Complete Hematologic Response Rate Research Articles

PCN24 Treatment and Response Patterns in Chronic Myeloid Leukemia: Evidence from a Retrospective Study in Canada, Australia, and South Korea

TREATMENT AND RESPONSE PATTERNS IN CHRONIC MYELOID LEUKEMIA: EVIDENCE FROM A RETROSPECTIVE STUDY IN CANADA, AUSTRALIA, AND SOUTH KOREA Mitra D1, Whiteley J2, Iyer S2, Candrilli S3, Kaye JA4 1RTI International, Research Triangle Park, NC, USA, 2Pfizer, New York, NY, USA, 3RTI Health Solutions, Research Triangle Park, NC, USA, 4RTI Health Solutions, Waltham, MA, USA OBJECTIVES: To evaluate treatment and response patterns among patients with chronic myeloid leukemia (CML) in Canada, Australia, and South Korea (S.Korea). METHODS: Oncologists and hematologists in Australia (N 31), Canada (N 28), and South Korea (N 34) abstracted medical records of adults with CML between 1/1/ 2005 and 9/30/2010. Patient selection criteria included: chronic phase at diagnosis, either Ph or BCR-ABL , received 1st-line imatinib, and had not participated in a clinical trial. A subset received 2nd-line therapy with nilotinib or dasatinib. Rates of complete hematological response (CHR) at 3 months, complete cytogenetic response (CCyR) at 12 months, and complete or major molecular response (CMR/ MMR) at 18 months were assessed, stratified by 1stand 2nd-line therapy. RESULTS: Data on 610 patients ( 200/country) were collected. Patients’ mean age was 57 years and 59% were male. Patients received 1st-line therapy for 23 months on average (range: 16 [Canada] to 27 [S.Korea]). Among patients on 1st-line therapy, 78% had CHR at 3 months of treatment (67 [Australia] to 86 [Canada]), 48% had CCyR at 12 months (range: 42% [Australia] to 60% [S.Korea]), and 70% had CMR/MMR at 18 months (67 [S.Korea] to 77 [Australia]). Approximately 10% of patients (7% [Canada] to 14% [Australia]) had dose escalation to a median dose of 600mg. Twenty-two percent of patients discontinued imatinib (17% [S.Korea] to 27% [Australia]). Among those who discontinued, the most common reason was intolerance in Australia (60%) and Canada (37%), and other/no response in S.Korea (25%). Eighty-seven patients had 2nd-line treatment (68 dasatanib, 19 nilotinib). S.Korea had a greater proportion of 2nd-line nilotinib use (41%) than Australia (22%) and Canada (12%), and the mean time to 2nd-line therapy was 22 months post-diagnosis. CONCLUSIONS: This study further illustrates cross-country variations in CML treatment and response patterns, and emphasizes the need to understand CML populations in individual countries.

Treatment Response Patterns and Related Prognostic Indicators in Chronic Myeloid Leukemia (CML) Patients: A Multi-Country Medical Record Review Study

Abstract 3131 Objective:To assess treatment responses and prognostic indicators of response among patients with chronic myeloid leukemia (CML) in multiple countries. Methods:Physicians in United States (N=60), United Kingdom (N=45), Germany (N=49), and Japan (N=60) were recruited to abstract data retrospectively from medical records of patients diagnosed with CML between 1/1/2005 and 12/31/2009. Patients selected were age ≥18 years and in chronic phase at the time of diagnosis and were Philadelphia chromosome and/or BCR-ABL positive. Patients were also required to have received 1st-line treatment with imatinib and not be enrolled in a randomized clinical trial during the study period. We included a subgroup who had also received 2nd-line therapy with nilotinib or dasatinib. We assessed rates of complete hematological response (CHR) at 3 months (mos), complete cytogenetic response (CCyR) at 12 mos, and complete or major molecular response (MMR) at 18 mos, stratified by line of therapy. We used multivariable logistic regression models to evaluate the independent prognostic effects of age, gender, Sokal score, spleen size, race, Charlson comorbidity index score (CCIS), dose, and time to initiation of therapy. For patients on 1st line therapy, only those in chronic phase at the time of imatinib initiation and with non-missing data on the variables of interest (n=751) were included in the regression analyses. Results:Data were abstracted from medical records of 1, 063 patients in US (N=300), Japan (N=300), Germany (N=243), and in the UK (N=220). The average patient age was 55 years and a majority were male (60%). Response rates by line of therapy are listed in Table 1.Table 1:Response Rates Stratified by line of TherapyLine of TherapyTreatment (N)CHR at 3 months n (%)CCyR at 12 months n (%)MMR at 18 months n (%)1st LineImatinib (N=1,063)563 (53%)542 (53.1%)257 (25.1%)2nd LineDasatinib (N=148)72 (48.7%)44 (31.7%)25 (17.7%)Nilotinib (N=113)48 (42.3%)25 (22.9%)21 (18.9%)The proportion of patients achieving 1st-line response was similar across countries except that a greater percentage of patients from the UK obtained CHR at 3 mos (70.5%) compared to other countries (range: 46% [US] to [50.6% [Germany]) and MMR at 12 mos (55%) compared to the other countries (range: 26% [Japan] to 40% [Germany]). In 1st-line therapy, age ≤45 years (odds ratio [OR]=1.57, 95% CI=1.05–2.33 reference [ref] age 45–65) and low Sokal score (OR=1.64, 95% CI=1.16–2.33; ref intermediate) were associated with a greater likelihood of CHR response at 3 mos while Black race (OR=0.40, 95% CI=0.16–0.98; ref White race) and a CCIS score of 2 or higher (OR=0.48, 95% CI=0.25–0.75; ref: CCIS 0) were associated with a lower likelihood of CHR response at 3 mos. Age ≤45 years (OR=1.49, 95% CI=1.02–2.17) and Black race (OR=0.33, 95% CI=0.14–0.77) had similar associations with CCyR at 12 mos as for CHR at 3 mos. We did not find any significant prognostic indicators of MMR at 18 mos.In 2nd line therapy, choice of dasatinib as the 2nd-line drug (OR=2.77, 95% CI=1.19–6.43; ref: nilotinib), CHR to 1st-line therapy (OR=5.97, 95% CI=1.72–20.71; ref: no CHR), and low Sokal score (OR=7.93, 95% CI=2.93–21.51) were indicative of higher likelihood of CHR. Treatment with dasatinib (OR=7.43, 95% CI=2.36–23.40) and initial dose > 100mg for dasatinib or 600mg for nilotinib (OR=3.25, 95% CI=1.11–9.51; ref: dose ≤ 100mg for dasatinib or ≤ 600mg for nilotinib) predicted a greater likelihood of CCyR at 12 mos. We found no variables prognostic of MMR at 18 mos. Conclusions:We found several factors in addition to Sokal score to be prognostic for clinical response in 1st-line therapy, including younger age, White race, and no comorbidity. In addition, in 2nd-line therapy, the likelihood of response was higher in patients treated with dasatinib than in those who received nilotinib. To our knowledge, this difference has not been reported previously and could reflect a real difference in outcomes. However, it may also be due to residual confounding by factors that we could not control in a retrospective observational study. Disclosures:Trask:Pfizer: Employment. Mitra:Pfizer: Consultancy. Iyer:Pfizer: Employment. Candrilli:Pfizer: Consultancy. Kaye:Pfizer: Consultancy.

