ALBERT

Description: Introduction: Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3-TKD), representing point mutations in codon D835/I836 and rarely deletions of codon I836, induce constitutive tyrosine phosphorylation and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3-TKD in AML, particularly in the presence of NPM1 mutations, is not well established. The phase 3 RATIFY trial [NCT00651261; Stone et al. N Engl J Med. 2017] showed that in combination with standard chemotherapy, midostaurin (PKC412) improved survival outcomes across all 3 FLT3 stratification subgroups (ITD high allelic ratio [≥ 0.7], ITD low allelic ratio [〈 0.7], and TKD) vs placebo in patients with newly diagnosed FLT3-mutated AML. Here, we evaluated the prognostic impact of FLT3-TKD and NPM1 mutations in a post hoc analysis from the RATIFY trial. Methods: In RATIFY, newly diagnosed patients with AML 18-60 years old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by 12 28-day cycles of maintenance therapy with midostaurin or placebo. FLT3-TKD mutation was detected by PCR and capillary electrophoresis at 9 reference laboratories. Patients were categorized as NPM1 mutated (mut) or NPM1 wild-type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event-free survival (EFS) and disease-free survival (DFS). EFS and DFS analyses were performed considering CR within a 60-day window. P values presented have not been adjusted for multiplicity. Results: Of the total randomized 162 FLT3-TKD patients, 134 with available NPM1 data had consented for exploratory analysis and thus were included in this study (see Table for subgroup distribution). Overall, 47.8% of patients were male, and the median age was 49 years (95% CI, 45.5-51.1 years). The median white blood cell (WBC) count was higher in patients with NPM1-mut than in patients with NPM1-WT (34.1 vs 15.5 × 109/L, P = .0011). CR rates (during the first 60 days) were higher in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT (66% vs 53%); however, this was driven by the higher rate of CR in the midostaurin arm (76% NPM1-mut vs 44% NPM1-WT) rather than the placebo arm (53% NPM1-mut vs 60% NPM1-WT). The overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3-TKD patients. The prognostic effect of the NPM1 mutation concurrent with FLT3-TKD was seen for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower (Figures 1 and 2 and Table). Overall (regardless of treatment) OS, EFS, and DFS estimates at 3 years were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT. Whereas the HRs for midostaurin vs placebo were 0.73 for both OS and EFS, the impact of treatment on outcomes varied between the individual NPM1/TKD subgroups and was not consistently observed when endpoints were censored at stem cell transplant (SCT) (Table). It should be noted that the number of patients in each subgroup was small and therefore the HRs with 95% CIs should be interpreted with caution. Multivariate analyses in these FLT3-TKD patients revealed that NPM1 genotype was an independent prognostic factor for OS, EFS and DFS (2-sided P 〈 .05), whereas study drug, age, sex, WBC at baseline and SCT (no/yes) did not reach this level of significance in the Cox model. Conclusions: This post hoc analysis of the FLT3-TKD patient subset in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Whereas midostaurin showed an overall benefit in the FLT3-TKD patients for OS, EFS, CR and DFS, the impact of treatment on outcome varied between the individual NPM1 subgroups within these FLT3-TKD patients and was not consistently observed.Further analyses using additional endpoints and additional multivariate analyses are planned. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180791, U10CA180888, U10CA180863, (CCSRI) #704970, U24CA196171; ClinicalTrials.gov Identifier: NCT00651261 Disclosures Voso: Celgene: Research Funding, Speakers Bureau. Larson:Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Heuser:Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; StemLine Therapeutics: Consultancy; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; Tetralogic: Research Funding; Sunesis: Research Funding; Daiichi Sankyo: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Amgen: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Brandwein:Lundbeck: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding. de Witte:Novartis: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Research Funding. Medeiros:Celgene: Consultancy, Research Funding; Genentech: Employment. Tallman:Cellerant: Research Funding; Orsenix: Other: Advisory board; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Cheng:Novartis: Employment. Gathmann:Novartis: Employment. Tiecke:Novartis: Employment. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Stone:Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; Agios: Consultancy, Research Funding; Orsenix: Consultancy; Ono: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Arog: Consultancy, Research Funding; Merck: Consultancy; Cornerstone: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Pfizer: Consultancy; Sumitomo: Consultancy; AbbVie: Consultancy.

