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  • 1
    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
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  • 2
    Online Resource
    Online Resource
    Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 357-357
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 357-357
    Abstract: Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of 〈 0,01 on the International Scale. From July 2002 – April 30, 2009 1022 newly diagnosed patients with CML in chronic phase were randomized, 1012 were evaluable (338 with imatinib 800 mg, 324 with imatinib 400 mg, 350 with imatinib plus IFN). Median observation time was 40 months. The median average daily imatinib doses were 628 mg in the 800 mg arm and 400 mg in the 400 mg based arms. The actual median daily doses in the 800 mg arm per 3-months periods were: 555 mg, 737 mg, 613 mg, 600 mg, and 600 mg thereafter, reflecting the run–in period with imatinib 400 mg for 6 weeks in the first period and the adaptation to tolerability from the third 3-months period onwards. Median daily imatinib doses in the 400 mg arms were 400 mg throughout. Adaptation of imatinib dose in the 800 mg arm according to tolerability is reflected by similar higher-grade adverse events rates (WHO grades 3 and 4) with all treatments. Significantly higher remission rates were achieved with imatinib 800 mg by 12 months. The cumulative incidences of CCR by 12 months were 63% [95%CI:56.4-67.9] with imatinib 800 mg vs 50% [95%CI:43.0-54.5] with the two 400 mg arms. The cumulative incidences of MMR by 12 months were 54.8% [95%CI:48.7-59.7] with imatinib 800 mg vs 30.8% [95%CI:26.6-36.1] with imatinib 400 mg vs 34.7% [95%CI:29.0-39.2] with imatinib + IFN. The cumulative incidences of CMR4 compared with the MMR incidences over the first 36 months are shown in Table 1. Imatinib 800 mg shows superior CMR4 rates over the entire 36 months period, CMR4 is reached significantly faster with imatinib 800 mg as compared to the 400 mg arms. The CMR4 rates reach 56.8% by 36 months [95%CI:49.4-63.5] as compared to 45.5% with imatinib 400 mg [95%CI:38.7-51.0] and 40.5% with imatinib plus IFN [95%CI:34.6-46.3] . Most patients have stable CMR4 over the entire period. Time after start of treat-ment (months) Cumulative incidences MMR(%) CMR4 (%) IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 6 8.6 9.5 18.1 9.7 8.4 3 0.7 3.7 1.3 2.4 12 30.8 24.0 54.8 20.1 34.7 7.5 12.3 19.8 7.4 12.4 18 50.3 18.1 68.4 14.3 54.1 21.2 12.2 33.4 9.8 23.6 24 63 13.0 76.0 13.2 62.8 30.7 12.3 43 13 30.0 36 79.3 2.3 81.6 10.9 70.7 45.5 11.3 56.8 16.3 40.5 In summary, superior CMR4 rates are achieved with high-dose imatinib adapted to good tolerability, and more patients in the tolerability-adapted 800 mg arm have stable CMR4 qualifying for treatment discontinuation as compared to the 400 mg based arms. With improved application imatinib remains first choice for early CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. 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.V116.21.357.357
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Online Resource
    Molecular Response 〈1% BCR-ABL IS at 12 Months Is Associated with Improved Overall and Progression-Free Survival. the Randomized German CML-Study IV
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 669-669
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 669-669
    Abstract: Abstract 669 Introduction: The prognostic relevance of major molecular remission (MMR, 〈 0.1% BCR-ABL according International Scale, IS) for survival has remained uncertain. Gold standard for the evaluation of treatment response is the achievement of complete cytogenetic remission in spite of its limited sensitivity and the requirement of bone marrow puncture. The standardization of PCR methods and the introduction of conversion factors to account for differences among European laboratories, has resulted in a uniform reporting system allowing comparable BCR-ABL expression levels derived from peripheral blood samples. We sought to evaluate an association of the degree of molecular response and survival. Patients and Methods: We have analyzed 848 patients within the CML-Study IV (randomized comparison of imatinib 800 mg vs 400 mg vs 400 mg + IFN). BCR-ABL (IS) was determined by quantitative RT-PCR. Patients with atypical BCR-ABL transcripts were excluded from the analysis. Median observation time was 40 months (minimum 12). Landmark analyses have been performed at 12 months for overall and progression-free survival using 3 groups of response ( 〈 0.1%, 0.1%-1%, 〉 1% BCR-ABL IS). Results: 341 patients achieved a BCR-ABL expression 〈 0.1% (MMR), 240 patients between 0.1% and 1% and 267 patients 〉 1% by 12 months. Independent of treatment approach, the groups of patients achieving MMR and 0.1%- 〈 1% at 12 months showed significantly higher progression free survival (PFS) (p=0.0023; 99% [95% CI: 97–100%] vs 97% [95% CI: 94–99%] vs 94% [95% CI: 90–97%] at 3 years) and better overall survival (p=0.0011; 99% [95% CI: 97–100%] vs 98% [95% CI: 95–100%] vs 93% [95% CI: 90–96%] at 3 years) compared to the group with 〉 1% BCR-ABL by 12 months (Figure). Conclusion: Faster and deeper response to imatinib-based treatment by 12 months revealed to be associated with improved PFS and overall survival. The critical cutoff level seems to be 1% BCR-ABL IS which has been shown to closely correlate with complete cytogenetic remission. Disclosures: Müller: Novartis: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. 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.V116.21.669.669
