GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Effect of dose-optimized imatinib (IM) 800 mg on deep molecular responses (CMR 4.5) and prediction of survival: Results from the randomized CML-study IV.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 7051-7051
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 7051-7051
    Abstract: 7051 Background: Since complete molecular remission (CMR 4.5) defines a subgroup of patients who may stay in remission even after discontinuation of treatment, we analysed whether CMR 4.5 is reached faster with dose optimized IM 800 mg and whether the achievement of CMR 4.5 at specified points in time results in better survival than the achievement of less deep remissions. Methods: Confirmed CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4 log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from standardized baseline as determined by real-time PCR in 2 independent analyses. Details on CML-Study IV have been published (Hehlmann et al., JCO 2011). Cumulative incidences were estimated under consideration of competing risks. Landmark analyses were performed to evaluate the prognostic impact of different remissions at 4 years on survival. Results: Of 1551 randomized patients with newly diagnosed chronic phase CML 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk. 113 patients were transplanted (73 in first chronic phase), 246 received 2nd generation TKI. 152 patients have died. After a median observation time of 67.5 months, 6-year OS was 88.2%.CMR 4.5 was reached after a median of about 76.1 months with IM 800 and 107.3 months with IM 400. EUTOS low-risk patients reached all remissions faster than high-risk patients. Independent of treatment approach CMR 4.5 at 4 years predicted OS significantly better than complete cytogenetic remission (p=0.043), but not significantly better than major molecular remission (MMR) or CMR4. After a median observation of 3.9 years 1 of 626 patients with CMR 4 has progressed. Only six of the 394 patients with CMR 4.5 have died after a median observation time of 3.0 years, no patient has progressed. An additional finding was that achieving MMR at 3 and at 6 months predicts faster achievement of CMR 4.5. Conclusions: We conclude that dose optimized IM 800 induces CMR 4.5 faster than IM 400 and that CMR 4.5 at 4 years is associated with a survival advantage. Dose optimized IM 800 may provide an improved therapeutic basis for treatment discontinuation in patients with CML. Clinical trial information: NCT00055874.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.7051
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 5 ( 2014-02-10), p. 415-423
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 5 ( 2014-02-10), p. 415-423
    Abstract: Deep molecular response (MR 4.5 ) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR 4.5 under different treatment modalities and whether MR 4.5 predicts survival. Patients and Methods Patients from the randomized CML-Study IV were analyzed for confirmed MR 4.5 which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR 4.5 on survival. Results Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR 4.5 after 9 years was 70% (median, 4.9 years); confirmed MR 4.5 was 54%. MR 4.5 was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR 4.5 at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR 4.5 . No patient with confirmed MR 4.5 has experienced progression. Conclusion MR 4.5 is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.49.9020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Concept, Feasibility and Results of the Randomized Comparison of Imatinib Combination Therapies for Chronic Myeloid Leukemia: The German CML-Study IV.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1083-1083
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1083-1083
