Abstract: Abstract 3411 Background: Dose of therapy and time to response may be different in the elderly as compared to younger patients with CML. This has been reported previously for interferon α (Berger et al., Leukemia 2003). For imatinib, contradictory results have been presented (Rosti et al. Haematologica 2007, Guliotta et al. Blood 2009). Aims: An analysis comparing dose-response relationship in patients more or less than 65 years (y) of age is warranted. Methods: We analysed the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, dose escalation and transplantation. Patients older and younger than 65y randomized to imatinib 400 mg (IM400) or 800 mg (IM800) were compared with regard to time to hematologic, cytogenetic and molecular remissions, imatinib dose, adverse events (AEs) and overall survival (OS). Results: From July 2002 to April 2009, 1311 patients with Ph+ CML in chronic phase were randomized, 623 patients were evaluable, 311 patients for treatment with IM400 and 312 for IM800. 84 (27%) and 66 (21%), respectively, were older than 65 years. All patients were evaluable for hematologic, 578 (140 〉 65y and 438 〈 65y) for cytogenetic, and 600 (143 and 457, respectively) for molecular responses. Median age was 70y vs. 49y for IM400 and 69y vs. 46y for IM800. The median dose per day was lower for elderly patients with IM800 (517mg vs. 666mg) and the same with IM400 (400mg each). Patients' characteristics at baseline were evenly distributed in all groups regarding gender, follow-up, hemoglobin, platelet count and spleen size. Leukocyte counts were significantly lower in elderly patients (IM400: 50/nl vs. 78/nl, IM800: 36/nl vs. 94/nl). EURO score was different due to age in elderly patients (low risk: IM400: 11% vs. 43%, IM800: 14% vs. 42%; intermediate risk: IM400: 79% vs. 44% and IM800: 73% and 43%). There was no difference in cytogenetic and molecular analyses between treatment groups. With regard to efficacy, there was no difference for older patients in achieving a complete cytogenetic remission (CCR) and major molecular remission (MMR) if IM400 and IM800 were compared together. If treatment groups were analyzed separately, older patients treated with IM400 reached CCR and MMR statistically significant slower than younger patients (CCR: median 14.2 months vs. 12.1 months, p=0.019; MMR: median 18.7 months vs. 17.5 months, p=0.006). There was no difference with IM800 (CCR: median 7.7 months vs. 8.9 months, MMR: median 9.9 months vs. 10.0 months). 3y-OS for older patients 〉 65y was 94.7% and for patients 〈 65y was 96.1%. Some differences were observed in the safety analyses. 530 patients (IM400: 278, IM800: 252) were evaluated on common toxicity criteria (WHO). Some hematologic AEs were documented slightly more often in the elderly than in the younger patients: for IM400 anemia grade 1–2 (60 vs. 42%) and leukopenia grade 3–4 (5.6 vs. 1.4%) and for IM800 anemia grade 1–4 (64 vs.47% and 7.2 vs. 5.7%) and thrombocytopenia grade 3–4 (9.3 vs. 7.1%). Non hematologic AEs were more prominent in IM800 and were mainly gastrointestinal symptoms (IM400: 33 vs. 31%, IM800: 48 and 44%) and edema (IM400: 28 vs. 29%, IM800: 35 vs. 50%). There was no difference for grade 3/4 non-hematological AEs in older patients in both groups. Conclusions: Imatinib 400 mg and 800 mg are well tolerated also in the elderly. The IM800 dosage was more tolerability-adapted for the elderly, but there was no difference in reaching a CCR and MMR in contrast to the IM400 where a significantly slower response was detected in the elderly. Whether this difference is clinically relevant has yet to be determined. Updated results will be presented. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