Description: A total of 551 pts with newly diagnosed CML-CP received imatinib (IM) 400 mg orally once daily as part of the IRIS study (O’Brien et al, NEJM 2003). We now summarize the correlation of clinical responses with the steady-state trough plasma concentrations (Cmin) of IM and its major active metabolite CGP74588. Cmin is a reflection of IM clearance and metabolism in CML pts. Trough PK samples (24 hrs post dose) were obtained in IM pts at Day 1 and steady state (Day 29). The plasma concentrations of IM and CGP74588 were determined by liquid chromatography/mass spectrometry. Estimated rates of complete cytogenetic response (CCyR - 0% Ph+) and major molecular response (MMR - ≥ 3 log reduction in BCR-ABL/BCR ratio from a standardized baseline value for untreated pts) were given for the lower and upper quartiles (below Q1=25th percentile, above Q3=75th percentile) and the inter-quartile range of PK trough levels. After 4 weeks of IM at 400 mg, the overall mean (±SD, CV%) steady-state trough levels (Cmin) for IM and CGP74588 (n=351 pts) were 979 (±530, 54.1%) and 242 (±106, 43.6%) ng/mL, respectively. Median (Q1–Q3, min-max) values (in ng/mL) were 879 (647–1170, 153–3910) for IM and 223 (169–291, 50–841) for CGP74588. Times to CCyR and MMR within CCyR pts were significantly different between the three groups of IM plasma exposure (low/intermediate/high; p

Description: Background: Early allogeneic stem cell transplantation has been considered the only curative treatment for CML. The advent of imatinib provided a new chance to suppress long-lastingly the disease without risk of early deaths. As there is no randomized trial comparing transplantation with imatinib therapy, we compared the outcome between transplanted and imatinib-treated patients of two randomized trials. Data base: We used the survival data of patients randomly allocated to imatinib in the IRIS trial (Druker et al. N Engl J Med2006;355:2408) and compared them with the genetically randomized transplanted (matched related donors) patients of the German CML III and IIIA studies (Hehlmann et al. Blood;109:4686). Methods: Applying uniform inclusion criteria for age (18–55 yrs at diagnosis) to generate comparable samples, survival time was determined according to the intention-to-treat principle and after stratification for the Euro and EBMT scores using Kaplan-Meier curves. Information about Sokal and Euro score was missing for 123 and 128 patients from the IRIS trial and for 4 resp. 6 patients from the German CML III/IIIA studies. Results: 377 CML patients in chronic phase treated with imatinib and 285 patients with early allogeneic stem cell transplantation were analyzed. In the imatinib arm of the IRIS trial, 42 patients had been transplanted and 12 patients have died subsequently. Five-year-survival in this subgroup of 377 younger patients of the IRIS trial was 94.7%. The patients’ characteristics of the two groups were comparable (CML III/IIIA vs IRIS), median age: 38 vs 44 yrs., female sex: 40% vs 39%, Sokal Score low 49.8% vs 58.3%, intermediate 30.2% vs 25.2%, high risk 19.9% vs 16.5%; Euro Score low 62.7% vs 58.6%, intermediate 31.5% vs 34.9%, high risk 5.7% vs 6.4%. Median observation time was 75 months for transplanted patients and 61 months for imatinib-treated patients. Patients of both groups have not yet reached median survival times. Five-year survival rates were 94.7 % (all imatinib treated patients) and 71.1 % (all transplanted patients). In all prognostic strata, irrespective of the prognostic score used, five-year-survival with imatinib was evidently superior compared to transplantation: Euro score: low risk 97.8% vs 78.3%, intermediate risk 93.6% vs 58.9%, EBMT score 0–2: 94.7% vs 78.8%, EBMT score 3–4: 94.7% vs 52.2%. There were just 5 transplanted patients with an EBMT score 〉4. Neither the censoring of the 42 transplanted patients of the IRIS trial affected the results nor the in- or exclusion of the 12 subsequent deaths. Conclusions: We could not identify any subgroup of patients with CML who clearly showed a benefit from early transplantation compared to treatment with imatinib, given an observation time of 5–6 years.

Description: Background: In the International Randomized Study of Interferon and STI571 (IRIS), 553 patients (pts) with newly diagnosed CML-CP were randomized to receive imatinib (IM) 400 mg/d. The 5-year analysis of these pts showed that first-line IM yielded an estimated 87% cumulative CCyR rate and an estimated 89% overall survival (OS) and was generally well tolerated (Druker et al, NEJM 2006). We analyzed the IM pharmacokinetic (PK) exposure and evaluated its effect on efficacy and safety parameters. Methods: Pts were grouped into quartiles according to IM trough plasma concentrations at steady state (day 29 of therapy; Q1 1170 ng/mL). Adverse events (AEs) and discontinuations as well as CCyR (0% Ph+) rates were summarized based on these groups. A multivariate analysis was performed using stepwise logistic regression to examine whether IM plasma levels are prognostic for ability to achieve a CCyR independently of Sokal risk group, patient demographics, and laboratory data. Criteria for inclusion of variables into the statistical model was a P