    Abstract: Targeted therapy with the BCR-ABL tyrosine kinase inhibitor imatinib induces high response rates in chronic myeloid leukemia (CML) patients (pts). Nevertheless, residual disease remains in virtually all pts on imatinib monotherapy as a potential cause of relapse. In July 2002, the German CML-Study Group activated the four-armed randomized controlled trial comparing imatinib 400mg/d with imatinib+IFN, imatinib+Ara-C, and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High-risk pts are randomly assigned to primary imatinib-based therapies including a treatment arm with 800mg/d imatinib. By 7/05, 632 pts were randomized: imatinib 400mg/d (n=129), imatinib+IFN (n=179), imatinib+Ara-C (n=156), imatinib after IFN failure (n=157), and imatinib 800mg/d (n=11). According to the Hasford score, 35% of pts were low risk, 54% intermediate risk, and 11% high risk. At baseline, median WBC count was 67/nl (3–529), median platelet count 391/nl (34–2,799) and median hemoglobin 12.6 g/dl (6.1–16.6). We sought to evaluate results of pts with a & gt;12 months follow-up (n=416), recruited between 7/02 and 6/04 (imatinib 400mg/d, n=102; imatinib+IFN, n=126; imatinib+Ara-C, n=104; imatinib after IFN failure, n=81; imatinib 800mg/d, n=3) and of pts with a & gt;24 months follow-up (n=232), recruited between 7/02 and 6/03 (imatinib 400mg/d, n=55; imatinib+IFN, n=74; imatinib+Ara-C, n=54; imatinib after IFN failure, n=49) with respect to response, resistance, and progression. After 12 months of treatment cytogenetic data are available from 238/335 pts (71%) randomized to primary imatinib based therapies. 209 pts (63%) achieved a major cytogenetic remission (MCR; Ph+ & lt;35%), being complete in 53%. Q-PCR data were available in 270 pts (81%). 89 pts (27%) achieved a major molecular response (MMR; ratio BCR-ABL/ABL & lt;0.12%). After 24 months cytogenetic data are available from 141/183 pts (77%). 126 pts (69%) achieved a MCR, being complete in 60%. Q-PCR data were available in 149 pts (81%). 73 pts (40%) achieved a MMR. 12/177 pts lost CCR (7%) during the 1st year and 6/110 pts (5%) during the 2nd year of treatment. Within the 1st year 13/335 pts (6 low, 3 intermediate, 4 high risk; 4%) progressed to blast crisis, 4 of them revealed clonal evolution (complex aberrant karyotype, n=3; +8, n=1), two others BCR-ABL mutations (E355G and M244V). Within the 2nd year 3/232 pts (1 each low, intermediate, and high risk; 1%) progressed to blast crisis. During the 1st year of treatment imatinib therapy was stopped due to side effects or resistance in 6% of pts in the imatinib 400mg arm, in 2% of pts in the imatinib+IFN, and in 2% of pts in the imatinib+Ara-C arm. IFN was stopped in 21%, Ara-C in 18% of pts. This interim analysis of a prospective randomized trial with imatinib and imatinib in combination for newly diagnosed pts with CML has proven feasibility of imatinib combinations in addition to high response and low progression rates. Long-term observation will demonstrate whether the promising results will be maintained and will improve survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1083.1083
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Nilotinib Vs Nilotinib Plus Pegylated Interferon-alpha2b Induction and Nilotinib or Pegylated Interferon-alpha2b Maintenance Therapy for Newly Diagnosed BCR-ABL+ Chronic Myeloid Leukemia Patients in Chronic Phase: Interim Analysis of the Tiger (CML V)-Study
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 460-460
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 460-460
    Abstract: Introduction: The TIGER (CML V)-study (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon alpha2b (Peg-IFN) and the option to discontinue therapy after Peg-IFN maintenance as first line therapy for chronic myeloid leukemia (CML) patients in chronic phase. Methods: Recruitment started in August 2012 with a pilot phase, aiming to validate the recommended dose of PEG-IFN. 25 pilot phase patients (pts) were treated with the combination of NIL 2*300 mg daily and PEG-IFN (30-50μg/week according to tolerability and commenced after 〉 6 weeks NIL monotherapy). During the main phase of the study, newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/PEG-IFN combination in accordance with the approach which was confirmed to be feasible during the pilot phase. After at least 2 years NIL based induction therapy and achievement of major molecular remission (MMR, BCR-ABL transcript level ≤0.1% according to the international scale, IS), maintenance therapy (NIL vs PEG-IFN) started. Requirements for treatment discontinuation were treatment duration of at least 3 years with stable MR4 (BCR-ABL ≤0.01%) for at least one year. NIL therapy was reinitiated in case of molecular recurrence, defined as loss of MMR. The major co-endpoints of the study are (i) rate of MMR at 18 months (NIL vs NIL+PEG-IFN), and (ii) rate of continuous MMR 12 and 24 months after discontinuation of NIL vs PEG-IFN. Efficacy and safety data are presented without specification of the randomized therapy during the ongoing study. Results: Within 5 years, a total of 717 pts (429 male; median age 51, range 18-85 years; 13.3% EUTOS high risk) were recruited from 111 sites in Germany, Switzerland, and the Czech Republic. Median observation time since recruitment was 30.3 months. 