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Optimaization of Imatinib Therapy by Combination. 5 Year Survival and Response Results of the Pilot Phase of the Randomized German CML STUDY IV.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 862-862
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 862-862
    Abstract: Abstract 862 Rapid relapse after discontinuation of imatinib, the need for indefinite therapy and residual disease in most patients are the major challenges in management of CML. Combinations of imatinib with IFN simultaneously, or consecutively preceding imatinib, or with araC may improve treatment outcome. The German CML Study Group therefore designed a randomized trial to compare standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN failure (for low- and intermediate-risk patients, high risk patients received imatinib 800 mg instead). The current evaluation represents the prefinal results of the pilot phase of the trial. Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase (CP). Primary aims are: prolongation of survival (overall, OS, and progression free, PFS), determination of rates of hematologic, cytogenetic and molecular remissions, adverse events (AE) and role of allografting. By the end of 2005, 670 patients were randomized, 13 had to be excluded (no CML (n=3), pregnancy, no CP (n=1 each), imatinib 800 mg (n=8)). Analysis was according to intention to treat. 657 patients were evaluable (174 with imatinib 400 mg, 196 with imatinib+IFN, 158 with imatinib+araC and 129 with imatinib after IFN-failure). 656 patients were evaluable for hematologic, 611 for cytogenetic, and 618 for molecular responses. Patient characteristics of treatment arms were similar for age (median 53 years), sex (40% female), median values for Hb (12.6 g/dl), WBC (66.2/μl), platelets (383/μl) and for Euro risk score (low 35%, intermediate 54%, high 10%). The median dose of imatinib was 400mg/die in all arms, of araC 10 mg per treatment day and of IFN 4.2 Mio I.U./die in the imatinib after IFN arm and 1.8 Mio I.U./die in the imatinib+IFN arm. Median observation time was 57.3 months. 55 patients died, 73 patients were transplanted in 1st CP, 81 patients progressed, 59 patients were switched to second generation TKIs. After 3 years 126 patients (72%) of the imatinib 400mg arm still received the initial therapy as well as 60 patients (30%) of the imatinib+IFN arm and 53 patients (34%) of the imatinib+araC arm. 9 patients (7%) of the imatinib after IFN arm are still on IFN. 5-year OS of all patients is 91%. 5-year PFS of all patients (no death, patient still in first chronic phase) is 87%. 5-year-OS and PFS according to treatment arm are shown in the Table. At 5 years, the cumulative incidences of achieving complete cytogenetic remission or major molecular remission (MMR) as determined by competing risks (death, progression) are not different (Table). Type and severity of adverse events (AE) over a 5-years period did not differ from those reported previously (Table). Hematologic AEs grade III/IV were similar in all therapy arms except leukopenia grade III/IV, which was more frequently observed in the imatinib after IFN arm (14%). Non hematologic AEs were mainly fluid retention, neurological and gastrointestinal symptoms and fatigue. Neurologic symptoms and fatigue were more often reported for the therapy arms with IFN. Imatinib 400mgImatinib+IFNImatinib+AraCImatinib after IFN5-Year Survival and Response RatesOS87%93%92%92% PFS84%91%88%84% CCR92%92 %89%83% MMR83%78%80%70% Adverse Events, WHO Grade III/IVAnemia7%1%3%3% Leukopenia4%5%2%14% Thrombocytopenia5%6%6%6% WHO Grade I-IVEdema15%13%5%0% Neurological5%15%5%22% Gastrointestinal17%27%21%15% Fatigue8%13%9%23% This analysis shows excellent survival and durable response rates in all arms. Currently, survival in all treatment arms is equal to, or better than in IRIS. To verify possible differences in survival, e.g. imatinib 400 mg vs. imatinib + IFN, longer observation is planned. Although cytogenetic and molecular responses in the imatinib after IFN failure arm at 5 years are inferior to that in the other treatment arms, the question of whether the consecutive therapy with IFN first and imatinib after IFN-failure provides a survival advantage requires long term follow-up. Imatinib in combination with, or after IFN, or with low dose araC are feasible and safe treatment modalities. We expect that the study will optimize and improve therapy outcome in CML. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German Competence Net : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.862.862
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Evolution of Blast Crisis (BC) in Chronic Myeloid Leukemia (CML) in the Imatinib-Era: A Rare Event with High Proportions of Low Risk Patients and of Early Bc; Need for Rapid Detection. Results of the German CML Study IV.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3287-3287
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3287-3287
