Abstract: Abstract 862 Rapid relapse after discontinuation of imatinib, the need for indefinite therapy and residual disease in most patients are the major challenges in management of CML. Combinations of imatinib with IFN simultaneously, or consecutively preceding imatinib, or with araC may improve treatment outcome. The German CML Study Group therefore designed a randomized trial to compare standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN failure (for low- and intermediate-risk patients, high risk patients received imatinib 800 mg instead). The current evaluation represents the prefinal results of the pilot phase of the trial. Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase (CP). Primary aims are: prolongation of survival (overall, OS, and progression free, PFS), determination of rates of hematologic, cytogenetic and molecular remissions, adverse events (AE) and role of allografting. By the end of 2005, 670 patients were randomized, 13 had to be excluded (no CML (n=3), pregnancy, no CP (n=1 each), imatinib 800 mg (n=8)). Analysis was according to intention to treat. 657 patients were evaluable (174 with imatinib 400 mg, 196 with imatinib+IFN, 158 with imatinib+araC and 129 with imatinib after IFN-failure). 656 patients were evaluable for hematologic, 611 for cytogenetic, and 618 for molecular responses. Patient characteristics of treatment arms were similar for age (median 53 years), sex (40% female), median values for Hb (12.6 g/dl), WBC (66.2/μl), platelets (383/μl) and for Euro risk score (low 35%, intermediate 54%, high 10%). The median dose of imatinib was 400mg/die in all arms, of araC 10 mg per treatment day and of IFN 4.2 Mio I.U./die in the imatinib after IFN arm and 1.8 Mio I.U./die in the imatinib+IFN arm. Median observation time was 57.3 months. 55 patients died, 73 patients were transplanted in 1st CP, 81 patients progressed, 59 patients were switched to second generation TKIs. After 3 years 126 patients (72%) of the imatinib 400mg arm still received the initial therapy as well as 60 patients (30%) of the imatinib+IFN arm and 53 patients (34%) of the imatinib+araC arm. 9 patients (7%) of the imatinib after IFN arm are still on IFN. 5-year OS of all patients is 91%. 5-year PFS of all patients (no death, patient still in first chronic phase) is 87%. 5-year-OS and PFS according to treatment arm are shown in the Table. At 5 years, the cumulative incidences of achieving complete cytogenetic remission or major molecular remission (MMR) as determined by competing risks (death, progression) are not different (Table). Type and severity of adverse events (AE) over a 5-years period did not differ from those reported previously (Table). Hematologic AEs grade III/IV were similar in all therapy arms except leukopenia grade III/IV, which was more frequently observed in the imatinib after IFN arm (14%). Non hematologic AEs were mainly fluid retention, neurological and gastrointestinal symptoms and fatigue. Neurologic symptoms and fatigue were more often reported for the therapy arms with IFN. Imatinib 400mgImatinib+IFNImatinib+AraCImatinib after IFN5-Year Survival and Response RatesOS87%93%92%92% PFS84%91%88%84% CCR92%92 %89%83% MMR83%78%80%70% Adverse Events, WHO Grade III/IVAnemia7%1%3%3% Leukopenia4%5%2%14% Thrombocytopenia5%6%6%6% WHO Grade I-IVEdema15%13%5%0% Neurological5%15%5%22% Gastrointestinal17%27%21%15% Fatigue8%13%9%23% This analysis shows excellent survival and durable response rates in all arms. Currently, survival in all treatment arms is equal to, or better than in IRIS. To verify possible differences in survival, e.g. imatinib 400 mg vs. imatinib + IFN, longer observation is planned. Although cytogenetic and molecular responses in the imatinib after IFN failure arm at 5 years are inferior to that in the other treatment arms, the question of whether the consecutive therapy with IFN first and imatinib after IFN-failure provides a survival advantage requires long term follow-up. Imatinib in combination with, or after IFN, or with low dose araC are feasible and safe treatment modalities. We expect that the study will optimize and improve therapy outcome in CML. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German Competence Net : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.

Abstract: Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR= 〈 0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p 〈 0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.

Abstract: Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of 〈 0,01 on the International Scale. From July 2002 – April 30, 2009 1022 newly diagnosed patients with CML in chronic phase were randomized, 1012 were evaluable (338 with imatinib 800 mg, 324 with imatinib 400 mg, 350 with imatinib plus IFN). Median observation time was 40 months. The median average daily imatinib doses were 628 mg in the 800 mg arm and 400 mg in the 400 mg based arms. The actual median daily doses in the 800 mg arm per 3-months periods were: 555 mg, 737 mg, 613 mg, 600 mg, and 600 mg thereafter, reflecting the run–in period with imatinib 400 mg for 6 weeks in the first period and the adaptation to tolerability from the third 3-months period onwards. Median daily imatinib doses in the 400 mg arms were 400 mg throughout. Adaptation of imatinib dose in the 800 mg arm according to tolerability is reflected by similar higher-grade adverse events rates (WHO grades 3 and 4) with all treatments. Significantly higher remission rates were achieved with imatinib 800 mg by 12 months. The cumulative incidences of CCR by 12 months were 63% [95%CI:56.4-67.9] with imatinib 800 mg vs 50% [95%CI:43.0-54.5] with the two 400 mg arms. The cumulative incidences of MMR by 12 months were 54.8% [95%CI:48.7-59.7] with imatinib 800 mg vs 30.8% [95%CI:26.6-36.1] with imatinib 400 mg vs 34.7% [95%CI:29.0-39.2] with imatinib + IFN. The cumulative incidences of CMR4 compared with the MMR incidences over the first 36 months are shown in Table 1. Imatinib 800 mg shows superior CMR4 rates over the entire 36 months period, CMR4 is reached significantly faster with imatinib 800 mg as compared to the 400 mg arms. The CMR4 rates reach 56.8% by 36 months [95%CI:49.4-63.5] as compared to 45.5% with imatinib 400 mg [95%CI:38.7-51.0] and 40.5% with imatinib plus IFN [95%CI:34.6-46.3] . Most patients have stable CMR4 over the entire period. Time after start of treat-ment (months) Cumulative incidences MMR(%) CMR4 (%) IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 6 8.6 9.5 18.1 9.7 8.4 3 0.7 3.7 1.3 2.4 12 30.8 24.0 54.8 20.1 34.7 7.5 12.3 19.8 7.4 12.4 18 50.3 18.1 68.4 14.3 54.1 21.2 12.2 33.4 9.8 23.6 24 63 13.0 76.0 13.2 62.8 30.7 12.3 43 13 30.0 36 79.3 2.3 81.6 10.9 70.7 45.5 11.3 56.8 16.3 40.5 In summary, superior CMR4 rates are achieved with high-dose imatinib adapted to good tolerability, and more patients in the tolerability-adapted 800 mg arm have stable CMR4 qualifying for treatment discontinuation as compared to the 400 mg based arms. With improved application imatinib remains first choice for early CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

Abstract: Abstract 669 Introduction: The prognostic relevance of major molecular remission (MMR, 〈 0.1% BCR-ABL according International Scale, IS) for survival has remained uncertain. Gold standard for the evaluation of treatment response is the achievement of complete cytogenetic remission in spite of its limited sensitivity and the requirement of bone marrow puncture. The standardization of PCR methods and the introduction of conversion factors to account for differences among European laboratories, has resulted in a uniform reporting system allowing comparable BCR-ABL expression levels derived from peripheral blood samples. We sought to evaluate an association of the degree of molecular response and survival. Patients and Methods: We have analyzed 848 patients within the CML-Study IV (randomized comparison of imatinib 800 mg vs 400 mg vs 400 mg + IFN). BCR-ABL (IS) was determined by quantitative RT-PCR. Patients with atypical BCR-ABL transcripts were excluded from the analysis. Median observation time was 40 months (minimum 12). Landmark analyses have been performed at 12 months for overall and progression-free survival using 3 groups of response ( 〈 0.1%, 0.1%-1%, 〉 1% BCR-ABL IS). Results: 341 patients achieved a BCR-ABL expression 〈 0.1% (MMR), 240 patients between 0.1% and 1% and 267 patients 〉 1% by 12 months. Independent of treatment approach, the groups of patients achieving MMR and 0.1%- 〈 1% at 12 months showed significantly higher progression free survival (PFS) (p=0.0023; 99% [95% CI: 97–100%] vs 97% [95% CI: 94–99%] vs 94% [95% CI: 90–97%] at 3 years) and better overall survival (p=0.0011; 99% [95% CI: 97–100%] vs 98% [95% CI: 95–100%] vs 93% [95% CI: 90–96%] at 3 years) compared to the group with 〉 1% BCR-ABL by 12 months (Figure). Conclusion: Faster and deeper response to imatinib-based treatment by 12 months revealed to be associated with improved PFS and overall survival. The critical cutoff level seems to be 1% BCR-ABL IS which has been shown to closely correlate with complete cytogenetic remission. Disclosures: Müller: Novartis: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

Abstract: Abstract 3287 Poster Board III-1 Blast crisis (BC) in CML in the imatinib era is a rare event with 1–3% of newly diagnosed BC patients per year in the IRIS study, but prognosis, once BC has occurred, remains poor. Historical and recent studies with imatinib and second generation tyrosine kinase inhibitors (TKI) reported a median survival time of 7–10 months and two year survival probabilities of 〈 30%. In order to recognize earlier time points for intervention we aimed to characterize the evolution to BC in the imatinib era using the prospective randomized German CML study IV which compares imatinib based strategies in chronic phase CML. By July 2009, BC was observed in 51 patients (pts) out of 1347 randomized pts (3.8%), with equal distribution amongst the treatment arms. 36 pts (67%) were male. 21 pts (41%) had myeloblastic, 16 pts (31%) lymphatic, 2 pts (4%) biphenotypic, and 2 pts (4%) megakaryoblastic BC; 10 pts (20%) were not classifiable. At diagnosis of CML, 23 pts (45%) had low, 17 intermediate (33%) and 11 high risk (22%) according to the Euro score (proportion of low risk in pts without BC was 34%). Median age at diagnosis was younger for male pts (41 years; range 18–79) than for female pts (57 years; range 19–77). Median time from diagnosis to onset of BC was 11.3 months (range 0.7–71). Prior to BC, all pts had received imatinib except one who received interferon alpha (IFN) and dasatinib. Two pts had received an allogeneic stem cell transplantation (alloSCT) and four a second generation TKI before diagnosis of BC. The BC rates per year comparing CML studies IV and IIIA (IFN based treatment vs. alloSCT) are shown in the Table. The probabilities to survive without BC are almost identical in both studies for year 1, but are higher in CML study IV afterwards. During CP, all pts were evaluable for hematologic, 44 for cytogenetic and 46 for molecular response to initial therapy. 29 pts (57%) had achieved a complete hematologic, 9 (20%) complete, 3 (7%) major cytogenetic and 4 (9%) major molecular remissions. Cytogenetics at diagnosis of CML were available for 47 BC pts: 29 pts (62%) had a t(9;22) translocation only and 18 (38%) additional chromosomal aberrations (ACA; variant Philadelphia chromosome n=5, complex aberrant karyotype n=9, other n=4) (for comparison: ACAs at diagnosis were detected in 95 of 1,095 pts (9%) without BC). Cytogenetics at onset of BC were available for 29 pts: 7 pts (24%) had a t(9;22) translocation only and 22 pts (76%) ACAs (complex n=13, other n=9). 17 (10 different) BCR-ABL mutations (8 P-loop including 5 E255V/K; 2 M244V; 2 T315I; 2 F317L and 3 others) were detected in 14 of 33 pts (42%). Median follow-up after BC was 34 months (range 2.3–53). 24 patients were transplanted, 10 pts were treated with second generation TKI (dasatinib n=9, nilotinib n=1), 4 of these were also transplanted, 16 received other therapies (imatinib dose escalation in combination with chemotherapy n=7, chemotherapy alone n=9), one no therapy. 32 pts died. Only 19 of the 51 pts (37%) were alive, 16 of them (84%) after allogeneic HSCT. 2 pts are alive on second generation TKI and one on busulfan. Median survival after BC was 11.6 months, survival probability at two years was 35% (s. Figure). BC occurred early after diagnosis, in a high proportion of low risk patients. There was a preponderance of young males, and a high proportion with ACA at diagnosis. The best chances for survival were by alloHSCT. The short median time to BC indicates that evolution to BCR-ABL independence may have occurred already prior to CML diagnosis and start of imatinib therapy. Early identification and rapid initiation of a donor search in patients with early failed response to imatinib is warranted. Progression to BC and survival BC rate per year Year 1 2 3 4 5 6 CML Study IV 2.3% 1.5% 0.5% 0.6% 0.3% 1.1% CML Study IIIA 3.3% 3.7% 1.5% 1.7% 1.2% 1.0% Survival probability without BC CML Study IV 98% 96% 96% 95% 95% 94% CML Study IIIA 97% 93% 91% 90% 89% 88% Figure Survival of BC patients after treatment with imatinib; data of the German CML Study IV Figure. Survival of BC patients after treatment with imatinib; data of the German CML Study IV Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German CompetenceNet : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.

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.

Abstract: 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.

Abstract: Abstract 3281 Poster Board III-1 Introduction: In the two consecutive German CML studies III and IIIA (recruitment periods from 1995 to 2001 and 1997 to 2004), eligible patients were assigned to early HSCT by genetic randomization according to availability of a matched related donor. After randomization, 113 patients of study III (84% of 135) and 144 of study IIIA (87% of 166) were eventually transplanted in first chronic phase (CP) using a related donor. Despite comparable transplantation protocols and most centers participating in both studies, survival probabilities in study IIIA were significantly better, even when adjusted for the established EBMT risk score (Gratwohl et al., Lancet 1998 [1]), p + 0.0097. For further explanation, the German Registry for Stem Cell Transplantation (DRST) and the Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT) were asked for data support. Patients and Methods: The main sample characteristics of the 257 transplanted CML study patients were also applied to the registry patients: diagnosis of CML between 1994 and 2004, first HSCT with a related donor performed in first CP between 1995 and 2004 at an age between 12 and 65 years, and blood or bone marrow as stem cell sources. Thus, additional data of 582 HSCT patients were retrieved from the two registries. Age, recipient sex, donor sex, time between diagnosis and HSCT, calendar year of HSCT, stem cell source, and HLA matching were investigated as potential predictive factors for survival. Then, a sample of patients with the same risk distribution as the 113 patients of study III was randomly drawn from the registry patients. By application of repeated resampling to this new patient group, bootstrap confidence intervals for survival probabilities at various times after HSCT were extractable. This provided the basis to judge whether the survival in study III could be seen as a typical random representation of a sample with an equivalent risk structure or not. The same method was applied to the 144 patients of study IIIA. Results: The 5-year survival probability of all 839 patients resulted in 73% (229 died). Median follow-up time of living patients was 6.7 years. Due to the characteristic plateau of post-transplant survival probabilities, the predictive influence was judged by the Kaplan-Meier method and the log rank statistic. Also consideration of age and time between diagnosis and HSCT as continuous variables seemed less appropriate than working with categorizations. Furthermore, the previously published cut-points “1 year” for time from diagnosis to HSCT ([1] ) and “44 years” for age at HSCT (Maywald et al., Leukemia 2006) were independently confirmed to be the best. Cox model and logistic regression with survival status after 3 years both indicated that age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT had independent statistically significant predictive influence on survival (p 〈 0.05). The first two factors had the strongest effects. Calendar year was only influential when distinction was made between HSCT until and after 1999. All possible combinations of the 4 factors could be summarized in 4 risk groups with significantly different survival probabilities (at 5 years: 87%, 76%, 63%, and 24%). Matched for the risk group distribution of study III [study IIIA], a maximum of 290 [428] registry patients could be drawn. For the 290 [428] patients, 5-year survival was 69% [77%] with a 95% bootstrap confidence interval from 63% to 74% [72% to 81%]. Thus, as for all yearly intervals within the first 5 years, the 5-year survival probabilities of studies III: 65% and IIIA: 79% lied within the corresponding confidence intervals. Conclusions: Along with the registry patients, the study data enabled the identification of age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT as factors with independent predictive impact on survival which led to 4 risk groups with statistically significantly different survival probabilities. More favorable-risk patients in study IIIA stood for a better transplantation strategy. In consideration of these different risks, the survival probabilities in both studies did not significantly vary from those of registry samples with matched risk structures. Accordingly, an improved transplantation strategy along with random variation could be considered as an explanation of the significantly different survival probabilities between the two studies. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Gratwohl:AMGEN, Roche, Bristol-Myers Squibb, Novartis, Pfizer: Research Funding; Novartis: Consultancy. German CML Study Group:Kompetenznetz Leukämie, European Leukemia Net, Roche, Essex, AMGEN: Research Funding.

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 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.