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Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patients report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society

Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort-study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002-2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near-complete nationwide coverage were utilized for data acquisition. Median follow-up was 6 (IQR, 3-10) years with a total follow-up of 8510 person-years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5-2.6), heart failure 2.6 (2.2-3.2), pneumonia 2.8 (2.3-3.5), and unspecified sepsis 3.5 (2.6-4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within-cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5-5.6) and chronic ischemic heart disease (2.2; 1.2-3.9), dasatinib for pleural effusion (11.6; 7.6-17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4-6.0). Our extensive real-world data reveal significant risk increases of severe morbidity in TKI-treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored. Funding Agencies|Karolinska InstitutetKarolinska Institutet; Region Stockholm (Clinical Research Appointment)

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity. Title in Web of Science: Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TKI resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score2 and reduced intensity conditioning, and for death, CP2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.

Objectives Translocations involving the Fibroblast growth factor receptor 1 (FGFR1) gene are associated with the 8p11 myeloproliferative syndrome (EMS), a rare neoplasm that following a usually short chronic phase progresses into acute myeloid or lymphoid leukemia. The treatment commonly involves chemotherapy and, if possible, allogeneic stem cell transplantation which is the only therapeutic option for long term survival. Given the aggressive course of EMS, we here evaluated tyrosine kinase inhibitors as treatment options to delay disease progression. Methods We described a new case of EMS and used chromosome analyses, PCR, and sequencing to investigate the underlying genetic aberrations. The sensitivity to several tyrosine kinase inhibitors were tested in vitro on the EMS cell line KG1 and on primary cells from the newly diagnosed EMS patient. Results A translocation involving chromosomes 8 and 22 was detected and a BCR/FGFR1 fusion gene was confirmed and characterized by sequencing. KG1 cells and primary EMS cells displayed distinct sensitivity to dovitinib, ponatinib and dasatinib as compared to normal bone marrow control cells. Conclusions These results suggest that treatment with tyrosine kinase inhibitors may be beneficial for EMS patients during the search for a suitable stem cell donor and for those not eligible for transplantation. This article is protected by copyright. All rights reserved.

The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

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 Disclosures Richter: Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Sjalander:Novartis: Honoraria.

No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia : a population-based study in Sweden

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents. Funding Agencies|Nordic Cancer Union; Finnish Society of Hematology; Biomedicum Helsinki Foundation; Research Foundation of Blood Diseases in Finland; Academy of Finland; Finnish Cancer Organizations; Signe and Ane Gyllenberg Foundation; Finnish Cancer Institute; Doctoral Programme in Clinical Research in the University of Helsinki

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 μg/week and it increased to 25 μg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of Imatinib : a Tyrosine Kinase Inhibitor withdrawal syndrome?

We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation © 2014 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd. 243 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made

Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100,000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (70 years) and 79% for older (80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.

Background: The etiology of chronic myeloid leukemia (CML) is essentially unknown with high doses of ionizing radiation being the only well established risk factor. We have recently published two large population-based studies showing an increased prevalence of other malignancies prior, as well as subsequent to a diagnosis of CML (Gunnarsson et al, Br J Haematol. 2015 Jun; 169(5): 683-8 and Gunnarsson et al, Leukemia. 2016 Jul; 30(7): 1562-7). One may therefore speculate that CML patients may have an increased congenital or acquired susceptibility to develop cancer. In the former case, one would expect an increased prevalence of malignancies among first-degree relatives (FDR) to CML patients. In a previous report based on the Swedish Cancer Registry, no increased aggregation of malignancies was detected among family members to CML patients diagnosed between 1958 and 2004 (Bjorkholm et al, Blood. 2013 Jul 18; 122(3): 460-1). However, a more strict definition of CML (requiring e.g. thepresence of a Philadelphia chromosome or the BCR/ABL fusion gene) was introduced with the updated WHO classification in 2002, making subsequently diagnosed CML cohorts more homogenous. Materials and methods: Aiming to establish the prevalence of malignancies among FDR of a large and well-defined contemporary CML cohort in Sweden compared to carefully matched controls, we have used four large Swedish population based registers. To identify Swedish patients with CML diagnosed between 2002 and 2013, we used the Swedish CML Register to which all CML patients diagnosed January 1st 2002 and later are reported. FDR were identified by use of the Swedish Multi-Generation Register, which comprises information about parent-sibling-offspring relationships of persons that has been registered in Sweden at some time since 1961 and born later than 1932. By linking this cohort to the Swedish Cancer Register, we retrieved information about malignancies for each FDR. Each CML patient was matched with five, age-, gender- and county of residence-matched controls, selected from the Swedish Total Population Register. All controls had to be alive and free of CML at the time of CML diagnosis for the matching CML patient. To calculate odds ratio (OR) and 95% confidence intervals (CI), conditional logistic regression were used. Results: In the Swedish CML register, 984 patients were identified. Among them 184 patients were excluded due to a birth year prior to 1932. Among the 800 remaining CML patients, 4 287 FDR were identified and included in the analysis (parents: 1 346, siblings: 1 497 and children: 1 444). Correspondingly, 20 930 matched controls were included in the analysis. In total, 611 malignancies were identified among the FDR of CML patients compared to 2844 in the control group yielding an OR of 1.057 (95% CI 0.962 - 1.162). Neither hematological malignancies nor solid tumors were increased in the CML-FDR group (Table 1). Notably, none of the FDRs in the CML-FDR group had a CML diagnosis. Conclusions: Using data from four large Swedish population based registers and based on the fate of more than 4 000 FDR of 800 CML patients diagnosed in the modern era of cytogenetics, as well as closely matched CML-free controls, we show that there is no familial aggregation of malignancies in FDRs of patients with CML. These results suggest that a hereditary predisposition to develop cancer is unlikely to be a part of the pathogenesis of CML. Disclosures Höglund: Akinion Pharmaceuticals: Consultancy; Janssen-Cilag: Honoraria. Lambe:AstraZeneca: Other: Stock Ownership ; Pfizer: Other: Stock Ownership . Richter:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Själander:ARIAD: Consultancy.

Background: In chronic myeloid leukemia (CML) the combination treatment of tyrosine kinase inhibitors (TKIs) with interferon-α (IFN-α) has proved to be effective and well-tolerated. IFN-α has long-term immunomodulatory effects, and when combined to TKI therapy, it may increase the success rates for treatment free remission. In our recent clinical trial NordCML007, a low-dose pegylated IFN-α was combined with dasatinib therapy. As dasatinib is also known to have immunostimulatory effects (activation of T and NK cells and downregulation of regulatory T cells), we aimed to monitor the immune effects of dasatinib and IFN-α combination treatment. Methods: 40 newly diagnosed CML patients participated in the NordCML007 clinical trial (NCT01725204). Patients were treated with 100 mg dasatinib QD and after 3 months IFN-α treatment was added (first 3 months 15 μg/week, then 25 μg/week of pegylated IFN-α). After 12 months of combination treatment, patients resumed to dasatinib monotherapy. In this immunological substudy, peripheral blood samples were collected at the diagnosis, 3, 12, and 24 months after the start of therapy. T- and NK-cells were phenotyped with multicolor flow cytometry, and their function (degranulation and cytokine secretion) was studied. In addition, a multiplexed cytokine and growth factor panel was performed (Proseek Multiplex Inflammation I96×96, Olink). Results: Dasatinib monotherapy led to an increase of NK-cell frequencies when compared to pre-treatment values (median diagnosis 6.8% vs. 3 months 12.8%, p The more detailed immunophenotyping showed that at 3 months NK cells were more mature when compared to pre-treatment values. This could be observed as the increased proportion of CD16+ (86% vs. 77%, p=0.008) and CD57+ (79% vs. 67%, p=0.0001) NK cells. Correspondingly, the frequencies of CD56bright (median 3 months 3.9% vs. dg 6.1%, p Similar effects of dasatinib treatment were also observed within the T cell population, and at 3 months patients had more CD8+ terminally differentiated effector memory CD45RA+ (Temra) cells (22% vs. 32%, p=0.03). Correspondingly, both CD8+ and CD4+ effector memory (EM) populations decreased (CD8+ EM 34% vs. 24%, p=0.007; CD4+ EM 21 % vs. 14 %, p=0.0003). As observed with the NK cells, the degranulation and Th1 type cytokine secretion of T cells decreased during dasatinib treatment (CD107a/b+ 19.4% vs. 18.4% of CD8+ T cells, p=0.02; CD107a/b+ 12.7% vs. 8.8% of CD4+ T cells, p=0.005). Interestingly, 3 out of 4 patients who suffered from pleural effusion (PE) had exceptionally high CD57+CD8+ T cell frequencies (>70% of CD8+ T cells, median 38% in all patients) at diagnosis and during the treatment. The combination of IFN-α did not significantly affect the number of NK cells. Interestingly however, the addition of IFN-α treatment seemed to have an opposite effect on the NK cell phenotype than dasatinib treatment. The proportion of CD56bright NK cells increased (median 3 months 3.9% vs. 12 months 5.2%, p=0.03), and a decreasing trend was observed among CD16+ and CD57+ NK cells at 12 months. Similarly, the T cell surface markers shifted towards more immature phenotype (CD4+ EM 14% vs. 19%, p=0.002; CD4+ CM 36% vs. 28%, p=0.002; CD8+ Temra 32% vs. 17%, p=0.003) and the degranulation of CD4+ T cells and NK cells returned to the diagnosis level. The initiation of dasatinib treatment was associated with a decrease in several plasma protein concentrations (IL-18, IL-8, CXCL5, MCP-2, MCP-3, VEGF-A, CD244, LAP TGFβ1, TGFA, 4E-BP1, ADA, STAMPB, Casp8, OSM) and an increase in others (SCF, MCP-1). After IFN-α addition, the concentration of MCP-1 was further increased. Conclusions: These results show that dasatinib and IFN-α modulate both innate and adaptive immune systems. Interestingly, where dasatinib seems to induce a more mature immunophenotype, IFN-α counteracts this by driving a shift towards a more immature phenotype. Comparative analysis of the changes in the immunophenotype and function with the clinical outcome of the patients is ongoing. Disclosures Stentoft: Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol-Myers-Squibb: Research Funding. Richter:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Höglund:Akinion Pharmaceuticals: Consultancy; Janssen-Cilag: Honoraria. Mustjoki:Ariad: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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 Conclusion: The combination of DAS and low dose PegIFN could be safely administered in newly diagnosed CP CML. No unexpected autoimmune phenomena were observed, and pleural effusions were rare. Efficacy appears very promising with high early MMR rates and deep molecular responses. A randomized comparison DAS +/- PegIFN is warranted. Support: Study drug from BMS and MSD. Grant from BMS. Figure 1. Figure 1. Disclosures Hjorth-Hansen: Ariad: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Off Label Use: Dasatinib and Pegylated IFN combination in CML. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding.