ALBERT

Description: Abstract 4452 Background: Molecular Monitoring of BCR-ABL through standardized qPCR according to the international scale (IS) has been recently included in the follow-up of CML patients treated with tyrosine kinase inhibitors (TKIs) at the IMSS. The Molecular Biology Laboratory of the “Hospital of Specialties” at the “National Medical Center Siglo XXI”, have recently achieved full standardization of the qPCR technique to the international scale (using a conversion factor provided by Adelaide lab). The use of the IS in the molecular monitoring expressed as Bcr-Abl/Abl ratio in percentage is very important, since this is the best way to adopt appropriate strategies with TKI therapy. Objective: To report the evaluation of molecular status of 485 patients with CML attended at the Instituto Mexicano del Seguro Social using the IS in a reference standardized Mexican laboratory. Material and Methods: From August 2011 to May 2012, peripheral blood samples of 485 patients with CML, were sent to our laboratory. We extracted RNA as previously described. A minimum of 5 ml of whole blood was required in order to maximize optimal results. Then we put these results in our database and classified patient samples in five groups according the percentage of Bcr-Abl/Abl in the international scale: The first group were patients with 〉10% of Bcr-Abl; the second group were patients with 〉1–10% of Bcr-Abl; the third group were patients with 〉0.1–1%; the fourth group were patients with ≤0.1% and the fifth group were patients with undetectable Bcr-Abl transcripts. Results: We found the following distribution: Group I (〉 10% Bcr-Abl): 91 patients (18.76%); Group II (〉1–10% Bcr-Abl): 65 patients (13.4%); Group III (〉0.1–1% Bcr-Abl) 83 patients (17.11%); Group IV (≤0.1% Bcr-Abl) 122 patients (25.15%); and Group V: undetectable Bcr-Abl: 124 patients (25.56%). Conclusion: Fifty percent of CML patients treated with nilotinib, imatinib or dasatinib, have reached a deep molecular response, that is, Major Molecular response (MMR) or better. Another 17% has reached a molecular response (〉0.1–1%) that is equivalent to Complete Cytogenetic response (CCyR). This information is very useful for clinicians and should be interpreted individually according the lenght of treatment with TKIs, following current CML guidelines and recommendations. Until now, molecular monitoring using the IS was only possible through sending samples to US laboratories. It is important that Mexican clinicians at our institution have now the opportunity to rely on a Mexican validated and standardized laboratory. The results of the molecular response in this cohort of CML patients can be compared to the data of another countries using the IS. Classifying patients according to their molecular status could help to optimized therapies at our institution. Disclosures: Nacho-Vargas: Novartis Oncology: Employment.

Description: Abstract 6 Acute promyelocytic leukemia (APL) is a curable disease, and contemporary treatment based on the combination of all-trans retinoic acid (ATRA) with anthracyclines results in overall survival (OS) rates of around 90% at five years. Unfortunately, the treatment outcome of patients with APL in developing countries is significantly less. A recent Brazilian study had reported an OS of 53% with a first 5-days mortality of 13.4%. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, México and Uruguay. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. Results of the immunofluorescence for PML was obtained within hours and upon confirmation of the diagnosis, patients were enrolled in a protocol identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin. Supportive care aimed at maintaining platelet counts above 30,000/μl and fibrinogen levels above 150 mg/dl. In each country, cases were discussed every other week through internet and whenever needed international experts were involved. As of June 2009, 102 (70 Brazil, 25 Mexico, 7 Uruguay) APL patients were enrolled. The median age was 34 y (range: 9–72y) with 55 males (54%).The median white blood cell counts (WBC) at baseline was 3.6×109 /L(range: 0.2–149.7). The distribution of the relapse risk score at diagnosis according to PETHEMA-GIMEMA criteria was 14 low (14%), 54 intermediate (53%) and 34 high risk(33%) respectively. The incidence of low risk APL appeared lower than the values reported in developed countries. Of 102, 97 patients have toxicity and response data available. Of these 97, 12 (12.3%)experienced at least three symptoms/signs of differentiation syndrome (DS) and 77 (79%) patients achieved a complete remission (CR). Twenty-three deaths occurred and the cause of deaths included 9 hemorrhage, 8 infection, 2 DS . The 7 and 30 day mortality rates were 8% and 