ALBERT

Description: In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P 〈 .001, P = .004, and P 〈 .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.

Description: Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC 〉2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values 〉33% and 〉ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Description: Abstract 944 Background: In a phase II study (MDS-003), lenalidomide (LEN) resulted in RBC transfusion-dependence (RBC-TI; ≥8 consecutive wks) in 67% of pts and complete cytogenetic response (CyR) in 45% of pts with RBC transfusion-dependent IPSS Low- or Int-1-risk MDS with del5q. The optimal LEN dose in these pts is unclear. This phase III study (MDS-004) compared the efficacy and safety of 2 LEN doses (5 and 10 mg) vs placebo (PBO). Methods: In this multicenter, randomized, double-blind (DB) study, LEN naïve pts with RBC transfusion-dependent Low- or Int-1-risk MDS with del5q were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of a 28-day cycle, or PBO. Erythroid response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. PBO and LEN 5 mg pts who did not respond by wk 16 were considered as treatment failures and received LEN 5 or 10 mg, respectively (resp), in an open-label (OL) extension phase. Pts who completed 52 wks of therapy could enter the OL phase at their current LEN dose. The primary end point was RBC-TI for ≥26 consecutive wks. Secondary end points included duration of TI, CyR (IWG 2000), progression to AML, and adverse events. Efficacy analyses used the modified intent-to-treat (mITT) population: pts with centrally-confirmed Low- or Int-1-risk MDS with del5q and documented RBC transfusion dependence who had received ≥1 dose of study drug. Results: Overall, 205 pts were randomized (LEN 5 mg, n=69; LEN 10 mg, n=69; PBO, n=67). The mITT population comprised: 138 pts (LEN 5 mg, n=46; LEN 10 mg, n=41; PBO, n=51); median age 69 y (range, 36–86 y); 76% female; 48% Low- and 52% Int-1-risk; and 75%, 16%, and 9% with isolated del5q, del5q + 1 abnormality, and del5q + ≥2 abnormalities, resp. Median time since diagnosis was 2.8, 2.5, and 2.4 y in LEN 5 mg, LEN 10 mg, and PBO groups, resp. Median baseline RBC transfusion requirement was 6 units/8 wks in each treatment group. Key efficacy results are reported in the Table. At 52 wks, significantly more LEN 5 mg (41%) or LEN 10 mg (56%) pts had achieved TI (≥26 consecutive wks) vs PBO (6%; both p

