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  • 1
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    Molecular Response After 3 Months of 1st Line Imatinib Therapy Is Predictive for Treatment Failure and Disease Progression In Patients with Chronic Phase Chronic Myeloid Leukemia - a Follow-up Analysis of the German CML Study IV
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 360-360
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 360-360
    Abstract: Abstract 360 Introduction: The lack of a sufficient response to first line imatinib treatment has been observed in a substantial proportion of CML patients and has been associated with an inferior survival. Therefore, response criteria have been defined to identify patients with treatment failure. A change of drug therapy to 2nd generation tyrosine kinase inhibitors or allogeneic stem cell transplantation is recommended for this group of patients (European LeukemiaNet, ELN, Baccarani et al., JCO 2009). We sought to evaluate the predictive value of early molecular response landmarks for treatment failure and disease progression to identify patients at risk and to provide a guidance for the interpretation of BCR-ABL levels. Patients and methods: 949 patients included into the randomized German CML Study IV and treated with an imatinib based therapy consisting of standard dose imatinib (400 mg/d), high dose imatinib (800 mg/d) and combinations of standard dose imatinib with low dose cytarabine or interferon alpha were evaluable for molecular and cytogenetic analysis. BCR-ABL (IS) was determined by quantitative RT-PCR. The type of BCR-ABL transcript (b2a2, n=424; b3a2, n=464; b2a2 and b3a2, n=148) was defined by multiplex PCR. Patients with atypical BCR-ABL transcripts were excluded from the analysis. Cytogenetic response (CyR) was determined by G-banding metaphase analyses. Treatment failure has been defined according to ELN criteria as a lack of major CyR after 12 months and a lack of complete CyR after 18 months of imatinib treatment, respectively. CyR data were available for 479 pts between 12 and 18 months with a subset of 289 pts evaluable for 3 month molecular response (CyR data after 18 months, n=532; 3 month molecular subset, n=289). Disease progression comprises the incidence of accelerated phase, blast phase and death. Median follow-up for disease progression was 35 months (range 2–85). Fisher's exact test has been performed to evaluate the prognostic significance of 3 month BCR-ABL landmarks for 12 month and 18 month treatment failure. A landmark analysis has been performed for disease progression (logrank test). Results: In 20 of 289 evaluable pts treatment failure has been observed after 12 months, and in 29 of 289 pts after 18 months. 24 of 570 evaluable pts showed a disease progression after a median of 18 months (range 5–71). A stratification into three groups at 3 months reveals a significant difference concerning treatment failure between pts with BCR-ABL levels between 1% and 10% and those with BCR-ABL levels 〉 10%. With regard to disease progression there is a statistical trend. Comparing two groups the 10% BCR-ABL cut-off is highly significant for both, treatment failure and disease progression. Missing the 10% BCR-ABL landmark after 3 months of imatinib treatment defines a poor risk group with a 20.7% risk of treatment failure after 18 months and a 8.1% risk of disease progression (Table). Conclusion: Early assessment of molecular response after 3 months of imatinib therapy allows the identification of a patient cohort with an increased risk of treatment failure and disease progression. Disclosure: Müller: Novartis Corporation: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis Corporation: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.360.360
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase
    American Society of Hematology ; 2017
    In:  Blood Vol. 130, No. Suppl_1 ( 2017-12-07), p. 897-897
    Details
    In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 897-897
    Abstract: Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V130.Suppl_1.897.897
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
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  • 3
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    Molecular Response to First Line Imatinib Therapy Is Predictive for Long Term Event Free Survival in Patients with Chronic Phase Chronic Myelogenous Leukemia – An Interim Analysis of the Randomized German CML Study IV
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 333-333
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 333-333
    Abstract: The introduction of imatinib has significantly changed prognosis of CML patients. Despite favourable hematologic and cytogenetic response (CyR) data, patients (pts) on first line imatinib therapy may relapse. Thus, studies have been conducted to improve initial therapy by dose escalation or combination with other drugs. CML Study IV was designed to compare imatinib in standard dose (400 mg/d) vs high dose (800 mg/d) vs combinations with low dose cytarabine or interferon alpha. We sought to evaluate the predictive impact of early molecular response for long term event free survival (EFS). 539 pts (59% m, median age 54 years, range 16–84) randomized to imatinib based therapies by December 2005 were investigated, the median follow up was 39 mo (range, 0–69). At baseline, multiplex PCR was applied to determine the dominating BCR-ABL transcript: b2a2 (n=204), b3a2 (n=247), b2a2 and b3a2 (n=80), e1a2 (n=2), e19a2 (n=4), b3a3 (n=1) and e8a2 (n=1). Quantitative PCR from 5,419 peripheral blood samples was performed using the LightCycler technology in two central labs. PCR data were aligned to the international scale (IS) by introduction of conversion factors (Hughes et al., BLOOD 2006). Cumulative molecular response of 539 pts at 3, 6, 12, 18, and 24 mo after randomization is summarized in the Table: Month 3 6 12 18 24 BCR-ABLIS Achieved by % of pts ≤10% 41 66 81 85 86 ≤1% 16 41 65 76 78 ≤ 0.1% (MMR) 3 16 37 51 59 ≤0.01% 1 3 10 21 28 For analysis of prognostic impact, events were defined as (i) loss of complete hematologic response, (ii) loss of major CyR following loss of complete CyR, (iii) accelerated phase, (iv) blast crisis, and (v) death for any reason. Pts were censored at the time of allogeneic stem cell transplantation or switch to 2nd generation tyrosine kinase inhibitors because of imatinib intolerance or resistance. The minimum molecular response levels predictive for EFS were BCR-ABLIS of 10% after 6 mo (p=0.0029), 1% after 12 mo (p 〈 0.0001), and 0.1% (major molecular response, MMR; p=0.0016) after 18 mo of imatinib based therapies. In order to investigate the reasons for unsatisfying responses BCR-ABL kinase domain mutations were assessed in 175 pts. 30 pts (17%) harbored 35 mutations affecting 18 different aminoacids. In conclusion, prospective molecular surveillance of CML shows that early response predicts stable remissions on first line imatinib therapy. After 6 mo of treatment, PCR data start to be predictive for EFS. In pts with unsatisfactory response or molecular, cytogenetic and hematologic relapse, BCR-ABL mutations have been detected in only 17% of pts. Calculation of molecular response rates dependent on the various imatinib based therapies will be performed after stop of randomization which is expected by the end of 2009.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.333.333
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 4
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    Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3762-3762
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3762-3762
    Abstract: Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL 〈 =0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels 〈 0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score. Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p 〈 0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p 〈 0.001, Fig. 1b). The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p 〈 0.001). OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3762.3762
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Randomized Comparison of Imatinib 400 Mg Vs. Imatinib + IFN Vs. Imatinib + AraC Vs. Imatinib after IFN Vs. Imatinib 800 Mg: Optimized Treatment and Survival. Designed First Interim Analysis of the German CML Study IV
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 184-184
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 184-184
    Abstract: In spite of favorable response and survival results for the majority of CML patients on imatinib therapy, in a substantial minority imatinib fails or shows suboptimal responses. A treatment optimization study was therefore designed to compare in a randomized fashion standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN (for low- and intermediate-risk patients) or vs. imatinib 800 mg (for high-risk patients). Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase. In July 2005, randomization to the arms imatinib + araC and imatinib after IFN was discontinued and recruitment for imatinib 800 mg was expanded to low- and intermediate-risk patients. Primary goals are: rates of hematologic, cytogenetic and molecular remissions, duration of chronic phase, overall survival, adverse events and analysis of subsequent allografting. Since its activation in 7/2002, 1203 patients have been randomized. The current evaluation represents the first of three designed, statistically adjusted interim analyses of 710 patients randomized by the end of 2005 with a followup of at least 2 years. Analysis was according to intention to treat. 666 patients (545 with primary imatinib, 121 with primary IFN) were evaluable for hematologic, 621 for cytogenetic, and 631 for molecular responses. Median age was 53 years, 60% were male, median values were for Hb 12.5 g/dl, WBC 71.2/nl and platelets 384/nl, 35% had low, 53% intermediate and 12% high risk (Euro score). Median observation time was 3.5 years. Median duration of IFN pretreatment was & lt;4 months. At 1 year, the cumulative incidence of complete hematologic remission (CHR) was 82.3% and 74.4%, of major cytogenetic remission (MCR) 65.6% and 40.6%, of complete cytogenetic remission (CCR) 52% and 19.7%, and of major molecular remission (MMR) 33.2% and 4.7% for primary imatinib and IFN therapies, respectively. At 3 years, the cumulative incidence of CHR was 96.4% and 93.8%, of MCR 89.5% and 89.1%, of CCR 85.2% and 78.5%, and of MMR 79% and 63% for primary imatinib and IFN therapies, respectively. 