19.6%, respectively, and the one- year overall survival was 75% (95%CI:68%–84%). The median follow-up time among survivors was 14 months (range: 1.3–35). Among 77 patients who achieved CR, the 1-year OS and disease-free survival from the date of CR was 95% (95% CI: 89%–100%). Only one patient relapsed. For patients surviving a minimum of 30 days the outcome was similar to that reported by the twin PETHEMA-LPA 2005 protocol in European patients. Prognostic factors for overall survival were examined using log-rank test as well as multivariate Cox models. Factors predicting OS were a high relapse risk score at baseline (1-year OS: 59% for high, 87% for intermediate, 91% for low, p=0.0007) and age. The 1-year OS was 85% for age

Description: Abstract 2292 Background: This ongoing international, prospective registry provides 5-year longitudinal data on diagnosis methods, management strategies, and outcomes for CML patients (pts) worldwide. Deviations from published disease management recommendations and differences by region or center setting were examined. Methods: Pts (≥ 16 yrs of age) within 6 months of CML diagnosis were enrolled from Latin America (LA), United States (US), Asia Pacific (AP), Middle East and Africa (MEA), and Russia and Turkey (RT). Baseline demographics, medical history, current disease status and management information were collected at approximately 6-month intervals or with a change in disease status or management. Results: With a cut-off of May 10, 2010, data were reported on 1667 patients from 175 centers, including 456 (27.4%) from LA, 287 (17.2%) from US, 462 (27.7%) from AP, 175 (10.5%) from MEA, and 287 (17.2%) from RT. Most (62%) sites participated in CML studies within the past 5 yrs. The majority (93.7%) of patients were in chronic phase CML, similar across all regions, although more pts were diagnosed in accelerated phase or blast crisis (9.9%) in LA than in any other region (US, 4.5%; AP, 4.3%; MEA, 5.7%; RT, 5.9%). Centers most commonly described themselves as government hospitals in LA (42.1%), private hospitals/practices in US (62.7%), academic institutions in AP and MEA (57.9% and 66.7%) and regional/community hospitals in RT (50%). Median age was 47 yrs, with the lowest median age in AP (41) and the highest in US (53). Overall, 57.4% of pts were male and 9.3% of pts with a cytogenetic (Cy) assessment at diagnosis had an additional chromosomal abnormality detected in the Philadelphia chromosome-positive cell. Hematologic (91.2%) and Cy (85.6%) assessments were used for CML diagnosis in most pts. For Cy assessment, the method used varied widely by region and center (Table 1). Molecular assessments at diagnosis were performed in 63.2%, 50.5%, 60.6%, 62.9%, and 32.4% of pts in LA, US, AP, MEA, and RT, respectively, and were most common at regional/community hospitals (65.9%) and least common at private hospitals/practice (34.9%). Only 23.4% of centers utilizing molecular assessments at diagnosis reported results using the international scale. The most common co-morbidities at baseline were cardiac disorders in 377 (22.6%) pts, including hypertension in 329 (19.7%) pts, and diabetes in 134 (8.0%) pts. Pulmonary disorders were present at baseline in 49 (2.9%) pts. While imatinib was the most widely used therapy, hydroxyurea was being used as primary CML treatment (not merely for leukocyte reduction) in 401 (24.1%) pts prior to registry entry. Conclusions: The WORLD registry has included over 1,600 pts worldwide. In a ‘real world' setting, many patients are not managed according to published disease recommendations or guidelines. For example, a substantial percentage of pts did not have karyotyping or molecular assessments performed at diagnosis, even though karyotyping can detect additional chromosomal abnormalities in Philadelphia chromosome-positive CML and molecular monitoring is the most sensitive means of disease detection. Furthermore, hydroxyurea is still used as primary therapy in a significant proportion of pts. The WORLD CML Registry will continue to assess global trends in the diagnosis and management of CML, particularly as new frontline therapies become available. Disclosures: Pasquini: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Cortes: Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Joske: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Meillon: Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Mongay: Novartis: Employment. Reynolds: Novartis Oncology: Employment, Equity Ownership. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kim: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Key Points For patients in developing countries with APL, a clinical network of institutions made it possible to reduce significantly the early mortality and improve the OS.