Abstract: Abstract 781FN2 Introduction: Data on second line therapy with second generation tyrosine kinase inhibitors (TKI) in CML treatment were generated mainly from phase II/III industry initiated trials (Review Hehlmann Exp Op. 2011). 24-month overall survival (OS) varies between 88% and 94% after intolerance and/or resistance to imatinib for chronic phase (CP) and between 67% and 72% for accelerated phase (AP) or blast crisis (BC). Intention to treat analyses including outcome of patients after discontinuation of first line therapies have not been available as yet. We thought to evaluate overall and progression-free survival (OS and PFS) of imatinib intolerant vs. resistant patients under second line TKI with long-term follow-up within an investigator initiated trial. Methods: We analyzed data of the German CML study IV, a randomized 5-arm trial to optimize imatinib therapy on an intention to treat basis. According to protocol, follow-up of patients on and after second generation TKI after imatinib intolerance and/or resistance was continued for OS and PFS. Analysis of PFS was only relevant, if intolerance and resistance to imatinib therapy occurred while a patient was still in chronic phase (CP). Patients were censored at the time of allogeneic stem cell transplantation (allo-SCT). Results: From July 2002 to December 2010, 1,502 patients with Philadelphia chromosome and /or BCR-ABL positive CML in CP were randomized. 129 patients of the “imatinib after interferon arm” and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1337 were randomized to primary imatinib treatment (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with either interferon alpha or araC). Of these, 234 (17%) discontinued imatinib therapy. 156 patients were treated with 2nd generation TKI, 61 were directly referred to allo-SCT, 17 patients received other regimens (including interferon alpha only or hydroxyurea). 120 of 156 patients started second generation TKI therapy (nilotinib, n=41, dasatinib, n=75, bosutinib, n=2, nilotinib and dasatinib, n=2) within 3 months after stopping imatinib, received treatment for at least one week and were evaluable for PFS and OS. 36 patients received second TKI later (median 10 months, range 3.5–61.4). Median age was 50 years (range 16–78), 42.5% were female. 48 patients were intolerant, 48 failed imatinib within CP and 24 after loss of CP (accelerated phase, n=10, blast crisis, n=14). Median time to second generation TKI was 17 months (range 1.4–97 months) and median follow-up after start of second-line TKI 31 months (range 0.2–71 months). Risk stratification according to the EUTOS Score was high in 20 patients (17%) and low in 94 patients (78%) and unknown in 6 patients (5%). OS for all 120 patients 3 years after start of second generation TKI was 73%, 96% for intolerant and 80% for resistant patients in CP and 19% for resistant patients in advanced disease (s. Fig. 1). According to EUTOS score, 3-year OS was 78% for low and 56% for high risk patients. Probability of PFS of the 96 patients in 1st CP after 3 years was 96% for intolerant and 76% for resistant patients. After 2nd generation TKI, 18 patients received an allo-SCT: all were in CP, 2 patients after imatinib intolerance, 16 patients after imatinib resistance. Conclusion: Survival on second generation TKI is high for imatinib intolerant patients in first CP but much lower for resistant patients in first CP or for patients with advanced disease phases. Alternative treatment strategies are warranted for these patient groups. Disclosures: Krause: Micromet: Research Funding. Kneba:Hoffmann La Roche: Honoraria. 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.

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: 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.

Abstract: Abstract 3746 Introduction: The increase of overall survival in chronic myeloid leukemia (CML) requires closer long-term observation in the face of a potential carcinogenicity of tyrosine kinase inhibitors (TKIs). Preclinical studies with imatinib in rats showed neoplastic changes in kidneys, urinary bladder, urethra, preputial and clitoral glands, small intestine, parathyroid glands, adrenal glands, and nonglandular stomach. Two epidemiologic studies on patients with chronic myeloproliferative neoplasms (CMPN) and CML (Frederiksen H et al., Blood 2011; Rebora P et al., Am J Epidemiol 2010) found an increased risk of secondary malignancies compared with the general population independent of treatment. In contrast, in a recent analysis of patients with CML and CMPN treated with TKI (Verma D et al., Blood 2011) a decreased risk of secondary malignancies was reported. Aims: To further elucidate the risk of TKI treated CML patients for the development of secondary malignancies we analysed data of the CML study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib 400 mg in combination with interferon alpha vs. imatinib 400 mg in combination with AraC vs. imatinib 400 mg after interferon failure). Patients and methods: From February 2002 to April 2012, 1551 CML patients in chronic phase were randomized, 1525 were evaluable. Inclusion criteria allowed the history of primary cancer if the disease was in stable remission. Forty-nine malignancies were reported in 43 patients before the diagnosis of CML. If relapses occurred within 5 years after diagnosis of primary cancer they were not considered for further analysis. Median follow-up was 67.5 months. Age-standardized incidence rates were calculated from the age-specific rates using the European standard population (1976). Results: In total, 67 secondary malignancies in 64 patients were found in CML patients treated with TKI (n=61) and interferon alpha only (n=3). Twelve of these patients developed neoplasms after diagnosis of a primary cancer before diagnosis of CML, 5 patients with metastases or recurrence of the first malignancy (range of diagnosis 5–19 years after primary cancer). Median time to secondary malignancy was 2.5 years (range 0.1–8.3 years). The types of neoplasms were: prostate (n=9), colorectal (n=6), lung (n=6), non Hodgkin's lymphoma (NHL; n=7), malignant melanoma (n=5), skin tumors (basalioma n=4 and squamous cell carcinoma n=1), breast (n=5), pancreas (n=4), kidney (n=4), chronic lymphocytic leukemia (n=3), head and neck (n=2), biliary (n=2), sarcoma (n=2), and esophagus, stomach, liver, vulva, uterus, brain, cancer of unknown origin (each n=1). With these numbers the age-standardized incidence rates of secondary malignancies in CML patients were calculated: 534 cases per 100,000 for men (confidence interval [350;718]), and 582 for women (confidence interval [349;817] ). The incidence rates of the general population in Germany were 450 and 350 cases, respectively (“Krebs in Deutschland 2007/2008”, 8th ed., Robert Koch Institute, 2012). The incidence rate of NHLs was higher for CML patients than for the general population but this is not significant. Conclusions: In our cohort, the incidence rate of secondary neoplasms in CML patients was slightly increased compared to the general population. The most common secondary malignancies in CML patients under treatment were cancers of the skin, prostate, colon, lung and NHL. Since the occurrence of secondary neoplasia increases over time, long-term follow-up of CML patients is warranted. Disclosures: Müller: Novartis, BMS: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Hehlmann:Novartis: Research Funding.

Abstract: Abstract 67 Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival. 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 IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes. After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800. Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population. We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML. Disclosures: Hehlmann: Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding.

Abstract: Abstract 1681 Introduction: The prognostic impact of different levels of molecular remission (BCR-ABL transcript expression according to International Scale, IS) at various time points on survival under imatinib treatment is still unclear. Whereas recently published data from the IRIS trial described relevant milestones at 6, 12, and 18 months for event-free and progression-free survival (PFS; Hughes et al., Blood 2010), little is known about an association of molecular response with overall survival (OS). The aim of this evaluation of the German CML Study IV was to elucidate the risk of disease progression and death as a function of the depth of molecular response in order to provide guidance in the interpretation of BCR-ABL levels in the clinical setting. Methods: 1,340 patients (median age 52 years, range 16–88, 60% male) were recruited into the randomized German CML Study IV and treated with an imatinib-based therapy as follows: imatinib 400 mg/d, n=381; imatinib 800 mg/d, n=399; imatinib 400 mg/d + interferon alpha, n=402; imatinib 400 mg/d + low-dose cytarabine, n=158. A total of 1,262 patients with typical b2a2 and b3a2 BCR-ABL transcripts were evaluable. Molecular responses were assessed in 811, 764, 671, and 619 patients at 6, 12, 18, and 24 months, respectively. Disease progression was defined as accelerated phase or blastic phase, or death from any reason. Landmark analyses and log-rank tests for OS and PFS were performed according to the achievement of different BCR-ABL response levels at different time points. Results: Patients were grouped according to the degree of molecular response ( 〈 0.1%, 0.1%-1%, 1%-10%, 〉 10% BCR-ABL IS) at each of the 4 time points and evaluated for 5-year OS and PFS. Estimated 5-year OS for the different molecular response categories was: 97% vs 96% vs 90% vs 88% (6 months, p=0.009); 96% vs 95% vs 89% vs 69% (12 months, p 〈 0.001); 98% vs 97% vs 92% vs 66% (18 months, p 〈 0.001); 97% vs 96% vs 96% vs 68% (24 months, p 〈 0.001). Applying the 4 response categories revealed estimated 5-year PFS of 97% vs 96% vs 91% vs 86% (p=0.004) at 6 months, 97% vs 92% vs 89% vs 72% (p 〈 0.001) at 12 months, 99% vs 95% vs 90% vs 77% (p 〈 0.001) at 18 months, and 97% vs 97% vs 93% vs 65% (p 〈 0.001) at 24 months (s. Table). Conclusions: Faster and deeper response to imatinib-based treatment revealed to be associated with improved overall and progression-free survival. Inferior OS and PFS can be deducted from the synopsis of BCR-ABL expression and treatment duration, e.g. 〉 1% BCR-ABL IS at 6 months or 12 months might be, and 〉 10% BCR-ABL IS should be a trigger for a treatment change. Thereby this analysis might provide decision guidance for alteration or continuation of primary imatinib treatment. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. German CML Study Group:EU: Research Funding; BMBF: Research Funding; Novartis: Research Funding; Deutsche Krebshilfe: Research Funding; Roche: Research Funding; Essex: Research Funding.