ALBERT

Description: Introduction: Most of the knowledge about treatments and outcome of CML patients originates from clinical studies. To get new and unbiased insights in the epidemiology, treatment and outcome of CML, the EUTOS population-based registry of newly diagnosed CML patients was established, - as part of the European Treatment and Outcome Study (EUTOS) for CML. The aim was to collect the data of all adults with newly diagnosed CML, irrespective of treatment and of enrolment in studies. Patients and Methods: The EUTOS population-based registry collected data of newly diagnosed CML patients, 18 years or older, over a specified period of time from 2008 till 2012 living in defined regions. The data were collected by 22 study groups in 20 European countries. Data were gathered via a web-based CRF-system. For comparison we used the already published data from five Company-sponsored registration studies IRIS (O’Brien et.all, NEJM, 2003), TOPS (Cortes et al, JCO, 2009) ENESTnd (Saglio et al, NEJM, 2010), DASISION (Kantarjian et al, NEJM, 2010) and BELA (Cortes et al, JCO, 2012), from three Investigator-sponsored studies GIMEMA (Castagnetti et al, JCO, 2010 and Gugliotta et al, Blood, 2011), French SPIRIT (Preudhomme et al, NEJM, 2010) and German CML IV (Hehlmann et al, JCO, 2011) and from two single referral centers HAMMERSMITH (De Lavallade et al, JCO, 2008) and MDA (Jain et al, Blood, 2013). Results: Till 15.05.2014 2978 patients were registered in the EUTOS Population-based registry. 94.3% of the patients were diagnosed in chronic phase (CP), 3.6% in accelerated phase (AP), and 2.2% in blastic phase (BP). For the calculation of the prognostic scores 361 patients had to be excluded because they were pretreated. For the comparison we used 2350 patients in Chronic Phase with laboratory values before any treatment. 54% of the patients in the EUTOS Population-based registry were male, less than in all studies (56.6 - 60.6%). The median age at diagnosis was 56 years, higher than in all studies (46 - 55). In EUTOS the proportion of patients more than 60 years and more than 65 years old was 40.4 % and 21.9 % respectively. Similar data were rarely reported in all other studies. Median value of the spleen size below costal margin was 0. 46.1% of the patients had a palpable spleen and 15.2% had a spleen size ≥ 10 (spleen size is always reported in cm under costal margin in this abstract). The % of palpable spleen is only reported by IRIS, 25.0% and by the FRENCH Spirit group, 49.8%. The median spleen is only reported by GIMEMA, 2.0. Spleen size ≥ 10 is reported by IRIS, 6.0%, ENESTnd, 12.4% and HAMMERSMITH 25.5%. While the median values for Platelets and Hemoglobin show no big differences, the median WBC in EUTOS is 83.9 x109/l and in the Company-sponsored registration studies: IRIS 18-20 x109/l , in ENESTnd 23-26 x109/l, in DASISION 23-25 x109/l , and in BELA 22-23 x109/l, in the Investigator-sponsored studies: GIMEMA 55 x109/l , in the FRENCH SPIRIT 83-104 x109/l , in the GERMAN CML IV 75-91 x109/l , and in the single referral center study HAMMERSMITH 140 x109/l, clearly indicating that in company-sponsored, registration studies, the reported values of the WBC were not recorded prior to any treatment. The median values for Blasts, Basophils and Eosinophils show also not so big differences. The % of Sokal low risk patients is in EUTOS with 34.5% lower than in all studies (35.2 - 60%) with the exception of HAMMERSMITH 28.9%. Discussion: The EUTOS Population-based registry provides the first European wide real-world series of patients with newly diagnosed Ph+, BCR-ABL+ CML. The age and sex distribution and some baseline characteristics such as Sokal Score as well as median WBC count in the EUTOS population-based registry are different from many prospective studies. This should be taken in due consideration before extrapolating the results of treatment studies to real life. Spleen size, which is known as an important value for prediction, is only very rarely reported in clinical studies. With further follow-up, this registry will provide a population-based insight on treatment, survival, and causes of death. Disclosures Baccarani: Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Hoffmann:Novartis: Research Funding. Rosti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy. Saussele:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Mayer:Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy. Clark:Novartis Pharmaceuticals Corporation: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Lindoerfer:Novartis: Research Funding.

Description: Introduction. Chronic myeloid leukemia(CML) is a very rare disease in children and adolescents. The international registry of CML in children and adolescents gives us the opportunity to assess the prognostic relevance of variant t(9 ;22) and additional cytogenetic abnormalities at diagnosis on prognosis. Patients and Methods. We used clinical and biological characteristics and outcome of 239 children and adolescents less than 18 years to assess the impact of additional cytogenetic abnormalities and variant t(9 ;22) on the rate and the time to achieve a complete cytogenetic response (CCyR). Cytogenetic analysis was performed 24 or 48 hour culture on G-banded metaphases. Results. Overall, 17/239 children (7.1%) presented with additional cytogenetic finding at diagnosis: 5/239 children (2.1%) had a variant of the t(9;22), 10 children (4.2%) had other additional cytogenetic (numerical/structural) abnormalities (ACA), and 2/239 (0.8%) had both. Characteristics of the patients and phase of the disease are reported in Table 1. In the 7 patients with variant t(9;22), one (chromosome 1 in 3 patients, chromosome 8 in 2 patients and chromosome 14 in one patient) or two further chromosomes (chromosomes 8 and 17) were involved in 6 and one patient(s), respectively. In the 12 patients with ACA, 9 patients have one type of ACA, 2 patients have 2 type of ACA and one patient have 3 type of ACA. Regarding the patients in chronic phase at diagnosis (n=219), the cumulative incidence of complete cytogenetic response at 18 months was 88% (95% CI: 82 % - 93%) and 70% (95% CI: 42% - 93%) for patients without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.151), respectively. Three deaths were recorded (among them one patient had ACA at initial diagnosis). With a median follow up of 43 months (range 1 – 161) the probability of 3 years overall survival was 99% (95% CI: 94 % - 100%) and 88% (95% CI: 39 % - 98%) for patients in chronic phase without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.042), respectively. Conclusion. Additional chromosomal abnormalities at diagnosis in children with CML in chronic phase may have an impact on the outcome. A larger cohort of patient and a longer follow up is needed to confirm such findings. Table 1. Cytogenetic No variant t(9;22) or ACA Variant t(9;22) ACA Variant t(9;22) and ACA Number of patients 222 5 10 2 Sex (% males) 56% 60% 50% 100% Median age, yrs (range) 12 (1-18) 14 (9-17) 12 (5-16) 6 and 17 Phase of the disease (n) chronic accelerated blastic 208 12 2 3 1 1 7 1 2 1 0 1 Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company Disclosures No relevant conflicts of interest to declare.

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

Description: Abstract 4272 The incidence of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) in Europe is still difficult to estimate, due to insufficient information. Currently, it is believed to range between 8 and 22 cases per million people per year, age adjusted. Prior to the introduction of the tyrosine kinase inhibitor (TKI) imatinib the annual death rate was about 10% for the first 2 to 3 years, and about 20% from the 4th year on, with less than 10% of patients alive after 10 years. Interferon-alfa treatment and allogeneic hematopoietic stem cell transplantation were very effective treatments but only in a minority of patients. Following the introduction of IM, and of the second generation TKI nilotinib and dasatinib the annual death rate has decreased to less than 5%, and more than 75% of patients are projected to be alive 10 years after diagnosis. Based on these figures, the prevalence of the disease is expected to double every 5 years and the management of the disease will rapidly become an important social and pharmacoeconomic issue. To govern this progress it is necessary to improve the level of information on the epidemiology of CML, on the treatment of CML in clinical practice, and on the outcome of treatment outside prospective, controlled clinical trials on which current outcome estimates are based. With that purpose, the European Leukemia Network (ELN) has established a registry of all new cases of Ph+ CML. In a public private partnership with Novartis Oncology Europe this registry has been expanded to also include treatment and quality controlled outcome (European Treatment and Outcome Study [EUTOS] for CML). The infrastructure of the registry is based on a EUTOS Central Scientific Headquarter (Dpt. Hematology-Oncology “L. and A. Seràgnoli”, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy) and a EUTOS Central Data Center (Dpt. For Medical Informatics, Biometric and Epidemiology, University of Munich, Munich, Germany), interacting with each national hub. Registry is population-based, covers completely most European countries with less than 12 millions inhabitants (Portugal, Belgium, Sweden, Finland, Lithuania, Latvia, Estonia, Czech Republic, Slovakia, Slovenia, Croatia, Serbia, Hungary, Austria, Greece, Cyprus), and covers partially (for larger countries, only sub-regions with roughly 10 millions inhabitants have been selected) most of the countries with more than 12 millions inhabitants, including Spain, the United Kingdom, The Netherlands, Germany, Poland, France, Romania, Russia and Italy. About 2500 newly diagnosed cases are planned to be registered over one year and to be followed for treatment and outcome including cytogenetic response, molecular response, and BCR-ABL KD mutations. Moreover, flanking projects have been implemented in the EUTOS frame: a network of standardized laboratories across Europe, to provide a molecular monitoring with quality controlled data, a central facility for imatinib blood level testing, soon in many European countries, and an educational effort (symposia, training workshops, internet platform). The EUTOS registry joins epidemiological and outcome data: its implementation requires considerable efforts and resources, but in the long run CML could become a model for epidemiologi and management of other cancers. Disclosures: Hasford: Novartis Pharma: Research Funding.