Clinical or Sub-Clinical Pancreatitis (PA) Associated with Nilotinib (Nb) As Frontline for Chronic Myelogenous Leukemia (CML)

Abstract 4443 Background:Nilotinib is now standard therapy in chronic phase (CP) CML, both as initial therapy and after imatinib failure. One of the adverse effects of nilotinib is the increase in serum amylase and/or lipase levels with or without clinical pancreatitis.The mechanism by which nilotinib increases serum pancreatic enzymes is not clear. Nilotinib is able to inhibit the non-receptor tyrosine kinase c-abl with high affinity. It is possible that c-abl inhibition might interfere with the molecular mechanisms regulating pancreatic cell death, inducing pancreatic damage. Nilotinib may release calcium from the intracellular acinar stores which regulate exocrine pancreatic secretion, or it may promote the accumulation of fatty acid inside the pancreatic acinar cells which disturbs exocytose. (JOP. J Pancreas (Online) 2010 May 5; 291–293). Purpose:To understand the frequency, risk factors and management strategy for patients who develop pancreatitis (clinical or subclinical) during nilotininb frontline therapy for CML. Method:We reviewed the records of 105 CML patients treated at our institution on a clinical trial from 7/2005 to 7/2011 with nilotinib 400 mg twice daily as initial therapy for CML in chronic phase. Results:The median age for the total population was 52 yrs (range, 17 to 89), and 63 were males (60%). Thirteen (12%) pts experienced pancreatitis at least once, most frequently asymptomatic (ie, grade 1). Pancreatitis episodes occurred 28 times (2 episodes were grade 3, 2 episodes were grade 4, 10 episodes were grade 2, and 14 episodes were grade 1). Thirteen episodes (47%) occurred at a dose of 200 mg daily, 4 (14%) at 400 mg daily, and 11 (39%) at 800 mg daily. In 3 instances total bilirubin was also elevated (2 grade 2 and 1 grade 4). One patient experienced recurrent elevations (16 episodes) of lipase and amylase despite dose reduction to 200mg once daily. Concurrent use of hydrochlorothiazide and moderate alcoholic intake were identified as risk factors associated with pancreatitis in the patient who experienced recurrent episodes. Diabetes was identified as a risk factor for pancreatitis in other 4 pts. Twenty four episodes (86%) were characterized by an elevation of lipase and amylase without any clinical symptoms. In four instances, patients experienced a moderate abdominal pain without other symptoms of pancreatitis. In 3 instances, imaging (ultrasound and/or CT scan) demonstrated normal pancreases. Management of pancreatitis included transient nilotinib interruption in most instances. In most patients, lipase and amylase values returned to normal within 14 days of stopping nilotinib. Three patients eventually required change from nilotinib to other tyrosine kinase inhibitors (TKI) (imatinib 2, dasatinib 1) without recurrence of pancreatitis. One of these pts switched to imatinib because of recurrent pancreatitis and the other 2 were switched because of nilotinib toxicities (liver and cardiac toxicity). At the time of pancreatitis episodes, 54% had achieved complete cytogenetic response (CCyR), and 8% complete molecular response (CMR). Rates of (CCyR) were 92% and 94% in patients who experienced and who did not experience pancreatitis, respectively. Rates of major molecular response (MMR) were 100%and 87% in patients who experienced and who did not experience pancreatitis, respectively. Rates of complete hematologic response (CHR) were 100% and 98% in patients who experienced and who did not experience pancreatitis, respectively. The 3-year event-free survival (EFS), treatment- free survival (TFS), and overall survival (OS) rates were 100% in patients who experienced and 93%, 97%, and 100% in patients who did not experience pancreatitis, respectively. Conclusion:Pancreatitis associated with nilotinib is most frequently grade 1 and 2 (asymptomatic enzyme elevation). Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit. Rarely, pancreatitis may require treatment discontinuation. Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Deciphera: Research Funding.

Evaluation of tolerability and efficacy of imatinib mesylate in elderly patients with chronic phase CML: ELDERGLI study

Imatinib mesylate (IM) is the treatment of choice in patients with newly diagnosed chronic myeloid leukemia (CML), irrespectively of their age. Nevertheless, information regarding tolerability and responses in advanced-age patients, a subgroup in which co-morbidities and other factors may influence outcome, is scarce, since they were excluded from most clinical trials. In this observational study (ELDERGLI), information regarding demographics, concomitant medication, physical examination, performance status, hemogram, biochemistry, hematologic, cytogenetic and molecular responses, time to progression, adverse events (AE) and severe adverse events (SAE) were prospectively recorded in a series of 36 elderly patients with CML, with a median age of 76.6 years. Most patients had cardiovascular co-morbidities, especially hypertension. Regarding IM toxicity, around one third of patients required treatment interruptions because of adverse events, especially hematologic toxicity (66% of cases that needed dose interruptions). When analyzing non hematologic adverse events, the most frequent ones were superficial edemas and GI symptoms. Of note, 9 of patients experienced an infection episode during the follow-up, and 4 were diagnosed during the study period of another type of cancer. Finally, cardiovascular events were reported in 7 patients, most of them with prior cardiovascular risk factors. Regarding responses, after 12 months of imatinib therapy, the rate of complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMolR) were 89%, 72% and 55% respectively. In summary, IM display, in advanced-age patients with chronic phase CML, an efficacy and safety profile comparable to younger patients.

The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study)

BackgroundThe median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs). Design and methodsWe conducted a dose-escalating study of daunorubicin combined to fixed doses of IM (imatinib mesylate, 600mg/d) and cytarabine (200mg/d for 7 days), followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs. ResultsThirty-six patients were evaluated. Median follow-up is 6.1 years. Daunorubicin was escaladed up to 45mg/m2/d 3 days. Twenty eight patients (77.7%) had hematologic response including 20 patients (55.5%) in complete hematologic response (CHR). Patients who received daunorubicin at 30–45mg/m2/d had higher CHR rates compared to other patients. Median overall survival was 16 months. Overall survival in patients with hematological response was 35.4 months. Better results were observed in patients diagnosed with MBC-CML at onset. ConclusionsThe combination of IM with a standard “3+7” regiment was well tolerated and provided a high response rate. More than 55% of the patients achieved CHR and hematopoietic stem cell transplantation (SCT) was feasible in half of the cases. This trial was registered at www.clinicaltrials.gov as # NCT00219765.

