Abstract: Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the balanced reciprocal translocation t(9;22)(q34;q11) or the variant translocation t(v;22) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show ACA already at diagnosis and more than 80% of patients acquire ACA during the transformation process into BC. Therefore, alterations at diagnosis as well as acquisition of chromosomal changes during treatment are considered as a poor prognostic factor. Differences in progression-free survival (PFS) and overall survival (OS) have been detected depending on the type of ACA. Patients with major route ACA (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and with other alterations like -X, del(1)(q21), del(5)(q11q14), +10, -21 at diagnosis resulting in an unbalanced karyotype have a worse outcome. Patients with minor route ACA (for example reciprocal translocations other than the t(9;22)(q34;q11) (e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20)) resulting in a balanced karyotype show no differences in OS and PFS compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). Here we compare the type of chromosomal changes (i.e. balanced vs. unbalanced karyotypes) during the course of the disease from CP to BC aiming to provide a valid parameter for future risk stratification. Patients and Methods Clinical and cytogenetic data available from 1,346 out of 1,524 patients at diagnosis (40% females vs. 60% males; median age 53 years (range, 16-88)) with Philadelphia and BCR-ABL positive CP CML included until March 2012 in the German CML-Study IV (a randomized 5-arm trial to optimize imatinib therapy) were investigated. ACA were comparatively analyzed in CP and in BC. Results At diagnosis 1,174/1,346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). Ninety-seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had ACA. Regarding the patients with ACA thirty-six of the 53 patients (68%) had an unbalanced karyotype and 17/53 patients (32%) a balanced karyotype. During the course of the disease 73 patients (out of 1,524 patients) developed a BC during the observation time (5%). Cytogenetic data were available in 52 patients with BC (21 patients with BC had no cytogenetic analysis). Three patients had a normal male or female karyotype after stem cell transplantation. Nine patients showed the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) (six and three patients, respectively) only and in 40 patients ACA could be observed in BC (40/49 (82%)). Out of these 40 patients with ACA, 90% showed an unbalanced karyotype whereas only 10% of patients had a balanced karyotype. No male patient in BC showed the loss of the Y chromosome pointing to a minor effect of this numerical alteration on disease progression. Conclusion We conclude that patients with CML and unbalanced karyotype at diagnosis are under higher risk to develop CML BC compared to patients with balanced karyotypes or compared to patients without ACA. In BC, 90% of CML patients showed unbalanced karyotypes (only 68% of CML patients at diagnosis have unbalanced karyotypes) supporting the hypothesis that the imbalance of chromosomal material is a hallmark of disease progression, representing the natural history of the disease from CP to BC and indicating therefore a strong prognostic impact. Consequently, different therapeutic options (such as intensive therapy or stem cell transplantation) should be considered for patients with unbalanced karyotypes in CP CML at diagnosis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer : Consultancy, Honoraria; Ariad : Consultancy, Honoraria. Müller:Ariad: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other.

Abstract: Background Five-year overall survival (OS) of chronic myeloid leukemia (CML) patients treated with imatinib exceeds 90%. With many tyrosine kinase inhibitors (TKI) available as treatment options for CML, the influence of TKI therapy on OS is difficult to define. Comorbidities can complicate randomized trials. Their influence on OS in CML has not been studied so far. Aims We sought to evaluate the influence of comorbidities at diagnosis of CML on remission rates and OS of patients with Philadelphia and/or BCR-ABL positive chronic-phase CML. The CML-Study IV, a randomized five-arm trial designed to optimize imatinib therapy alone or in combination, used very few exclusion criteria as compared to other studies which typically excluded patients with severe illnesses. Methods The age-adjusted Charlson Comorbidity Index (CCI) is the most extensively studied comorbidity index (Charlson ME et al., 1987) and has been validated for long-term studies. The score weighs a) the severity of comorbidities (e.g. one point is allocated to myocardial infarction and diabetes, two points to non-active malignancies) and b) the age of patients (with one point for each decade above 40 years). The CCI at diagnosis was calculated for each randomized patient. For the analyses, patients were grouped into CCI 2, 3-4, 5-6, and ≥7. Performance