Description: The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations.

Description: Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

Description: Imatinib (IM) at 400 mg daily is the first line therapy for newly diagnosed CML patients (pts); however, less than 50% of major molecular responses (MMR) are obtained at 12 months. To improve these results, we designed a phase III, multicenter, open-label, prospective randomized trial. The reference arm was IM 400 mg daily (n=159). The 3 experimental arms were IM 600 mg daily (n=160), IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles)(n=158) and IM 400mg in combination with Peg-IFN alfa-2a (Peg-IFN2a, 90 μg weekly) (n=159). Treatment was delivered at least 12 months or until treatment failure (disease progression) or major toxicity. The primary endpoint is the overall survival. Other endpoints are: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response (major molecular response ie MMR) and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization was stratified according to Sokal risk groups. The current interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization was planned in order to select the best experimental arm for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months was centralized, blinded and calculated according to International score (IS). Pts were recruited between 9/2003 and 10/2007.[median age 51 yrs (18–82), 62% of pts were male; Sokal distribution was low risk 33%, intermediate risk 41% and 27% high risk]. Median follow-up is 36 months (range 8–57) at the time of analysis. Overall, at 3 months 86 % of pts achieved complete hematologic response. The MCyR, CCyR and MMR rates at 6 and 12 months are: IM-400 IM-600 IM-Ara-c IM-PegIFN *p〈 10−2 (overall); ** p

Description: Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS 〉0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p

Description: Background Chronic myeloid leukemia (CML) stem cells are inherently insensitive to tyrosine-kinase inhibitors (TKI). However, an important minority of CML patients was shown to discontinue TKI without experiencing molecular relapse. Underlying mechanisms are currently unknown. Plasmacytoid dendritic cells (pDCs) are critical regulators of immune responses. Following activation, pDC upregulate MHC-class II and other DC activation markers such as CD86 (also known as B7.2). CD86 is a co-stimulatory molecule during T-cell activation, but also ligand of the inhibitory immune checkpoint receptor CTLA-4, which counteracts T-cell activation. The origin and function of pDC in CML biology is unknown. Within a sub-study of the EUROSKI TKI discontinuation trial we prospectively tested the hypothesis that pDC counts and CD86 expression status govern relapse risk following TKI discontinuation. Methods: Using flow cytometry, cell sorting and fluorescence in situ hybridization (FISH), CD86 expression and BCR-ABL status were analyzed in PDCA-2+/CD123+ peripheral blood (pB) pDC of untreated CML patients (CML pDC), normal donors and 123 patients, who had stopped TKI therapy in deep molecular remission within the international EUROSKI study (EUDRACT 2011-000440-22). All 123 EUROSKI patients had given written informed consent to participate in the immunological sub-study of the EUROSKI trial. Fresh samples from 19 EUROSKI centers in Germany were centrally analyzed prior, as well as 1, 2, 3 and 6 months after TKI discontinuation. PB CD86+ pDC counts were calculated per 105 cells in the lymphocyte gate. Decision trees and 10-fold cross validation were employed to establish relapse prediction accuracy for this value. Results CML pDC were BCR-ABL-FISH positive (median: 81%; range, 57 to 100%). In contrast, the proportion of CD86+ CML pDC varied substantially (median: 25.9%, range 3.2% to 82.4%), suggesting that CD86 expression on CML pDC was not a direct consequence of oncogenic BCR-ABL signaling. This was confirmed experimentally in a murine CML model. In contrast to CML pDC, remission pDC were always BCR-ABL FISH negative (n=10), but still displayed a comparable high proportion of CD86 positive pDC (median: 21%; range, 2.2% to 62%). In contrast, normal donor pDC were rarely CD86 positive (median: 6.8%; range, 4.2% to 17%), reinforcing the aberrant, and BCR-ABL-independent nature of CD86 expression on CML and remission pDC. As a result, healthy donors displayed only between 26 to 84 CD86+ pDC per 105 lymphocytes, whereas EUROSKI remission patients exhibited between 6 to 309 CD86+ pDC per 105 lymphocytes. Based on the important role of CD86 as a high affinity ligand of the inhibitory immune checkpoint receptor CTLA-4, we next asked, whether CD86+ pDC counts are associated with relapse risk after TKI discontinuation. Strikingly, statistical models suggested that a CD86+ pDC count below or above 95 CD86+ pDC/105 lymphocytes optimally separated two relapse categories of EUROSKI patients. Whereas relapse free survival (RFS) (loss of MMR) for patients with more than 95 CD86+ pDC/105 lymphocytes was 30% (n=32), RFS was 69% for patients (n=91) with less than 95 CD86+ pDC/105 lymphocytes (p

Description: Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.