Description: Abstract 3293 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of Ph+ CML patients (pts) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional efficacy and safety information in pts with imatinib-resistant or -intolerant CML in CML-CP, CML-AP, or blast crisis (BC) in a clinical practice setting outside of a registration program. Methods: Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Cytogenetic and hematological responses were provided by investigator assessment and monitored according to the current European Leukemia Network (ELN) recommendations. Safety assessments included monitoring for all adverse events (AEs), serious AEs and cardiac procedures. A centralized approach to molecular testing in France facilitated matching of the PCR results to ENACT pts who were monitored for molecular response as a standard of care. BCR-ABL/ABL ratio (in %) were reported on the international scale (IS), French physicians followed the current ELN recommendations and monitored pts by PCR at baseline and every 3 months thereafter. Major molecular response (MMR) was defined as IS ≤ 0.1%. In addition, pts with ≤ 0.003% IS are reported. Confirmed loss of MMR was defined as IS 〉 0.1% on two consecutive PCR tests in pts previously in MMR Results: A total of 168 French CML-CP pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008 with molecular response data available for 77% of pts. The median age of pts was 57 years, 56% were imatinib-resistant and 43% were imatinib-intolerant as determined by physician assessment. At study completion, 108 (64%) pts were continuing on nilotinib. The main reasons for treatment discontinuation were unsatisfactory therapeutic effect and AEs (16% for both). Median (range) duration of nilotinib exposure was 363 (4–765) days; median (range) average dose intensity was 793 (222–913) mg/day. Dose interruptions and reductions lasting longer than 5 days occurred in 36.9% and 11.9% of pts, respectively, with AEs being the main reason. The majority of nilotinib-related grade 3/4 AEs were hematologic, with thrombocytopenia (22.6%) and neutropenia (14.9%) being the most common. Non-hematologic AEs were mostly grade 1/2, not study drug-related and included fatigue, headache and rash. No incidence of grade 3/4 QT prolongation (QTcF 〉 500 msec) was observed and no pts experienced study drug-related grade 3/4 pancreatitis or pleural effusion on study. Overall major cytogenetic response (MCyR) and complete hematologic response (CHR) rates were both 54%, which are higher than those observed in the overall ENACT CML-CP cohort at 45% and 43%, respectively. Among the pts with molecular response data, 10 (7.8%) came to the study with MMR, one had a confirmed loss of MMR but subsequently regained MMR. The proportion of pts with post-baseline MMR (regardless of baseline response) was 42% (55 pts); 38% of pts achieved an MMR on study. The proportion of pts with a post-baseline ratio ≤ 0.003% IS was 16% (21 pts). The achieved molecular responses were durable with only 4 pts with confirmed loss of MMR, while another 3 pts met the criteria for loss of response but subsequently regained MMR. Of the 61 pts with CCyR and molecular data available, 72% also achieved MMR (see Table). Conclusions: This analysis of the French CML-CP subset of a large expanded access study further demonstrates that nilotinib is well tolerated and effective in heavily pretreated pts with CML-CP. A majority of pts (72%) with CCyR also had MMR. This data supports the use of nilotinib at 400 mg bid as the recommended dose in French pts. Disclosures: Nicolini: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Bordessoule:Novartis Pharmaceuticals: Honoraria. Belanger:Novartis Pharmaceuticals: Employment. Lamy:Novartis Pharmaceuticals: Honoraria. Gardembas-Pain:Novartis Pharmaceuticals: Honoraria. Maloisel:Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Calgene: Research Funding. Rea:Novartis Pharmaceuticals: Honoraria. Johnson-Ansah:Novartis: Consultancy. Lenain:Novartis Pharmaceuticals: Honoraria. Szczudlo:Novartis: Employment. Wang:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.

Description: Abstract 3803 Poster Board III-739 Background Transfusional iron overload can cause hepatocellular injury, which manifests as increased liver transaminase levels and, in some cases, may progress to cirrhosis. The once-daily oral iron chelator deferasirox (Exjade®) has been shown to reduce iron overload in patients with various transfusion-dependent anemias, and a previous analysis demonstrated a correlation between decreased iron overload and improved transaminase levels [Brissot P et al. Blood 2006;108(11):abst 3817]. As liver dysfunction is a common complication in patients with myelodysplastic syndromes (MDS), this analysis evaluates the relationship between serum ferritin (as a marker of iron overload) and alanine aminotransferase (ALT; as a marker of liver function) during deferasirox treatment in a large MDS population. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy

Description: Abstract 3806 Poster Board III-742 Background Although iron overload in patients with myelodysplastic syndromes (MDS) is a negative prognostic factor for survival, many chronically transfused patients are not regularly evaluated for iron overload and remain unchelated. The once-daily oral iron chelator deferasirox (Exjade®) maintains or reduces body iron in patients with MDS, however, it has not previously been assessed based on chelation history. This analysis therefore evaluates the efficacy and safety of deferasirox in a large population of chelation-naïve and previously chelated patients with MDS. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy 10 × ULN on two consecutive visits. Conclusions Although baseline serum ferritin levels were 〉2500 ng/mL, almost 50% of patients were chelation-naive, suggesting that the importance to treat iron overload continues to be underestimated in the MDS population. For previously chelated patients these data suggest that iron burden was not adequately managed with previous regimens. Irrespective of chelation history, with appropriate dosing based on transfusion requirements, serum ferritin levels and safety markers, deferasirox effectively decreased serum ferritin to