ALBERT

Description: 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

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: 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.

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: A substantial minority of patients with chronic myelogenous leukemia (CML) achieve a complete response (CR) to treatment with interferon- (IFN), defined as the disappearance of Philadelphia chromosome-positive metaphases. Currently it is unclear how long IFN treatment should be continued for such patients. We used a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify levels of BCR-ABL transcripts in 297 peripheral blood specimens collected from 54 patients who had achieved CR with IFN. The median duration of observation was 1.9 years (range, 0.3-11.0 years). Total ABL transcripts were quantified as internal control and results were expressed as the ratio BCR-ABL/ABL. All 54 patients had molecular evidence of residual disease, although 3 patients were intermittently PCR negative. The median BCR-ABL/ABL ratio at the time of maximal response for each patient was 0.045% (range, 0%-3.6%). During the period of observation 14 patients relapsed, 11 cytogenetically to chronic phase disease and 3 directly to blastic phase. The median ratio of BCR-ABL/ABL at maximal response was significantly higher in patients who relapsed than in those who remained in CR (0.49% versus 0.021%,P 

Description: Abstract 4272 The incidence of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) in Europe is still difficult to estimate, due to insufficient information. Currently, it is believed to range between 8 and 22 cases per million people per year, age adjusted. Prior to the introduction of the tyrosine kinase inhibitor (TKI) imatinib the annual death rate was about 10% for the first 2 to 3 years, and about 20% from the 4th year on, with less than 10% of patients alive after 10 years. Interferon-alfa treatment and allogeneic hematopoietic stem cell transplantation were very effective treatments but only in a minority of patients. Following the introduction of IM, and of the second generation TKI nilotinib and dasatinib the annual death rate has decreased to less than 5%, and more than 75% of patients are projected to be alive 10 years after diagnosis. Based on these figures, the prevalence of the disease is expected to double every 5 years and the management of the disease will rapidly become an important social and pharmacoeconomic issue. To govern this progress it is necessary to improve the level of information on the epidemiology of CML, on the treatment of CML in clinical practice, and on the outcome of treatment outside prospective, controlled clinical trials on which current outcome estimates are based. With that purpose, the European Leukemia Network (ELN) has established a registry of all new cases of Ph+ CML. In a public private partnership with Novartis Oncology Europe this registry has been expanded to also include treatment and quality controlled outcome (European Treatment and Outcome Study [EUTOS] for CML). The infrastructure of the registry is based on a EUTOS Central Scientific Headquarter (Dpt. Hematology-Oncology “L. and A. Seràgnoli”, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy) and a EUTOS Central Data Center (Dpt. For Medical Informatics, Biometric and Epidemiology, University of Munich, Munich, Germany), interacting with each national hub. Registry is population-based, covers completely most European countries with less than 12 millions inhabitants (Portugal, Belgium, Sweden, Finland, Lithuania, Latvia, Estonia, Czech Republic, Slovakia, Slovenia, Croatia, Serbia, Hungary, Austria, Greece, Cyprus), and covers partially (for larger countries, only sub-regions with roughly 10 millions inhabitants have been selected) most of the countries with more than 12 millions inhabitants, including Spain, the United Kingdom, The Netherlands, Germany, Poland, France, Romania, Russia and Italy. About 2500 newly diagnosed cases are planned to be registered over one year and to be followed for treatment and outcome including cytogenetic response, molecular response, and BCR-ABL KD mutations. Moreover, flanking projects have been implemented in the EUTOS frame: a network of standardized laboratories across Europe, to provide a molecular monitoring with quality controlled data, a central facility for imatinib blood level testing, soon in many European countries, and an educational effort (symposia, training workshops, internet platform). The EUTOS registry joins epidemiological and outcome data: its implementation requires considerable efforts and resources, but in the long run CML could become a model for epidemiologi and management of other cancers. Disclosures: Hasford: Novartis Pharma: Research Funding.

Description: Interferon alpha (IFN) induces complete hematologic remission in 70% to 80% of patients with CML in early chronic phase, with up to 8–30% of cases achieving a complete cytogenetic response (CCR). Although patient responses correlate with Hasford and Sokal risk scores, the molecular basis for this heterogeneity remains poorly understood. We hypothesized that polymorphic differences in the IFN signal transduction cascade might account for different patient responses. IFN binds the heterodimeric type I interferon receptor, the two subunits of which are encoded by IFNAR1 and IFNAR2. Binding activates the JAK1 and TYK2 non-receptor tyrosine kinases, which phosphorylate and activate STAT proteins. We studied 187 cases treated with IFN based regimens as part of the German CML studies I-III. Of these, 105 were defined as non-responders (no cytogenetic response) and 82 as responders (achievement of