5-year-survival probability of all patients currently exceeds 90% (94% for imatinib-, 91% for IFN-based therapy, Figure 1). Event free survival after two years (no progression, no death, CCR within the first 18 months, no loss of CHR or MCR) was 80.3%. 36 patients died, 51 patients were transplanted in first chronic phase, and 80 patients progressed, 43 of which were switched to alternative treatments (16 to new drugs, 18 to transplantation, 9 received both). Type and severity of adverse events (AE) did not significantly differ from those reported previously. Hematologic AEs (leukopenia, thrombocytopenia) were most frequent in the imatinib 800 mg arm. Nonhematologic AEs (gastrointestinal) were most frequent in the combination arms and with imatinib 800 mg. In no case recruitment had to be changed due to superiority or inferiority of any arm. This applies also to the high dose imatinib arm where earlier response might translate into better survival. In conclusion, this first interim analysis shows favorable survival and long term response rates. Imatinib in combination with, or after, IFN or with low dose araC are feasible and equally safe treatment alternatives. More definite information will be provided by the next interim evaluation after recruitment has been terminated. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.184.184
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
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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
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 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
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    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:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 8
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    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
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  • 9
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    Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV
    Springer Science and Business Media LLC ; 2014
    In:  Annals of Hematology Vol. 93, No. 1 ( 2014-1), p. 71-80
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 93, No. 1 ( 2014-1), p. 71-80
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-013-1937-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
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  • 10
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    Ten-year survival after randomized comparison of imatinib (IM) 400 mg vs. IM 800 mg vs. IM + IFN vs. IM + Ara C vs. IM after IFN in chronic myeloid leukemia (CML).
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 7049-7049
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 7049-7049
    Abstract: 7049 Background: It is unclear whether IM 400 mg is the optimum choice for the successful treatment of CML. Treatment optimization was therefore attempted. Methods: From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase (CP) were randomized into a 5-arm study to analyze 2 IM doses and 3 combinations. 1536 patients were evaluable, 400 for IM 400 mg, 420 for IM 800 mg, 430 for IM + Interferon (IFN), 158 for IM + Ara C and 128 for IM after IFN. Recruitment to the latter two arms was stopped after a pilot phase. Results: 10-year overall survival (OS) of all patients was 82%, 10-year progression free survival (PFS) 80%. 10-year OS was 80% with IM 400 mg, 79% with IM 800 mg, 84% with IM + IFN, 84% with IM + Ara C and 79% with IM after IFN. The differences were not significant. 10-year PFS was 80% with IM 400mg, 77% with IM 800mg, 83% with IM + IFN, 82% with IM + Ara C and 75% with IM after IFN. The differences were not significant either. Survival with any treatment was not significantly different from IM 400mg at any risk level by any risk score (Euro Sokal, EUTOS, ELTS). 87 patients progressed to blast crisis (BC). The 10-year cumulative incidence of BC was 5.8% (95% CI: 4.7%; 7.1%) equally distributed across treatment arms. Most BC occurred in the first 2 years. Median survival after BC was 7.9 months across treatment arms. 275 patients have died, 23 after stem cell transplantation in first CP. Two thirds of deaths were unrelated to CML. Incidence of death due to CML by competing risk analysis with death unrelated to CML as competing risk was not different between the 5-treatment arms. 10-year relative survival probability was 92% when compared to matched general population data. Patients reaching the cytogenetic or molecular response landmarks according to European LeukemiaNet criteria ( 〈 10% BCR-ABL IS at 3 months, 〈 1% BCR-ABL IS or complete cytogenetic remission at 6 months, 〈 0.1% BCR-ABL IS (MMR) at 12 months) had a significantly better survival than those not reaching the landmarks regardless of therapy. Conclusions: In conclusion, outcome of CML is currently more determined by prognostic markers than by choice of therapy. IM400 mg remains an excellent choice for initial therapy of CP-CML. Clinical trial information: NCT00055874.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.7049
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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