Description: Background Imatinib is effective in L-CP CML patients (Pts), but response duration is unknown. From 12/1999 to 05/2000, the Novartis study STI571A110 recruited 454 Pts with confirmed diagnosis of CP CML. Pts were hematologically (n=133) or cytogenetically resistant/refractory (n=160) or intolerant (n=161) to IFN. Median time since diagnosis was 34 months (m). Pts were evaluated for best major and complete cytogenetic response (MCyR and CCyR), time to progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). This abstract includes data up to 56 m after the first patient and more than 48 m after last patient started treatment. Results: Median drug exposure as of 31-Jul-04 was 50 m. The initial daily dose was 400 mg. Dose increases after a median of 14 m were reported in 227 (50%) Pts. The table below summarizes discontinuation reasons, best responses observed and the estimated long-term outcomes at 48 m. n=454 (%) [95% Conf intervals] Still on Treatment 269 (59.3) Discontinued 185 (40.7) Progression/deaths from any cause 105 (23.1) AEs/toxicities 32 (7.0) BMT 5 (1.1) Withdrew consent/Lost/Admin. problems 43 (9.5) Pts achieving MCyR (includes CCyR) 301 (66.3) Pts achieving CCyR 248 (54.6) % Pts free of progression to AP/BC at 48 m (74.6) [70.4–78.9] OS at 48 m (82.4) [78.9–86.0] Median time to CCyR was 8.3 m [8.3–8.6 m]; 45 of the 248 Pts achieved CCyR after dose increase. The yearly risk of progression to AP/BC did not increase when considering all patients (7.8%, 6.0%, 7.2% and 7.1% within year 1,2,3,4 respectively). The corresponding risk rates for patients in MCyR at 3 m were 2.7%, 0.7%, 2.2%, 2.4%. Using the 3-m (and 12 m) landmark (n=446 or 421), Pts with CCyR, PCyR and minor CyR had an estimated OS at 48 m of 94(94)%, 93(94) %, 86(92) %, whereas Pts with only minimal CyR or no CyR had estimated 4-year OS of 85(78) % and 77(71) %, respectively. Among Pts who achieved MCyR and arrived to 48m of follow-up, 79% [74–84] maintain it; this value compares with 86% [80–92] for Pts with MCyR within 3 m. The following figure shows the duration of MCyR according to the time when MCyR was reached. Pts who had MCyR by the 3rd m did significantly better than the other groups (p= 0.02). However a MCyR obtained at a late time point (〉12 m) has a duration similar to the entire cohort. Half of the Pts who lost MCyR did not progress to AP while on study. Conclusion: Imatinib treatment for L-CP CML Pts failing IFN therapy is effective and produces durable cytogenetic responses and survival, with more than 80% Pts alive at 48 m and no evident increase in progression rate over time. Even Pts who failed to achieve any CyR reached OS of 71%. Obtaining a MCyR at 3–12 m resulted in 〉90% OS. Duration of MCyR was longer in Pts who responded within 3m, than in the other groups. The results will be updated for the meeting including 60-m data up to 31-July-05. Figure Figure

Description: The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1st line or 2nd line who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1st line IM 82% achieved CCyR, an estimated 69% during the 1st year (yr) of treatment. Of 359 pts who received 2nd line IM, 80% achieved CCyR, 62% during the 1st yr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p

Description: In the ongoing randomized, placebo-controlled, phase 3 study in patients with newly diagnosed FLT3-mutation-negative acute myeloid leukemia (AML; NCT03512197) investigating the effect of adding midostaurin to standard chemotherapy, event-free survival (EFS) is the primary endpoint. EFS is a standard endpoint in clinical studies in AML. In a recent FDA submission, EFS was confirmed by an advisory committee to be clinically meaningful in AML (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM570800.pdf. Accessed August 1, 2018). With the release of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E9 draft addendum, we describe EFS in the estimand framework to address the scientific question of interest and illustrate the power of this concept to transparently define the relevant population, the variable of interest, and the management of relevant incidents that can occur in a clinical trial ("intercurrent events"). The objective is to determine the benefit of adding midostaurin to the whole standard chemotherapy sequence, consisting of induction, consolidation therapy, hematopoietic stem cell transplant (HSCT; if applicable), and postconsolidation therapy, in patients with newly diagnosed AML without a FLT3 mutation. The main interest is the interventional effect of the whole treatment sequence and not the contribution of an individual part of it. The study population includes all randomized patients following the treatment policy approach. Patients can be randomized only if there is confirmation from the central laboratory that there is no FLT3 mutation. EFS is a composite endpoint defined as the time from randomization until death, relapse, or induction failure. Induction failure is defined as no achievement of remission until end of the induction period. The definition of induction failure also includes instances in which HSCT is conducted as salvage therapy in nonresponding patients. Per convention, the EFS event date of induction failure is set to the randomization date. The option to receive HSCT can be an outcome of the treatment. Therefore, clinical benefit is assessed regardless of whether patients received HSCT. This treatment policy approach mandates collection of disease assessments after HSCT has been completed. In the same consideration, the option to receive consolidation and postconsolidation treatment is also an outcome of the induction treatment as only patients achieving remission with induction qualify to continue with consolidation and postconsolidation treatment. As such, the benefit is assessed regardless of treatment duration. The analysis plan defines a supportive estimand to assess the treatment effect of midostaurin, excluding potential benefit from HSCT. Another supportive estimand assesses the effect of discontinuation of induction treatment due to toxicities. This approach addresses a hypothetical scenario in which patients did not receive HSCT, for instance, to estimate the midostaurin-only effect. However, the outcome of the treatment is not limited to the direct effect of an experimental compound but also includes which new treatment option the compound allows for the patients (eg, HSCT). The estimand framework is an efficient tool to ensure consistency between the scientific question and the definition of the study objectives. It ensures transparency in unfavorable yet unavoidable situations in clinical trials ("intercurrent events"). It facilitates communication within the clinical team and with health authorities. The outcome of studies that are following the estimand framework can be interpreted in a consistent manner. Disclosures Bengoudifa: Novartis: Employment. Weber:Novartis: Employment. Gathmann:Novartis: Employment. Hoenekopp:Novartis: Employment. Berkowitz:Novartis: Employment.

Description: Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (Cmins) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (± SD, CV%) steady-state Cmin for imatinib and CGP74588 were 979 ng/mL (± 530 ng/mL, 54.1%) and 242 ng/mL (± 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). Cmin of imatinib was significantly higher in patients who achieved CCyR (1009 ± 544 ng/mL vs 812 ± 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.

Description: Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon-α plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the IRIS patient population is summarized. Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations. Results: The downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients (4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent, 32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis. Conclusions: The 6-year follow-up analysis of the IRIS population indicates that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.

Description: Iron overload is a potentially life-threatening medical problem for patients with chronic transfusion-dependent anemias who cannot receive adequate iron chelation with existing therapies. ICL670 (deferasirox) is an investigational, tridentate, once-daily oral iron chelator that has demonstrated high iron binding potency and selectivity. The efficacy and safety of ICL670 is being investigated across a broad range of patient ages in a Phase II multicenter study in 7 countries in patients who are transfusion-dependent due to a variety of chronic anemias. The study population includes patients with various rare chronic anemias (n=98) and β-thalassemia patients who cannot be adequately treated with deferoxamine (n=86). The rare anemia category comprises 47 patients with myelodysplastic syndrome, 28 with Diamond-Blackfan anemia and 23 with other anemias of diverse etiologies. Between March and November 2003, 184 patients were enrolled in the following countries: Italy (57), US (36), France (20), UK (20), Canada (18), Germany (17), Belgium (16). Based on liver iron content (LIC) at baseline (2–3, 〉3–7, 〉7–14 and 〉14 mg Fe/g dw), patients were allocated to receive once daily oral ICL670 at doses of 5, 10, 20 or 30 mg/kg, respectively. Treatment was for one year initially, to be followed by an extension phase. LIC, the primary outcome measure, was assessed at baseline by liver biopsy or, when biopsy was contraindicated and also in some pediatric patients, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US) are performing SQUID assessments. At baseline, median (25–75th percentiles) LIC was 19.6 mg Fe/g dw (15.1–28.8) by biopsy and 9.1 (6.8–13.3) in those patients assessed by SQUID. Baseline patient demographics and disease characteristics (median values) are summarized in the table. ICL670 has been generally well tolerated. As of 30 April, 28 patients, predominantly with rare anemias, had discontinued the study due mainly to complications of the underlying disease. The key efficacy and safety data from the initial 12 months of therapy will be available for presentation in early December 2004. Disease group (by initial dose) Rare anemias (n = 98) β-thalassemia (n = 86) ≤ 10 mg/kg n = 16 20 mg/kg n = 29 30 mg/kg n = 53 ≤ 10 mg/kg n = 10 20 mg/kg n = 23 30 mg/kg n = 53 Age (yrs) median 56 39 49 21 23 25 No. of ≥ pts 2 -