Description: Epidemiological information on chronic myeloproliferative disorders (CMPD), notably Philadelphia (Ph) and/or bcr/abl positive chronic myeloid leukemia (CML), is rare. National cancer registries and clinical trials differ with regard to median age of CML patients by 10 to 20 years (Table). Therefore, an evaluation was conducted in a defined area in Germany between 1998 and 2000 to determine incidences and compare clinical characteristics of Ph and/or bcr/abl positive CML patients participating and not participating in trials. 68 (37.4%) hospitals and 241 specialty practices (16.4%) reported 893 newly diagnosed CMPD patients. CML patients represented 24.9% of all cases with CMPD. The crude incidence of CML cases (n=218) was 0.79, that of the 172 Ph and/or bcr/abl positive CML cases 0.62 and that of CMML (n=61) 0.22. The incidence of CML and CMML cases combined was 1.01. 110 (64.0%) of the 172 Ph and/or bcr/abl positive CML patients participated in clinical studies, mainly CML Studies III and IIIA of the German CML Study Group. Median age was significantly different between patients participating and not participating in clinical trials: (54.1 vs. 64.8 years, p=0.0001). The chance for a Ph and/or bcr/abl positive CML patient 〈 65 years to be enrolled in a clinical study was 3.8 times higher than for a CML patient ≥ 65 years (OR=3.8, CI: 1.9–7.3). Male patients had a slightly higher probability to be enrolled in a study than females (OR=1.5 (CI: 0.8–2.8)). Our data indicate that 36% of the Ph and/or bcr/abl positive CML patients registered in a defined area of Germany are not treated in clinical trials, that elderly patients have a lower probability to be included in trials than younger patients and that patients participating in trials are 10.7 years younger than those who do not. Age of CML Patients in Population based Registries and in Clinical Trials A) Registries Age mean (years ± S.D.) / Thames Cancer Registry, U.K. 65 (20–98) SEER Cancer Statistics Review, 1975–2004 68 (range not available) SEER cancer statistics review, 1973–1998 64 (range not available) B) Trials The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 1994 48 ± 14 Hehlmann et al., Blood 1994 48 (17–85) Guilhot et al., N Engl J Med 1997 50 (7–70) Hasford et al., JNCI 1998 49 (10–85) The Benelux CML Study Group. Blood 1998 56 (20–83) Baccarani et al., Blood 2002 45 ± 13 Hehlmann et al., Leukemia 2003 48 (10–83) O’Brien et al., N Engl J Med 2003 50 (18–70) Hehlmann et al., Blood 2007 49 (11–90)

Description: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with preclinical activity against 20/21 imatinib resistant BCR-ABL mutations and clinical phase I/II efficacy in patients with chronic myelogenous leukemia (CML) and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of preexisting BCR-ABL mutations associated with imatinib resistance and efficacy of dasatinib in patients (pts) with CML and ALL. We have investigated 872 peripheral blood samples from 394 pts (53% male, median age 60 yrs, range 17–85) who had been enrolled in international phase II studies investigating the activity of 70mg dasatinib BID after imatinib failure (chronic phase, CP, n=198; accelerated phase, AP, n=78; myeloid blast crisis, MyBC, n=53; lymphoid blast crisis, LyBC, or ALL, n=65). Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. During follow up, pts were monitored in 3-monthly intervals by RQ-PCR for BCR-ABL mRNA transcripts and by mutation analysis to determine the quantitative course of the preexisting mutation or the emergence of new mutations. Hematologic and cytogenetic response data have been collected sequentially for a median of 8 months (range, 2–11) after start of therapy. Prior to dasatinib, 46 different BCR-ABL mutations involving 36 amino acids were detected in 202/394 pts (51%). 162 pts showed one, 33 pts two, 6 pts three, and 1 pt four mutations. Mutations were observed in 84 pts in CP (42%), 47 pts in AP (60%), 23 pts in MyBC (43%), and 48 pts in LyBC and ALL (74%). In patients with mutations, hematologic response was 91% in CP, 62% in AP, 41% in MyBC, and 34% in LyBC/ALL (p

Description: The advent of imatinib has considerably changed treatment in chronic myeloid leukemia (CML). Although response rate and duration of response with imatinib monotherapy continue to be impressive, the majority of patients (pts) in complete cytogenetic remission (CCR) retain BCR-ABL transcripts as markers of residual disease and potential cause of relapse. In addition rapid evolvement of blast crises from CCR has been reported. Therefore, we designed an investigator-initiated phase IV prospective trial aiming to address the role of imatinib in combination with interferon alpha (IFN) or Ara-C and treatment intensification with high dose imatinib. In July 2002, the German CML-Study Group has activated the four-armed randomized controlled trial comparing imatinib 400 mg/d with imatinib+IFN, imatinib+Ara-C and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High risk pts are randomly assigned to primary imatinib-based therapies including a 4th treatment arm with imatinib 800 mg/d. The treatment arm imatinib after IFN failure retains the chance of an IFN-induced CCR with 10 year-survival rates of 70–80%. In case of IFN failure pts are crossed over to imatinib. Allogeneic SCT is recommended for all pts with high risk, imatinib failure and EBMT-score 0–1. By August 2004, 429 pts were randomized: imatinib 400 mg/d (n=103), imatinib+IFN (n=130), imatinib+Ara-C (n=108), imatinib after IFN failure (n=84), and imatinib 800 mg/d (n=4). According to the New CML score, 34% of patients were low risk, 56% intermediate risk, and 10% high risk. At baseline, median WBC count was 63/nl (3.5–513), median platelet count was 385/nl (49–2,799) and median hemoglobin was 12.7 g/dl (6.1–16.6). We sought to evaluate results of the first cohort of pts (n=217) with a 〉12 months follow-up, recruited between 7/2002 and 5/2003 (imatinib 400 mg/d, n=52; imatinib+IFN, n=70; imatinib+Ara-C, n=49; imatinib after IFN failure, n=46). Median age was 56 yrs (16–82), 62% of pts were male. Cytogenetic data are available from 117 pts (68%) randomized to primary imatinib-based therapies. At 12 months, 104 pts (89%) achieved a major cytogenetic remission (Ph+