ALBERT

Description: Abstract 783FN2 Introduction: The advent of second generation tyrosine kinase inhibitors (TKI) in the front line treatment setting of chronic myeloid leukemia (CML) has tightened the evaluation of imatinib response. Early assessment of response markers might identify slow responders harboring a BCR-ABL positive clone with an inferior susceptibility to tyrosine kinase inhibition. This group of patients could benefit from an early dose escalation or a change of treatment to a second generation TKI thus avoiding the risk of disease progression. Therefore we sought to evaluate the impact of molecular and cytogenetic response levels after 3 months of imatinib treatment on the further course of disease. Patients and methods: A total of 1,340 patients (median age 52 years, range 16–88, 40% female) were included into the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg/d (n=381), imatinib 800 mg/d (n=399) and combinations of standard dose imatinib with interferon alpha (n=402) and low-dose cytarabine (n=158). Median follow-up was 4.7 years (range 0–9). Molecular response after 3 months was assessed in 743 patients, cytogenetic response in 498 patients. The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABL IS). Only patients expressing typical BCR-ABL transcripts (b2a2, b3a2, b2a2 and b3a2) were considered. Cytogenetic response was determined by conventional metaphase analysis. 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). Results: Disease progression was observed in 149 patients (11.1%), 127 patients died (9.5%). After 3 months of treatment the median BCR-ABL IS was 2.6% (0-100), the median proportion of Philadelphia chromosome positive metaphases (Ph+) was 8% (0-100). The BCR-ABL landmarks of 1% and 10% after 3 months of imatinib both proved to discriminate significantly for PFS and OS: BCR-ABL IS 65% (n=84), p=0.004 for PFS and p=0.011 for OS. A 3 group stratification did not reach statistical significance. Conclusions: The achievement of molecular and cytogenetic response landmarks after 3 months of imatinib treatment is predictive for long term progression free and overall survival. At 3 months a BCR-ABL IS of 10% or more is associated with a 5-year overall survival of 87% suggesting an early change of treatment, whereas a BCR-ABL IS of 1% or less indicates a favorable 5-year overall survival of 97%. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

Description: Introduction 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.

Description: Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of

Description: 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

Description: 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

Description: Abstract 355 Introduction: The prognostic relevance of variant t(9;22) and additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) is conflicting. Patients and Method: We used baseline and outcome data of 1028 patients (607 male, 421 female, median age 53, range 16–88) with chronic phase CML randomized to the German CML-Study IV (imatinib [IM] 800 mg [n=264] vs IM 400 mg [n=253] vs IM 400 mg + IFN [n=281] vs IM 400 mg after IFN failure [n=108] vs IM 400 mg + AraC [n=122]) to investigate the impact of variant t(9;22) and of clonal ACA at diagnosis on time to complete cytogenetic remission (CCyR) and major molecular response (MMR), accepted markers of prognosis. Cytogenetic analysis was performed after 24- and/or 48 h culture on G-banded metaphases. If appropriate, fluorescent-in-situ-hybridization on metaphases was used in addition. Since lack of the Y chromosome is regarded as a negligible age-related, not leukemia-associated event, those patients were excluded from evaluation. Result: In total, 123/1028 patients (12%) showed additional cytogenetic findings at diagnosis: 52/1028 patients (5.1%) had variants of the t(9;22), 33/1028 patients (3.2%) lacked the Y chromosome, 38/1028 patients (3.7%) had other additional numerical or structural aberrations. 105/1028 patients (10.2%) had only one type of additional cytogenetic finding, while 18/1028 patients (1.8%) showed ≥ 2 types of additional cytogenetic findings. 905/1028 patients (88%) had no variant t(9;22) or ACA. Median age, sex and treatment were similarly distributed (Table 1). In 45/52 patients (86.5%) with variant t(9;22), one further chromosome was involved (three way translocation), whereas in 7/52 patients (13.5%) ≥ 2 chromosomes were involved (complex variant). No involvement of the chromosomes 10, 18, 20, 21, X, or Y has been found. For patients without variant t(9;22) and ACA, with variant t(9;22), with variant t(9;22) and ACA other than –Y, and with ACA other than -Y and variant t(9;22), median time (years) to CCyR was 0.98, 0.84, 1.08 and 1.34, median time (years) to MMR was 1.4, 1.55, 1.8 and 2.17, and probability (%, confidence interval) for 2 years overall survival was 0.97 (0.96-0.98), 0.96 (0.89-0.99), 0.95 (0.90-0.99) and 0.94 (0.85-0.99), respectively. There was no difference regarding time to CCyR, time to major molecular response (MMR) and 2 years overall survival between patients with variant t(9;22) or ACA compared to those without variant t(9;22) or ACA. Conclusion: We conclude that additional chromosomal abnormalities at diagnosis have no negative prognostic impact. This finding is hypothesis generating. For confirmation of this hypothesis longer observation of the course of patients with variant t(9;22) and ACA is needed. Disclosure: 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.

Description: Introduction: With many treatment options for chronic myeloid leukemia (CML), endpoints like health-related quality of life (HRQoL) move into focus and might be essential for deciding on treatment strategies. We sought to evaluate HRQoL in CML patients who had been registered in four consecutive studies of the German CML study group. Methods: The EORTC QLQ-C30 questionnaire was used to assess HRQoL of CML patients. Functional scales and global health status were calculated in accordance with Aaronson (1993) and Fayers (2001). With scales ranging from 0 to 100, 8 points are regarded as a minimally important difference (Efficace et al., 2013). Baseline data of responders (R) and non-responders (NR) were compared. Associations between two variables were assessed by the Fisher or Mann-Whitney tests, as appropriate. The global health status and the functioning scores were compared between groups with the van Elteren test, if the groups were stratified for another variable. Furthermore, results of the global health status and the functioning scores in our sample were standardized in accordance with the age (18-29, 30-39, 40-49, 50-59, 60-69, ≥70 years) and sex distribution of the 2448 participants of the German HRQoL outcome study reported by Hinz et al. 2014. The outcome of our sample was then compared with the outcome of these 2448 patients representing QoL of the German population in general. Comparison was performed using a t test. Results: A questionnaire was sent to 1634 patients. During January to April 2011, 858 questionnaires (53%) were sent back. Compared to NR, R were older (median age: 55 vs. 58, p=0.0426); years since diagnosis (median 6.5 vs. 7.4) and the percentage that had been transplanted were lower (24%vs.18%). No differences were observed regarding sex, Euro score, or time after allogeneic hematopoietic stem cell transplantation (HSCT). When answering the questionnaire, 517 (60%) patients received imatinib 400mg (IM400) and 102 (12%) were off therapy after HSCT. Less than 10% of patients received imatinib 800mg, imatinib+AraC or interferon alpha, nilotinib, or dasatinib. Time since diagnosis was ≤3 years in 156 (18%), 〉3 and ≤7 years in 309 (36%), and 〉7 years in 393 (46%) of the patients. Women (352, 41%) perceived a significant reduction in global health status (mean: 62.7, p

Description: 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

Description: Introduction 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.

Description: Introduction: Early prediction of outcome using response-related predictive landmarks has become a major paradigm in the clinical management of chronic myeloid leukemia (CML). Several studies have shown the predictive impact of 10% BCR-ABLIS at 3 and 6 months for different tyrosine kinase inhibitors. The question, which landmark should define treatment failure and determine treatment intervention has been discussed vividly. However, an objective analysis of quality criteria for different early prognostic landmarks is lacking up to now. Here we compare sensitivity, specificity and the proportion of later disease progressions predicted by 3-month and 6-month landmarks in imatinib-treated patients of the CML-study IV. Methods: A total of 1,303 newly diagnosed patients were assigned to an imatinib-based treatment arm of CML-Study IV by April 2010. Median follow-up was 7.1 years. The number of molecular assessments was as follows: n=789 (at 6 months), n=692 (at 3 months) and n=301 (at 3 months and at diagnosis, without pretreatment). Gene expression levels were determined by quantitative RT-PCR. At 3 and 6 months, a BCR-ABL ratio was calculated using ABL as reference gene and standardized according to the international scale (BCR-ABLIS). In addition, at 3 months and at diagnosis a BCR-ABL ratio was calculated using beta-glucuronidase (GUS) as reference gene in order to ensure linearity of measurement at diagnosis. The log reduction at 3 months was calculated from the BCR-ABL ratio at 3 months and at diagnosis. Due to the time-dependent nature of censored survival data, the sensitivity and specificity at eight years were calculated using the method by Heagerty et al. (Biometrics 2000). Overall survival (OS) is defined by the absence of death from any reason, progression-free survival (PFS) is defined as survival in the absence of progression to accelerated or blastic phase. Landmark analyses were performed to compare survival outcomes according to Kaplan-Meier. Results:Comparing the 10% BCR-ABLIS landmark at 3 and 6 months, 8-year OS and PFS rates are equal or comparable (table). In contrast, sensitivity and specificity differ substantially with an advantage in favor of sensitivity for the 3-month landmark and in favor of specificity for the 6-month landmark. This difference is paralleled by a smaller proportion of high-risk patients and less progressions identified by the 6-month landmark. From a clinical point of view the 6-month landmark is not only less than half as sensitive, moreover a treatment intervention at 6 months might also prevent less progressions due to the delay of 3 months. The half-log reduction landmark at 3 months is as sensitive as 10% BCR-ABLIS at the same time. However, it shows improved specificity and defines the smallest proportion of high-risk patients. Conclusion: The 10% BCR-ABLIS landmark, which is currently defining treatment failure at 6 months according to European LeukemiaNet (ELN) criteria, fails to detect the majority of patients with later disease progression. Less than a half-log reduction of individual baseline BCR-ABL transcript levels at 3 months on treatment identifies patients with later progressions as sensitive but with higher specificity as compared to 10% BCR-ABLIS. Abstract 156. Table Prognostic landmark 8-year OS (%) 8-year PFS (%) P-value for PFS Sensitivity to predict progression (%) Specificity to predict progression (%) High-risk patients Disease progressions classified as high-risk / total 3 months (n=692) 10% BCR-ABLIS 88 vs. 96 82 vs. 90 0.001 41.1 74.6 191 (28%) 32/74 (43%) 6 months (n=789) 10% BCR-ABLIS 88 vs. 96 84 vs. 95 0.001 18.2 93.8 95 (12%) 17/74 (23%) 1% BCR-ABLIS 90 vs. 97 89 vs. 97