Clinical Activity of Bosutinib by Mutational Status In Patients with Previously Treated Philadelphia Chromosome–positive Leukemias.

AbstractAbstract 3434Bosutinib (SKI-606) is a dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. Previous reports of this open-label, phase 1/2 study have demonstrated the efficacy and safety of oral daily treatment with 500 mg bosutinib in adult patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (second-line setting; Cortes JE, et al. ASCO 2010. Abstract #6502) and dasatinib or nilotinib (third-line setting; Khoury HJ, et al. ASCO 2010. Abstract #6514), or with Ph+ advanced leukemias (ie, accelerated or blast phase CML, acute lymphocytic leukemia) following imatinib failure in the second- and third-line settings (Gambacorti-Passerini C, et al. ASCO 2010. Abstract #6509). Failure of therapy with imatinib and other TKIs may result from mutations in the Abl kinase domain that affect drug binding. Therefore, the current analysis compared the rates of hematologic and cytogenetic responses to 500 mg bosutinib in patients with and without Bcr-Abl kinase domain mutations. Of the 570 patients treated, 53% were male and the median age was 53 years (range, 18–91). Median duration of follow-up was 24.1 months (range, 0.6–53.8) for patients with CP CML in the second-line setting, 22.6 months (range, 0.3–47.3) for patients with CP CML in the third-line setting, and 12.1 months (range, <0.1-45.5) for patients with advanced leukemias. Among the 222 (39%) patients with baseline sequencing analyses across all study cohorts, 119 (54%) patients had 27 unique Bcr-Abl mutations (Table). Patients with and without mutations had similar rates of complete hematologic response (CHR; 78% vs 82%, respectively) and major cytogenetic response (MCyR; 56% vs 53%, respectively). Comparable rates of response to bosutinib were observed across P-loop and non–P -loop Bcr-Abl kinase domain mutations, except for the T315I mutation. In particular, although a small number of patients was evaluable for individual mutations, hematologic and cytogenetic responses were observed with mutations such as F317L, F359V/I/C, and E255K/V, which are commonly associated with resistance following sequential treatment with multiple TKI therapies. Although response rates among patients with the T315I mutation were lower, 2 of 6 (33%) evaluable patients achieved a CHR and 1 of 7 (14%) patients achieved a MCyR. Among patients with mutations, the rate of CHR was higher for those with CP CML in the second-line (95%) and third-line (83%) settings than for those with advanced leukemias (46%). The rate of MCyR was highest among patients with CP CML in the second-line setting (73%). In conclusion, bosutinib was associated with substantial clinical activity in multiple patient populations independent of the presence or absence of Bcr-Abl kinase domain mutations and across all types of mutations, with the exception of the T315I mutation. Disclosures:Gambacorti-Passerini:Pfizer Inc: Research Funding. Khoury:BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli:BMS: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria. Kelly:Pfizer: Employment, Equity Ownership. Besson:Pfizer: Employment, Equity Ownership. McMullan:Pfizer: Employment, Equity Ownership. Brummendorf:Pfizer: Membership on an entity's Board of Directors or advisory committees. Cortes:Pfizer Inc: Consultancy, Research Funding.

The Achievement of a 3-Month Complete Cytogenetic Response (3-mo CCyR) to Second Generation (2nd) Tyrosine Kinase Inhibitors (TKI) Post Imatinib Failure Is the Only Predictive Factor for Event-Free (EFS) and Overall Survival (OS)

AbstractAbstract 22892nd TKIs such as dasatinib and nilotinib have shown significant activity post imatinib failure, with high rates of hematologic and cytogenetic responses. Achieving early cytogenetic response is a known major determinant of outcome in patients (pts) treated with imatinib. In a previous report from our institution, we reported that the achievement of a previous cytogenetic response to imatinib therapy is a major predictive factor in pts receiving a 2nd TKI. The aim of our study was to assess the impact of a 3-mo CCyR on EFS and OS of pts treated with 2nd TKI post imatinib failure. 123 pts with chronic phase (CP) CML after imatinib failure were treated with dasatinib (n=78) or nilotinib (n=45). Median age was 56 years (range, 21–83). Median duration of CP (CML diagnosis to start of second generation TKI) was 67 months (range, 2–268). Their best response to imatinib was complete hematologic response (CHR) only in 24%, and cytogenetic response in 63% (28% complete, 17% partial, 18% minor). The CHR rates were 87% and 84% in pts treated with dasatinib and nilotinib, respectively (p=0.75). The major cytogenetic response rates were 64% and 62% (p=0.85), and the complete cytogenetic response rates were 60% and 56% (p=0.70). The rates of cytogenetic response at 3-, 6- and 12-mo were 59%, 63% and 69% (p=0.39) and 60%, 55% and 51% (p= 0.7) in pts treated with dasatinib and nilotinib, respectively, and the rates of CCyR at these same time-points were 32%, 41% and 48% (p= 0.13) and 36%, 36% and 35% (p= 0.99), respectively. The 3-year EFS and OS rates were 53% and 84%, respectively. Factors associated with poor EFS in the univariate were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, more than ≥90% Philadelphia-positive metaphases (Ph) at the start of 2nd TKI therapy, and lack of a 3-mo CCyR to 2nd TKI therapy. In a multivariate analysis, the lack of a 3-mo CCyR to 2nd TKI therapy (HR= 4.5; p<0.001) was selected as the only independent factor associated with poor EFS, with a 3-year EFS rates of 74% and 43% for pts with and without 3-mo CCyR, respectively. Factors associated with poor OS in the univariate analysis were older age (>55 years), increasing marrow blasts, lack of any cytogenetic response to previous imatinib therapy, and lack of a 3-mo CCyR to 2nd TKI therapy. In a multivariate analysis, only a lack of a 3-mo CCyR to 2nd TKI therapy (HR=5.4; p = 0.03) was independently associated with a lower probability of survival; the 3-year OS rates were 98% and 79% for pts with and without 3-mo CCyR, respectively.Therefore we analyzed factors that were associated with the 3-mo achievement of a CCyR. In the univariate analysis, high hemoglobin level, previous cytogenetic response to imatinib therapy, and ≤90% Ph, and increasing marrow blast% were associated with the achievement of a CCyR at 3 months of therapy with 2nd TKI. In the subsequent multivariate analysis for response, Ph% >90 and Hgb <12.0 were independent poor predictive factor for 3-mo CCyR. In conclusion, the achievement of a 3-mo CCyR is the only predictor of outcome in pts treated with 2nd TKI post imatinib failure. Pts with high tumor burden (defined Ph >90%) and anemia (Hgb< 12.0) have a low likelihood of achieving a 3-mo CCyR to 2nd TKI therapy and therefore should be offered additional options. Disclosures:Jabbour: BMS: Honoraria; Novartis: Honoraria. Cortes: Novartis: Research Funding; BMS: Consultancy; Pfizer: Consultancy, Research Funding.

Pegylated Interferon Alpha-2a Therapy for Patients with High Risk Essential Thrombocytemia: a Retrospective Analysis on 59 Patients.On Behalf of the French Intergroup of Myeloproliferative Disorders (FIM)

AbstractAbstract 1974 Background:Conventional therapeutic guidelines in essential thrombocytemia (ET) are based on established criteria of higher incidence of vascular complications: age more than 60 years, history of thrombosis, platelets more than 1000–1500 ×109/L and cardio-vascular risk factors. Hydroxyurea or anagrelide are the most commonly used cytoreductive therapy for high risk ET. Despite a proven activity of Interferon-alpha (IFN-α) in Ph negative myeloproliferative disorders, generalized use and efficacy have been hampered by frequent side effects. Nonetheless it is still a nonleukemogenic therapeutic option for younger patients and during pregnancy. More recently, phase II trials using Pegylated (Peg-) forms of IFN-α in patients with polycythemia vera (PV) or high risk ET have provided interesting results: first the superior toxicity profile is generally associated with a rapid hematologic response Second the molecular response described for a subset of JAK2 V617F positive PV or ET patients treated with Peg-IFN α-2a have indicated a selective targeting of the malignant clone with that latter agent. Methods:We revised cases of high risk ET having being or currently treated with IFN-α and reported by centres of the French Intergroup of myeloproliferative disorders (FIM). The current retrospective analysis was performed on data collected for the first 67 patients (pts) that have been observed for a median of 72 months (range 11–273). Among them, 59 pts have received Peg-IFNα-2a therapy. Assessment of the hematologic responses was performed at months 1, 2, 3 and then every 6 months. Results:For the entire cohort, median age was 37 years (range 17–64) and sex ratio F/M of 2.33. Previous thrombosis was observed in 19 cases and micro vascular disturbance in 4 pts. At diagnosis, median platelets count was 926.0×109/L (range 428.0; 4000.0), haemoglobin 14g/dl (8.0-14.1), leucocytes count 9.7×109/L (2.7-28.0). Detection of the Jak2V617F mutation was positive in 33 cases and negative for 26 pts.Median time from diagnosis to IFN-α was 50 months (1-256 months). IFN-α was generally administered as second line after Hydroxyurea. No prior therapy has been used for 6 pts. Reasons for IFN-α initiation were absence of hematologic response (31%), toxicity to the prior treatment (14%), pregnancy (16%), or medical decision for younger pts (39%).Of 67 pts of the cohort, 59 pts have been treated with Peg-IFNα-2a with a median duration of Peg-IFNα-2a of 16 months (range 1 day to 45 months). Efficacy and safety of the Peg-IFNα-2a were assessed in that subgroup. Thus 58 pts were evaluable for the hematologic response with at least 1 month exposure to Peg-IFNα2a.Overall, absence of response was observed in 4/58 (7%) pts, partial hematologic responses in 9/58 (16%) and complete hematologic response (CHR) was achieved for 45/58 (76%) of patients according to the European LeukemiaNet criteria. Cumulative incidence of CHR at 1, 3, and 6 months was 29%, 52% and 65% respectively. At 18 months, estimated probability of CHR was 83% (95%CI 71–92). At the last follow up 47/58 (81%) of the pts were still treated with Peg-IFNα-2a and overall 36 pts are in CHR. Median time to achieve CHR was 3 months. Median dose of Peg-IFNα-2a was 88μg weekly (range 28–180μg weekly). Reasons for discontinuation of Peg-IFNα2a (11pts) were related non hematologic toxicity in 7/59 pts (12%), 1 failure, and 3 pregnancies.By analysing the response according to the Jak2 status (58 pts), the overall CHR rates were 31 and 14 for the 37 JAK2 V617F mutated and the 21 JAK2 negative pts respectively. The median time to achieve CHR was 6 and 3 months. At 18 months the estimated CHR rates were 87% (73-95) and 66% (45-86). The difference is not statistically significant. Median doses of Peg-IFNα2a were 90μg (12-180) and 75μg (45-144) weekly. Duration of exposure to Peg-IFNα2a was 16 months (1-36) and 15 months (1-45). Conclusion:This retrospective analysis is the first attempt to present results on efficacy and tolerance of Peg-IFN on a large cohort of high risk ET not included in clinical trials. These results support the use of Peg-IFN in HR ET pts. Increase patients number, molecular analysis and update of these preliminary data will be presented. Disclosures:Off Label Use: Interferon alpha and Pegylated-Interferon alpha for myeloproliferative disorders.

Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

AbstractAbstract 2290 Introduction:Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods:We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results:A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions:OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. [Display omitted] Disclosures:Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

Impact of Prior Therapy and Suboptimal Response to Imatinib On the Efficacy and Safety of Nilotinib Among 1,422 Patients with Imatinib-Resistant or —Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): Sub-Analyses of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 2201 Poster Board II-178 Introduction: Nilotinib, a potent and highly selective BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib 400 mg twice daily in 1,422 pts with CP who were resistant and/or intolerant to imatinib. It is the largest single source of efficacy and safety information of any available TKI in CML. Study results are presented for all CP pts as well as 2 subpopulations: (1) 2nd-line pts who received imatinib as the only prior CML therapy with no prior exposure to other therapy including interferon (IFN), busulfan and ara-c; and (2) pts with 6- and 12-month suboptimal cytogenetic response (SoR) to prior imatinib therapy. Methods: In addition to all CP pts, ENACT study results are presented for 2 subpopulations, defined as follows. (1) Pts who received nilotinib as 2nd-line therapy received only imatinib (hydroxycarbamide was allowed) prior to nilotinib. Pts with any other therapy, including interferon, busulfan and ara-c were excluded. (2) Pts with 6- or 12-month cytogenetic SoR to imatinib were identified as: a) received imatinib as 1st-line therapy within 12 months of CML diagnosis; b) did not have imatinib resistance; and c) met ELN criteria for cytogenetic SoR (<PCyR at month 6 or <CCyR at month 12.) Results: A total of 1,422 CP pts were enrolled in the ENACT study between Jan. 2006 and Oct. 2008 from 293 study sites worldwide. The median age of pts was 52 years. At study completion, 857 (60%) pts were continuing on nilotinib. Median (range) duration of nilotinib exposure was 266 (1 - 807) days; median average dose intensity was 783 mg/day. The main reasons for treatment discontinuation were inadequate response (16%), AEs (14%) and other (10%). The majority of grade 3/4 AEs suspected of being study drug related were hematologic and the most common hematologic toxicities were thrombocytopenia (22%) and neutropenia (14%). Nonhematologic AEs were mostly grade 1/2. Grade 3/4 nonhematologic AEs were infrequent and included rash ( 5 days was similar between these pts and overall (interruption: 39% and 41%; reduction: both 5%), as was the median dose intensity for nilotinib (788 and 783 mg/day). MCyR and CHR rates were also similar between 2nd-line therapy pts and overall (MCyR: 47% and 45%; CHR: both 43%). (2) 12 pts were identified with cytogenetic SoR to prior imatinib therapy; 11 pts were 6-month cytogenetic SoR, 1 pt was 12-month cytogenetic SoR. The median duration of nilotinib exposure for these pts was higher than overall at 344 days (vs. 266) while their median dose intensity was slightly lower than overall at 741 mg/day (vs. 783). Of pts with cytogenetic SoR to imatinib, 75% (9) achieved MCyR, 50% (6) achieved CCyR and 67% (8) achieved CHR, compared to 45%, 34% and 43% for overall, respectively. MCyR and CCyR rates among pts with hematologic response were 60% and 80%, respectively. Median time to achieving MCyR and CHR among cytogenetic SoR pts was 3.8 and 3.4 months, respectively, faster than in the overall study (MCyR: 6.1 months; CHR: 4.9). Conclusions: This analysis further demonstrates that nilotinib is well tolerated in heavily pretreated pts with CML-CP with the efficacy and safety profile reported in ENACT being similar to that observed in the pivotal phase II registration study. The first sub-analysis of CP pts showed that prior exposure to therapeutic agents including IFN, busulfan and ara-c in addition to imatinib does not affect nilotinib dose intensity or response rates. The second sub-analysis demonstrates that pts with 6- or 12-month cytogenetic SoR experience higher CHR, MCyR and CCyR rates, and faster time to CHR and MCyR than pts who were imatinib failures, suggesting that nilotinib may be a suitable treatment option in pts with cytogenetic SoR on imatinib therapy. Studies are ongoing with nilotinib in suboptimal imatinib responders. Disclosures: Nicolini: Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Kim: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek: Novartis Pharmaceuticals: Honoraria. Turkina: Novartis Pharmaceuticals: Honoraria. Shen: Novartis Pharmaceuticals: Honoraria. Smith: Novartis Pharmaceuticals: Honoraria. Rizzieri: Novartis: Honoraria, Research Funding, Speakers Bureau. Szczudlo: Novartis: Employment. Berton: Novartis Pharmaceuticals: Employment. Wang: Novartis Pharmaceuticals: Employment. Bieri: Novartis Oncology: Research Funding. le Coutre: Novartis : Honoraria, Research Funding; Bristol Myers Squibb: Honoraria.

Imatinib Is Efficient but Has a Negative Impact On Growth in Children with Previously Untreated chronic Myelogenous Leukaemia (CML) in Early Chronic Phase (CP): Results of the French National Phase IV Trial.

Abstract 863 Aims:In order to investigate the efficacy and the safety of imatinib in children and adolescents with untreated Philadelphia-positive CML, the CML working party of the Société Française des Cancers de l'enfant (SFCE) conducted an open label, multicentric phase IV study trial (Clinical Trials.gov.NCT00845221). Patients and methods.Patients less than 18 yrs of age with newly diagnosed CP CML were eligible. Imatinib was administered orally at a dose of 260 mg/m2 which is equivalent in terms of drug exposure to the total dose of 400 mg in adults. Forty four children (64% boys) with a median age of 11.5 yrs (range 10 months-17 yrs) have been enrolled from 15 French pediatric centres between July 2004 and December 2008. Side effects were reported prospectively using the NIH CTCv2.0 criteria. Results.Median follow up is currently 17 months (range:1-67). The complete hematologic response rate was 86% and 98% (ITT) at 3 months and 6 months, respectively. The rate of complete cytogenetic response (CCyR) was 62% (ITT) at 12 months. The rate of major molecular response (MMR) defined as a BCR-ABL/ABL ratio ≤ 0.1% according to the International Scale was 34% (ITT) at 12 months. The median daily dose of imatinib was close to the intended doses, 250 mg/m2 (range 176-405) with a median treatment duration of 16 months (2 w to 67 mo). Three pts (7%) had a dose reduction of more than 25% of the theoretic dose. Nine pts (20%) interrupted imatinib temporarily at least once for a median duration of dose interruption of 12 days (range 2-70). Ten pts (23%) discontinued imatinib. The reasons for discontinuation were the following: allogeneic HSCT in CCyR or MMR (2 pts) according to the investigator choice, adverse event (2 pts: muscle pain 1 pt, liver enzyme elevation 1 pt), disease progression or failure (6 pts: loss of CHR [L248V mutation] 1pt, loss of CCyR [L384M mutation] 1pt, no cytogenetic response 1 pt, no molecular response 1 pt, loss of MMR 2 pts). One of them (loss of hematologic response) transformed to blastic phase shortly after coming off study and died. Grade III or IV toxicity was recorded in 14 pts (32%). GradeIII-IV hematologic toxicity was recorded in 8 pts (18%) including neutropenia in 18% and thrombocytopenia in 5%. Nine pts (21%) developed grade III or IV non-hematologic toxicity: muscle pain (2.5%), arthralgia (5%), weight gain (13%), liver enzyme (GOT/GPT) increase (6.5%). Change of body height was observed during the first year of treatment with imatinib in the 22 pts with a sufficient follow-up: a significant decrease of height standard deviation scores (SDS) was observed with a median of the difference of -0.37 (range, -1.09 to +0.14)(p<0.0001) between the start of the treatment and 12 months later. Conclusion.Imatinib is efficient in children and adolescent with previously untreated CML in early chronic phase. However, we report for the first time, a negative impact of imatinib on the growth in a cohort of children and adolescents treated with imatinib. Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 3286Poster Board III-1 Introduction:Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods:The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results:Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions:In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures:le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Sustained Responses and Resistance to Imatinib Mesylate in the First 173 Chronic Myeloid Leukemia Patients Accrued by the SCREEN Multicenter Study: First Interim Report.

