Abstract: The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bo sutinib Do se Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2 nd or 3 rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II–IV, primary study endpoint) to  〈  40% (overall rate of 60%; 95% CI: 45–74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

Abstract: Background Since 2012, the Study Alliance Leukemia (SAL), a group of over 50 clinical trial and research centers (university hospitals, community hospitals, private practice), is establishing a systematic assessment of MPN patients in a German-wide registry, partly supported by Novartis. The main goal of this registry is the evaluation of the epidemiological distribution of clinical characteristics and outcome parameters, to enhance the understanding of MPN disease pathogenesis and disease progression. An important characteristic of our registry is that in addition to large centers, also small institutions are included which allows the collection of real-life data in MPN, due to the fact that these diseases are frequently treated outside large clinical centers in Germany. Methods The registry is a non-interventional, prospective and multi-centered epidemiological study. Inclusion criteria was the diagnosis of MPN according to WHO criteria (2008). Furthermore a minimum age of 18 and a written informed consent were conditions for entering the registry, independently of therapy regime and comorbidities. In addition to prospective collection of patients, data of patients who died or were lost to follow-up was evaluated once, covered by the central ethics approval. Epidemiological data and clinical characteristics were assessed at date of enrollment and every 12 months for an unlimited period of time. For this analysis only initial data was included. For statistical analysis, descriptive methods were used to describe the data with mean and median including standard deviations, range and/or 95%-confidence intervals. Results So far, 506 patients have been registered, comprising 243 evaluable patients with a mean age of 55 years (range 21-85). An updated analysis will be presented at the meeting. The proportion of male patients was 52%. The distribution of sex within the entities and other critical parameters are given in Table 1. 62% of all patients were JAK2V617F positive. As expected, complications like thrombosis and thromboembolism were mostly associated with PV and ET (38% and 29%). In 22 % of MPN patients, life-threatening thrombotic or thromboembolic events occurred during the clinical history. Similarly severe bleedings, as defined by a hemoglobin-level decrease 〉 2 mg/dl, were common in MPN; including 11 % of patients suffering from acute bleeding, most frequently from the upper gastrointestinal tract (56% of all hemorrhages). Acute bleedings occurred most common in PV, followed by PMF patients. Hydroxyurea was the most frequently administered substance (42%) followed by watch and wait strategies (22%). Other drugs were applied in 36% of all patients. Conclusions MPN are still associated with life-threatening events, such as thrombosis or severe bleeding. 33% of patients experiencing such an event had already been diagnosed with MPN and thus were already under medical surveillance. Novel strategies to pre-define risk factors and optimal therapeutic strategies are required to improve prevention strategies with the ultimate goal to avoid thromboembolic complications and improve survival and quality of life in MPN. Abstract 5561. Table 1 Clinical and laboratory results for PV, ET, PMF and Post PV/ET-MF Variable, mean (SD) All Patients PV ET PMF Post PV/ET- MF Age n = 132 56 (15) 56 (16) 49 (14) 58 (12) 65 (11) Male (%) n = 243 52 65 40 76 48 Leukocytes (/nl) n = 206 12.02 (8.0) 11.17 (6.7) 11.8 (6.0) 12.07 (8.3) 10.57 (6.0) Hemoglobin (g/dl) n = 206 13.4 (8.9) 13.3 (2.9) 12.94 (3.0) 11.69 (2,7) 13.17 (3.0) Platelets (/nl) n = 205 521.7 (404) 558.8 (390) 550.1 (423) 477.6 (372) 497.7 (415) LDH (U/l) n = 195 482.0 (377.8) 417.2 (258.7) 394,9 (256,1) 573.7 (413.7) 444.0 (295.6) Spleen Length (cm) n = 106 17.0 (6.6) 16.6 (5.9) 17.5 (8.9) 18.3 (7.5) 18.9 (7.1) Thromboembolism (%) n = 202 21.8 38.5 29.3 22.9 15.8 Severe Bleeding (%) n = 197 10.5 23.1 7.3 14.3 5.3 Therapy regime n = 203 Watch and wait (%) 21.7 27.8 29.7 26.9 28.6 Hydroxyurea (%) 42.4 44.4 48.7 34.6 42.9 Other Substances (%) 36.0 27.8 21.6 38.5 28.6 Disclosures Wolf: Novartis: Consultancy, Honoraria, Research Funding, Travel and Accommodation Other. Gattermann:Novartis: Honoraria, Research Funding. Lang:Novartis: Research Funding, Travel, Accommodation Other. Bennemann:Novartis: Consultancy, Honoraria. Bruemmendorf:Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Research Funding, Travel, Accommodation Other.

