ALBERT

Description: Abstract 205 Background: Little progress in terms of improving survival in patients with chronic myeloid leukemia (CML) was made until the introduction of interferon alpha and allogeneic stem cell transplantation for selected patients in the 1980s. The management changed dramatically with the development of imatinib mesylate, the first tyrosine kinase inhibitor (TKI) that targets the BCR-ABL1 oncoprotein. In Sweden clinical trials started in December 2000 and the drug was approved for clinical use in November 2001. This study evaluates the impact of treatment developments in CML by studying temporal trends in short-term and long-term excess mortality in a population-based setting. Materials and Methods: Using data from the nationwide, population-based Swedish Cancer Registry and Swedish population life-tables stratified by age, sex, and calendar time we characterized trends in relative survival for all patients diagnosed with CML in Sweden 1973–2008 (n=3,173; 1,796 men and 1,377 women; median age 62 years). Patients were categorized into five age groups (79 years) and five calendar periods (1973-1979, 1980–1986, 1987–1993, 1994–2000 and 2001–2008). Six hundred and nine stem cell transplants (539 allogeneic and 70 autologous) were reported to the EBMT registry during the study period. Results: Incidence remained stable over time with a consistent male predominance. Relative survival improved with calendar period with the greatest improvement in the last two calendar periods (figure). Five-year cumulative relative survival ratios (RSRs; 95% confidence intervals) were 0.21 (0.17-0.24), 0.23 (0.20-0.27), 0.37 (0.33-0.41), 0.54 (0.50-0.58) and 0.80 (0.75-0.83) in the five calendar periods, respectively. Ten-year RSRs were 0.06 (0.04-0.08) and 0.78 (0.73-0.83) in the first and last calendar periods, respectively. This improvement was confined to age groups up to 79 years of age but most pronounced in patients below 60 years. The 5-year RSRs for patients diagnosed 2001–2008 were 0.91 (0.85-0.94), 0.87 (0.78-0.92), 0.82 (0.72-0.90), 0.75 (0.61-0.86), and 0.25 (0.10-0.47) for the five age groups, respectively. Older age at diagnosis and male sex were associated with significantly higher excess mortality rates in models adjusted for potential confounding factors. Conclusion: In this large population-based study including 〉 3,000 CML patients survival increased significantly after 2001 (when imatinib mesylate was approved for clinical use in Sweden) for patients up to 79 years of age. Future studies are needed to assess if very old (〉79 years) CML patients may benefit from an increased use of TKIs. Also newly introduced, targeted treatment options for CML need to be evaluated in future population-based studies. Disclosures: No relevant conflicts of interest to declare.

Description: Chimeric antigen receptor (CAR) T cells have shown promising results in patients with B cell malignancy. In preclinical studies we showed that CD19-targeting third generation (3G) CAR T cells containing signaling domains from both CD28 and 4-1BB as co-stimulatory molecules have greater activation and proliferation in response to antigens than 2G CARs containing CD28 only. Herein we report results from a phase I/IIa study (NCT:02132624) using these 3G CAR T cells. Patients with relapsed or refractory CD19+ B-cell malignancy were eligible, provided there was no curative treatment available. Of the first eleven patients reported, nine had lymphoma and two had acute lymphoblastic leukemia (ALL). Autologous CAR T cells were manufactured using a gamma retrovirus encoding the CAR and expanded by αCD3/αCD28/IL2. During CAR T cell production, all lymphoma patients received treatment to control tumor burden (-90 to -3 days before T cell infusion). Their treatment depended on the type of lymphoma and previous treatments. In addition, prior to T cell infusion (day -2 to -1) patients #6-11 received cyclophosphamide (500mg/m2) and fludarabine (25mg/m2) as conditioning to decrease immunosuppressive cells. The patients received one infusion of CAR T cells (2x107 cells/m2 patients 1 and 2; 1x108 patients 4, 5, 7, 8, 9; and 2x108 patients 6, 10, 11, 12). Patient #1 (DLBCL) had a mild cytokine release syndrome (CRS) after four weeks (never requiring treatment), followed by a complete response of his lymphoma. A relapse and a second CRS occurred after six weeks and he was treated with prednisone with good symptomatic effect and reduction of tumor size. The patient progressed after three months. Patients #2, 4, 5 (CLL, MCL, MCL) all progressed after 2, 1, and 3 months, respectively. Patient #6 (DLBCL) responded to treatment (CR) prior to T cell infusion and remained in complete remission for 6 months post T cell infusion. Patients #7 (CLL) and #9 (DLBCL) also responded to treatment prior to T cell infusion and remains in complete remission +4 and +5 months,respectively. The CLL patient has a tumor negative bone marrow. Patient #8 (FL-DLBCL) had a mild CRS but progressed after 1 month but. Patient #10 (ALL) experienced transient CNS toxicity followed by a complete response. However, at 3 months the patient relapsed with a CD19 negative ALL, accompanied by increased levels of immunosuppressive cells such as T regulatory cells and myeloid derived suppressor cells. Patient #11 (ALL) is in complete remission after a CRS (+3 month) and patient #12 (FL/Burkitt) had a major CRS requiring intensive care and a stable disease for one month before progression. The CAR transgene could be detected in blood at the time of clinical symptoms of response and most patients that progressed lost CAR signal. In summary, 6 of 11 patients (3 DLBCL, 1 CLL and 2 ALL) treated with increasing doses of 3rd generation CAR T cells in Sweden had CR or CCR. CRS occurred in 4/11 but was mild in all but one and CNS-toxicity occurred in 2/11 patients of which one required hospitalisation. Correlations between the levels of T regulatory cells and myeloid derived suppressor cells in blood and patient response are currently under investigation. Disclosures Brenner: Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Other: Licensing Agreement; Celgene: Other: Collaborative Research Agreement. Loskog:Alligator Bioscience AB: Patents & Royalties; RePos Pharma AB: Membership on an entity's Board of Directors or advisory committees; Lokon Pharma AB: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; NEXTTOBE AB: Membership on an entity's Board of Directors or advisory committees; Vivolux AB: Membership on an entity's Board of Directors or advisory committees.

Description: Rationale: Dasatinib (DAS) and interferon have different modes of action and may have synergistic activity in CML, due to both antineoplastic and immunostimulatory mechanisms. Addition of pegylated interferon (PegIFN) to imatinib therapy in CP-CML has in previous clinical trials (French SPIRIT and NordCML002) resulted in deeper molecular responses. Thus, an optimal combination of DAS and PegIFN may increase the proportion of patients who reach deep molecular response with potential for treatment-free remission (TFR). Design: Newly diagnosed CP-CML patients were treated with DAS (Sprycel, BMS) 100 mg OD as single drug for three months. Thereafter weekly subcutaneous injections of Peg-IFN α2b (PegIntron, MSD) were added to DAS; from end of month 3 (M3) to M6, 15µg/week, thereafter 25µg/week until M15. Primary end points were safety and the rate of MMR at M12. The doses of PegIFN were lower than in the SPIRIT and NordCML002 studies to increase adherence. Population: Forty patients were included at 14 university centers. One patient was lost to follow-up after M6. All patients were included in analysis up to M12. Mean and median age was 48 years (range 19-71). The proportions of high risk patients were 25% (Sokal), 15% (Hasford), and 15% (EUTOS). Safety and dosing: Treatment was well tolerated with expected DAS and PegIFN related side effects. Six patients had seven serious adverse events (AEs), all hospitalizations. 1 episode each of bradycardia/atrial fibrillation (possibly PegIFN-related), headache (DAS), fever (PegIFN), anaphylaxis-like reaction (PegIFN), fever/malaise/headache (PegIFN), pneumonia and a knee effusion (both unrelated). One pleural effusion occurred (grade 2, 3%). Grade 3-4 neutropenia and thrombocytopenia occurred in 6 and 9 patients respectively. Prolonged hematological toxicity (〉2 months) occurred in 8 patients, causing dosing problems in 5. One patient suffered grade 3 depression. Grade 3 flu-like symptoms occurred in 2 patients. One patient had lipase elevation grade 3 and one patient developed hypothyroidism attributed to PegIFN. Grade 2 dermal AEs like rash and acne occurred in about 20%, attributable to both drugs. 