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Introduction: Tyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML. Patients and methods: This multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers. Results: For patients who started treatment with ponatinib in chronic phase (CP) (n=23) and in accelerated phase (AP) (n=3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation – none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%. Conclusion: Our analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups. Microabstract: Ponatinib is a new pan-inhibitor of tyrosine kinase active in resistant chronic myeloid leukemia (CML). Evaluation of outcomes in 43 patients confirmed ponatinib efficacy in a significant proportion of subjects heavily pre-treated with tyrosine kinase inhibitors achieving durable responses in both chronic phase and accelerated/blastic phase CML groups.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.FUNDING: Sierra Oncology.

The impact of the mutation status on the clinical course and the outcome of essential thrombocythemia (ET) patients has not yet been completely established. A total of 171 patients with diagnosed ET were tested and subsequently grouped, according to their mutation status – Janus Kinase 2 (JAK2) – 112 patients, calreticulin (CALR) – 36 patients, and thrombopoietin receptor (MPL) – 5 patients. Moreover, 18 individuals were triple-negative (with non-mutated JAK2, CALR, and MPL). CALR-mutated patients preferentially were male, with higher platelets (PLT) counts (mean PLT = 1 002.3) and lower hemoglobin and hematocrit levels at the diagnosis, compared to the JAK2 (mean PLT = 933.6), MPL (mean PLT = 940.8) and triple-negative patients (mean PLT = 822.6) (p = 0.0035). The patients with CALR mutated, and the triple-negative ones had a lower risk of arterial and venous thrombosis (3% and 5.6% cases at the time of diagnosis, respectively) than the patients with JAK2 mutation (7.2%) (p = 0.9210). The overall survival rate did not differ statistically between the groups.

Mutations in the additional sex combs like 1 (ASXL1) gene are frequently involved in clonal hematopoiesis and are connected with an increased risk of hematologic cancer. These aberrations are frequently detected in a number of different hematological neoplasms including acute myeloid leukemia (AML). Patients harboring ASXL1 mutations tend to have a poor prognosis and poor response to therapy. Here, we report the coexistence of four different mutations in ASXL1 gene in a patient with AML. Such accumulation of mutations, in this gene, has not been described yet. Our findings suggest that accumulations of mutations in ASXL1 gene may play an important role in the development and/or progression of AML.

Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. Many patients (pts) with MF treated with ruxolitinib (rux) develop worsening anemia and may become RBC transfusion-dependent (TD). Objective: Evaluation of pelabresib monotherapy or as add-on to rux in advanced MF pts. Design: In Arm 1, pts refractory, intolerant, or ineligible for JAKi were treated with pelabresib monotherapy. In Arm 2, pts receiving rux but not deriving adequate benefit were treated with add-on pelabresib. The primary endpoint was achievement of transfusion independence (TI) ≥12 wks in TD cohorts and ≥35% spleen volume reduction at wk 24 in non-TD cohorts. Results: As of 29 Sept. 2020, 19 TD pts and 27 non-TD pts were treated in Arm 1. Seventy-six percent of pts had baseline Hgb Conclusions: Pelabresib monotherapy was associated with a mean increase in Hgb ≥1.5 g/dL in majority of non-TD pts and conversion of one-fifth of TD pts to TI in Arm 1. Pelabresib add-on to rux in Arm 2 resulted in mean increase in Hgb ≥1.5 g/dL in 17% of non-TD pts and conversion to TI in more than one-third of TD pts.

Canadian Institutes of Health Research, Grant/ Award Number: 81274; Huntsman Cancer Institute Pilot Funds; Leukemia Lymphoma Society, Grant/Award Number: 6067-09; the National Institute of Health/National Cancer Institute, Grant/Award Numbers: P30 CA016672, P30 CA042014, P30 CA13148, P50 CA186781, R01 CA107476, R01 CA134674, R01 CA168762, R01 CA186646, R01 CA235026, R21 CA155951, R25 CA092049, R25 CA47888, U54 CA118948; Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah; VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414; Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database; Mayo Clinic Cancer Center; University of Pisa and DKFZ, The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah PopulationDatabase, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah StateDepartment of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center.Open Access funding enabled and organized by ProjektDEAL., The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions., Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10(-7) either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., Canadian Institutes of Health Research (CIHR) 81274, Huntsman Cancer Institute Pilot Funds, Leukemia and Lymphoma Society 6067-09, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30 CA016672 P30 CA042014 P30 CA13148 P50 CA186781 R01 CA107476 R01 CA134674 R01 CA168762 R01 CA186646 R01 CA235026 R21 CA155951 R25 CA092049 R25 CA47888 U54 CA118948, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council 1074383 209057 396414, Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database, Mayo Clinic Cancer Center, University of Pisa, Helmholtz Association

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Background: Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in patients with myelofibrosis (MF). Here we present results from MANIFEST (NCT02158858), an ongoing, global, open-label Phase 2 study investigating pelabresib monotherapy in patients with advanced MF who are intolerant/refractory to, or ineligible for ruxolitinib (RUX) and typically have very poor prognosis. Methods: Eligibility criteria are MF patients intolerant/refractory to or ineligible for JAKi, Dynamic International Prognostic Scoring System (DIPSS) risk category of ≥intermediate-2, platelets ≥75 × 10 9/L, and ≥2 symptoms measurable (score ≥1) per Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. Additional criteria include red blood cell (RBC) transfusion dependent (TD) per Gale criteria in TD cohort or spleen volume of ≥450 cc by computed tomography/magnetic resonance imaging in non-TD cohort. Patients were enrolled as TD (defined as ≥2 U RBCs/month over 12 wks) and non-TD if TD criteria are not met. The primary endpoint in TD cohort is RBC transfusion independence (TI; defined as no transfusion for ≥12 wks), and ≥35% spleen volume reduction (SVR35) at wk 24 in the non-TD cohort. Secondary endpoints include number of patients with ≥50% total symptom score reduction (TSS50) per MFSAF v4.0 at wk 24, and safety. Additional exploratory endpoints include changes in plasma levels of proinflammatory cytokines and bone marrow (BM) morphology/fibrosis. Patients with assessment at wk ≥24 and those discontinuing after wk 12 are included in the analysis of the corresponding endpoint; these were the evaluable patients. Results: As of 29 September 2020, 27 pts were treated in the non-TD cohort for a median duration of 51 wks (2, 147 wks). At wk 24, 30% (7/23) evaluable pts achieved SVR35 (median change: -29%), and 48% (10/21) pts achieved TSS50 (median change: -56%). In the TD cohort, 19 pts were treated for a median duration of 32 wks (5, 78 wks). 21% (3/14) evaluable TD pts achieved RBC TI for ≥12 wks. Updated 24-wk data with a larger data set and new long-term data at 48 wks will be presented. Pt subgroup analyses revealed evidence of activity of pelabresib in a subset of pts who were ineligible to receive RUX, a patient population that generally has few therapeutic options. Clinical benefits observed with pelabresib included achievement of SVR35 and TSS50, improvements in bone marrow fibrosis, and increases in hemoglobin levels. A panel of 68 cytokines, including those known to be nuclear factor kappa B (NF-κB) targets linked to inflammation and elevated in MF pts, were evaluated in plasma samples obtained at baseline (BL) and during therapy. Cytokines were clustered to show different patterns of change during treatment with pelabresib. Overall, pelabresib significantly reduced plasma levels of several cytokines in RUX naïve or experienced pts (Figure). Cytokine changes with pelabresib in cluster 3 (which includes IL-6, CRP, RANTES, TNFa and IL-18, and is characterized by higher BL values and bigger decreases over time) and in cluster 5 (which includes EPO, TARC, ICAM-1 and IL-8, and is characterized by relatively lower BL values and less profound decreases over time) were more pronounced in RUX-naïve pts. 46 pts were evaluable for safety. The most common hematological treatment emergent adverse events (TEAEs) of any grade were thrombocytopenia (30%; ≥Grade 3: 15%) and anemia (15%; ≥Grade 3: 13%). The most common (≥20%) nonhematological TEAEs were nausea (39%; no ≥Grade 3), diarrhea (37%; ≥Grade 3: 4%), dysgeusia and asthenic conditions (30% each; no ≥Grade 3 for either), respiratory tract infections (28%; ≥Grade 3: 2%), cough (26%; no ≥Grade 3) and constipation and weight decrease (22% each; ≥Grade 3: 2% each). Conclusions: Preliminary data suggested pelabresib monotherapy was generally well tolerated and demonstrated signals of clinical activity in MF pts intolerant/refractory to or ineligible for JAKi, who have limited treatment options and poor outcomes. Figure 1 Figure 1. Disclosures Kremyanskaya: Astellas: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Astex: Research Funding; Chimerix: Research Funding. Mascarenhas: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galecto: Consultancy; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Research Funding; Prelude: Consultancy. Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy. 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. Verstovsek: Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Harrison: 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; Abbvie: 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; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Incyte Corporation: Speakers Bureau; Constellation Pharmaceuticals: Research Funding; BMS: 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; Keros: 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; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: 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; 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. Bose: CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Promedior: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Schiller: Ono-UK: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Deciphera: Research Funding; FujiFilm: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sangamo: Research Funding; Actuate: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Geron: Research Funding; Genentech-Roche: Research Funding; Tolero: Research Funding; Takeda: Research Funding; Forma: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell Ltd.: Research Funding; Arog: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; PrECOG: Research Funding; Regimmune: Research Funding; Mateon: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Bio: Research Funding; Delta-Fly: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Elevate: Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Rampal: Jazz Pharmaceuticals: Consultancy; BMS/Celgene: Consultancy; Stemline: Consultancy, Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy; Pharmaessentia: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Memorial Sloan Kettering: Current Employment; Incyte: Consultancy, Research Funding; Kartos: Consultancy; Constellation: Research Funding. Drummond: BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gupta: Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy; Incyte: Honoraria, Research Funding; BMS-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. Patriarca: Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Argenix: Honoraria. Scandura: Constellation: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees . Teichmann: Pfizer: Membership on an entity's Board of Directors or advisory committees. Hoffman: Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Kartos Therapeutics, Inc.: Research Funding. Colak: Constellation Pharmaceuticals: Current Employment. Ren: Constellation Pharmaceuticals: Current Employment. Bobba: Constellation Pharmaceuticals: Current Employment. Cui: Constellation Pharmaceuticals: Current Employment. Efuni: Constellation Pharmaceuticals: Current Employment. Talpaz: Imago: Consultancy; Constellation: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Composition of the gut microbiota seems to influence early complications of allogeneic hematopoietic cell transplantation (HCT) such as bacterial infections and acute graft-versus-host disease (GVHD). In this study, we assessed the impact of colonization with multidrug-resistant bacteria (MDRB) prior to HCT and the use of antibiotics against anaerobic bacteria on the outcomes of HCT. We retrospectively analyzed the data of 120 patients who underwent HCT for hematologic disorders between 2012 and 2014. Fifty-one (42.5%) patients were colonized with MDRB and 39 (32.5%) had infections caused by MDRB. Prior colonization was significantly correlated with MDRB infections (P 40 years (P = 0.002). Colonization had a negative impact on overall survival (OS) after HCT (64 vs. 47% at 24 months; P = 0.034) and infection-associated mortality (P

Introduction Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML). Patients who respond to imatinib, have a life expectancy comparable with that of the global population, however, up to 40% of patients discontinue imatinib due to resistance or intolerance. Ponatinib is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations, including the T315l mutation. This report presents the results of a prospective analysis of 3-year ponatinib therapy available in Poland by Angelini's donation program for patients in all phases of CML resistant or intolerant to previous TKI therapy. Methods 43 CML patients (20 women, 24 men, aged 19 to 76 years, mean age 49 ± 15 years) were treated in 20 Polish Hematology Centers with ponatinib initiated between March 2016 and December 2019. 23 pts (53%) were in the chronic phase (CP), 3 pts (7%) in accelerated phase (AP), and 17 pts (40%) in blastic phase (BP) (9 myeloblastic and 8 lymphoblastic). The majority of patients received three lines of TKI therapy. The T315I mutation was detected in 30% of patients (the initial characteristics of the 43 analyzed patients are shown in Table 1). The indication for ponatinib and its dose schedule was made according to the discretion of the attending physician. The initial dose of ponatinib was 45 mg/d in 60% of all patients (without statistically significant differences in the initial dose between patients starting treatment in CP, AP, and BP). Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % [IS] in all patients. Treatment responses were calculated at each specific time points recommended by ELN. Statistica 12 software (StatSoft, Tulsa, OK, USA) was used for calculations. Results The follow-up ranged from one week to 35.4 months (median 11.4 months) (one male patient died on infection one week after ponatinib introduction and was excluded from further analysis, he did not achieve CHR and he transformed to blast phase-BP). The responses to ponatinib are shown in Table 2. Among 23 CP patients, 18 achieved CHR (78%), 6 (26%) MCyR, 5 (22%) CCyR, and 1 (4%) MMR at 1 month of treatment. There were only 2 patients in this group (9%) who did not achieve CHR. Eleven CP patients (48%) achieved stable MMR. In all 3 AP patients, the best responses (CHR, CCyR, and MMR) were maintained until the end of observation (Table 2). Among 17 BP patients, 8 (47%) achieved CHR. The overall survival was significantly better in those patients who achieved CHR at 1 month of therapy (Figure 1). 19 patients (44%) experienced toxicity of ponatinib including: increase in blood pressure overall 9 patients (21%), hematological toxicity grade 3-4- 12 patients (28%).A total of 19 patients (44%) remained on ponatinib at the end of the observation. Ponatinib dose was reduced during the study in 18 patients (42%): in 11 (61% of those requiring dose reduction) because of toxicity, in 6 (33%) because of good response to treatment, and in 1 patient (6%) because of both reasons. The need for dose reduction was not significantly associated with comorbidities (p=0.4). Eight patients (19%) underwent allo-SCT during the observation. Ponatinib was discontinued in eight patients (19%), in six CP and two BP-patients. In five patients (12%), ponatinib was discontinued because of toxicity (hematological in one, non-hematological in two, and both in one patient); all were CP patients. In two patients (one CP, one BP patient), ponatinib was discontinued as they underwent allo-SCT. Overall, 16 patients (37%) died during the study: 12 of them (28%) due to CML progression. In all 43 patients, median survival was not reached. The estimated 2-year survival was 60% (95% confidence interval 44-76%) (Figure 2A) 84% in CP patients, 100% in AP patients (Figure 2B), and 20% in BP patients. None of the CP patients progressed to AP or BP during the study, i.e. progression-free survival was 100% at the end of observation (35.4 months). The presence of T315I mutation (p=0.2) or the initial dose of ponatinib (p=0.4) was not significantly associated with the overall survival. Conclusion Our study confirmes that ponatinib could induce durable responses with acceptable toxicity profiles in highly pretreated patients with CML resistant or intolerant to previous TKIs treated in standard clinical practice. Disclosures Sacha: Adamed:Consultancy, Honoraria;Bristol-Myers Squibb Company:Consultancy, Honoraria, Speakers Bureau;Pfizer:Consultancy, Honoraria, Speakers Bureau;Novartis:Consultancy, Honoraria, Speakers Bureau;Incyte:Consultancy, Honoraria, Speakers Bureau.Niesiobedzka-Krezel:Angelini Pharma:Other: lecture fee and meeting partcipation.Ciepluch:Copernicus Wojewodzkie centrum Onkologii:Current Employment.

Momelotinib (MMB), a JAK1, JAK2 and ACVR1 inhibitor, has demonstrated clinically comparable splenic and symptomatic benefits to ruxolitinib (RUX), the standard-of-care JAK1/JAK2 inhibitor for myelofibrosis (MF), a condition marked by splenomegaly, constitutional symptoms and progressive anemia and thrombocytopenia. MMB also uniquely restores iron homeostasis and red blood cell production, reduces or eliminates the need for transfusions and improves or maintains platelet (PLT) counts. Consistent with MMB's differentiated biological profile, low myelosuppressive potential and favorable hematological tolerability, prolonged, near-maximal MMB dose intensity can be maintained regardless of underlying PLT values. In contrast, RUX's hematological toxicity profile necessitates attenuated starting doses for thrombocytopenic (TCP) patients with PLTs A retrospective analysis of spleen, symptom and TI response rates at week 24 was conducted in the TCP and ITT groups from SIMPLIFY-1 (S1), a double-blind Phase 3 study in intermediate/high risk MF patients randomized 1:1 to MMB or RUX over a 24-week treatment period, and SIMPLIFY-2 (S2), a Phase 3 study comparing MMB to best available therapy (BAT) in previously RUX-exposed MF patients. A baseline PLTs ≥50 × 109/L was required in S1, while there was no lower PLT limit for S2. Most subjects randomized to BAT (88%) received RUX during the 24-week randomized period. In S1, 9.5% and 24% of 432 subjects randomized had a PLT count of In S2, 44% of 156 subjects randomized had a PLT count of These retrospective analyses of data from the two Phase 3 SIMPLIFY studies demonstrate that MMB efficacy is maintained in TCP patients and is comparable to that observed in the broader JAKi-naïve and previously JAKi-treated ITT populations in S1 and S2. These data contrast with RUX data from S1 where the SRR was markedly decreased and the TSS moderately decreased in TCP patients, consistent with reduced RUX dose intensity and higher rates of early discontinuation in this subset. Consequently, for patients in S1 with low PLTs, MMB and RUX demonstrated similar symptomatic benefit, while MMB had a more favorable profile for splenic volume reduction and TI. Response rates for the three parameters in the MMB arm of S2 were comparable between the TCP and ITT groups. Response rates in the control arm were low and not substantially different between the TCP and ITT groups, with most patients receiving very low dose intensity of RUX. Together, the findings of comparable spleen, symptom and TI response in the TCP and ITT groups treated with MMB suggest that the compound could become the optimal JAK inhibitor therapy for intermediate/high risk MF patients with underlying disease-related or prior RUX-induced thrombocytopenia. Disclosures Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Mayer:Principia Biopharma: Research Funding; AbbVie: Research Funding. Illés:Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nagy:MorphoSys AG: Patents & Royalties. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; YuhanPharma: Research Funding. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Verstovsek:Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding. Klencke:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Donahue:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding.

e19039 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 was conducted in JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). MMB demonstrated a statistically non-inferior splenic response rate (SRR) to RUX at the W24 landmark analysis in S1 but did not meet significance for total symptom score (TSS) response. Low SRR and TSS response was observed for RUX in patients with low platelets, while MMB elicited consistent SRR and TSS response across the platelet subsets, comparable to the response in the ITT. Transfusion independence (TI) at W24 was higher for MMB vs RUX patients across all PLT strata. Methods: Progressive anemia is a common occurrence in MF with nearly all MF patients requiring transfusions as their disease advances. Given the prognostic importance of Hgb and transfusion status in MF patients including evidence that achieving or maintaining transfusion independence by Week 24 with momelotinib is associated with improved OS in S1 and S2, we expanded the previously reported retrospective platelet subset analysis to explore the W24 TI response rates for MMB and RUX randomized patients in S1 by baseline Hgb and PLT levels and transfusion status. Results: The data presented here suggest that the prognostically-important W24 TI rate was substantively higher in anemic patients receiving MMB versus RUX, irrespective of the degree of anemia. MMB is also more effective relative to RUX in achieving or maintaining TI in JAKi naïve patients irrespective of baseline PLT count or baseline transfusion status. Conclusions: Together with data suggesting that TI response at W24 with momelotinib is associated with a survival advantage, these data further support the potential TI benefits of inhibiting ACVR1 in addition to JAK1 and JAK2 with MMB in MF patients. Clinical trial information: NCT01969838, NCT02101268. [Table: see text]

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known on the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7 - 2.6]). Patients with 20-29% had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2 - 4.0], p = 0.008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs. non-high risk) with an HR of 3.01 (95%-CI: [1.81 - 5.00], p

Introduction Allogeneic hematopoietic cell transplantation (HCT) was a standard therapy in chronic phase (CP) chronic myeloid leukemia (CML). As a result of the effective therapy with tyrosine kinase inhibitors (TKI), HCT was shifted to defined clinical situations. We present the results of observational prospective analysis of 28 CML patients undergoing HCT after exposure to, at least, two lines of TKI (including dasatinib and/or nilotinib), with respect to response, overall survival (OS), treatment toxicity, graft versus host disease (GVHD), and progression/relapse incidence. Results All the patients but one engrafted with median time 19 days. OS for patients in CP1 and CP2/accelerated phase (AcP) were 92.9 and 85.7 %, respectively. Six patients allotransplanted in blast crisis (BC) CML died early after HCT. Eighteen patients achieved deep molecular remission (MR4.5 or MR4.0). Relapse incidence was 29.6 %. Median time to progression (TTP) differs significantly depending on the CML phase prior to HCT, the best response achieved after HCT and development of chronic GvHD. NRM yielded the values 7.1, 12.5, and 50 % in CP1, CP2/AcP, and BC, respectively. Fatal outcome, due to veno-occlusive disease (VOD), was observed in two (7 %) patients. In five (17.9 %) patients, mild or moderate VOD was observed with no negative impact of preceding therapy with TKI2. Acute GvHD was diagnosed in 25.9 % of patients, while chronic GvHD developed in 42.9 % of individuals. Conclusion Pretransplantation therapy with TKI2 in CP CML is safe and reasonable. In BC, the optimal approach before HCT is to reduce the leukemic burden and achieve subsequent CP.

Polycythemia vera is mainly diagnosed in the age of 40–80. In people under 20 years of age, it is very rare. A typical marker for confirmation of the diagnosis of polycythemia vera is a mutation of gene JAK 2 in exon 14, in position 617, which is found in about 95% of patients with this diagnosis. Patients without the mutation require additional examination to state the final diagnosis. A search for the mutations in other exons due to the diversity of mutations and the related complexity of molecular testing is not applicable in routine laboratory diagnostics. Here we present a case of polycythemia vera diagnosed in a patient aged 19 without typical mutation of gene JAK 2 in exon 14. Conducted additional tests revealed presence of the mutation in exon 12 of gene JAK 2 . The most common complication of polycythemia vera is the arterial and venous thrombosis, which could be the result of not only an increased hematocrit, but also coexisting congenital disorders leading to thrombophilia, as occurred in the presented case.

The introduction of tyrosine kinase inhibitors (TKI) in the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) has revolutionized the outcome, but the prognosis of the disease is still based on prognostic systems that were developed in the era of conventional chemotherapy and interferon (IFN)-alfa. A new prognostic score including only two variables, spleen size and basophils, was developed for the prediction of complete cytogenetic response (CCyR) and progression-free survival (PFS). The score was based on a large series of patients who were enrolled in prospective multicenter studies of first-line imatinib treatment. The prognostic value of the EUTOS (European Treatment and Outcome Study for CML) score has now been tested in an independent, multicenter, multinational series of 1288 patients who were treated first-line with imatinib outside prospective studies. It was found that also in these patients, the EUTOS prognostic score was predictive for CCyR, PFS and overall survival (OS). In addition, the prognostic value of the score was reported to be significant in seven of the eight other independent studies of almost 2000 patients that were performed in Europe, the Americas and Asia. The EUTOS risk score is a valid tool for the prediction of the therapeutic effects of TKI, particularly imatinib.

BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND Identification of patients with myelofibrosis being at increased risk of acquired von Willebrand syndrome (avWS) would likely facilitate individualization of treatment and improve its outcomes. OBJECTIVES To determine the prevalence of avWS in patients with myelofibrosis, and to verify if individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters. MATERIAL AND METHODS The study included 32 consecutive patients with myelofibrosis. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters. RESULTS Concomitant avWS was found in 5 patients (15.6%). In 1/5 patients with avWS and in 8/27 persons without this bleeding disorder, myelofibrosis developed secondarily to polycythemia vera (n = 7) or essential thrombocytopenia (n = 2). As many as 4/5 individuals with avWS presented with clinical evidence of a bleeding disorder. The subjects with avWS differed from the remaining patients with myelofibrosis in terms of significantly lower activity of von Willebrand factor (vWF) and lower vWF to vWF antigen ratio. CONCLUSIONS All patients with myelofibrosis should be routinely evaluated for avWS with the panel of specific tests. Further, avWS should be the primary suspicion in each patient with myelofibrosis in whom clinical evidence of a bleeding disorder has emerged.

Treatment of chronic myeloid leukemia with tyrosine kinase inhibitors (TKI) is very effective. The vast majority of patients achieve deep and long-lasting therapeutic responses including those on molecular level. Understanding the adverse effects of TKIs is of great importance during life-long therapy. The safety profile of TKI should be considered especially when used in patients suffering from various co-morbidities. In this paper, treatment recommendations for patients suffering from diabetes mellitus, atherosclerosis with circulation disturbances in peripheral arteries, congestive heart failure, pulmonary hypertension and pleural effusions are presented. Drug interactions between TKIs and medicaments used in the treatment of the above-mentioned co-morbidities are discussed.

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p = 0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p = 0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p = 0.89) or overall survival (p = 0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient.

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sezary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

Introduction The identification of patients with essential thrombocythemia (ET) who are at increased risk of acquired von Willebrand syndrome (AVWS) would likely facilitate individualization of treatment and improve its outcomes. Objectives The aim of the study was to determine the prevalence of AVWS in patients with ET and to verify whether individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters. Patients and methods The study included 170 consecutive patients with ET. AVWS was diagnosed on the basis of reduced levels of von Willebrand factor and abnormal results of other routine tests. Patients with and without concomitant AVWS were compared in terms of their demographic characteristics, past and current medical histories, and laboratory parameters. Results Concomitant AVWS was found in 34 patients (20%). Individuals with AVWS were diagnosed with ET at a significantly younger age than those without the syndrome. In addition, these patients significantly less often were in remission at the time of testing, had significantly higher erythrocyte and platelet counts, and showed abnormalities of the coagulation profile corresponding to defects of primary hemostasis as well as abnormal values of most parameters used i n the routine diagnosis of AVWS. Conclusions Even every fifth patient with ET may develop AVWS. Young age at diagnosis of ET and the lack of response to its previous treatment are potential risk factors for AVWS that should be considered during the management of the primary condition. All patients with ET and signs of a bleeding disorder, irrespective of the platelet count, should be tested for the presence of AVWS.

Introduction The aim of this study was to verify if PV patients with and without avWS differ in terms of their baseline clinical parameters. Material and Methods The study included 142 consecutive patients with PV. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters. Results Concomitant avWS was found in 17 PV patients (12.0%). Individuals with avWS have been diagnosed with PV at significantly younger age than those without, and significantly less often were in remission at the time of testing for bleeding disorders. Most of them (58.8%) presented with typical signs of bleeding disorder. Moreover, they showed significantly higher erythrocyte, leukocyte and platelet counts, abnormalities of coagulation profile corresponding to defects of primary hemostasis and abnormal values of all parameters used in the routine diagnosis of avWS. Conclusions Even every tenth patient with PV may develop avWS. Young age at diagnosis of PV and poor response to previous treatment of this condition are potential risk factors of avWS that should be considered during history taking. Sings of bleeding disorder observed in a person with PV necessitate evaluation for avWS.

It is unknown whether imatinib prior to myeloablative haematopoietic stem cell transplantation (HSCT) increases transplant-related toxicity. Among the side effects induced by imatinib, myelosuppression and liver injury might worsen HSCT outcomes. We retrospectively analysed engraftment, liver toxicity, acute graft-versus-host disease (aGVHD) incidence and 100-day mortality in 30 patients with BCR/ABL-positive leukaemias who received imatinib before HSCT and compared results of 48 age-matched controls who did not receive preceding imatinib. Both neutrophil and platelet engraftment occurred more rapidly among imatinib patients but the differences adjusted for Gratwohl scale were not statistically significant (P = 0.18 and 0.22, respectively). The adjusted hazards of having liver function tests (LFTs) >1.5 normal increased and the adjusted durations of elevated LFTs were not significantly different. The estimated adjusted difference in mean peak bilirubin values was also not significantly different (P = 0.48). However, the adjusted hazard of increased creatinine >1.5 normal was significantly higher in the imatinib group (HR = 4.09, P = 0.02). The adjusted odds of grades II-IV aGVHD were similar in both groups (OR = 0.86, P = 0.78), and while the adjusted odds of 100-day mortality were lower among imatinib patients, the difference was not significant (OR = 0.65, P = 0.60). These data do not provide any evidence that imatinib preceding HSCT increases acute transplant-related toxicities.

Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR. As previous investigations demonstrated that the plasma protein alpha-1 acid glycoprotein might inactivate circulating levels of free imatinib by protein binding with high affinity, we assessed plasma alpha-1 acid glycoprotein concentrations in our study cohort as well. Median bcr/abl fusion transcripts declined gradually over the entire treatment period and became significantly lowered at month 3 after initiation of imatinib therapy. Further, we observed elevated pretreatment levels of alpha-1 acid glycoprotein in patients who relapsed with leukemia, whereas initial bcr/abl mRNA copy numbers were not of predictive value. In addition, we provide data showing molecular response to this therapy in the vast majority of patients. Finally, our results support the hypothesis, that initially elevated plasma levels of alpha-1 acid glycoprotein might serve as a predictive marker for the clinical outcome of treatment with imatinib.

Tyrosine kinase inhibitors (TKIs) have dramatically improved the results of therapy of chronic myeloid leukemia. However the management with more potent second generation TKIs (2GTKIs) is required for imatinib-intolerant and imatinib-resistant patients. The frontline use of 2GTKIs results in higher rates of deeper and faster responses than with imatinib, it can enable many patients to qualify for participation in studies of treatment-free remission. The BCR/ABL transcript level at 3 months of TKI treatment has become a new prognostic factor. In this paper the recent clinical results of chronic myeloid leukemia therapy with imatinib in first line and with 2GTKIs in first and second line settings are reviewed, and updated PALG recommendations regarding the diagnosis, standard monitoring procedures, definitions of responses and treatment are presented.

In this chapter molecular methods that are clinically useful in the diagnosis of myeloproliferative neoplasms are presented. The methods described are the essential elements of contemporary hematological diagnostic procedures and allow a diagnosis to be reached more easily and precisely. Detailed protocols for the detection of mutations in JAK2, MPL, and KIT genes, as well as for the detection of the fusion gene FIP1L1/PDGFRA, are presented.

Five patients with type 2 diabetes, three of them treated with insulin and two with oral antidiabetic drugs, receiving imatinib due to chronic myeolid leukaemia are reported. Treatment with imatinib 400 mg/day for 7 to 37 (mean 24.2) months had no positive effect on clinical course of type 2 diabetes.

Introduction: The in-study and out-study sections of the European Treatment and Outcome Study (EUTOS) registry comprise data on imatinib-treated adult patients with chronic myeloid leukemia (CML) who were prospectively enrolled in clinical studies or registries between 2002 and 2006. All patients diagnosed with chronic-phase Philadelphia chromosome-positive CML were eligible for analysis. The new EUTOS long-term survival (ELTS) score was developed in 2,205 in-study patients (Blood 2014; 124(21):153). Its purpose is the discrimination of three risk groups with clinically significantly different probabilities of dying from CML. The score was validated in 1,120 out-study patients. Aims: Up to now, many investigators still apply the Sokal score for the prognostic discrimination of CML-patients treated with tyrosine kinase inhibitors (TKIs). The Sokal score allocated more than 20% of chronic-phase patients to the high-risk group while it was 12% with the new ELTS score. Long-term outcome with tyrosine kinase inhibitors (TKIs) suggests that the allocation of more than 20% chronic-phase CML patients into a high-risk group is too pessimistic. The focus of this analysis was the comparison of risk group allocations and prognosis between the two scores. Methods: Survival time was calculated from the date of start of treatment to death or to the latest follow-up date. Survival was censored at the time of allogeneic stem cell transplantation in first chronic phase. Cumulative incidence probabilities (CIPs) of dying of CML were compared with the Gray test and overall survival probabilities with the log-rank test. As "death due to CML", only death after confirmed disease progression was regarded. Progression was defined in accordance with the recommendations of the ELN (Baccarani et al, Blood 2013). Level of significance was 0.05. Results: Both registries combined, the 3,325 patients had a median observation time of 6.1 years. Six-year overall survival probability was 91% (95% confidence interval (CI): 89-92%). Death was due to CML in 142 of 309 deceased patients (46%).The 6-year CIP of dying of CML was 4% (CI: 4-5%). From low to high risk groups, the Sokal score resulted in 6-year CIPs of 3% (n=1358 (41%), CI: 2-4%), 4% (n=1209 (36%), CI: 3-5%), and 8% (n=758 (23%), CI: 6-11%) and the ELTS score in 6-year CIPs of 2% (n=2030 (61%), CI: 2-3%), 6% (n=898 (27%), CI: 4-7%), and 13% (n=397 (12%), CI: 10-17%). Of the 758 patients allocated to high risk by the Sokal score, the ELTS score classified 165 (22%) as low risk and 265 (35%) as intermediate risk. Compared to the 328 high-risk patients (43%) according to both scores (6-year CIP of dying: 13%, CI: 9-17%), the CIPs of dying were significantly lower for the 165 low-risk patients (p=0.0062, 6-year CIP: 5%, CI: 2-9%) and for the 265 intermediate-risk patients (p=0.0050, 6-year CIP: 5%, CI: 3-9%). These 430 Sokal high but ELTS non-high-risk patients (6-year OS: 89%. CI: 86-92%) showed significantly higher OS probabilities than the 328 Sokal and ELTS high-risk patients (p=0.030, 6-year OS: 81%. CI: 76-85%). Of the 2030 patients identified as low risk by the ELTS score, the Sokal score allocated 603 (30%) to the intermediate- and 165 (8%) to the high-risk group. Without significant CIP differences to the latter group, at 6 years, the CIP of dying was 2% (CI: 1-3%) in the 1262 low-risk and also 2% in the 603 intermediate-risk patients (CI: 1-3%). The OS probabilities of the 768 non-low-risk patients according to the Sokal score (6-year OS: 93%. CI: 91-95%) were not significantly different from the 1262 classified as low-risk by both scores (6-year OS: 95%. CI: 93-96%). Conclusions: To be able to perform comparisons between the various prognostic groups suggested by the Sokal and the EUTOS survival score with a reasonable power, data of in- and out-study samples were combined. The Sokal score allocated an absolute difference of 12% (n=430) more patients to the high-risk groups than the EUTOS survival score. As these patients had significantly and clinically relevantly lower CIPs and higher OS probabilities, the allocation of the Sokal score was not appropriate. Contrarily, the long-term outcome of 768 patients assessed as low-risk by the ELTS and non-low-risk by the Sokal score was not different from the outcome of 1262 assesses as low-risk patients by both scores. For prognosis of long-term survival outcome, the use of the EUTOS survival score is recommended. Disclosures Pfirrmann: BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Hasford:Novartis: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; BMS: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy. Prejzner:Novartis Pharma: Honoraria; BMS: Honoraria. Steegmann:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Simonsson:Novartis Pharma: Research Funding. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Zackova:Novartis Pharma: Consultancy; Bristol Myers Squibb: Consultancy. Janssen:Novartis: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; ARIAD: Consultancy. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Hehlmann:Novartis Pharma: Research Funding; BMS: Consultancy. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Imatinib mesylate is a very effective treatment in patients with Philadelphia (Ph)-positive chronic myeloid leukaemia (CML). However, in patients with advanced phase CML, it is still unclear whether, in the presence of myelosuppression, therapy with imatinib should be continued. It has been reported that intermittent filgrastim treatment may overcome imatinib-associated neutropenia and allow improved delivery of imatinib. Such combined sequential treatment is theoretically attractive as it may lead to better disease response. Here, we report a patient with blastic phase CML who developed severe and prolonged myelosuppression during imatinib treatment. Despite cessation of imatinib and 2 months of filgrastim therapy neither recurrence of Ph-positive or Ph-negative cells occurred. We conclude that filgrastim treatment may not always reverse imatinib-associated neutropenia therefore the decision of continued imatinib therapy in patients with advanced CML should be taken with caution.

Chronic myeloid leukemia is characterized by the presence of the Philadelphia chromosome. At the molecular level a fusion of part of the ABL and BCR genes is observed. The breakpoint locations in the BCR gene fall between exons b2a2 or b3a2 (5' and 3', respectively). Depending on the BCR gene breakpoint two types of mRNA are created. Differences in the types of transcripts and/or the breakpoint site may have an influence on the clinical course of the disease. This prompted the present author to separate subtypes of chronic myeloid leukemia on the molecular level.71 patients diagnosed with chronic myeloid leukemia in the chronic phase were enrolled in the study. In 61 patients the type of BCR/ABL transcript was determined, and in 27 patients BCR breakpoints were established. Possible correlations between the clinical course, prognostic indexes, survival and the type of transcript and breakpoint were examined.No correlation between the clinical course, prognostic index, or survival was observed in patients with 5' and 3' breakpoints. The patients with b3a2 transcript experienced longer survival than the patients expressing b2a2 transcript. However, no significant differences were observed in the duration of the chronic phase between the two groups.The type of BCR gene breakpoint seems to have no prognostic value in patients with chronic myeloid leukemia. The longer survival of patients expressing the b3a2 transcript may be caused by the less aggressive course of the accelerated or blastic phase.

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

Background: Inherited background in mechanisms regulating cellular uptake, elimination and metabolism of imatinib and other BCR-ABL tyrosine kinase inhibitors may influence treatment outcome in chronic myeloid leukemia (CML). Despite good efficacy of imatinib in CML therapy, a proportion of patients show suboptimal responses or even primary resistance. Imatinib is a well-established substrate of ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). However, the results of published studies regarding impact of ABCB1 and ABCG2 single nucleotide polymorphisms (SNPs) on imatinib treatment outcome have shown discrepant results. Moreover, little is known on the potential role of polymorphisms of regulators of xenobiotic transport and metabolism, pregnane X receptor (PXR, NR1|2) and constitutive androstane receptor (CAR, NR1|3) in imatinib efficacy. Aim: In this study we verified whether 61 tagging SNPs in drug transporters genes (ABCB1 and ABCG2) and regulators of xenobiotic transport and metabolism gene (PXR and CAR) genes affect imatinib therapy outcomes in CML. Methods: Genotyping was performed in 256 patients of Polish Caucasian origin (141 men and 117 women) treated with imatinib as first line treatment (229; 89.5%) or after second-line after interferon therapy (27; 10.5%). Tagging SNP approach was used to select the genetic variants and resulted in a selection of 61 tagging SNPs including 26 SNPs for ABCB1, 17 SNPs for ABCG2, 11 SNPs for PXR and 7 SNPs for CAR gene. Complete clinical data on imatinib treatment outcome were assessable for analyses of associations with tested SNPs. The influence of SNPs on imatinib outcomes including achievement of complete cytogenetic response (CCyR) at 12 months, achievement of major molecular response (MMR) at 18 months, progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. Three inheritance models (co-dominant, dominant and recessive) were tested for all allelic variants. Results: In this study we found that carriers of minor allele of CAR rs4073054A>C SNP significantly associated with shorter TTF on imatinib therapy (OR=2.42, 95%CI 1.41 - 4.17; p=0.0014; Bonferroni corrected p=0.048). In contrast, no impact of other tested allelic variants in ABCB1, ABCG2, PXR and CAR genes on proportion of patients who achieved CCyR at 12 months, MMR at 18 months as well as on probability of PFS, TTF and OS was observed. Conclusion: Our data suggest that inherited variants in the regulator of xenobiotic transport and metabolism CAR gene may modify results of imatinib therapy in CML patients. In contrast, the results of this relatively large study indicate that polymorphic variants in ABCB1, ABCG2 and PXR genes do not seem to play major role as determinants of response to imatinib in CML. Disclosures Robak: MorphoSys AG: Research Funding.

Allogeneic bone marrow transplantation for hypereosinophilic syndrome: long-term follow-up with eradication of FIP1L1-PDGFRA fusion transcript