Abstract: In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL+ Lin−Sca-1+c-kit+ (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin−Sca-1−c-kit+), nor mature granulocytes (CD11b+Gr-1+), nor potential stem cell niche cells (CD45−Ter119−) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation. However, prolonged BCR-ABL expression abrogates the potential of LSK cells to induce full-blown disease in secondary recipients and increases the fraction of multipotent progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow. BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development, probably contributing to the reduced LT-HSC frequency within BCR-ABL+ LSK cells. Reversion of BCR-ABL, or treatment with imatinib, eradicates mature cells, whereas leukemic stem cells persist, giving rise to relapsed chronic myeloid leukemia on reinduction of BCR-ABL, or imatinib withdrawal. Our results suggest that BCR-ABL induces differentiation of LT-HSCs and decreases their self-renewal capacity.

Abstract: There is an unmet need for novel therapies with distinct modes of action to offer clinical benefit for patients with myelofibrosis (MF) who become resistant or intolerant to JAK inhibitors. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal potential of malignant myeloid cells for hematopoietic differentiation, e.g., LSD1 licenses maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, mutant cell burden and overall survival (Jutzi et al. 2018). IMG-7289-CTP-102 is a global, open-label Phase 1/2 study evaluating bomedemstat dosed once daily in MF patients (NCT03136185). Data from this ongoing study are presented. Key eligibility criteria include IPSS int.-1 or -2 or high-risk patients refractory or resistant to, inadequately controlled by or intolerant of available approved therapy, or in the Investigator's judgment, are not candidates for available approved therapy, peripheral blast count ≤10%, absolute neutrophil count ≥0.5 x 10 9/L, and platelet count ≥100 x 10 9/L. Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the MPN-SAF instrument. Serial bone marrow (BM) biopsies and imaging studies are read centrally. Of 261 genes recurrently mutated in AML/MPN/MDS, germline and somatic baseline and follow-up sequencing is conducted to quantify existing or new mutant alleles frequencies (MAF). Dosing is individually tailored using platelet count as a biomarker of bomedemstat activity on megakaryocyte function, targeting a range between 50-100 x 10 9/L and titrating as needed. At data cutoff (15 July 2021), the study is fully enrolled with 89 patients: 49% primary MF, 30% post-essential thrombocythemia-MF, 21% post-polycythemia vera-MF. Median age is 68 (35-88) with 52% males. Prior treatment with ruxolitinib was reported in 81% (72/89), 43% (38/89) had also received up to 3 different treatments. 30% of patients (25/83) had received ≥1 RBC transfusion prior to dosing. By IPSS, 54% were high-risk, 40% int.-2, and 6% int.-1. At screening (N=88), sequencing to an average depth of & gt;1000, JAK2 was mutated in 70%, CALR in 22%, and MPL in 7%; 64% had ≥2 mutations of which 66% had high-molecular risk mutations in ASXL1, IDH1/2, EZH2 and/or SRSF2. The median duration of treatment is 17 weeks (2-102). Of all enrolled patients for whom data is available (evaluable) at 24 weeks for TSS with baseline value ≥20, 89% recorded a reduction in TSS (mean change -36%; -81% to 21%) with 39% reporting ≥50% reduction. Of all patients evaluable for SVR at 24 weeks (N=27), 78% had a reduction in spleen volume from baseline (mean SVR: -4%; -41% to 107%) with 37% showing ≥20% SVR. Of evaluable patients (N=29), 86% had stable (∆ & lt;±1.0 g/dL) or improved hemoglobin ( & gt;1.0 g/dL). Of patients evaluable for BM fibrosis scoring post-baseline (N=29), 17% improved by 1 grade and 66% were stable. Serially sequencing 43 patients, MAFs in one or more alleles were reduced in 42% with 1 patient in complete molecular remission, and stable in 44%. Clones with JAK2 and/or ASXL1 mutations were most frequently reduced. MAF reduction also correlated with efficacy: SV and/or TSS were improved in patients in whom MAFs were also decreased. No new mutations were identified in any patient. No patient transformed to AML during this study. The most common non-hematologic AEs reported by patients were diarrhea and dysgeusia, each at 28% (25/89). There have been 13 related SAEs with 3 Grade 2, 9 Grade 3 and 1 Grade 4 (thrombocytopenia). Thirty-nine patients remain on study. Early terminations ( & lt;24 weeks) due to AEs occurred in 13 (15%) patients with 5 related to bomedemstat, and 15 discontinued for other reasons. There have been no safety signals, DLTs, or deaths related to drug. In a patient population with advanced disease, a heavy mutation burden and limited treatment options, once-daily bomedemstat as monotherapy had an acceptable tolerability profile, relieved symptoms, reduced spleen volume and improved anemia without any significant safety signals. Additionally, reductions in the allele frequency of both driver and high molecular risk mutations were observed and correlated with improved efficacy metrics. The study is now fully enrolled and additional data will be presented. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in publicly-traded company. Bradley: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gerds: AbbVie: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Novartis: Consultancy. Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Göthert: AOP Orphan Pharmaceuticals: Honoraria, Other: Travel reimbursement; zr pharma & : Honoraria; Proteros Biostructures: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel reimbursement; Incyte: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel reimbursement. Koschmieder: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Abbvie: Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Image Biosciences: Other: Travel support; Alexion: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Karthos: Other: Travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding. Jones: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Peppe: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Natsoulis: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Hong: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months. Harrison: BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: 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. Talpaz: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Celgene: Consultancy; Takeda: Other: Grant/research support . Rienhoff: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company.

