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  • 1
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    Step-in dosing of bosutinib in pts with chronic phase chronic myeloid leukemia (CML) after second-generation tyrosine kinase inhibitor (TKI) therapy: results of the Bosutinib Dose Optimization (BODO) Study
    Springer Science and Business Media LLC ; 2023
    In:  Annals of Hematology Vol. 102, No. 10 ( 2023-10), p. 2741-2752
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    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 10 ( 2023-10), p. 2741-2752
    Abstract: The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bo sutinib Do se Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2 nd or 3 rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II–IV, primary study endpoint) to  〈  40% (overall rate of 60%; 95% CI: 45–74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-023-05394-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
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    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
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 3
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    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
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    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
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 4
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    Reply to H. Kantarjian et al
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 27 ( 2014-09-20), p. 3078-3078
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 27 ( 2014-09-20), p. 3078-3078
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2014.56.3908
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 5
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    ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia
    Springer Science and Business Media LLC ; 2022
    In:  Leukemia Vol. 36, No. 9 ( 2022-09), p. 2242-2249
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    In: Leukemia, Springer Science and Business Media LLC, Vol. 36, No. 9 ( 2022-09), p. 2242-2249
    Abstract: Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected ( n  = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
    URL: Article
    DOI: 10.1038/s41375-022-01648-4
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 6
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    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
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    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
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  • 7
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    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
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  • 8
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    Therapy with Imatinib In Elderly CML Patients (〉65years): Results of the German CML-Study IV.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3411-3411
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3411-3411
    Abstract: Abstract 3411 Background: Dose of therapy and time to response may be different in the elderly as compared to younger patients with CML. This has been reported previously for interferon α (Berger et al., Leukemia 2003). For imatinib, contradictory results have been presented (Rosti et al. Haematologica 2007, Guliotta et al. Blood 2009). Aims: An analysis comparing dose-response relationship in patients more or less than 65 years (y) of age is warranted. Methods: We analysed the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, dose escalation and transplantation. Patients older and younger than 65y randomized to imatinib 400 mg (IM400) or 800 mg (IM800) were compared with regard to time to hematologic, cytogenetic and molecular remissions, imatinib dose, adverse events (AEs) and overall survival (OS). Results: From July 2002 to April 2009, 1311 patients with Ph+ CML in chronic phase were randomized, 623 patients were evaluable, 311 patients for treatment with IM400 and 312 for IM800. 84 (27%) and 66 (21%), respectively, were older than 65 years. All patients were evaluable for hematologic, 578 (140 〉 65y and 438 〈 65y) for cytogenetic, and 600 (143 and 457, respectively) for molecular responses. Median age was 70y vs. 49y for IM400 and 69y vs. 46y for IM800. The median dose per day was lower for elderly patients with IM800 (517mg vs. 666mg) and the same with IM400 (400mg each). Patients' characteristics at baseline were evenly distributed in all groups regarding gender, follow-up, hemoglobin, platelet count and spleen size. Leukocyte counts were significantly lower in elderly patients (IM400: 50/nl vs. 78/nl, IM800: 36/nl vs. 94/nl). EURO score was different due to age in elderly patients (low risk: IM400: 11% vs. 43%, IM800: 14% vs. 42%; intermediate risk: IM400: 79% vs. 44% and IM800: 73% and 43%). There was no difference in cytogenetic and molecular analyses between treatment groups. With regard to efficacy, there was no difference for older patients in achieving a complete cytogenetic remission (CCR) and major molecular remission (MMR) if IM400 and IM800 were compared together. If treatment groups were analyzed separately, older patients treated with IM400 reached CCR and MMR statistically significant slower than younger patients (CCR: median 14.2 months vs. 12.1 months, p=0.019; MMR: median 18.7 months vs. 17.5 months, p=0.006). There was no difference with IM800 (CCR: median 7.7 months vs. 8.9 months, MMR: median 9.9 months vs. 10.0 months). 