396 pts concluded the induction phase and reached the maintenance phase of the study. 138 pts achieved and maintained MR4 (BCR-ABL ≤0.01% IS) for at least one year during the maintenance phase and discontinued all therapy. With regard to efficacy in the two treatment arms, 79.5% reached MMR at 12 mo. (95% confidence interval (CI): [76.1-82.7%]), 84.9% at 18 mo. (95% CI: [81.4-88.0%] ), and 89.4% at 24 mo. (95% CI: [86.0-92.2%]) after randomization. Probabilities of adverse events of grade 1-5 after 12 mo. of therapy were 83.7 (95% CI: [79.2-87.3%] ) and 90.0% (95% CI: [85.8-93.0%]), and of grade 3-5 after 3 years 39.6 (95% CI: [33.4-45.7%] ) and 49.5% (95% CI: [42.7-56.0%]) for the two treatment arms. Twelve pts progressed to accelerated phase or blast crisis; four of them died from blast crisis. A total of 13 patients received 14 allogeneic stem cell transplantations in chronic phase (n=7) or blast crisis (n=7). In total, 19 pts died, five related to CML, three from vascular complications. Conclusions: This interim analysis demonstrates feasibility of 1st-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Molecular response during the first 24 mo. favourably compares with data from recent NIL based studies (ENESTnd, NCT00471497; ENEST1st, NCT01061177) and permits access to the maintenance phase (NIL vs PEG-IFN monotherapies) for the majority of patients - with the potential of treatment-free remission. The study was conducted by the German CML Study Group in cooperation with the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO). Figure. Figure. Disclosures Hochhaus: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Saussele:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding. Baerlocher:Novartis: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Research Funding. La Rosée:Novartis: Research Funding. Hasford:Novartis: Research Funding. Heim:Novartis: Research Funding. Krause:Novartis: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Niederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Lange:Novartis: Research Funding. Haenel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria. Gil:Novartis: Research Funding. Ernst:Novartis: Research Funding. Fabisch:Novartis: Research Funding. Pfirrmann:Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-112119
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Achievement Of a MR5.0 Within the Randomized CML-Study IV: Feasibility, Differences Between Treatment Arms, and Prognostic Implications
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4008-4008
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4008-4008
    Abstract: Depth of molecular remission on tyrosine kinase inhibitor (TKI) treatment is of rising importance for chronic myeloid leukemia (CML) patients (pts) with regard to possible treatment discontinuation and competing TKIs available to improve molecular response. At present, it is unknown which level of deep molecular response is necessary for optimal prognosis and for successfully stopping therapy. The aim of this work is both to evaluate the technical feasibility of molecular monitoring at the mentioned level and to search for factors allowing to predict MR5.0 in pts on imatinib (IM)-based treatment. Methods Real-time quantitative PCR on mRNA BCR-ABL transcripts in addition to total ABL transcripts as internal control has been performed on a LightCycler platform in 1,442 pts within the randomized CML-Study IV and adapted according to the International Scale (IS). In order to qualify for MR5.0 the BCR-ABLIS expression should meet one of the following criteria: a positive result ≤0.001% or a negative result with a minimum sample quality of 100,000 ABL copies (Cross et al., Leukemia 2012). Calculating cumulative incidences of remission or progression, the competing risks progression and/or death before possible progression were considered. Cox models were estimated for the multivariate analysis. Results In 1,198 of the 1,442 molecularly examined pts at least one sample fulfilled the sensitivity criteria for a MR5.0 (8,266 of 24,101 samples, 34.3%). Cumulative incidence of MR5.0 was 