    Abstract: Abstract 3287 Poster Board III-1 Blast crisis (BC) in CML in the imatinib era is a rare event with 1–3% of newly diagnosed BC patients per year in the IRIS study, but prognosis, once BC has occurred, remains poor. Historical and recent studies with imatinib and second generation tyrosine kinase inhibitors (TKI) reported a median survival time of 7–10 months and two year survival probabilities of 〈 30%. In order to recognize earlier time points for intervention we aimed to characterize the evolution to BC in the imatinib era using the prospective randomized German CML study IV which compares imatinib based strategies in chronic phase CML. By July 2009, BC was observed in 51 patients (pts) out of 1347 randomized pts (3.8%), with equal distribution amongst the treatment arms. 36 pts (67%) were male. 21 pts (41%) had myeloblastic, 16 pts (31%) lymphatic, 2 pts (4%) biphenotypic, and 2 pts (4%) megakaryoblastic BC; 10 pts (20%) were not classifiable. At diagnosis of CML, 23 pts (45%) had low, 17 intermediate (33%) and 11 high risk (22%) according to the Euro score (proportion of low risk in pts without BC was 34%). Median age at diagnosis was younger for male pts (41 years; range 18–79) than for female pts (57 years; range 19–77). Median time from diagnosis to onset of BC was 11.3 months (range 0.7–71). Prior to BC, all pts had received imatinib except one who received interferon alpha (IFN) and dasatinib. Two pts had received an allogeneic stem cell transplantation (alloSCT) and four a second generation TKI before diagnosis of BC. The BC rates per year comparing CML studies IV and IIIA (IFN based treatment vs. alloSCT) are shown in the Table. The probabilities to survive without BC are almost identical in both studies for year 1, but are higher in CML study IV afterwards. During CP, all pts were evaluable for hematologic, 44 for cytogenetic and 46 for molecular response to initial therapy. 29 pts (57%) had achieved a complete hematologic, 9 (20%) complete, 3 (7%) major cytogenetic and 4 (9%) major molecular remissions. Cytogenetics at diagnosis of CML were available for 47 BC pts: 29 pts (62%) had a t(9;22) translocation only and 18 (38%) additional chromosomal aberrations (ACA; variant Philadelphia chromosome n=5, complex aberrant karyotype n=9, other n=4) (for comparison: ACAs at diagnosis were detected in 95 of 1,095 pts (9%) without BC). Cytogenetics at onset of BC were available for 29 pts: 7 pts (24%) had a t(9;22) translocation only and 22 pts (76%) ACAs (complex n=13, other n=9). 17 (10 different) BCR-ABL mutations (8 P-loop including 5 E255V/K; 2 M244V; 2 T315I; 2 F317L and 3 others) were detected in 14 of 33 pts (42%). Median follow-up after BC was 34 months (range 2.3–53). 24 patients were transplanted, 10 pts were treated with second generation TKI (dasatinib n=9, nilotinib n=1), 4 of these were also transplanted, 16 received other therapies (imatinib dose escalation in combination with chemotherapy n=7, chemotherapy alone n=9), one no therapy. 32 pts died. Only 19 of the 51 pts (37%) were alive, 16 of them (84%) after allogeneic HSCT. 2 pts are alive on second generation TKI and one on busulfan. Median survival after BC was 11.6 months, survival probability at two years was 35% (s. Figure). BC occurred early after diagnosis, in a high proportion of low risk patients. There was a preponderance of young males, and a high proportion with ACA at diagnosis. The best chances for survival were by alloHSCT. The short median time to BC indicates that evolution to BCR-ABL independence may have occurred already prior to CML diagnosis and start of imatinib therapy. Early identification and rapid initiation of a donor search in patients with early failed response to imatinib is warranted. Progression to BC and survival BC rate per year Year 1 2 3 4 5 6 CML Study IV 2.3% 1.5% 0.5% 0.6% 0.3% 1.1% CML Study IIIA 3.3% 3.7% 1.5% 1.7% 1.2% 1.0% Survival probability without BC CML Study IV 98% 96% 96% 95% 95% 94% CML Study IIIA 97% 93% 91% 90% 89% 88% Figure Survival of BC patients after treatment with imatinib; data of the German CML Study IV Figure. Survival of BC patients after treatment with imatinib; data of the German CML Study IV Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German CompetenceNet : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3287.3287
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
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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
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 7
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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
    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
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  • 8
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    A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia
    Springer Science and Business Media LLC ; 2020
    In:  BMC Pharmacology and Toxicology Vol. 21, No. 1 ( 2020-12)
    Details
    In: BMC Pharmacology and Toxicology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2020-12)
    Abstract: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients 〉  18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL ( n  = 11) or AML ( n  = 12) or CML-BP ( n  = 1) were enrolled. All patients had failed one ( n  = 5) or more lines of therapy ( n  = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov , identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118 .
    Type of Medium: Online Resource
    ISSN: 2050-6511
    URL: Article
    DOI: 10.1186/s40360-020-00446-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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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
    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:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 10
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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
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