Description: Abstract 1695 Background: A global, prospective registry was established to document the frequency of diagnostic testing, management (mgmt) strategies, and outcomes of patients (pts) with CML. Here, we summarize the reported deviations from published disease mgmt recommendations and the overall efficacy achieved by pts. Methods: 1853 pts (≥ 16 years of age) within 6 months (mo) + 2 weeks of CML diagnosis were enrolled from Latin America (LA; n = 497), United States (US; n = 379), Asia Pacific (AP; n = 465), Middle East and Africa (MEA; n = 209), and Russia and Turkey (RT; n = 303). Baseline demographics and medical history were collected at enrollment; current disease status and mgmt information were collected at approximately 6-mo intervals or with a change in disease status or mgmt. Results: From February 2008 to June 2011, data were available for 1831 (99%) pts. Across all regions, nearly all (93.8%) screened pts were in chronic phase CML. Regardless of the time of evaluation (eval), disease burden was mostly assessed through the use of hematologic counts (Table 1). Cytogenetic testing and molecular monitoring were used in a minority of pts at any timepoint. Hydroxyurea (HU) and imatinib were the first agents used in 61.9% and 29.5% of pts, respectively (Table 2). Overall, 81.1% of pts received imatinib therapy at some time and it was the most common second agent (48.1%) pts received. Among the 49% of pts who had response assessments, subsequent treatment changes occurred most frequently (23.9% of pts) at the 3-mo timepoint (Table 1). The median time from disease eval to dose/regimen modification was 3 days. Of those who received imatinib, 32% had dose modifications primarily for: lack of efficacy (20%), physician request (20%), and adverse events (19%). Of the pts with a corresponding eval at 12 mo after diagnosis, 88% had a CHR, 65.4% had a CCyR, and 42.5% had a MMR (BCR-ABLIS ≤.1%). These data are preliminary; response assessments by treatment, as well as further efficacy analyses, are ongoing. Conclusions: Overall, the majority of pts did not have cytogenetic or BCR-ABL transcript level testing performed per the European LeukemiaNet recommendations. Furthermore, despite availability of more effective therapies for the treatment of CML, HU is still used as a primary therapy in a substantial proportion of pts. Based on this analysis, pts outside the US primarily receive HU as initial therapy rather than tyrosine kinase inhibitors (TKIs). Overall, second-generation TKIs, such as nilotinib and dasatinib, are infrequently used. These results illustrate the need for continuing education on the mgmt of CML in order to improve outcomes for all pts. Disclosures: Pasquini: Bristol Myers Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuitcals: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Zernovak:Novartis: Employment, Equity Ownership. Sivarathinasami:Novartis: Employment. Collins:Novartis: Employment. Hughes: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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 1701 Mutations within the BCR-ABL domain are the most frequent mechanism of imatinib (IM) resistance. The second generation inhibitors (SGI) are indicated for imatinib intolerance or resistance and the initials trials showed similar response rates in IM resistant patients after IM failure, independent of mutation status, with exception of T315I. The aim of this work was to report the frequency of BCR-ABL mutations in chronic myeloid leukemia (CML) patients of a Latin American population and to evaluate the clinical impact of the presence and type of mutations in overall survival (OS), progression free survival (PFS) and in the response to second generation inhibitors (SGI). Methods: retrospective analysis of 17 centers from Latin America. A total of 529 CML patients with mutation analysis performed in samples collected between 2002 and 2011 were included. Mutations were detected by direct sequencing from bone marrow or peripheral blood samples, collected from CML patients. After imatinib resistance, patients were treated with SGI (69%) or other treatments. Overall survival (OS) was calculated from date of mutation detection until last follow-up or death, and progression-free survival (PFS) from date of mutation detection until progression to accelerated phase or blast crisis, last follow-up or death. Survival curves were calculated using the log-rang test (SPSS 14.0 software).Results: the median age of patients at diagnosis was 45 years (5–87). 