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Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML.We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726.From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B.Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients.Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 2271

Eligibility criteria were: diagnosis of chronic phase Ph+ or bcr/abl positive CML between 2002 and 2006, age ≥ 18 years, and start with any kind of imatinib-based treatment in a prospective study within six months after first diagnosis. For hematologic (HR), cytogenetic (CgR), and molecular (MR) remission the ELN criteria were used. Competing risk estimations and Landmark analyses were applied when indicated. Patients from the FI-LMC-group in France (n=526), Germany (n=644), Italy (n=513), The Netherlands (n=119), the Nordic Countries (Denmark, Finland, Norway, Sweden, n=140)) and Switzerland (n=13) were included (date: 07/11/2009), for an overall n of 1955 patients.Median age was 52.5 years and 45% were female. The Euro prognostic score profile was for 38% of the patients low, for 51% intermediate and for 11% high risk. Imatinib 400 mg was allocated to 41%, Imatinib 600 mg to 8%, Imatinib 800 mg to 17%, and Imatinib-based combinations with IFN or Ara C to 34% of the patients. Median observation time was 24 months (range: 1-81). Complete hematologic remission (CHR) was finally achieved by 97%, complete cytogenetic remission (CCgR) by 94%, and major molecular remission (MMR) after 18 months by 62%. Overall survival (OS) after 60 months was 92%. Euro score clearly separated high risk vs. non high risk patients with regard to CHR (p=.0002), CCgR (p=.0023), but not for MMR, whereas Sokal score did so for CCgR (p<.0001). Deletion 9q did not show any impact on CHR, CCgR or MMR.Using Landmark-analysis with those 1012 patients who provided complete data for CHR, CCgR and MMR, CHR within 6 months from day 1 of imatinib treatment showed an impact on the chance to achieve CCgR (96.1% vs. 87.5% p=.0003) and MMR at 18 month (56.1% vs. 48.5%, p=.087). CHR within 3 months did not show a relevant impact on CCgR and MMR. Partial CgR (Ph+ < 35%, n=725)) within 6 months was associated with a higher chance to achieve MMR at 18 month (62.8% vs. 51.4% p=.0003).Patients who did not achieve CCgR within 3 (93%), 6 (70%), 12 (29%) or 18 (18%) months experienced an increasing risk for disease progression of 6%, 7%, 11% and 14% respectively but still showed a chance to eventually achieve CCgR of 87%, 83%, 60%, and 36%. Conclusions: This combined analysis of multinational European data showed very good response data regarding CHR, CCgR, MMR, and OS. Current prognostic CML scores seem to not separate prognosis of CML-patients sufficiently well. Early response markers like CHR and CgR after 6 months allow to differentiate the prognosis with regard to MMR but their clinical relevance may be questioned. Patients without CCgR within 6 months have a higher risk for disease progression and thus a closer follow up is indicated. With accumulating observation time the European CML Registry will allow to answer many clinically relevant questions about the prognostic value of early response markers.Hasford: Novartis Pharma: Research Funding. Rosti:Novartis Pharma, Bristol Myers Squibb: Consultancy, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Montrucchio:Novartis Pharma : Employment. Rancati:Novartis Pharma: Employment. Simonsson:Novartis, BMS, Schering-Plough: Consultancy, Honoraria, Research Funding. Ossenkoppele:Novartis Pharma, BMS: Consultancy. Hehlmann:Novartis Pharma: Research Funding.

Hasford: Novartis Pharma: Research Funding.

Abstract 4272

Abstract 1109

Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio < 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib > 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio < 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib > 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

Idiopathic hyper-eosinophilic syndrome (HES) is a rare haematological disorder characterized by persistent peripheral blood greater than 1,500 cells/μL lasting for more than 6 months, in the absence of other apparent aetiologies for eosinophilia with signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder with evidence of clonal proliferation, in which latter case it is usually referred to as chronic eosinophilic leukemia (CEL). Patients with HES generally have a poor prognosis, but the course of the disease may be variable. Severe visceral complications, including cardiopathies, are common and are often fatal illness. Treatment of HES includes corticosteroids, chemotherapeutic agents (such as cyclophosphamide, vincristine, and hydroxyurea), and, more recently, interferon-alpha (IFN-alpha). Recently, Cools et al. reported the involvement of PDGFRA, fused with FIP1L1, in a number of HES patients responsive to imatinib therapy. We treated with imatinib mesylate (100 to 400 mg daily) 59 patients affected by Hyper-Eosinophilic Syndrome (HES) enrolled in a multicentric Italian phase 2 clinical trial. All the patients were studied by molecular analysis for expression of FIP1L1-PDGFRA, TEL-PDGFRB, FGFR1-BCR and BCR-ABL chimerical transcripts. 32 patients (45%) were positive for the FIP1L1-PDGFRA rearrangement. Rapid, haematological complete responses (HCR) were recorded after one month of therapy in all FIP1L1-PDGFRA positive. In 36 patients resulted negative for FIP1L1-PDGFRA rearrangement we observed 8 (22%) hematological improvement (HI) and one HCR (HI+HCR 25%). Furthermore, a molecular complete remission (defined as the disappearance of FIP1L1-PDGFRA at qualitative RT-PCR evaluation) was recorded in 13 (68%) patients of the 19 valuable after three months of therapy, and all but one (94%) patients resulted negative for the presence of the rearrangement after six months of therapy. No significant toxicity was seen during the treatment. The median follow up was 4 months (range: 2–39). This is the largest series of HES patients treated with Imatinib with strong evidence of hematological and molecular effectiveness and absence of long term significant toxicity. This phase II study supports the use of Imatinib as first line therapy in FIP1L1-PDGFRA rearrangements positive HES patients. Acknowledgments: COFIN 2003, by FIRB 2001, by the University of Bologna (60%), by the Italian Association for Cancer Research (A.I.R.C.), by the Italian National Research Council (C.N.R), by Fondazione Del Monte of Bologna and Ravenna (Italy), A.I.L. grants, European LeukemiaNet grants.