Abstract: Introduction: Ph-negative myeloproliferative neoplasms (MPN) represent a heterogeneous group of hematological malignancies which differ in various aspects such as clinical manifestation, underlying genetic aberrations, cytomorphological features and life expectancy. However, across all subtypes, patients (pts) with MPN often suffer from severe symptoms, resulting in an impairment of the quality of life (QoL). Methods: The German Study Group for MPN (GSG-MPN) Bioregistry is a non-interventional prospective study including pts of at least 18 years with diagnosis of Ph-negative MPN according to WHO criteria (2008) having provided written informed consent. The Bioregistry study also includes assessment of QoL at baseline and on an annual basis, with all pts completing the standardized MPN-SAF-TSS questionnaire (German version) and an additional item indicating pts' subjective overall QoL on an 11-point Likert scale. Total scores range from 0 to 90 and were calculated if at least 6 items were answered (Emanuel RM et al., J Clin Oncol. 2012; 30 (33): 4098-103.)). Clinical variables, as documented in the registry, included comorbidities, reported symptoms as assessed by the physician, bleeding, and thromboembolic events (TEE). For statistical analysis, standard descriptive methods, Spearman correlation coefficient, Wilcoxon test/Kruskal-Wallis test for significance testing, and Kendall´s tau-b statistics were used. Results: 1,403 pts who had completed at least six items of the QoL assessment at baseline were included in this analysis. Median age at diagnosis was 58 years (interquartile range [IQR] 22), 98% were Caucasian, 50% were female. 494 pts were diagnosed with essential thrombocythemia (ET, 35%), 444 pts with polycythemia vera (PV, 32%), 302 pts with primary myelofibrosis (PMF, 22%), 83 pts with MPN-unclassifiable (MPNu, 6%), 43 pts with post-ET-myelofibrosis (pET-MF, 3%) and 37 pts with post-PV-myelofibrosis (pPV-MF, 3%). The most common complaint reported via the MPN-SAF-TSS was fatigue, occurring in more than 80% of the pts in all entities except MPNu (77%). More than 50 % of pts in each entity reported to suffer from early satiety, night sweats, concentration problems, or overall impairment of QoL. Table 1 summarizes all 9 symptoms and overall QoL from the questionnaire categorized by entity. Interestingly, the pts suffering from PET-MF reported the highest symptom burden, while PPV-MF pts showed the lowest overall symptom burden (median total QoL score of 23 vs. 16; p=0.01). The strongest correlations among the different symptoms were seen for fatigue and overall QoL (Spearman´s rho 0.57, p 〈 0.001) as well as concentration problems and overall QoL (Spearman´s rho 0.33, p 〈 0.001). Furthermore, the impact of variables such as age, comorbidities and TEE on QoL was assessed. Abdominal discomfort increased with age (rho = -0.14, p 〈 0.001). A history of TEE before baseline assessment correlated significantly with fatigue scores (Spearman rho= 0.07, p 〈 0.01) and with concentration problems (rho=0.07, p 〈 0.01). With an increasing number of TEE, scores for both of these items worsened over time (p 〈 0.01, respectively). Moreover, MPN-total score (MPN-TSS) was higher in pts with more comorbidities (Median: 18 (IQR:23), and 25 (27) for pts with 〈 3 versus ≥3 comorbidities, respectively, p= 0.017). Next, we compared data on 5 of the pts symptoms (reported in the questionnaire) to their assessment by the treating physician (only 5 items were available both in the questionnaire and in our registry database) in order to understand whether the "physician´s opinion" is congruent with the patient´s reported outcome in the questionnaire. While there were clear associations between the two data sources, there were also significant discrepancies, e.g., the physician did not indicate fatigue in about 20% of pts with self-assessed fatigue score of 〉 =6 points. The most concordant symptom was night sweats (further details in table 2). Conclusions: Most MPN pts suffer from a significant symptom burden which impairs their QoL. TEE influence fatigue and concentration problems. The perception of symptoms (particularly with respect to fatigue) differs between pts and treating physician which suggests that questionnaires should be used on a routine basis in order to faithfully reflect patient´s degree of suffering from MPN and/or treatment. Disclosures Isfort: Amgen: Other: i.e. travel support; Mundipharma: Other: i.e. travel support; Roche: Other: i.e. travel support; Incyte/Ariad: Consultancy; Pfizer: Consultancy, Honoraria, Other: i.e. travel support; BMS: Honoraria; Novartis: Consultancy, Honoraria, Other: i.e. travel support; Alexion: Other: i.e. travel support; Hexal: Other: i.e. travel support. Stegelmann:Novartis: Consultancy, Honoraria. Al-Ali:Gilead: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Alexion: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Goethert:BMS: Consultancy, Honoraria, Other: i.e. travel support; Incyte: Consultancy, Honoraria, Other: i.e. travel support; Pfizer: Consultancy, Honoraria; Novartis: Honoraria; Proteros Biostructures: Honoraria; AOP Orphan: Other: i.e. travel support. Haenel:Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria; Amgen: Honoraria. Platzbecker:Celgene: Research Funding. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy.

Abstract: Inflammation-induced thrombosis represents a severe complication in patients with myeloproliferative neoplasms (MPN) and in those with kidney dysfunction. Overlapping disease-specific attributes suggest common mechanisms involved in MPN pathogenesis, kidney dysfunction, and thrombosis. Data from 1420 patients with essential thrombocythemia (ET, 33.7%), polycythemia vera (PV, 38.5%), and myelofibrosis (MF, 27.9%) were extracted from the bioregistry of the German Study Group for MPN. The total cohort was subdivided according to the calculated estimated glomerular filtration rate (eGFR, (mL/min/1.73 m2)) into eGFR1 (≥90, 21%), eGFR2 (60–89, 56%), and eGFR3 ( 〈 60, 22%). A total of 29% of the patients had a history of thrombosis. A higher rate of thrombosis and longer MPN duration was observed in eGFR3 than in eGFR2 and eGFR1. Kidney dysfunction occurred earlier in ET than in PV or MF. Multiple logistic regression analysis identified arterial hypertension, MPN treatment, increased uric acid, and lactate dehydrogenase levels as risk factors for kidney dysfunction in MPN patients. Risk factors for thrombosis included arterial hypertension, non-excessive platelet counts, and antithrombotic therapy. The risk factors for kidney dysfunction and thrombosis varied between MPN subtypes. Physicians should be aware of the increased risk for kidney disease in MPN patients, which warrants closer monitoring and, possibly, early thromboprophylaxis.