81% were in chronic phase (CP), 13% in accelerated phase (AP), 6% in blast crisis (BC). According to Sokal score, patients were stratified in low (36%), intermediate (30%) and high risk (34%); 36% had previously used Interferon. The median time from diagnosis until Imatinib treatment was 8 months (0–310) and from Imatinib start until mutation detection was 31 months (1–104). Mutations were found in 188 patients, in the following sites: P-loop (75/40%), nucleotide contact site (34/18%), catalytic domain (44/23%), A-loop (11/6%) and others (24/13%). The most frequent mutations detected were: T315I (30/16%), F359V/C/I (27/14%), M244V (18/9.6%), E255K/V (17/9%), G250E (17/9%), Y253H/F/Y (15/8%), M351T/L (12/6%); Ten patients presented concomitant mutations. On dasatinib treatment 29 mutations (27% T315I) were detected whereas 18 during nilotinib (16.5% T315I). Overall survival in the total group was 61% (95%CI: 51–71%) with a median time of 12 months. There was a significant difference in OS and PFS between non-mutated and mutated patients (76% vs 44% and 64% vs 44% respectively (P= 0.008 and P= 0.001). There was no difference in survival comparing P-loop mutations and others, excluding T315I. Patients with T315I mutations had a poorer outcome in comparison with other mutations (OS 21% vs 62%; PFS 35% vs 55%) (P= 0.04 and 0.06, respectively). In the group with BCR-AL mutations, OS was superior in patients that received a SGI in comparison with other treatments after resistance (50% vs 36% P= 0.007). One hundred patients (19%) died due to: disease progression (72), infections (8), graft versus host disease (2), central nervous system bleeding (2), cardiac failure (1), second neoplasia (1). 14 causes were not reported. Conclusions: Patients with BCR-ABL mutations had an inferior OS and PFS. T315I mutations were associated to a poor outcome. Treatment with SGI prolonged survival of patients after imatinib failure. Disclosures: Pagnano: Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 3750 Background: The WORLD CML Registry is a multinational, prospective registry established to longitudinally assess global patterns of current and evolving methods for diagnosis, treatment, and clinical outcome measures in pts with CML and to compare clinical practice patterns to management recommendations provided by the European LeukemiaNet (ELN; Baccarani M, et al. J Clin Oncol. 2009;27:6041–6051). Here, we report overall efficacy and safety data from this registry, as well as clinical monitoring practices and outcomes in the subgroup of pts with CML in chronic phase (CP) treated with first-line imatinib. Methods: Pts (≥ 16 y of age) with CML in CP, accelerated phase (AP), or blast crisis (BC) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled at sites in Latin America, Asia-Pacific, the United States, Russia, Turkey, the Middle East, and Africa. Baseline demographics and medical history were collected at enrollment; disease status and management information were collected at approximate 6-mo intervals or when there was a change in disease status/management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: A total of 1837 of the 1889 pts enrolled between February 2008 and December 31, 2010, were evaluable (ie, had confirmed informed consent forms and no protocol deviations) and are the basis for this analysis. Median age was 47 y (range, 16–92 y), and 58% of pts were male. CML diagnosis was established using hematologic (91% of pts), bone marrow (82%), cytogenetic (83%), and molecular (polymerase chain reaction [PCR]; 53%) assessments. Nearly all pts (94%) were initially diagnosed in CP (Table). As of the data cutoff (December 31, 2010), median overall survival (OS) and median event-free survival (EFS) in all pts were not reached. Estimated OS and EFS rates at 3 y were 90.4% and 74.8%, respectively. AEs reported in ≥ 1% of pts were thrombocytopenia (3%) and neutropenia (2%). In the CML-CP subgroup, imatinib (Glivec®/Gleevec®) was administered as first-line therapy (in clinical practice or in a clinical trial) to 63% of pts (n = 1083). Disease burden in CML-CP pts on imatinib over time was most commonly assessed via blood counts (Table). Cytogenetic and molecular assessments were used in a minority of CML-CP pts at most time points. Only 50% of pts had a disease assessment at 3 mo (hematologic, 49%; cytogenetic, 10%; molecular, 15%). Of the pts on first-line imatinib outside of a clinical trial setting (n = 1024), 95 (9%) had their dose increased, 77 (8%) had their dose decreased, and 82 (8%) were switched to nilotinib or dasatinib. In all CML-CP pts treated with first-line imatinib, estimated OS and EFS rates at 3 y were 92.1% and 76.6%, respectively (Table). Estimated OS and EFS rates at 3 y were higher in pts who had higher imatinib exposure (treatment received ≥ 85% of total days) vs pts who received imatinib treatment on 〈 85% of days. Conclusions: The majority of CML-CP pts treated with first-line imatinib did not have cytogenetic or molecular assessments in accordance with current ELN recommendations, particularly at early time points. Additionally, pts who had higher drug exposure to imatinib had higher estimated OS and EFS rates at 3 y than those who did not. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Piccolo:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Sivarathinasami:Novartis Healthcare Pvt. Ltd,: Employment. Eng:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Kim:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Consultancy, Honoraria, Research Funding. Hughes:Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding.