Bull Cancer

[Language] fre

[Publication-type] English Abstract; Journal Article; Practice Guideline

[Publication-country] France

[Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Recombinant Proteins; 11096-26-7 / Erythropoietin; 143011-72-7 / Granulocyte Colony-Stimulating Factor; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Chronic myeloid leukemia in 2007.

PURPOSE: Chronic myeloid leukemia (CML), a hematopoietic stem cell cancer representing 15-20% of adult leukemias, is discussed.

SUMMARY: CML is a myeloproliferative disorder that affects all lineages of hematopoiesis.

Final confirmation of CML comes with detection of the Philadelphia Chromosome (Ph) or BCR-ABL transcripts.

The disease presents in one of three phases: chronic phase, accelerated phase, or blast crisis.

Progression from chronic phase to accelerated phase usually involves the accumulation of additional cytogenetic aberrations and the arising of resistance to therapy.

Although at one point mortality associated with CML was high, new kinase inhibitor therapies have markedly extended the life-span of these patients.

These inhibitors were derived through the initial observation of the association of the Ph with CML and the eventual identification of the BCR-ABL oncogene which arises from this translocation.

Analysis of the mechanism by which BCR-ABL transforms cells identified this protein as a tyrosine kinase and led to the targeting of this activity.

The majority of patients present in chronic phase, which is where these kinase inhibitors have their greatest efficacy.

Monitoring of disease progression is of critical importance as the prognosis drops significantly for patients with advanced disease.

Blood counts, cytogenetics, and polymerase chain reaction (PCR) are currently used to assess disease.

CONCLUSION: Our understanding of BCR-ABL has allowed the development of therapies, which may keep patients with CML in chronic phase indefinitely.

This has created a situation in which patient monitoring is essential for detecting changes in the status of CML.

The tests described here provide a comprehensive assessment of disease status allowing for effective patient management.

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis

[MeSH-minor] Clinical Trials as Topic. Drug Resistance, Neoplasm. Humans. Leukemia, Myeloid, Chronic-Phase / diagnosis. Leukemia, Myeloid, Chronic-Phase / genetics. Leukemia, Myeloid, Chronic-Phase / therapy. Neoplasm Staging

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(PMID = 18056931.001).

[ISSN] 1535-2900

[Journal-full-title] American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists

[ISO-abbreviation] Am J Health Syst Pharm

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents

[Number-of-references] 13

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Chronic myeloid leukemia: why does it evolve from chronic phase to blast transformation?

Clinically chronic myeloid leukemia is a biphasic or triphasic disease that is usually diagnosed in the initial 'chronic', 'indolent' or 'stable' phase and then spontaneously evolves after some years into an advanced phase.

This advanced phase can sometimes be subdivided into an earlier accelerated phase and a later blast phase or blast transformation--in about one-half of patients the chronic phase transforms unpredictably and abruptly to a blast phase, while in the other half of patients, the disease evolves somewhat more gradually, through an accelerated phase, which may last for months or years, before a blast phase ensues; this may have myeloblastic or lymphoblastic features.

Although much is now known about the molecular biology of the disease, the molecular basis of disease progression is still obscure.

The popular thinking has been that one or more probably a sequence of additional genetic events occurs in the BCR-ABL positive clone.

Here we review what is known of the mechanisms underlying the evolution of chronic myeloid leukemia from a chronic phase to a blast transformation.

[MeSH-major] Gene Expression Regulation, Neoplastic. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology. Lymphocyte Activation

[MeSH-minor] Animals. Apoptosis. Biological Evolution. Blast Crisis. Cytogenetics. Cytokinesis. DNA Repair. Disease Progression. Fusion Proteins, bcr-abl / chemistry. Humans. Janus Kinase 1. Lymphocytes / metabolism. Models, Biological. Mutation. Philadelphia Chromosome. Phosphatidylinositol 3-Kinases / metabolism. Proteasome Endopeptidase Complex / metabolism. Protein Structure, Tertiary. Protein-Tyrosine Kinases / metabolism. Proto-Oncogene Proteins c-myc / metabolism. RNA, Messenger / metabolism. Recombinant Fusion Proteins / metabolism. STAT5 Transcription Factor / metabolism. Time Factors

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(PMID = 16146725.001).

[ISSN] 1093-9946

[Journal-full-title] Frontiers in bioscience : a journal and virtual library

[ISO-abbreviation] Front. Biosci.

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] United States

[Chemical-registry-number] 0 / Proto-Oncogene Proteins c-myc; 0 / RNA, Messenger; 0 / Recombinant Fusion Proteins; 0 / STAT5 Transcription Factor; EC 2.7.010.2 / JAK1 protein, human; EC 2.7.1.- / Phosphatidylinositol 3-Kinases; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl; EC 2.7.10.2 / Janus Kinase 1; EC 3.4.25.1 / Proteasome Endopeptidase Complex

[Number-of-references] 95

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

BACKGROUND: Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment.

We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML.

METHODS: In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients).

The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001).

Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%).

Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247. )

[MeSH-major] Antineoplastic Agents / therapeutic use. Leukemia, Myeloid, Chronic-Phase / drug therapy. Piperazines / therapeutic use. Protein Kinase Inhibitors / therapeutic use. Pyrimidines / therapeutic use. Thiazoles / therapeutic use

[MeSH-minor] Adolescent. Adult. Aged. Aged, 80 and over. Benzamides. Blast Crisis / prevention & control. Dasatinib. Disease Progression. Female. Fusion Proteins, bcr-abl / antagonists & inhibitors. Humans. Imatinib Mesylate. Kaplan-Meier Estimate. Male. Middle Aged. Young Adult

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[Copyright] 2010 Massachusetts Medical Society

[CommentIn] Expert Opin Pharmacother. 2011 Jan;12(1):157-63 [21108601.001]

[CommentIn] N Engl J Med. 2010 Jun 17;362(24):2314-5 [20525994.001]

[CommentIn] N Engl J Med. 2010 Oct 21;363(17):1672; author reply 1673-5 [20961253.001]

[CommentIn] N Engl J Med. 2010 Oct 21;363(17):1673; author reply 1673-5 [20973146.001]

[CommentIn] N Engl J Med. 2010 Oct 21;363(17):1673; author reply 1673-5 [20973145.001]

[CommentIn] N Engl J Med. 2010 Oct 21;363(17):1672-3; author reply 1673-5 [20973144.001]

(PMID = 20525995.001).

[ISSN] 1533-4406

[Journal-full-title] The New England journal of medicine

[ISO-abbreviation] N. Engl. J. Med.

[Language] eng

[Databank-accession-numbers] ClinicalTrials.gov/ NCT00481247

[Grant] United States / NCI NIH HHS / CA / P30 CA016672

[Publication-type] Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Fusion Proteins, bcr-abl; RBZ1571X5H / Dasatinib

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Nonmyeloablative peripheral blood stem cell transplantation for chronic myeloid leukemia in chronic and accelerated phases].

The aim of this study was to investigate the effect of nonmyeloablative peripheral blood stem cell transplantation in treatment of chronic myeloid leukemia in chronic phase (CML-CP) and accelerated phase (CML-AP).

24 patients with CML including 16 in CML-CP and 8 in CML-AP were treated with nonmyeloablative conditioning regimen for peripheral blood stem cell transplantation (PBHSCT).

2 cases died of severe acute GVHD and 1 case died of chronic GVHD, 2 cases died of interstitial pneumonia and 1 case died of relapsed.

In conclusions, nonmyeloablative peripheral blood stem cell transplantation is an effective therapeutic method for CML patients in chronic phase and accelerated phase.

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(PMID = 18426668.001).

[ISSN] 1009-2137

[Journal-full-title] Zhongguo shi yan xue ye xue za zhi

[ISO-abbreviation] Zhongguo Shi Yan Xue Ye Xue Za Zhi

[Language] CHI

[Publication-type] English Abstract; Journal Article

[Publication-country] China

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase.

BACKGROUND: Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP).

Treatment guidelines propose dose escalation based on clinical assessments of disease response.

METHODS: Response and survival were analyzed in a cohort of patients (n = 106) with newly diagnosed CML-CP who were enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 mg or 800 mg daily.

RESULTS: Among all 106 patients who underwent dose escalation, the rates of freedom from progression to accelerated phase or blast phase and overall survival were 89% and 84% at 3 years after dose increase, respectively.

CONCLUSIONS: The results from this retrospective analysis supported imatinib dose escalation as an appropriate initial option for patients with CML-CP who were experiencing suboptimal cytogenetic response or resistance.

[MeSH-major] Leukemia, Myeloid, Chronic-Phase / drug therapy. Piperazines / administration & dosage. Pyrimidines / administration & dosage

[MeSH-minor] Benzamides. Clinical Trials as Topic. Disease-Free Survival. Drug Administration Schedule. Imatinib Mesylate. Survival Analysis. Treatment Outcome

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[Copyright] (c) 2008 American Cancer Society.

[ErratumIn] Cancer. 2010 Aug 1;116(15):3750. Santini, Valeria [added]

(PMID = 19117345.001).

[ISSN] 0008-543X

[Journal-full-title] Cancer

[ISO-abbreviation] Cancer

[Language] eng

[Databank-accession-numbers] ClinicalTrials.gov/ NCT00006343

[Grant] United States / NCI NIH HHS / CA / P30 CA016672; United States / NCI NIH HHS / CA / P50 CA100632

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate

[Other-IDs] NLM/ NIHMS676524; NLM/ PMC4445370

[Investigator] Durant S; Schwarer A; Joske D; Seymour J; Grigg A; Ma D; Arthur C; Bradstock K; Joshua D; Louwagi A; Martiat P; Bosly A; Shistok C; Lipton J; Forrest D; Walker I; Roy DC; Rubinger M; Bence-Bruckler I; Stewart D; Kovacs M; Turner AR; Birgens H; Bjerrum O; Facon T; Harousseau JL; Tulliez M; Guerci A; Blaise D; Maloisel F; Michallet M; Andreesen R; Nerl C; Freund M; Gattermann N; Ehninger G; Deininger M; Ottmann O; Peschel C; Fruehauf S; Neubauer A; le Coutre P; Aulitzky W; Fanin R; Rosti G; Mandelli F; Lazzarino M; Morra E; Carella A; Petrini M; Nobile F; Liso V; Ferrara F; Rizzoli V; Fiortoni G; Martinelli G; Ossenkoppele G; Browett P; Gedde-Dahl T; Tangen JM; Dahl I; Odrizoala J; Hernandez Boulda JC; Steegman JL; Canizo C; Diaz J; Grenena A; Fernandez MN; Stenke L; Paul C; Bjoreman M; Malm C; Wadenvik H; Nilsson PG; Turesson I; Hess U; Solenthaler M; Clark RE; Green AR; Holyoake TL; Lucas GS; Smith G; Milligan DW; Rule SJ; Burnett AK; Moroose R; Wetzler M; Bearden J; Cataland S; Robinowitz I; Meisenberg B; Thompson K; Graziano S; Emanuel P; Gross H; Cobb P; Bhatia R; Dakhil S; Irwin D; Issell B; Pavletic S; Kuebler P; Layhe E; Butra P; Glass J; Moore J; Grant B; Neill H; Herzig R; Burris H; Petersen B; Kalaycio M; Stirewalt D; Samlowski W; Berman E; Limentani S; Seay T; Shea T; Akard L; Smith G; Becker P; Devine S; Hart R; Veith R; Wade J; Brunvad M; Kalman L; Strickland D; Shurafa M; Bashey A; Shadduck R; Safah H; Rubenstein M; Collins R; Keller A; Tallman M; Pecora A; Agha M; Homes H; Guidice R; Santini V

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Molecular and cellular bases of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients.

Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis.

Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet.

CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase.

Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML.

However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML.

In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors.

In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.

[MeSH-major] Fusion Proteins, bcr-abl / metabolism. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology. Neoplastic Stem Cells / enzymology. Neoplastic Stem Cells / pathology. Protein-Tyrosine Kinases / metabolism

[MeSH-minor] 5-Lipoxygenase-Activating Proteins / metabolism. Animals. Benzamides. Disease Models, Animal. Humans. Imatinib Mesylate. Male. Mice. PTEN Phosphohydrolase / metabolism. Philadelphia Chromosome. Piperazines / therapeutic use. Point Mutation. Protein Structure, Tertiary. Pyrimidines / therapeutic use

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(PMID = 21203982.001).

[ISSN] 1674-8018

[Journal-full-title] Protein & cell

[ISO-abbreviation] Protein Cell

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] Germany

[Chemical-registry-number] 0 / 5-Lipoxygenase-Activating Proteins; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl; EC 3.1.3.67 / PTEN Phosphohydrolase

[Other-IDs] NLM/ PMC4875160

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Survivin expression in chronic myeloid leukemia.

In this study, we investigated the expression of survivin (SVV) in 44 patients with typical Ph-positive chronic myeloid leukemia (CML) in different phases of the disease as well as in 20 matched healthy donors.

We found a very high SVV expression in a predominant percentage of CML patients.

We also observed a significantly increased SVV expression in patients in accelerated/blastic phase of the disease compared to patients in chronic phase.

Moreover, SVV expression levels correlated in all CML patients with % of Ph-chromosome positive cells, with Bcr-Abl expression levels and with WBC-count.

Based on this finding we suggest that SVV detection and monitoring in CML could represent both a useful biomarker and attractive candidate for devising new targeted and combined therapies in CML.

[MeSH-major] Biomarkers, Tumor / blood. Gene Expression Profiling. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics. Microtubule-Associated Proteins / biosynthesis. Microtubule-Associated Proteins / blood

Genetic Alliance. consumer health - Chronic Myeloid Leukemia.

Genetic Alliance. consumer health - Leukemia, Myeloid.

MedlinePlus Health Information. consumer health - Chronic Myeloid Leukemia.

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(PMID = 15922862.001).

[ISSN] 0304-3835

[Journal-full-title] Cancer letters

[ISO-abbreviation] Cancer Lett.

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] Ireland

[Chemical-registry-number] 0 / BIRC5 protein, human; 0 / Biomarkers, Tumor; 0 / Inhibitor of Apoptosis Proteins; 0 / Microtubule-Associated Proteins; 0 / Neoplasm Proteins