51% at 8 years. The median time to MR5.0 according to randomized treatment arms differed as follows: IM 800mg 79.7 months (mos), IM 400mg 95.0 mos, IM 400mg + IFNα 98.0 mos, IM 400mg + AraC 103.3 mos, IM 400mg after IFN failure 112.9 mos. A Cox model examining the different treatment arms compared to IM 400mg revealed a significantly higher chance for MR5.0 in the IM 800mg arm (HR 1.305, 95% CI 1.003-1.698, p=0.048). Baseline factors like thrombocytosis 〉 450/nl were associated with better responses (HR 1.701 compared to 〈 450/nl, 95% CI 1.405-2.059, p 〈 0.001) and higher leukocyte counts 〉 100/nl (HR 0.503 compared to 〈 50/nl, 95% CI 0.400-0.632, p 〈 0.001) and 50-100/nl (HR 0.746 compared to 〈 50/nl, 95% CI 0.591-0.942, p=0.014) with unfavorable responses. Other upfront factors like age, gender, blasts, eosinophils, hemoglobin, and EUTOS score did not significantly influence the probability for MR5.0. Taken all treatment arms together, our analyses have shown that the chance of achieving a MR5.0 by 8 years was considerably reduced if the pts had a BCR-ABLIS 〉 10% at 3 mos (40.2% vs 58.0%), 〉 1% at 6 mos (40.3% vs 68.7%), 〉 0.1% at 12 mos (37.7% vs 72.0%), and 〉 0.1% at 24 mos (21.5% vs 60.5%). Conclusion This evaluation of a large randomized trial reveals feasibility of MR5.0 detection in the majority of pts underlining the benefits of standardized molecular monitoring on the IS with optimized highly sensitive technologies. Baseline low leukocyte count, high thrombocyte count and high dose IM treatment are predictors of future MR5.0. Further, early molecular landmarks qualify for excellent outcome giving hope to a rising number of pts to successfully discontinue treatment and avoid possible side effects or comorbidities. Disclosures: Müller: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4008.4008
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    The Impact Of Balanced and Unbalanced Karyotypes On Prognosis Of CML: From Chronic Phase To Blast Crisis
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3996-3996
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3996-3996
    Abstract: Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the balanced reciprocal translocation t(9;22)(q34;q11) or the variant translocation t(v;22) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show ACA already at diagnosis and more than 80% of patients acquire ACA during the transformation process into BC. Therefore, alterations at diagnosis as well as acquisition of chromosomal changes during treatment are considered as a poor prognostic factor. Differences in progression-free survival (PFS) and overall survival (OS) have been detected depending on the type of ACA. Patients with major route ACA (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and with other alterations like -X, del(1)(q21), del(5)(q11q14), +10, -21 at diagnosis resulting in an unbalanced karyotype have a worse outcome. Patients with minor route ACA (for example reciprocal translocations other than the t(9;22)(q34;q11) (e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20)) resulting in a balanced karyotype show no differences in OS and PFS compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). Here we compare the type of chromosomal changes (i.e. balanced vs. unbalanced karyotypes) during the course of the disease from CP to BC aiming to provide a valid parameter for future risk stratification. Patients and Methods Clinical and cytogenetic data available from 1,346 out of 1,524 patients at diagnosis (40% females vs. 60% males; median age 53 years (range, 16-88)) with Philadelphia and BCR-ABL positive CP CML included until March 2012 in the German CML-Study IV (a randomized 5-arm trial to optimize imatinib therapy) were investigated. ACA were comparatively analyzed in CP and in BC. Results At diagnosis 1,174/1,346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). Ninety-seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had ACA. Regarding the patients with ACA thirty-six of the 53 patients (68%) had an unbalanced karyotype and 17/53 patients (32%) a balanced karyotype. During the course of the disease 73 patients (out of 1,524 patients) developed a BC during the observation time (5%). Cytogenetic data were available in 52 patients with BC (21 patients with BC had no cytogenetic analysis). Three patients had a normal male or female karyotype after stem cell transplantation. Nine patients showed the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) (six and three patients, respectively) only and in 40 patients ACA could be observed in BC (40/49 (82%)). Out of these 40 patients with ACA, 90% showed an unbalanced karyotype whereas only 10% of patients had a balanced karyotype. No male patient in BC showed the loss of the Y chromosome pointing to a minor effect of this numerical alteration on disease progression. Conclusion We conclude that patients with CML and unbalanced karyotype at diagnosis are under higher risk to develop CML BC compared to patients with balanced karyotypes or compared to patients without ACA. In BC, 90% of CML patients showed unbalanced karyotypes (only 68% of CML patients at diagnosis have unbalanced karyotypes) supporting the hypothesis that the imbalance of chromosomal material is a hallmark of disease progression, representing the natural history of the disease from CP to BC and indicating therefore a strong prognostic impact. Consequently, different therapeutic options (such as intensive therapy or stem cell transplantation) should be considered for patients with unbalanced karyotypes in CP CML at diagnosis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer : Consultancy, Honoraria; Ariad : Consultancy, Honoraria. Müller:Ariad: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3996.3996
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    A Two-Fold Rise of BCR-ABL Transcript Levels Advises BCR-ABL Mutation Analysis in Imatinib-Treated Chronic Myeloid Leukemia (CML) - an Analysis of the Randomized CML-Study IV
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3138-3138
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3138-3138
    Abstract: Introduction: The clonal selection of a mutant BCR-ABL positive clone can be observed in about one of two patients with imatinib-resistant chronic myeloid leukemia (CML). The early detection of BCR-ABL kinase domain mutations is crucial, since it allows to change the tyrosine kinase inhibitor (TKI) regimen in a timely manner and may therefore prevent disease progression and the accumulation of further genetic lesions. European LeukemiaNet (ELN) recommendations suggest a mutation analysis if optimal response criteria are not achieved at 3, 6, 12 or 18 months, or whenever a loss of optimal response occurs (Soverini et al., Blood 2011). Several attempts have been made to derive this indication from a specific increase of BCR-ABL levels. Here we report on the correlation of a rise in BCR-ABL transcript levels and the prevalence of BCR-ABL kinase domain mutations in imatinib-treated patients of the CML-Study IV. Methods: A total of 1,173 patients were enrolled until 2009 and randomized to one of four imatinib-based treatment arms. BCR-ABLIS of 988 patients was determined in 7,876 samples by quantitative RT-PCR in the central laboratory (median sample number per patient: 8.4, range 1-37; median follow up: 34 months, range 0-86), representing the eligible patients for the study. Thereby, the estimated intra-laboratory variance is assumed to be about 20%. A first rise of BCR-ABLIS to at least two-fold and 〉 0.1% between two samples of a patient's molecular course defined a sample suspected of bearing a mutant BCR-ABL positive clone. A mutation analysis was performed on this critical sample by direct sequencing of ABL exons 4 to 10. Results: A critical rise in BCR-ABLIS was observed in 231 of 988 patients (23%) after a median of 15.2 months on treatment (range 2.8-59.4). In the corresponding sample 33 mutant clones could be detected in 31 patients (13%). Thereby a steeper rise of BCR-ABLIS was correlated with a higher incidence of BCR-ABL mutations in the respective group (table). A total of 18 different mutations could be detected, the most frequent were: M244V, n=7 (21%); E255K, n=4 (12%); T315I, n=3 (9%); L248V, G250E, L387M and F486S, n=2 (6%), respectively. Mutations occur in a substantial proportion (8%) of patients with an only 2 to 3-fold rise of BCR-ABLIS transcript levels (table). Therefore, the most sensitive cut-off should be applied and mutation analysis may be triggered by a doubling of BCR-ABL transcripts at levels 〉 0.1% IS. Conclusion: BCR-ABL kinase domain mutations occur already in a substantial proportion of patients with a doubling of BCR-ABL transcript levels, which should determine mutation analysis. Table 1. Rise of BCR-ABL expression Patients (n) Patients with BCR-ABL mutations (n) Patients with BCR-ABL mutations (%) Inter-sample interval(median, days) 2 to 3-fold 72 6 8.3 98 3 to 5-fold 50 3 6.0 100 5 to 10-fold 39 4 10.3 99 10 to 100-fold 49 10 20.4 98 〉 100-fold 21 8 38.1 125 〉 2-fold (total) 231 31 13.4 101 Disclosures Hanfstein: Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Pfizer: Consultancy, Research Funding; ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3138.3138
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Absolute BCR-ABL Transcript Levels At 3 Months but Not At Diagnosis Predict Survival of Chronic Myeloid Leukemia (CML) Patients On Imatinib Therapy
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3761-3761
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3761-3761
    Abstract: Abstract 3761 Introduction: Early assessment of molecular and cytogenetic response at 3 months of imatinib treatment has been shown to predict survival and might trigger treatment intensification in slow responders who are supposed to harbor a BCR-ABL positive clone with inferior susceptibility to tyrosine kinase inhibition (Hanfstein et al., Leukemia 2012). BCR-ABL transcript levels at 3 months depend on levels at diagnosis and the subsequent decline under treatment. Which of both parameters determines the clinical course and allows for prediction of survival is unclear. The BCR-ABL/ABL ratio is supposed to be skewed for high values, e.g. 〉 10%, due to the fact that ABL transcripts are also amplified from the fusion gene and in fact BCR-ABL/(ABL + BCR-ABL) is determined. Therefore, Beta-glucuronidase (GUS) was used as reference gene to determine high transcript levels at diagnosis. In addition, the linearity of the BCR-ABL/GUS scale allowed for an optimization of prognostic cut-off levels. We compared the significance of 1) BCR-ABL/GUS at diagnosis, 2) BCR-ABL/GUS at 3 months, 3) the individual reduction of transcripts given by (BCR-ABL/GUS at 3 months)/(BCR-ABL/GUS at diagnosis), and 4) the established 10% BCR-ABL/ABL landmark expressed on the international scale (BCR-ABLIS). Patients and methods: A total of 337 patients (pts) were investigated. According to the protocol of the German CML study IV pts could have been pre-treated with imatinib up to 6 weeks before randomization. 56 pts with imatinib onset before initial blood sampling within the study were excluded from the analysis. A total of 281 evaluable patients (median age 51 years, range 17–85, 42% female) were treated with an imatinib-based therapy consisting of imatinib 400 mg/d (n=76), imatinib 800 mg/d (n=110) and combinations of standard dose imatinib with interferon alpha (n=84) and low-dose cytarabine (n=11). Median follow-up was 4.8 years (range 1–10). Transcript levels of BCR-ABL, ABL, and GUS were determined by quantitative RT-PCR from samples taken before imatinib onset (“at diagnosis”) and 3 month samples. Only patients expressing typical BCR-ABL transcripts (b2a2 and/or b3a2) were considered. Disease progression was defined by the incidence of accelerated phase, blastic phase or death from any reason. A landmark analysis was performed for progression free survival (PFS) and overall survival (OS) after dichotomizing patients by a cut-off optimized by the cumulative martingale residuals method. Results: The median BCR-ABL/GUS ratio was 15.5% at diagnosis (0.07–271) and 0.62% at 3 months (0–34.7) reflecting a decline by 1.4 log. Disease progression was observed in 17 patients (6.0%), 14 of them died (5.0%). With regard to the above described parameters the following findings were observed: 1) at diagnosis no cut-off level could be identified for BCR-ABL/GUS ratios to separate two prognostic groups according to long-term PFS or OS. 2) At 3 months an optimized 2.8% BCR-ABL/GUS cut-off separated a high-risk group of 61 pts (22% of pts, 8-year PFS 78%, 8-year OS 81%) from a good-risk group of 220 pts (78% of pts, 8-year PFS 94%, 8-year OS 94%, p 〈 0.001, respectively). 3) At 3 months an individual reduction of BCR-ABL transcripts to at least 40% (0.4 log) of the initial level separated best and divided a high-risk group of 33 pts (12% of pts, 8-year PFS 74%, 8-year OS 80%) from a good-risk group of 248 pts (88% of pts, 8-year PFS 93%, 8-year OS 93%, p 〈 0.001, respectively). 4) When the established 10% BCR-ABLIS at 3 months was investigated, 63 pts were high-risk (22% of pts, 8-year PFS 82%, 8-year OS 85%) and 218 good-risk (78% of pts, 8-year PFS 91%, 8-year OS 93%, p=0.002 for PFS, p=0.011 for OS). Conclusions: Initial BCR-ABL transcript levels at diagnosis did not show prognostic significance. To predict survival at 3 months of treatment the absolute transcript level normalized by ABL or GUS can be used. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3761.3761
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Randomized Comparison of Imatinib 800 Mg Vs. Imatinib 400 Mg +/- IFN in Newly Diagnosed BCR/ABL Positive Chronic Phase CML: Analysis of Molecular Remission at 12 Months; The German CML-Study IV.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 339-339
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 339-339
    Abstract: Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR= 〈 0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p 〈 0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.339.339
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Feasibility of Imatinib Combination Therapies in a Randomized Trial for Chronic Myeloid Leukemia: The German CML-Study IV - Pilot Phase.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 24-24
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 24-24
    Abstract: The advent of imatinib has considerably changed treatment in chronic myeloid leukemia (CML). Although response rate and duration of response with imatinib monotherapy continue to be impressive, the majority of patients (pts) in complete cytogenetic remission (CCR) retain BCR-ABL transcripts as markers of residual disease and potential cause of relapse. In addition rapid evolvement of blast crises from CCR has been reported. Therefore, we designed an investigator-initiated phase IV prospective trial aiming to address the role of imatinib in combination with interferon alpha (IFN) or Ara-C and treatment intensification with high dose imatinib. In July 2002, the German CML-Study Group has activated the four-armed randomized controlled trial comparing imatinib 400 mg/d with imatinib+IFN, imatinib+Ara-C and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High risk pts are randomly assigned to primary imatinib-based therapies including a 4th treatment arm with imatinib 800 mg/d. The treatment arm imatinib after IFN failure retains the chance of an IFN-induced CCR with 10 year-survival rates of 70–80%. In case of IFN failure pts are crossed over to imatinib. Allogeneic SCT is recommended for all pts with high risk, imatinib failure and EBMT-score 0–1. By August 2004, 429 pts were randomized: imatinib 400 mg/d (n=103), imatinib+IFN (n=130), imatinib+Ara-C (n=108), imatinib after IFN failure (n=84), and imatinib 800 mg/d (n=4). According to the New CML score, 34% of patients were low risk, 56% intermediate risk, and 10% high risk. At baseline, median WBC count was 63/nl (3.5–513), median platelet count was 385/nl (49–2,799) and median hemoglobin was 12.7 g/dl (6.1–16.6). We sought to evaluate results of the first cohort of pts (n=217) with a 〉 12 months follow-up, recruited between 7/2002 and 5/2003 (imatinib 400 mg/d, n=52; imatinib+IFN, n=70; imatinib+Ara-C, n=49; imatinib after IFN failure, n=46). Median age was 56 yrs (16–82), 62% of pts were male. Cytogenetic data are available from 117 pts (68%) randomized to primary imatinib-based therapies. At 12 months, 104 pts (89%) achieved a major cytogenetic remission (Ph+ 〈 34%), being complete in 86 pts (74%). Quantitative RT-PCR data are available from 148 pts (87%). 56 pts (38%) achieved a ratio BCR-ABL/ABL 〈 0.12%, which is equivalent to a 3-log reduction of the tumor load. 16 pts (11%) had at least one follow-up sample with undetectable BCR-ABL by real-time RT-PCR, in one patient additional nested RT-PCR was also negative. Cytogenetic response rates were not different between imatinib-based treatment arms. Estimated rate of freedom from progression to advanced disease was 97%. The first analysis of a prospective randomized trial with imatinib and imatinib in combination for newly diagnosed pts with CML has proven feasibility of imatinib combinations in addition to high response rates. The intention of combination therapy is to delay or avoid treatment resistance. Long-term observation will demonstrate whether these promising results will be maintained and will have the potential to improve survival of CML pts.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.24.24
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...