3y-OS for older patients 〉 65y was 94.7% and for patients 〈 65y was 96.1%. Some differences were observed in the safety analyses. 530 patients (IM400: 278, IM800: 252) were evaluated on common toxicity criteria (WHO). Some hematologic AEs were documented slightly more often in the elderly than in the younger patients: for IM400 anemia grade 1–2 (60 vs. 42%) and leukopenia grade 3–4 (5.6 vs. 1.4%) and for IM800 anemia grade 1–4 (64 vs.47% and 7.2 vs. 5.7%) and thrombocytopenia grade 3–4 (9.3 vs. 7.1%). Non hematologic AEs were more prominent in IM800 and were mainly gastrointestinal symptoms (IM400: 33 vs. 31%, IM800: 48 and 44%) and edema (IM400: 28 vs. 29%, IM800: 35 vs. 50%). There was no difference for grade 3/4 non-hematological AEs in older patients in both groups. Conclusions: Imatinib 400 mg and 800 mg are well tolerated also in the elderly. The IM800 dosage was more tolerability-adapted for the elderly, but there was no difference in reaching a CCR and MMR in contrast to the IM400 where a significantly slower response was detected in the elderly. Whether this difference is clinically relevant has yet to be determined. Updated results will be presented. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3411.3411
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
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    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
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    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
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    Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Imatinib-Era: Update on the Survival Outcome Following Allogeneic HSCT after Imatinib Failure; Results of the German CML Study IV
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2567-2567
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2567-2567
    Abstract: Allogeneic HSCT has been established as the only curative treatment option for patients with chronic myeloid leukemia (CML). However, after the advent of tyrosine kinase inhibitors (TKI) the proportion of transplanted patients has decreased dramatically. After imatinib failure, most patients receive second or third line therapy with alternative TKIs. In an important minority of patients, SCT is performed too late as more patients are transplanted after disease progression to accelerated phase or blast crisis than in first chronic phase (CP, Saussele et al. BMT 2012). A possible reason is the uncertainty on long-term outcome after SC T in the imatinib-era as reports are scarce and accurate comparative data on the impact of salvage TKI therapy vs allogeneic transplantation are missing. We therefore investigated the outcome of transplanted patients within the CML study IV. Preliminary data were published (Saussele et al. BLOOD 2010). Here, we sought to re-evaluate the outcome of these patients with a longer follow-up. In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in CP CML. Elective early HSCT was considered for patients with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of March 2012, 1551 patients were randomized. In 2008, HSCT was documented in 84 patients. One patient was not evaluable any more due to withdrawal of consent. 52 patients were male (65%), 23 high risk patients (28%) according to the Euro CML score. Median age at diagnosis was 37 years (range, 16-62), median time to HSCT was 12.6 months (range, 3.5-54). EBMT score was 0-1 in 8 (10%), 2 in 10 (12%), 3-4 in 44 (55%), and 〉 =5 in 18 patients (23%), three patients were missing. Median follow-up after HSCT was 86.9 months (range, 0.3-122). Based on the indication for HSCT three groups are defined: 1) early HSCT, n= 19 (23%; low EBMT score (n=9), high risk patients (n=7), patient request (n=3); 2) HSCT after imatinib failure or intolerance in first CP (n=36 patients, 43%), and 3) HSCT in second CP or higher, accelerated phase or blast crisis (n=28 patients, 34%). 26 patients died, 13 deaths were transplant related, 9 CML related 4 either unrelated or unknown. Overall survival rate at 6 years after HSCT was 89% (95%-confidence interval (CI): 72-99%) for group 1, 80% (95%-CI: 66-91%) for group 2, and 49% (31-68%) for group 3. A matched pair analysis could be performed for 53 transplanted patients of group 1 and 2. To each of the transplanted patients two imatinib-treated patients could be matched with regard to age, sex, risk profile, disease phase, and interval to transplantation. Median follow up of this population was 87 months. Overall survival after 8 years was 83% (95%-CI: 71-92%) for transplanted and 89% (95%-CI: 82-94%) for imatinib treated patients without any statistical difference. Data from this update with a longer follow-up support the role of HSCT as an attractive and important salvage therapy for CML patients with imatinib failure or intolerance. In a matched pair comparison of transplanted and non-transplanted patients, we did not find significant differences. Disclosures Saussele: Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hehlmann:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2567.2567
    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
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