Abstract 4276 IntroductionImatinib mesylate (IM) has shown unprecedented effectiveness in the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. As most of the data concerning the efficacy of the drug derive either from a single sponsored trial or from single institution reports, we decided to accrue all CML pts diagnosed in the Italian region of Sicily to the observational SCREEN (Siciliy CML Regional Enterprise) study, to evaluate the hematological, cytogenetic and molecular responses of this unselected population to IM. Patients and MethodsAlthough the study is still ongoing, 173 consecutive CML pts have been enrolled between January 2005 and June 2009 (cutoff time for the first interim analysis) by one of the 12 institutions involved. Each center was responsible for the diagnosis, treatment (IM 400 mg qd) and follow-up of the pts accrued, while all molecular analyses were centralized in Catania. Median follow-up time was 31 months. Eleven pts (6.3%) are currently off study. ResultsPts characteristics were as follows: 95 males (54.9%) and 78 females (45.1%) were enrolled with a median age of 53 years (range 24-90). Eighty-nine pts (51.4%) were low Sokal risk, 62 (35.8%) were intermediate risk and 22 (12.8%) were high risk. Nine pts (5.2%) displayed additional chromosomal abnormalities. Median leukocyte counts (1×109L) were 67.6 (range 3.4-718), median hemoglobin (g/L) was 122 (range 75-170) while median platelet counts (1×109L) were 317 (range 67-2620). Cumulative incidences of complete hematologic response (CHR) and complete cytogenetic response (CCyR) were 98.3% and 85% respectively, while 59.2% of pts obtained a major molecular response (MMR). At 54 months, estimated overall survival was 95.6%. Estimated progression free survival (accounting for all pts that failed IM according to the European Leukemia Net criteria) was 75.1%. Thirty pts (17.3%) presented resistance to IM, either because of failure to obtain a satisfactory response (primary resistance, 21 pts) or because of loss of previously obtained responses (secondary resistance, 9 pts). Thirty-three pts (19%) presented a suboptimal response, 8 because of failure to achieve a CCyR by 12 months of therapy and the remaining 25 because of lack of a MMR after 18 months of IM. Only 3 pts (1.7%) were intolerant to IM. Interestingly, the median amount of BCR-ABL transcript at diagnosis (measured according to the International standardized Scale) displayed by pts that failed IM or achieved a suboptimal response (106.5IS) was significantly higher than that of pts obtaining an optimal response (61.9 IS p=0.0031). ConclusionsIM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR and CCyR. Approximately 60% of cases will also achieve a MMR. 35-40% of pts will either fail IM or obtain only partially satisfying results (suboptimal response). High levels of BCR-ABL transcript at diagnosis might allow a rapid identification of this less responsive pt population. Disclosures:No relevant conflicts of interest to declare.

Retrospective Study of the Efficacy of Bortezomib in Primary Systemic Amyloidosis.

Abstract 4953 IntroductionPrimary systemic (AL) amyloidosis occurs as a result of the production a monoclonal protein by a clonal plasma cell or B-cell proliferative disorder. Reduction or complete eradication of the underlying clonal cell disorder is essential for an organ response. Melphalan/ dexamethasone or high dose chemotherapy with autologous hematopoietic stem transplant is currently considered the standard of care. Bortezomib a proteosome inhibitor is effective in reducing or eradication clonal plasma cells and has been shown to produce high complete hematologic response (CHR) rates in multiple myeloma. We therefore hypothesized that Bortezomib will produce a high CHR rate and hence a higher organ response in patients with AL. Material and MethodsOur amyloidosis data base which is prospectively collected was searched for patients with primary amyloidosis (AL) who were treated with Bortezomib containing regimen during their disease course. We identified 20 patients. We then assessed clinical features, hematologic and organ response based on the amyloidosis consensus working group criteria. We also evaluated overall survival and time to next therapy. ResultsWe identified 20 patients who received a Bortezomib containing regimen. The median age at diagnosis was 57 yr (range 43 - 79). There were 12 (60%) males. All patients had clonal plasma cell disorder except one patient with lymphoplasmacytic lymphoma. Median bone marrow plasma cell involvement was 10%. The amyloid protein was Lambda light chain in 12 patients and Kappa in 6 patients. Data was missing in 2 patients. The median serum m-spike was 0.5g/dL (range 0 to 3.5). The median number of organs involved was 1 (range 1 – 4). Nine patients had 2 or more organs involved. The specific organs involved were Kidney (13), Cardiac (12), Nerve (5) and liver (2). Median number of prior regimen was 1(range 0 to 3). Seven patients had received no prior therapy. The remaining 13 patients had received various treatments including oral Melphalan/dexamethasone (9), Lenalidomide/dexamethasone (3), Thalidomide/dexamethasone (1) and one patient who received R-CHOP for underlying lymphoplasmacytic lymphoma. Four patients had received a prior autologous stem cell transplant. The median time form diagnosis to Bortezomib treatment was 5 months. The Bortezomib regimen was mainly Bortezomib/dexamethasone (17patients), Bortezomib/Thalidomide/dexamethasone (1), Bortezomib/cyclophosphamide/dexamethasone (1). The Bortezomib was given mainly in the standard dosing 1.3mg/m2 days 1, 4, 8, and 11. Treatment was well tolerated. Hematologic response was seen in 17 patients including CHR (11), VGPR (3), PR (1), and MR (2). Thus resulting in a better than PR response of 75%. Three patients had no response. The median number of cycles to best hematologic response was 4 (range 1 – 9). The median total number of cycles administered was 4 (range 1 – 10). Organ response was seen in 10 patients (50%). These were mainly partial responses was seen primarily in patients with renal amyloidosis. Median time to next treatment was 7.5 months (95% CI: 4-9). Seven patients have received further therapy after their Bortezomib treatment. Three patients received consolidation treatment with Autologous PBSCT although they had all achieved VGPR or CHR. The other four received salvage chemotherapy for disease progression or lack or response, BMT (1), FCR (1), Pomalidomde/dexamethasone (1) and Melphalan/dexamethasone (1). Median follow up of all patients from diagnosis is 12 months (range 2 – 64). The median survival from diagnosis is estimated at 44.7 months (95% CI; 29.1 – 64.8). Median follow up from Bortezomib treatment is 5 months and median survival from Bortezomib treatment has not been reached. ConclusionBortezomib produced high hematologic response in this population of patients. Organs response was seen in 50% of patients. The durability of these responses is not known, because of the short follow up time. This study suggests that Bortezomib containing regimen may be beneficial in amyloidosis patients. A larger prospective study, looking at single agent Bortezomib or in combination with alkylator agents compared to standard melphalan/dexamethasone or autologous stem cell transplant is needed to help define the role of Bortezomib in primary amyloidosis. DisclosuresLacy:celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg. A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49). At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012). After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.

Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase

AbstractSecond-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph+ ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph+ ALL treated with dasatinib or nilotinib after imatinib failure. Twenty patients received sequential treatment with both dasatinib and nilotinib for a total of 146 instances. CHR and MCyR rates were 54% and 37%, respectively in AP, 17% and 39% in BP, and 33% and 50% in Ph+ ALL. Failure to achieve a CHR at the time of achievement of a MCyR was associated with an inferior outcome, similar to that of patients without a MCyR (2-year survival rate, 37% and 35%, respectively). In contrast, patients with MCyR and concomitant CHR had a 77% 2-year survival rate. Twelve of 29 patients with MCyR without concomitant CHR later achieved a CHR; the 2-year survival rate for these patients was 55% compared with 22% for those who never achieved a CHR. These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome.

Dasatinib (Sprycel®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Positive ALL: Results of the First 22 Patients Included in the EWALL-Ph-01 Trial (on Behalf of the European Working Group on Adult ALL (EWALL))

Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood . 2007; 110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories.A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1).The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).

A Phase III, Randomized, Open-Label Study of 400 Mg Versus 800 Mg of Imatinib Mesylate (IM) in Patients (pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints: 1-Year Results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study

Background: IM 400 mg/d is the standard of care for pts with newly diagnosed CML-CP. Previous reports suggest the rate of major molecular response (MMR), defined as BCR-ABL/control gene (BAC) ratio of ≤ 0.1% on the International Scale, predicts for a benefit in long-term outcomes. Phase 2 trials demonstrated that IM 800 mg/d as initial treatment of CML-CP decreases the time to MMR and increases the depth of molecular response (MR), and may therefore improve long-term outcomes.Methods: TOPS is a prospective, open-label, randomized (2:1) Phase 3 trial that compared IM 800 mg/d to 400 mg/d in CML-CP. Pts were stratified by Sokal risk score. The primary endpoint is MMR rate at 12 months (mo) and secondary endpoints include: rates of complete hematological response, complete cytogenetic response (CCyR), time to CCyR and MMR, progression to accelerated phase (AP) or blast crisis (BC), eventfree survival (EFS), overall survival (OS), IM dose-intensity, pharmacokinetics, and safety. Rates were compared by Fisher's exact test and time to event outcomes by logrank test.Results: 476 pts were enrolled (800 mg/d, n=319; 400 mg/d, n=157) at 103 sites in 19 countries between 6/05 and 12/06. Median age at diagnosis was 47 yrs, and 24% of pts had high Sokal risk score. Significantly more pts receiving IM 800 mg/d achieved MMR at 3 mo and 6 mo, but not at 12 mo when compared with 400 mg/d (Table 1). Time to MMR was faster in the 800 mg/d arm compared to 400 mg/d; P = .0038.Table 1: MMR rate (%) over time according to randomized dose of IMMMR rate (%)Intent-to-treat (ITT) populationEvaluable pts (with polymerase chain reaction assessment)400 mg (N = 157)800 mg (N = 319)P-value400 mg %, (n)800 mg %, (n)P-valueMonth 3312.00114 (137)14 (283).0011Month 61734.000220 (135)39 (276).0001Month 93645.060441 (136)54 (267).0203Month 124046.203546 (133)54 (269).1386Achievement of MMR according to average dose over the first 12 mo of treatment was greatest when the intended dose intensity (DI) was achieved (Table 2).Table 2. MMR at 12 mo according to DI (evaluable patients)Randomized DoseMMRDI (first 12 mo) (n)MMR rate, % [95% CI]400 mg (n =133)46%≥ 400 mg (74)50 [38−62]< 400 mg (59)41 [28−54]800 mg (n =269)54%800 mg (52)63 [49−76]600 – 799 mg (134)62 [53−70]400 – 599 mg (69)38 [26−50]< 400 mg (14)21 [5−51]CCyR occurred faster in the 800 mg/d arm, indicated by a higher response rate at 6 mo (57% vs. 45%, P = .0146). At 12 mo rates of MMR and CCyR (ITT population) were higher for the 800 mg/d arm but were no longer significantly different (MMR 46% vs. 40%, P= .2035; CCyR 70% vs. 66%, P= .3470). In pts with high Sokal risk scores, rates of MMR at 12 mo were 41% and 26% (P = .1565) for the 800 mg/d and 400 mg/d arms, respectively. Exploratory analysis of MR at 3 mo and its correlation with achievement of MMR at 12 mo follow. Of the pts in the 400 mg arm with BAC ratios >0.1–≤ 1%, >1–≤ 10% or > 10% at 3 mo, 83%, 46%, and 11% later achieved an MMR at 12 mo. In the 800 mg arm 73%, 45% and 21% of the pts with respective BAC ratios achieved an MMR at 12 mo. Based on the BAC ratio at 6 mo, the observed MMR rate at 12 months was 52%, 11%, and 0% in the 400 mg/d arm compared to 46%, 14%, and 18% in the 800 mg/d arm. In the first year of follow-up, 6 pts had documented progression to AP/BC during treatment: 3 (1.9%) in the 400 mg/d arm and 3 (0.9%) in the 800 mg/d arm. At 12 mo, 85% of pts in the 400 mg/d arm were receiving the randomized dose compared to 62% of pts in the 800 mg/d arm. Median DI was 400 mg/d in the 400 mg arm and 750 mg/d in the 800 mg arm. Dose interruptions > 5 days occurred more frequently in the 800 mg/d arm (67% vs 38%). Earlier achievement of MMR correlated with IM plasma trough level at 1 mo for the overall TOPS cohort; pts with IM concentrations < 1165 ng/mL (lowest quartile of the aggregate group) achieved MMR slower than those with concentrations ≥ 1165 ng/mL (p=.0149). The most common grade 3/4 nonhematologic toxicities were rash, diarrhea and myalgia occurring slightly more frequently in the 800 mg/d arm. Grade 3/4 hematologic toxicity occurred more frequently in pts receiving 800 mg/d.Conclusions: TOPS confirms the efficacy and safety of IM in newly-diagnosed CML-CP. MMR occurred earlier in pts treated with 800 mg/d and in patients with plasma IM level above the lowest quartile, reinforcing the utility of IM blood level testing to optimize treatment. DI of IM 800 mg/d was maintained and tolerability was good. Additional follow-up is required to evaluate the effect of dose and MR on long-term clinical outcomes.

Serum Erythropoietin Dose Not Participate in Anemia That Persists in CML Patients after MMR Achievement by Imatinib Mesylate Therapy

Serum Erythropoietin dose not Participate in Anemia that Persists in CML Patients after MMR Achievement by Imatinib Mesylate TherapyThe IRIS study revealed that imatinib mesylate (IM) has resulted in durable responses in patients with CML in early chronic phase. Overall, 86% of patients on IM achieved complete hematologic response (CHR) by 3 months and 78% achieved complete cytogenetic response (CCR) by 18 months.According to the European LeukemiaNet guidelines, CHR is defined without evaluation of anemia. In the IRIS study, grade 3 or 4 of anemia was reported as 4% after 5 years of therapy, however, we found most patients remain mild to moderate anemia even after achievement of major molecular response (MMR). Persistent anemia sometimes deteriorates patients' quality of life and is thought to be clinically important.Here, we investigated frequency and severity of anemia, and participation of serum erythropoietin (EPO) among 23 patients, who have achieved MMR by IM at doses in excess of 300mg for more than 2 years. At diagnosis, the median age was 53 years (range 20–87) and 14 were male. 20 patients were in chronic, and 3 in accelerated phase. Median leukocyte count was 31.6 × 109/L (range 4.1–216.3 × 109), median hemoglobin (Hb) was 13.1 g/dl (range 6.2–16.2), and median platelet count was 629 × 109/L (176–1640). The cumulative rate of CHR by 3 months was 100% and that of CCR by 12 months was 77.3%. Among 18 patients who had MMR, hematologic adverse events were assessed. After reaching MMR, leukocytopenia was observed in 3 (16.6%) patients (grade 2; 2pts, grade 3;1pt), anemia was in 13 (72.2%) patients (grade 1; 10pts, grade 2; 2pts, grade 3; 1pt), and thrombocytopenia was in 3 (16.6%) patients (grade 1; 2pts, grade 2; 1pt). Mild to moderate anemia tends to persist at high rates as compared with other cytopenias. In anemic group, median MCV, MCHC, and reticulocyte was 99.4fL (range 91.6–113.1), 33.3% (range 30.4–35.2), and 53691/micro L (range 30450–72324), respectively, and serum urea and creatinine were normal. To reveal mechanism of persistent anemia, EPO levels were measured by a radioimmunoassay (normal range 9.1–32.8 mIU/ml). For control, we used the formula: log[EPO]=3.436–0.1675[Hb], which was led by 58 iron deficiency anemia (IDA) patients and had been previously reported (Toyoda A, et al. Exp Hematol 21:1085, 1993). The EPO corresponding to each Hb level from the formula was defined as the expected value. The median serum EPO level of CML patients with anemia was 46.0 mIU/ml (range 23.9–188.1). Comparison of the observed EPO with the expected EPO levels showed no significant differences (p=0.557). The equation of regression line for the observed EPO was y=−21.07x+284.2 (Figure 1. solid line, r=−0.732, p=0.0008), and that of the expected EPO was y=−22.65x+296.3 (Figure 1. dashed line, r=−0.939, p<0.0001). In addition, serial EPO measurement could be performed in one patient treated with IM. At the diagnosis of CML, Hb was 11.0g/dl and EPO was 47.7mIU/ml. He developed anemia with Hb of 7.8g/dl due to gastrointestinal bleeding, and EPO was 183.6 mIU/ml. After discontinuation of IM for 7days, Hb was 8.4g/dl and EPO was 64.9mIU/ml. These data show that IM has little influence on the serum EPO levels.In conclusion, grades 1–2 anemia frequently persist in CML patients after MMR achievement. The EPO response does not concern about the condition of persistent anemia, and IM have little influence on the serum levels of EPO. [Display omitted]

Long-Term Significance of Achieving a Major Cytogenetic Response (MCyR) without a Complete Hematologic Response (CHR) among Patients (pts) with Chronic Myeloid Leukemia (CML) in Advanced Phase Treated with Second Generation Tyrosine Kinase Inhibitors (TKI).

The BCR-ABL TKI, dasatinib (D) and nilotinib (N), are effective in Philadelphia chromosome-positive (Ph+) leukemias, including all stages of imatinib-resistant CML and Ph+ ALL. For both dasatinib and nilotinib, the reported rates of MCyR are higher than the rates of CHR; that is, some pts achieve MCyR but may have cytopenias that make their hematologic response less than a CHR; this has been attributed to myelosuppression induced by TKI. At present it is not known whether pts with MCyR who do not have CHR have a similar outcome as those with a CHR. We studied 135 pts with accelerated (AP; n=84) or blast phase (BP; n=47) CML or Ph+ ALL (n=4) treated with D (59) or N (76) for imatinib resistance, to see whether the presence of cytopenias at the time of best response affected the prognosis. The median age was 55 yrs (range, 15 to 98) and 62 were female. 56 (41%) had bcr/abl mutations at the start of therapy. Overall 36 pts (27%) achieved MCyR. All the 36 pts who achieved a MCyR after treatment with N or D had received imatinib for an average time of 34 mos (range 4–78) and 24/36 pts had obtained a MCyR under imatinib. They started the new TKI 66 mos after first diagnosis (12–336). 2-yr survival rates for pts that achieved MCyR was 72% compared to 35% for those without MCyR (p<0.001). There was a trend for an inferior survival for those not having a concomitant CHR at the time of MCyR compared to those with CHR (2-yr survival 58% vs 82%; p=0.11). The rates of CHR and MCyR were 68% and 29%, respectively in AP; 32% and 21% in BP, and 50% and 50% in Ph+ ALL. Among pts in AP, 17/24 (70%) who achieved a MCyR, had a CHR at the time of best cytogenetic response; 6 of these 17 (35%) pts eventually failed (lost response or transformed), compared to 3/7 (43%) of those with no CHR at the time of MCyR (p=0.28). The results are similar when analyzing separately pts treated with N or D. 2-yr survival was 88% and 66% for those with and without concomitant CHR (p=0.29). Among the 10 pts in BP that achieved a MCyR, 5 had a CHR at the time of best cytogenetic response. Three (60%) of these pts eventually failed (lost response), compared to 4 failures among the 5 pts with no CHR at the time of MCyR (p=1.0). Survival rates at 2 yrs were 60% and 40% for those with and without concomitant CHR (p=0.29). Among the 2 patients with ALL that achieved MCyR, one had comcomitant CHR (treated with N) and the other did not have CHR (D); both of them failed. Of the 18 pts who failed after having achieved an MCyR, 7 had a mutation before starting treatment with a 2nd TKI (A433T, G250E, E355G, E459K, M244V, M315T, F317L), and 6 developed a new mutation after treatment (F317L, F311I, Y253H, G476C, E255K, H359V). Five of them occurred in pts with a concomitant CHR and 1 without a CHR. These results suggest that achievement of MCyR with residual cytopenias (ie, without a concomitant CHR) may not have the same favorable outcome as that of MCyR with concomitant CHR. Whether this is related to pt- or disease-related characteristics remains to be determined.