94% (DAS) and 76% (PegIFN) of assigned dose was given. Dose reductions occurred in 19 patients for DAS and 20 patients for PegIFN. Two patients discontinued DAS and switched to nilotinib, 1 for headache at M3 and 1 at M12 for lack of efficacy/hematological toxicity. Two patients could not start PegIFN for hematological toxicity (one lost to follow-up after M6). PegIFN was discontinued because of bradycardia/atrial fibrillation (1 patient), anaphylaxis (1 patient), flu-like syndrome (2 patients) and long-term hematological toxicity (2 patients). At 12 months 31/38 pats (82%) were still on PegIFN, a higher proportion than in the French Spirit or NordCML002 studies. Efficacy: We have used the DAS arm of the Dasision study (Kantarjian NEJM 2010) as a historical control. Early response at M3 was very similar between studies. In the present and the Dasision cohorts respectively, 18% vs 16% missed the 10% BCR-ABLIS landmark, 66% vs 56% achieved a CCyR and 8% vs 8% achieved MMR. At M6, three months after introduction of PegIFN, a steep increase in MMR rate was observed compared with Dasision. This was also reflected in deep responses, MR4.0 (see tables) and MR4.5 at M12, 18% vs 5%. The primary efficacy endpoint was MMR at M12, 82% vs 46%. Table 1.MMRDAS+PegIFN (%)DAS (Dasision)(%)Difference (%)M3880M6532726M9663927M12824636Table 2.MR4.0DAS+PegIFN (%)DAS (Dasision) (%)Difference (%)M3303M620614M938830M12481236 Progressions and treatment failure defined by ELN 2013: Failures: No progression was noted. At M3, 2 patients still had 〉95% Ph+ metaphases (MF). At M6, four patients (11%) had 〉 35% Ph+MF or 〉10% BCR-ABL levels. At M12, one patient failed CCgR and two more patients failed

Description: Abstract 1054 Background: Patients with hematological malignancies are more susceptible for viral infections including influenza, which may be associated with prolonged illness, increased morbidity and mortality. In 2009, the World Health Organization classified the novel influenza A(H1N1) virus as pandemic. The impact of this viral infection in patients (pts) with hematological disorders was unknown, and there were concerns about the risk of serious complications. In Sweden, institutional guidelines recommended two doses of the AS03-adjuvanted inactivated H1N1 split vaccine Pandemrix™ from GlaxoSmithKline in these pts. Aims: Prospectively determine the safety, immunogenicity, and clinical efficacy of influenza A (H1N1) 2009 vaccination in patients with hematological diseases. Compare the immunological response to that obtained by the trivalent seasonal influenza vaccine (TIV). Patients and methods: 31 pts were included (myeloma 9, CLL 5, AML 6, ALL 2, CML 2, others 5), out of which 13 had undergone hematopoietic stem cell transplantation (HSCT). All received influenza A(H1N1) 2009 vaccine at day 0, and 28, and the majority (n=25) seasonal influenza vaccine at day 56. Serum for antibody analyses by validated HI-assays was taken at day 0, 28, 56 and 86 and at 1 year. The response to vaccination (seroconversion) was defined as at least a four-fold increase in antibody titer after vaccination or, in case prevaccination HI-titer was 〈 10, a post-vaccination titer of HI 〉 40 or greater. Considering that the HI-assay for influenza B differed from the A strains only the seroconversion rate was considered for the influenza B. Results: The A (H1N1) vaccine was well tolerated and no severe adverse events were reported. At day 28, a total of 16(52%) patients had protective levels of antibodies to A (H1N1) 2009 and 15(48%) had a seroconversion response. After the second dose of the vaccine, 25(81%) reached both protective levels of antibodies and seroconversion. At 1 year, protective levels of antibodies against A (H1N1) 2009 remained in 56% of responding patients. Seroconversion response was observed in 9/13 patients who had undergone HSCT, including 5/9 pts who had been transplanted within1–5 months, as well as in all (n=9) pts with myeloma having advanced disease and/or ongoing intense treatment. Following vaccination with TIV and evaluated at day 86, protective antibody levels and seroconversion response against A/Brisbane/59/2007 H1N1-like virus were detected in 10(40%) respective 7(28%), and against A/Uruguay/10/2007/H3N2-like virus in 14(56%) respective 10(40%). As for B/Brisbane/60/2008-like virus, seroconversion response was found in 5(20%) of all pts. Response to the pandemic influenza A (H1N1) 2009 vaccine was better than that to the three TIV strains (p

Description: Abstract 130 Secondary AML comprises AML patients with an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML; tAML). Population-based data on this patient group are scarce. Here, we report for the first time, data on secondary AML from the Swedish Acute Leukemia Registry covering 98% of all AML cases diagnosed in Sweden between 1997 and 2006. In total, 3372 AML patients were registered during this period. Of these, 949 (28%) had secondary AML; 655 (19%) had a history of AHD and 294 (8.7%) had tAML. The proportion of secondary AML increased from 8% in patients below the age of 40 years to 36% in patients between 70–79 years. Of patients with AHD, 423 (65%) had previously been diagnosed with myelodysplastic syndrome (MDS) and 227 (35%) with various types of myeloproliferative disorders (MPN). AML with AHD showed male predominance (57%), whereas tAML showed female predominance (64%). This distribution was significantly different (p

Description: Introduction As there are only few data available about the incidence, the stage of disease at diagnosis, the treatment and the outcome of chronic myeloid leukemia (CML) in Europe the European Treatment and Outcome Study (EUTOS) for CMLcollected such data in 27 European countries. The population-based registry was set up by EUTOS to further explore the epidemiology, characteristics, treatment and outcomes of CML in Europe. The present work focused on the estimation of incidence of CML in Europe, in the single countries participating in the registry and the comparison to existing incidence estimations from the US. Patients and Methods The EUTOS population-based registry aimed to document all newly diagnosed adult patients with Ph+ and/or BCR-ABL+ CML at any stage nationwide or in prespecified regions within countries of Europe. Croatia, Cyprus, Estonia, Latvia, Lithuania, Slovakia, Slovenia and Sweden were observed in total while for Austria, the Czech Republic[H1] , France, Germany, Italy, the Netherlands, Poland, Russia, Serbia, Spain, Sweden and the United Kingdom specified regions were selected. Population data from the United Nations database were used for calculations in countries that were observed nationwide, while the study groups provided the population numbers of the specified regions for countries that were observed partially only. The registration periodvaried between 12 and 60 months in the different countries, from January 2008 to December 2012, registration area covered over 92.5 million inhabitants overall. Raw and standardized incidenceswere calculated for the countries and regions and adjusted to the registration period. For standardization the Old Europe Standard Population was used (Waterhouse et al IARC 1976). The registry and the standard population were truncated so only patients from 20 years on were included for the calculation of standardized rates. To compare and validate the EUTOS estimations we chose the data of the Surveillance Epidemiology and End Results Program (SEER) which cover about 28% of the US population. The data were collected from 2007 to 2011. Results There were 2,936 patients registered into the EUTOS population-based registry. Raw incidences per 100,000 inhabitants per year ranged from 0.72 in Poland to 1.39 in Italy. The overall raw incidence for all countries was 1.02, with 0.90 in females and 1.14 in males. Estimations of standardized incidences ranged from 0.72 in the UK to 1.29 in Italy. Overall standardized incidence was 0.99, with 0.86 in females and 1.12 in males. Age specific incidences rose with age group. While the incidence in the 18 to 40 years old population was as low as 0.52 (0.61 in males and 0.42 in females) it increased to 1.61 (2.18 in males and 1.26 in females) in the population from 70 years up. Comparing the SEER data to our EUTOS results very similar incidences can be observed up to age group 55-59 years. From that age group up the SEER incidence estimations are considerably higher. The overall standardized SEER incidences ranged around 1.7 per 100,000 for the years observed. The higher rates can be explained by different inclusion criteria of the registries: While EUTOS includes only Ph+ and/or BCR/ABL+ patients, the SEER has more open inclusion criteria. Also patients without information on Ph-status, BCR-ABL1 negative patients and patients diagnosed with chronic myelomonocytic leukemia are included. Discussion The EUTOS population based registry is the first paneuropean prospective study of incidence of CML in Europe. For the first time data about the incidence of CML are available now for most European countries. Raw and standardized incidences from the EUTOS registry fit in well with earlier findings of study groups from countries like the UK (Bhayat et al., BMC Cancer 2009; 9; 252) (Phekoo et al Haematologica 2006), Sweden (Höglund et al Blood 2013), Germany (Nennecke et al Bundesgesundheitsblatt 2014) and France (Corm et al J Clin Oncol 2008) that range between 0.7 and 1.1 per 100,000 inhabitants. Thus the estimation of incidence over all regions participating in the EUTOS project can serve as a robust estimation of the incidence of CML in Europe. [H1]Wurde zwar voll beobachtet, zwei Regionen wurden aber ausgeschlossen, da sie nicht garantieren konnten pop-based gewesen zu sein! Disclosures Hoffmann: Novartis: Research Funding. Lindoerfer:Novartis: Research Funding. Castagnetti:Novartis, BMS,: Consultancy, Honoraria; Pfizer: Consultancy. Griskevicius:NOvartis: Research Funding. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Hehlmann:Novartis, BMS: Research Funding. Hasford:Novartis: Research Funding. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau.

Description: Abstract 231 Background: DNA methylation induces gene silencing in a nonrandom fashion in many types of malignancies. In AML there is no consensus regarding the clinical implications of DNA methylation on a global level. Normal karyotype AML (NK AML) can be prognostically stratified by molecular mutations in genes such as FLT3 and NPM1. We have previously reported that increased gene promoter methylation levels may have positive prognostic implications in AML. Now we have focused and expanded our analysis in a homogenous group of NK AML in an effort to illuminate these issues. Methods and patients: We analyzed genome wide DNA methylation signatures from the diagnostic bone marrow samples of 58 de novo NK AML with the IlluminaHuman27 Methylation array, covering 27000 CpG sites, mainly located in the promoter regions of 15000 individual genes. Global methylation was defined as the average methylation values of all measured CpG sites in the specific sample. All patients were between 18 and 67 years of age and received standard induction chemotherapy. All were eligible for intensive consolidation therapy including allogeneic transplantation. FACS sorted normal bone marrow separated into four stages of myeloid differentiation were analyzed as normal controls. Methylation data were correlated to clinical outcomes and molecular mutational status of NPM1 and FLT3. Functional annotation analyses were performed on differentially methylated genes to find epigenetically perturbed pathways. Further molecular analysis of CEBPA, IDH1 and IDH2 is currently performed. Results and discussion: Global methylation levels varied substantially between AML samples but remained mainly unchanged during normal myeloid differentiation. Methylation levels were significantly higher in AML cases than in the normal myeloid progenitors (p

Description: Background: In a recent, large population-based study we identified an increased risk of a second malignancy in patients following a diagnosis of Chronic Myeloid Leukemia (CML), as compared to an age- and gender-matched control cohort (Gunnarsson et al, Br J Haematol. 2015 Jun; 169(5): 683-8). If CML patients have an increased congenital or acquired susceptibility to develop any cancer, the prevalence of other prior malignancies would be expected to be increased already at the time of CML diagnosis. There is a known association between autoimmune disease (AD) or chronic inflammatory disease (CID) and the development of some hematological malignancies. However, to date, studies on the prevalence of AD or CID detected prior to the CML diagnosis are few and inconclusive. Our aim was to estimate the prevalence of other malignancies, AD or CID in CML patients at or before the time point of the CML diagnosis. Materials and methods: We used the population-based Swedish CML Register to identify patients diagnosed with CML in Sweden between 2002-2013. This cohort was linked to the Swedish Cancer Register to retrieve information about malignancies reported before the diagnosis of CML and the Swedish National Patient Register to retrieve information about AD and CID. For each of the 984 patients with CML, five age-, gender- and county of residence-matched controls were selected from the general population. All controls had to be free of CML and alive at the time of CML diagnosis for the corresponding case patient. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We excluded diagnoses registered during the year prior to the CML diagnosis to avoid detection bias. In separate steps, analyses were also performed based on diagnoses of AD, CID or cancer three years before the date of CML diagnosis. Results: A total of 984 CML patients were assessed with regard to a prior diagnosis of malignancy, AD or CID excluding the year immediately prior to their CML diagnosis, representing more than 45.000 person-years of follow-up. Compared to the matched population controls, the prevalence of prior malignancies and AD were elevated in CML patients: OR 1.47 (95%CI 1.20-1.82) and 1.55 (1.21-1.98), respectively. Breast-, gastrointestinal- and urinary tract cancers and melanomas were common cancer types and were all significantly more prevalent in the CML cohort, table I. After implementing a three-year exclusion period before the date of CML diagnosis, prior malignancies remained more prevalent in CML patients. Assessment of ADs was hampered by small numbers, sarcoidosis was the only AD with increased prevalence: OR 13.43; 95 % CI 3.56 - 50.73. No association was detected between CML and previous CID. Conclusions: Based on a large population-based cohort, our findings indicate that CML patients have an increased prevalence of other malignancies and AD prior to the diagnosis of CML, suggesting that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML. Table 1. Odds Ratios for malignancies prior to CML among 984 Swedish CML patients diagnosed between 2002 and 2013. Diagnoses of malignancy during the year immediately prior to CML diagnosis excluded to avoid detection bias. Participants Latency More Than 3 YearsBefore CML Diagnosis Variable CMLn=984 Controlsn = 4920 OR 95% CI CMLn=984 Controlsn = 4920 OR 95% CI Overall 128 453 1.47 1.20 - 1.82 113 381 1.55 1.24 - 1.93 Men 58 184 1.61 1.19 - 2.18 50 146 1.75 1.26 - 2.43 Women 70 269 1.32 1.01 - 1.74 63 235 1.36 1.02 - 1.82 Age

Description: In addition to therapeutic efficacy in imatinib-resistant BCR-ABL positive malignancies, dasatinib may have off-target immunomodulatory effects by inhibiting kinases (e.g. SRCs, c-KIT) in immune effector cells. In a proportion of patients, dasatinib treatment is associated with non-infectious pleural effusions and panniculitis, which may reflect aberrant immune reactivity. Here we describe a marked expansion of clonal LGL lymphocytes in blood among 11 BCR-ABL positive patients on dasatinib therapy (5 CML CP, 1 CML AP, 1 CML BC, 4 Ph+ALL). All patients were previously exposed to imatinib without similar changes in lymphocyte count or morphology. The median time to LGL lymphocytosis was 2 months from the start of dasatinib (range 1–8 months). It developed abruptly, with a peak lymphocyte count of 4–20 ×109/L, and was often preceded by low-grade fever. In all evaluable cases, lymphocyte counts normalized after drug discontinuation. By immunophenotyping, 6 patients had a CD3/CD8+ cytotoxic T-cell phenotype and 4 patients had a CD56+ NK-cell phenotype. The LGL lymphocytes were BCR-ABL negative. All CD3-positive cases had a clonal rearrangement of TCR gamma/delta genes by PCR; clonality was not detected in samples prior to dasatinib therapy (n=3). In TCR beta gene repertoire assay, oligoclonal patterns were seen in selected genes. All patients with HLA data had the A2 allele (n=8). Dasatinib-related complications were common: pleural effusions and/or pulmonary infiltrates (n=8), modest CMV reactivation (n=5), severe colitis (n=5), which developed after appearance of LGL lymphocytosis. Immunophenotyping was available from 2 patients with pleural effusions: in both cases the majority of cells were CD3+CD8+ T-cells and no leukemic cells were detected. TCR gamma assay was done from one patient sample and it showed similar clonal pattern as in peripheral blood. However, despite frequent side-effects, response to dasatinib treatment was very good in all cases, including complete molecular responses in 5 advanced phase patients. Transient clonal LGL lymphocytosis has been described in few patient cases with a primary herpesvirus infection. Our patients share striking pheno/genotypic similarities with LGL leukemia, in which an antigen driven expansion of LGLs precedes the occurrence of oncogenic events. However, in our patients LGL lymphocytosis appeared to be a benign phenomenon. We postulate that by virtue of inhibition of key non-BCR-ABL kinases, dasatinib induces a reversible state of autoimmune-like reactivity upon antigen challenge in a proportion of patients with a distinct genetic and/or environmental background. The aberrant immune response may also result in enhanced anti-leukemic control driven by the cytotoxic T/NK LGL cells. Dasatinib could be a valuable tool in uncovering the pathogenesis of LGL lymphoproliferation, putatively related to mutations in kinases targeted by the drug.

Description: Background Dasatinib is a potent BCR-ABL1 and SRC tyrosine kinase inhibitor, which in vitro is more effective against progenitor and putative leukemia stem cells than imatinib. This may translate into deeper molecular responses in vivo. Methods We randomized (1:1) 46 newly diagnosed CML patients to receive dasatinib 100 mg or imatinib 400 mg once daily. The primary endpoint of our study was treatment response in stem and progenitor cell fractions (Mustjoki et al, Leukemia 2013). We here summarize the clinical results of the study after a 24-month follow-up focusing on toxicity and standard response evaluation by quantitative BCR-ABL1 PCR and cytogenetics (NCT00852566 www.ClinicalTrials.gov). Results Both imatinib and dasatinib treated patients fared well with deeper and faster treatment responses than what has been reported in the registration studies. By karyotyping, dasatinib induced a faster response by 3 months (median of 5% of Ph+ cells in imatinib group vs. 0% in dasatinib group, p=0.01, n=21 in each group), but already by 12 months the difference disappeared, as all evaluable patients were in complete cytogenetic remission. The rate of molecular response MR3.0 was already at the 3 months time-point better in the dasatinib group (36% vs 8%, p=0.02; see Table), but within 18 months imatinib patients caught up the difference. In contrast, the achievement of deeper therapy responses, MR4.0 and MR4.5, was clearly different between the groups and increased over 24 months. After 18 months 64% and 71% of imatinib- and dasatinib-treated patients had achieved MR3.0 (p=0.59), while the MR4.0 rates were 23% and 62% (p=0.009) and MR4.5 rates 4% and 41% (0.003) (see Table below). The difference in median transcript levels was approximately 1 log (〉10-fold difference) in all time-points after 3 months of therapy (see Table below). A total of 7 patients (30%) in both groups discontinued assigned treatment. Main drug-related toxicities were as expected. Dasatinib-induced serosal inflammation (pleural/pericardial effusions) was more frequent than in registration studies (6 patients, 27%). In 4 patients (18%) this led to therapy discontinuation, despite of drug interruption and dose reductions. In the imatinib group 3 patients discontinued due to drug-related toxicity (liver toxicity, rash and severe hypogammaglobulinemia with recurrent infections). Disease progression occurred in one dasatinib-treated patient (cytogenetic progression with the appearance of V299L mutation at month 9) and two imatinib-treated patients (blastic transformation at month 2 and molecular progression at month 18). The patient in blast phase has been transplanted and is currently in molecular remission. No CML-related deaths occurred, but one patient died from lung cancer. Interpretation Dasatinib induced faster and deeper molecular responses than imatinib and overall responses were better in both groups than in the registration studies. Relatively high rate of serosal toxicity was observed among the dasatinib-treated patients, but this had no adverse effect on response. Upcoming studies will show if the deeper treatment responses induced by dasatinib therapy translate into increased probability of successful therapy discontinuation. Disclosures: Hjorth-Hansen: Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Travel Other; Merck: Research Funding. Richter:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Consultancy, Honoraria, Travel, Travel Other. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Mustjoki:Novartis: Honoraria; BMS: Honoraria, Research Funding.