status was measured by the Karnofsky Score (KS) and patients were grouped into 50-80, 〉 80- 〈 100, and 100. Correlation analyses were performed by the chi-square test. Survival probabilities were calculated by Kaplan-Meier curves. Calculating cumulative incidences, the competing risks progression and/or death were considered. Cox models were estimated for the multivariate analysis to analyse the prognostic influence of the candidate factors age, sex, leukocytes, hemoglobin, EUTOS score, KS, and CCI on OS. Results 1551 patients were randomized from 2002 to 2012, 1524 patients were evaluable. Median follow-up time was 67.5 months. Additional to CML, 521 index comorbidities were reported in 1519 patients resulting in the following CCI groups: i) CCI 2: 589 patients, ii) CCI 3 or 4: 599 patients, iii) CCI 5 or 6: 229 patients, and iv) CCI ≥ 7: 102 patients. Median value of the CCI was 3 (range: 2-12). The distribution of the CCI groups was not different between treatment arms. Most common comorbidities were diabetes (n=106), non-active cancer (n=102), chronic pulmonary disease (n=74), renal insufficiency (n=47), myocardial infarction (n=38), cerebrovascular disease (n=29), congestive heart failure (n=28), and peripheral vascular disease (n=28). Between patients with CCI 2, 3-4, 5-6, and ≥7 no significant differences in remission rates were found neither for time to complete cytogenetic remission (CCR) nor for time to major molecular remission (MMR). Median times to CCR were 12.9, 12.6, 13.7, and 13.1 months and to MMR 17.5, 15.9, 16.5, and 18.1 months, respectively. No differences were observed between the CCI groups for the cumulative incidences of progression. As expected, significant differences in OS according to CCI at diagnosis were observed (s. Fig. 1, p 〈 0.001). Probabilities of OS at 8 years for patients with CCI 2, 3-4, 5-6, and ≥7 were 93.6%, 89.4%, 78.7%, and 45.2%. We found a correlation between CCI and KS (p 〈 0.001). In multivariate analysis CCI (p 〈 0.001), KS (p=0.022), and EUTOS Score (p=0.012) were significant predictors of OS. Hazard ratios for the CCI group 3-4, 5-6, 〉 7 (each vs. 2), were 1.695 (95%-confidence interval, CI 1.066-2.695), 3.231 (CI 1.942-5.376) and 6.495 (CI 3.817-11.111), respectively. Separating the CCI into an age-related part and a comorbidity-related part, the comorbidity-related part was still an important risk factor (Wald test, p=0.002). Conclusions Comorbidities of CML-patients do not seem to have an impact on the success of imatinib treatment. In CML-Study IV, even patients with a considerable comorbidity benefitted from imatinib as the chances to achieve MMR and CCR did not differ from those of healthier CML-patients. Our data also indicate that OS alone is not any more an appropriate measure for the effectiveness of a specific treatment for CML, as TKI have reduced the CML-related lethality to too low levels. Adjusting for comorbidity is essential for a valid comparison and interpretation of OS observed with different TKIs in CML-patients. Disclosures: Saussele: Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Ariad: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract: In acute leukemias, specific cytogenetic aberrations frequently correlate with myeloid or lymphoid phenotype of blasts and influence risk stratification. In chronic myeloid leukemia (CML) blast crisis (BC) it is not clear whether myeloid or lymphoid phenotype of blasts could be distinguished by specific chromosomal aberrations and have prognostic value. At diagnosis of CML, major route additional cytogenetic aberrations (ACA) like +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) and minor route ACA like -X, del(1)(q21), del(5)(q11q14), +10,-21, resulting in an unbalanced karyotype have been described to adversely affect outcome. Patients with minor route ACA (for example reciprocal translocations other than the t(9;22)(q34;q11) (e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20)) resulting in a balanced karyotype did not show differences in overall survival and progression free survival compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome. Aim of this study was to analyze the impact of the phenotype (myeloid or lymphoid) on time to BC and on cytogenetic pattern. Methods 73 out of 1524 evaluable patients (4.8%) randomized until March 2012 to the German CML-Study IV (a 5-arm trial to optimize imatinib therapy) progressed to BC. Cytogenetic data of 23 out of 32 patients with myeloid BC and 14 out of 21 patients with lymphoid BC were available. In 15 patients, cytogenetic analysis were missing whereas 2 and 3 patients had megakaryoblastic and mixed phenotype, respectively and were not considered in this analysis. Karyotypes of lymphoid and myeloid BC were divided in major route and minor route ACA and balanced and unbalanced karyotypes. Categorical covariates were compared with Fisher’s exact test, while continuous covariates were compared with the Mann-Whitney-Wilcoxon test. Survival probabilities after BC were compared using the log-rank test. Results Out of 23 patients with myeloid BC, 14 (61%) had major route unbalanced ACA (n=10) or minor route unbalanced ACA (n=4), 4 had minor route balanced ACA and 5 patients had the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) without ACA.13 out of 14 (93%) patients with lymphoid BC had major route unbalanced (n=10) or minor route unbalanced ACA (n=3) and 1 had the standard translocation t(9;22)(q34;q11) only. Between myeloid and lymphoid BC, the difference in the distribution of unbalanced ACA was apparent, but not statistically significant (p=0.06). The most frequently observed major route ACA was trisomy 8 in both groups (7 vs. 6), +der (22)t(9;22)(q34;q11) was more frequently found in myeloid than lymphoid BC (6 vs. 2), +19 was found in both phenotypes (3 vs. 3) whereas an isochromosome i(17)(q10) and an isoderivative chromosome ider(22)t(9;22)(q34;q11) were less frequent and found only in myeloid BC (1 for each vs 0 for each aberration). In lymphoid BC, 5 of 14 patients (36%) had ACA which involved chromosome 7 (del(7)(q22) and -7) whereas in myeloid BC only 2 patients (9%) had -7 (p=0.08). The balanced karyotype with a translocation t(3;21)(q26;q22) and the translocation t(9;11)(p22;q23) described in acute myeloid leukemia was observed in 3 patients with myeloid CML (2 and 1, respectively) and in none with lymphoid phenotype. No differences were observed in time to BC for patients with lymphoid vs. myeloid BC (p=0.31, median time: 409 vs. 453 days) and survival after onset of BC (p=0.9, median time: 544 vs. 284 days). Conclusions The proportion of unbalanced karyotypes was higher in lymphoid than in myeloid BC. In lymphoid BC alterations of chromosome 7 were more often present whereas +der(22)t(9;22)(q34;q11) was observed more frequently in myeloid BC. The reciprocal translocations t(3;21)(q26;q22) and t(9;11)(p22;q23) described in acute myeloid leukemias were only observed in myeloid BC. However these cytogenetic differences do not seem to alter the course of BC. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other.

Abstract: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. Their efficacy leads to normal life expectancy in the vast majority of patients. With the advent of 2nd generation TKI and the now available choice of drugs, safety issues have gained interest. We have used the randomized CML-Study IV for a long-term safety evaluation of imatinib. Study and Patients CML-Study IV comprises 1551 patients randomized to 5 treatment arms with 3 imatinib-based combinations and 2 different imatinib-dose schedules. 1501 patients have received imatinib and were evaluable. Median age at diagnosis was 53 years, 88% were EUTOS low risk. At the last evaluation (04/11/2013) 1003 patients still received imatinib, 164 had died, 275 were switched to a 2nd generation TKI, 106 were transplanted. The longest observation time was 11.5 years, the median observation time was 6.5 years, with a 10-year survival probability of 84 %. The median time to imatinib discontinuation has not been reached after 10.2 years. 80 patients are under observation for more than 10 years, 18 of these have discontinued imatinib. Out of the 1501 patients that had received imatinib, 1375 patients received imatinib as first-line treatment and had a sufficient documentation of treatment. Methods AE were reported at each follow-up visit. The CTC AE list of the NCI was used for coding of AE and severity grading. Additionally, for detection of hematologic AE lab results were screened for deviations from reference ranges. The AE were analyzed according to the “as treated” principle, using Kaplan-Meier curves (virtually no competing risks, almost all patients died after end of imatinib treatment). Only the first event of the respective type was considered. All analyses started at the first day of imatinib treatment and were censored when the patient discontinued imatinib, received another treatment or died. To assess the differences between men and women, Cox models were estimated. Results In 1137 out of 1375 patients (83%) non-hematologic AE (5160 singular events) were reported during imatinib treatment (all grades), in 322 grade 3/4 AE (23%) (645 singular events). At 3 years, probability of a non-hematologic AE (any grade) was already 76% (95%-CI: 73-79%), at 6 years 85% (95%-CI: 82-88%) and at 8 years 91% (Fig.1). The probability of grade 3/4 non-haematologic AE was 38% (95%-CI: 34-42%) at 6 years and 43% (CI: 37-48%) at 8 years. 156 patients reported hematologic grade 3/4 AE (187 singular events).The probability of hematologic grade 3/4 AE was 17% at 6 years (95%-CI: 15-21%) with most events observed during the first year of treatment (probability after one year 10.5%). The most frequently reported non-hematologic AE (all grades, any time) were gastrointestinal (6-year-probability 52%, 95%-CI: 48-56%), fluid overload or edema (6y-prob. 45%, 95%-CI: 40-49%), rash (6y-prob. 32%, 95%-CI: 28-36%), myalgia or arthralgia (6y-prob. 30%, 95%-CI: 27-34%), fatigue (6y-prob. 26%, 95%-CI: 22-29%), flu-like symptoms (6y-prob. 22%, 95%-CI: 19-26%), infections (6y-prob. 24%, 95%-CI: 20-28%) and neurological symptoms (6y-prob. 26%, 95%-CI: 22-29%). AE probability profiles over time have been generated for each AE (Figs. 2-3). For women the risk for non-hematologic events was increased 1.35-fold (95% CI: 1.18-1.55) for all grades (Figs. 1-3) and 1.13-fold (95% CI: 0.91-1.41) for grade 3/4, and 1.26-fold (95% CI: 0.91-1.71) for grade 3/4 hematologic AE. In 5 patients peripheral arterial occlusive disease grade 2 or 3 was reported, but none could be clearly assigned to imatinib (vascular risk profile of one patient incompletely reported). A definite association between any AE and death was not found. Conclusion As AE by definition may or may not be considered related to the medical treatment an exact assessment of the safety of imatinib is difficult. Most AE were recorded during the first three years with decreasing frequency later on. The increased AE risk in women was mostly grade 1/2 and is commonly seen also in other treatment areas. Given that no imatinib-related death was recorded and that grade 3/4 AE could typically be properly treated we consider imatinib as a safe, comparably well tolerated TKI even after prolonged treatment. After 10 years imatinib continues to be an excellent choice for the treatment of CML in most patients. Disclosures: Hehlmann: Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.

Abstract: The outcome of elderly patients with chronic myeloid leukemia (CML) treated with imatinib has been studied in several trials. However, there are no reports on the effects of different imatinib dosages in older vs. younger CML patients. Methods To evaluate the efficacy of imatinib in the elderly, we analyzed data from the German CML-Study IV, a randomized 5-arm trial designed to optimize imatinib therapy alone or in combination. There was no upper age limit for inclusion. Patients with BCR-ABL positive CML in chronic phase randomized to imatinib 400 mg/d (IM400) or imatinib 800 mg/d (IM800) were compared, stratified according to median age at diagnosis in western populations ≥ 65 years vs. 〈 65 years, regarding effectively administered imatinib dose, time to hematologic, cytogenetic and molecular remissions, adverse events (AEs), rates of progression to accelerated phase (AP) and blast crisis (BC), survival, and causes of death. The full 800 mg dose was given after a 6 weeks run-in period with imatinib 400 mg/d to avoid excessive cytopenias. The dose could then be reduced according to tolerability for maximum patients' compliance. Results From July 2002 through March 2012, 1,551 patients were randomized, 828 of these to IM400 or IM800. Median age of these patients was 52 years (IM400: 53 years; IM800: 51 years). 784 patients were evaluable for follow-up (IM400: 382; IM800: 402). 193 patients were ≥ 65 years, 591 〈 65 years. 110 patients (29%) on IM400 and 83 (21%) on IM800 were ≥ 65 years. Median observation time on IM400 was 63.0 months in the elderly and 67.6 months in the younger group, on IM800 50.9 months in the elderly and 50.1 months in the younger group. The median dose per day was lower for elderly patients on IM800 (421 mg/d for patients ≥ 65 years vs. 556 mg/d for patients 〈 65 years), with the highest median dose in the first year (466mg/d for patients ≥ 65 years vs. 630mg/d for patients 〈 65 years). The median dose for patients on IM400 was 400 mg/d for both age groups. There was no difference between age groups in achieving a complete hematologic remission or a complete cytogenetic remission, neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Elderly patients on IM400 achieved major molecular remission (MMR) and deep molecular remission (MR4) significantly later than younger patients (18.1 vs. 15.9 months, p=0.013; 54.4 vs. 33.3 months, p=0.012, respectively) whereas no difference was detected for patients on IM800 (11.9 vs. 10.5 months; 24.2 vs. 26.1 months, respectively). Imatinib was well tolerated in elderly patients with only few WHO grade 3-4 AEs being more frequent in the elderly than in younger patients (dermatologic AEs on IM400: 5.4 vs. 0.4%; infections on IM800: 8.3 vs. 2.5%). There were no significant differences between age groups in probabilities of progression to AP or BC neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Five-year age-adjusted relative survival for elderly patients was comparable to that of younger patients. Conclusion We could demonstrate that elderly patients achieved molecular remissions significantly later when treated with standard dose imatinib but not when treated with higher imatinib dosages. As the safety profile of IM800 in senior patients was favorable too we conclude, that the optimal dose for elderly patients could be higher than 400 mg/d. Disclosures: Müller: Ariad: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Consultancy; ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.

Abstract: The impact of the type of therapy on cytogenetic evolution in chronic myeloid leukemia (CML) regarding the occurrence of additional cytogenetic aberrations (ACA) at the time point of blast crisis (BC) may be critical. The aim of this analysis was to elucidate whether patients (pts) treated with imatinib (IM) had ACA less frequently than pts treated with BU and other therapies used prior to IM as hydroxyurea (HU) and interferon alpha (IFN). We comparatively analyze the BC karyotype of CML pts treated in consecutive trials of the German CML Study Group (Studies I, II and IV) to answer the following question: Does CML therapy influence the occurrence or even induce ACA or do these alterations rather reflect the natural history and the biology of the disease and are independent of therapy? Materials and methods Cytogenetic data of 157 pts with Philadelphia chromosome and BCR-ABL positive CML in BC were analyzed from a total of 2,380 pts randomized to CML study I (BU vs. HU vs. IFN, recruitment 1983 – 1991), CML study II (IFN + HU vs. HU, recruitment 1991 – 1994), and CML study IV (IM 400 mg vs. IM 800 mg vs. IM 400 mg +IFN vs. IM 400 mg + AraC vs. IM 400 mg after IFN failure recruitment 2002 – 2012). Cytogenetic analysis was reported according to ISCN 2005. ACA were divided into major route (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and minor route alterations (reciprocal translocations other than the t(9;22)(q34;q11), e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20) (Fabarius et al., Blood 2011). Confirmatory testing of pairwise comparisons of therapies with regard to their frequency of major ACAs was performed using two-sided chi-square test. To keep the level of significance at 0.05 despite multiple testing, a priori hypotheses were hierarchically ordered: First, frequency of major route ACA of pts on IM was compared with that on BU, then, with HU and with IFN. Next, the comparisons of IFN vs. BU and IFN vs. HU were planned. Cumulative incidences were estimated under consideration of death before BC as a competing risk. Results 115 of 188 pts randomized to BU (CML study I), 117 of 194 pts randomized to HU (CML study I only) and 159 of 360 randomized to IFN-based therapy (CML studies I+II) progressed to BC. Eight-year cumulative incidence probability of BC was 0.63 [95%-confidence interval (CI): 0.56; 0.69], 0.60 [95%-CI: 0.53; 0.66] , and 0.49 [95%-CI: 0.43; 0.54] in pts randomized to BU, HU, and IFN-based therapy, respectively and 0.06 [95%-CI: 0.04; 0.07] in pts on IM (CML-study IV). Three-year survival probabilities after BC were 0.009 [95%-CI: 0.001; 0.043] with BU, 0.017 [95%-CI: 0.003; 0.055] with HU, 0.013 [95%-CI: 0.003; 0.042] with IFN, and 0.252 [95%-CI: 0.157; 0.368] with IM. Cytogenetic data at BC with banding analysis were available from 21 pts on BU, 31 on HU, 56 on IFN and 49 on IM. 81% of pts treated with BU, 52% with HU, 38% with IFN and 55% with IM showed major route ACA. All other pts had minor route ACA or translocation t(9;22)(q34;q11) and variant translocation (t(v;22)) without ACA (Table 1). The difference in major route ACA between BU and IM was significant (p = 0.04, two-sided chi-square test). There was no statistically significant difference in ACA between pts on HU and IFN in comparison to IM. According to the testing order, further comparative testing was not possible. However, the differences of induction of major route ACA between HU and BU and IFN and BU were even more pronounced than the difference between IM and BU. The most frequently observed major route ACA was trisomy 8 in all studies and therapy arms. Conclusions The type of cytogenetic aberrations in CML BC after different therapies is comparable. The characteristic major route ACA after various therapies points to a CML BC-related chromosomal pattern rather than a therapy-induced effect. Pts treated with IM showed a significantly lower rate of major route ACA than BU. IM not only reduces the frequency of BC and increases survival probabilities but appears to moderately change the biology of BC as compared to BU Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Kolb:Pierre Fabre, Therakos: Honoraria; Kolb Consulting UG: Consultancy, Equity Ownership. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.

Abstract: Background: In the current ELN recommendations (Baccarani et al., Blood 2013) the optimal time point to achieve major molecular remission (MMR) is defined at 12 months after diagnosis of CML. MMR is not a failure criterion at any time point leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. Aims: We sought to evaluate a failure time point for MMR using data of the CML-Study IV, a randomized five-arm trial designed to optimize imatinib therapy alone or in combination. In addition the optimal time-point to achieve a MMR should be evaluated. Methods: Patients with valid molecular analysis on MR4 level were divided randomly into a learning (LS) and a validation sample (VS). For the LS, MR2 (defined as BCR-ABL 〈 1% which corresponds to complete cytogenetic remission (Lauseker et al. 2014)), MMR and deep molecular remission levels (MR4 or deeper) monthly landmarks were defined between one and five years after diagnosis. A patient was considered to be in MR2, MMR or MR4 from the first diagnosis of the corresponding remission level and could only change to a higher level of response. Patients were censored after SCT. The best prediction time was found via dynamic prediction by landmarking (van Houwelingen, Scand J Stat 2007). For the failure time point analysis, for each of the resulting 48 landmarks, a Cox model was used to define the time to progression with age and EUTOS score as additional prognostic factors. Additionally, the regression coefficients of the model of one landmark were converted to hazard ratios (HR) and treated as dependent on the HRs of the other landmarks, using a cubic smoothing function (see Fig 1). The minimum of this function was considered to be the optimal landmark point for the prediction of progression-free survival (PFS). For the calculated time point, landmark analysis for probability of PFS (defined as appearance of accelerated phase, blast crisis or death) was performed in the VS. For the evaluation of the optimal time point of achieving a MMR the same analysis was done from 0.25 to 5 years to define the time to MR4 or deeper. Results: 1551 patients were randomized from 2002 to 2012, 1358 had a valid molecular analysis on the MR4 level. 114 patients in the imatinib after IFN arm and 16 patients with missing EUTOS score were excluded. Of the 1228 evaluable patients two thirds were randomly allocated to the LS (n=818) and one third to the VS (n=410). Percentage of patients of the LS in MR2, MMR and MR4 or deeper at one year was 28%, 29% and 14%, and at 5 years 5%, 21% and 71%, respectively. Monthly time points in between were also calculated. 44 patients of the LS reached MMR on second generation tyrosine kinase inhibitors.. The minimum of the cubic function of the HRs was found for MMR at 2.34 years with a HR of 0.25 (compared to patients without any remission) and 0.75 compared to those in MR2. For MR4 or deeper no exact time point could be calculated (see Fig. 1), although it was shown that the risk of progression was slightly lower for MR4 than for MMR. Since the time interval for molecular evaluation in the study is 3 months, the validation was done with 2.25 instead of 2.34 years. 364 of the 410 of the VS were still at risk at this time point and evaluable. A significant PFS advantage for patients in MMR could be demonstrated (p=0.018). At 8 years, the probability of PFS for patients in MMR was 90.8% (confidence interval 87.0-93.7%) vs. 80.5% (confidence interval 70.2-88.6%) for patients not in MMR (see Fig 2). For the optimal MMR analysis no singular time point could be calculated as the earlier a MMR was reached the higher was the chance to achieve a MR4. Conclusions: In this model, an optimal time point to predict PFS in patients with MMR was defined at 2.25 years after diagnosis and could be validated as significant. Nevertheless, patients being in MMR had a lower risk of progression than patients not being in MMR on any other time point as well. With this model we can give hints when to define MMR as failure and a change in therapy should be considered. Despite this we should keep in mind that the earlier MMR was achieved the higher was the chance to achieve deep molecular response later during therapy. Figure 1 Cubic smoothing function of the HR to predict PFS with confidence intervals Figure 1. Cubic smoothing function of the HR to predict PFS with confidence intervals Figure 2 Landmark analysis at 2.25 years for PFS of the VS Figure 2. Landmark analysis at 2.25 years for PFS of the VS Disclosures Saussele: Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Hehlmann:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.