HES (hypereosinophilic syndrome with organ damage), CEL (chronic eosinophilic leukemia with chromosome marker and/or myeloproliferation/dysplasia) and CIH (chronic idiopathic hypereosinophilia) are diseases that pose a therapeutic challenge and are potentially Glivec-sensitive. This drug inhibits BCR-ABL type tyrosine kinase (TK) as well as Platelet-Derived-Growth-Factor Alpha and Beta (FIP1L1-PDGFRA and ETV6-PDGFRB, detectable in HES and allied conditions) and c-kit related TKs. A study was planned to assess 1) the response to escalating doses of Glivec (starting dose 100 mg/d, maximum 400 mg/d, weekly increment 100 mg/d as necessary) and 2) the diagnostic profile of Glivec-responsive cases. Eligible patients had BCR-ABL- HES, CEL, or CIH with eosinophilia >5x10e9/l. Diagnostic work-up included marrow morphology and cytogenetics, PDGFRA/B rearrangement study, and immunophenotype for the detection of expanded (Vbeta) T-cell clones (TCC). Glivec was kindly provided by Novartis Oncology, Italy, to be administered for 12 consecutive weeks. A complete remission (CR) was defined by an eosinophil count <0.35x10e9/l with disappearance of clinical signs/symptoms. Starting 11/’04, 18 patients were identified (14 M), aged 26–80 years (median 54), with a disease history of 0.2–12 years (median 3.4). Blood eosinophilia was 0.67–17.5x10e9/l (median 2.1), with diagnosis of HES (n= 8), CEL (n= 6) or CIH (n= 4). Cytogenetics was abnormal in 5/14 (36%): 1 t(4;8), 1 der(5) t(1;5)(q25;q34) del(5)(q?), 1 del(5)(q32) i(17), and 2 -Y as possible constitutional anomaly; a TCC was detected in 3/9 (33%); FIP1L1-PDFGRA and ETV6-PDGFRA rearrangements were found in 4/17 (24%) and 0/9 (0%), respectively. As of 07/’05, 16 cases are evaluable (2/4 PDGFRA+), 8 having completed the study. Four patients were withdrawn very early because nonresponders at increased dosage (n=3) or noncompliant (n=1), and 4 are still on study. A CR was documented in 6/8 who completed the trial, 3 with CEL and t(4;8) or an involved chromosome 5, 2 with PDGFRA+ HES, and 1 with PDGFRA-/B- HES. No patient with TCC responded. As concerns dose-/time-response relationships, 4 cases were fully responsive to 100 mg/d through the 12 weeks of the study, and 2 required 200 mg/d from the 6th and 11th week, respectively (cases with longer HES history: 12 and 11 years; one with prior blastic transformation), whereas eosinophil blood counts (x10e9/l) varied as follows from baseline to 1st and 4th weeks: 1.95 (0.88–17.5) to 0.20 (0.02–2.09) to 0.15 (0.00–0.4). However, both PDGFRA+ cases remained molecularly positive, while the single evaluable patient achieved only a transient cytogenetic remission. Time to progression (>0.35) was short following drug withdrawal (5 patients: 1, 1, 3, 3, 3 months). Glivec is highly active in hypereosinophilic syndromes with PDGFR rearrangements and other gene lesions that need to be properly identified. These cases respond very early even at the lower dosage. However, an early stopping of therapy can be followed by rapid progression as indicated also by the persistence of cytogenetic/molecular lesions in some cases. This dictates a continuing molecular/cytogenetic monitoring for dose titration like in chronic myelogenous leukemia.

HES (hypereosinophilic syndrome with organ damage), CEL (chronic eosinophilic leukemia with chromosome marker and/or myeloproliferation/dysplasia) and CIH (chronic idiopathic hypereosinophilia) are diseases that pose a therapeutic challenge and are potentially Glivec-sensitive. This drug inhibits BCR-ABL type tyrosine kinase (TK) as well as Platelet-Derived-Growth-Factor Alpha and Beta (FIP1L1-PDGFRA and ETV6-PDGFRB, detectable in HES and allied conditions) and c-kit related TKs.

Idiopathic hyper-eosinophilic syndrome (HES) is a rare haematological disorder characterized by persistent peripheral blood greater than 1,500 cells/μL lasting for more than 6 months, in the absence of other apparent aetiologies for eosinophilia with signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder with evidence of clonal proliferation, in which latter case it is usually referred to as chronic eosinophilic leukemia (CEL). Patients with HES generally have a poor prognosis, but the course of the disease may be variable. Severe visceral complications, including cardiopathies, are common and are often fatal illness. Treatment of HES includes corticosteroids, chemotherapeutic agents (such as cyclophosphamide, vincristine, and hydroxyurea), and, more recently, interferon-alpha (IFN-alpha).