Abstract: Background: Anemia remains one cardinal symptom associated with reduced quality of life (QoL) in patients (pts) with myelofibrosis (MF) which is normally not being addressed by ruxolitinib (RUX). In our previous MPNSG-0109 trial, single-agent pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2.0 mg QD) of MF pts, respectively. In the MPNSG-0212 study, we sought to investigate the potential synergism of RUX plus POM to improve anemia and QoL in MF pts. Study Design: MPNSG-0212 is an ongoing multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts following a two-stage design (NCT01644110). Pts 1-40 in cohort 1 (co1) were treated with RUX (10 mg BID) plus low-dose POM (0.5 mg QD), while pts 41-90 in cohort 2 (co2) receive a step-wise dose increase of POM from 0.5 mg to 1 mg and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoints are safety of the combination therapy, anemia response after 12 cycles (according to IWG-MRT and RBC transfusion independence [RBC-TI] criteria), and clinical benefit (CB) defined as stable disease plus i) hemoglobin (Hb) increase ≥1 g/dL in pts with RBC-TI or ii) doubling of RBC transfusion intervals and/or iii) significant ( & gt;25%) improvement of QoL as measured by the MPN-SAF questionnaire. Main inclusion criterion is MF with anemia (Hb & lt;10 g/dL and/or RBC transfusion dependence [RBC-TD]). Pts suitable for allogeneic transplantation and pts with low platelet counts ( & lt;100/nL) are excluded. Results: At data cut-off (31-May-2019), 79 pts were included. Data from 67 pts were available for evaluation (co1, n=40; co2, n=27). Baseline characteristics of the pts were as follows: median age 72 years (range 49-84), prior treatment in 53% (RUX in 22%, POM in 4%), median Hb level at study start 8.6 g/dL (range 5.4-11.7), RBC-TD in 28%, median spleen diameter measured by ultrasound 17.7 cm (range 12-36), presence of constitutional symptoms in 76%, and 91% intermediate-2 (61%) or high-risk (30%) pts according to DIPSS; 55% of pts in co1 had ≥1 high molecular risk mutation (ASXL1, SRSF2, EZH2, and/or IDH1/2). Median number of cycles until data cut-off was 12 (range 2-63) in co1 and 11 (range 2-21) in co2. In total, 502 adverse events (AE) mainly grade 1/2 were recorded: AE grade 1/2 in & gt;20% of pts were fatigue (in 27% of pts), dyspnea (24%), diarrhea (22%), and muscle cramps (21%); AE grade ≥3 in & gt;3% of pts was Hb decrease in the first weeks of treatment occurring in 25% of pts. In total, 87 serious AE (SAE), were recorded: most common SAE (in ≥3 pts) were pneumonia (in 15% of pts), leukemic transformation (9%), worsening of general condition (6%), CNS ischemia, and sepsis (4% each); 7 SAE (in 10% of pts) were grade 5. Number or severity of (S)AE was not increased in co2. Treatment interruptions of RUX and/or POM were necessary in 11 pts (27%) of co1 and 3 pts (11%) of co2; 2 pts stopped treatment permanently due to hematotoxicity. Increase of the POM dose to 1 mg and 2 mg QD was feasible in the majority of pts after 3 and 6 cycles, respectively. In co1, 18/40 pts (45%) continued treatment beyond cycle 12 because of an objective anemia response (7/40, 18%: clinical improvement [CI, Hb increase ≥2 g/dL] n=5, partial remission and RBC-TI n=1 each) or CB (11/40, 27%): Hb increase ≥1 g/dL and/or doubling of RBC transfusion intervals (n=4) or improvement of QoL according to MPN-SAF (n=7). In co2, 17/27 pts (63%) reached cycle 12 and 10/17 (59%) continued treatment: 2/10 (20%) experienced CI, whereas 8/10 (80%) fulfilled the CB criterion; 19/27 pts (70%) were still on treatment at the time of data cut-off. Among all 67 pts analyzed, 42% (28/67) were on treatment for more than 12 cycles and 24% (16/67) for more than 24 cycles; 3 pts (4%) were treated for more than 60 cycles due to sustained response or CB. Of note, mean Hb increased from 8.7 g/dL at baseline to 9.6 g/dL at end of cycle 18 and remained stable thereafter (Figure 1). Conclusions: Combination treatment using RUX plus POM is feasible in pts with poor-risk MF and resulted in an objective anemia response rate of 18% in co1. Of note, 42% of pts were treated with & gt;12 cycles and showed a longer lasting stabilization of their disease with sustained improvement of Hb and QoL. Step-wise increase of the POM dose in co2 is safe and feasible with 70% of pts still on study treatment. Updated efficacy results of co2 with longer follow-up data will be presented at the meeting. Figure 1 Disclosures Stegelmann: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Koschmieder:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Foundation: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Isfort:Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria, Other: Travel reimbursement; Ariad: Consultancy, Honoraria; BMS: Honoraria; Hexal: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Göthert:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Proteros Biostructures: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel support. Schafhausen:Incyte: Consultancy, Equity Ownership, Honoraria; Novartis: Consultancy, Honoraria. Radsak:Daiichi Sankyo: Other: Travel Support, Advisory Boards; Novartis: Other: Travel Support, Advisory Boards; JAZZ: Other: Travel Support; Celgene: Other: Travel Support, Advisory Boards; Takeda: Other: Advisory Boards; Otsuka: Other: Advisory Boards. von Bubnoff:Novartis: Research Funding. Reiter:Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria.