Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3608-3608

Abstract: Introduction: The licenced starting dose of bosutinib is 400 mg QD for first line therapy and 500 mg QD in later lines in CML. Gastrointestinal (GI) adverse events (AE) are observed in up to 90% in similar patient cohorts (BYOND, Hochhaus et al; Leukemia 2020). The goal of this study was to evaluate whether a bosutinib step-in dosing regimen decreases GI toxicity while maintaining optimal efficacy in patients (pts) with CML after failure or intolerance to 2G-TKIs. Methods: This is the first and final analysis of the BODO "Bosutinib Dose Optimization Study" trial (NCT02577926), which is a multicenter, open-label single arm phase II study testing tolerability and efficacy of 2 nd & 3 rd line bosutinib step-in dosing in chronic phase CML pts intolerant and/or refractory to previous imatinib, and/or nilotinib, and/or dasatinib therapy. Bosutinib was commenced with 300 mg QD and was (in the absence of & gt;G1 toxicities) dose-increased by increments of 100 mg daily dosing every 14 days if applicable up to a maximum dose of 500 mg QD. The primary endpoint (PE) was the incidence of grade 2 to 4 GI toxicity AEs within 6 months after registration. 127 pts were planned to be recruited. However, due to slow recruitment, the trial had to be stopped prematurely after inclusion of 57 pts. The 95% confidence interval (CI) around the estimated rate of the PE was calculated in accordance with Clopper and Pearson. Results: Pts´ characteristics are presented in Table 1. 23 (40.4%) pts were intolerant, 20 resistant (35.1%), and 14 (24.6%) both intolerant and resistant to previous TKI treatment. 20 (35.1%) pts entered the study in molecular response (at least MMR at screening). The probability of MMR after 24 months of treatment was 79% (95% CI: 65.8% to 87.5%); probabilities of MMR, MR4, MR4.5 are shown in Figure 1. Six out of 7 intolerant pts without MMR at baseline reached MMR or better molecular response with bosutinib. Thirty pts were refractory to previous therapy (19 being resistant; 11 being resistant and intolerant) lacking baseline MMR, of which 19 pts achieved MMR or better (2 pts with MR4.5, 2 with MR4 and 15 with MMR). Eight out of 30 pts did not achieve MMR and 3 experienced complications (2 pts with SAEs that led to discontinuation and 1 death). No patient progressed to accelerated/blast phase on treatment. Two pts died (1 CML progression (no MMR with bosutinib, death 6 months after allogenic stem cell transplant); 1 cerebral cavernoma unrelated to bosutinib). In the overall patient population (N = 57), all pts had ≥1 any grade TEAE and 71.9% of patients had ≥1 grade 3/4 TEAE. SAEs occurred in 28.1% of pts. A total of 949 AEs were reported during the study. The most frequently reported AEs (SOC terms) were GI disorders (n=346, 36.5%) and investigations (n=206, 21.7%). Among the GI events (n=346) diarrhea (55.5%), nausea (16.2%) and abdominal pain (9.8%) were most common; among investigations (n=206) liver enzyme increases were most frequent (ALT increase (26.7%), AST increase 17%). The PE was evaluated for 50 out of 57 pts (4 pts with treatment & lt; 14 days + 3 pts with observation & lt; 6 months were excluded from the analysis). Twenty pts did not develop any clinically relevant GI-toxicity during the first 6 months. Thus, the rate of GI-toxicity (grade 2 to 4) within the first 6 months of treatment was 60.0% (95% confidence interval: 45.2% to 73.6%), accordingly, the alternative hypothesis of the trial (GI-toxicity was assumed to be less than 40%) could not be accepted. However, only in 1 patient GI-toxicity led to discontinuation. Twenty-five pts discontinued bosutinib prematurely (17 due to AEs; 5 with insufficient response; 3 with other reasons). Conclusion: This is 1 of the largest cohorts published on the efficacy and safety of bosutinib after intolerance/failure to first-line 2G-TKIs. Given the limitations of a single-arm study with incomplete recruitment, we could not demonstrate an advantage of the step-in dosing concept chosen here to reduce the frequency of grade 2-4 GI toxicity overall. However, using this regimen, bosutinib was able to induce optimal responses in almost two thirds of pts previously resistant to 2G-TKIs while GI toxicity rarely led to treatment discontinuation. We conclude that treatment with bosutinib is safe (rates of AEs being similar to other trials (e.g. BYOND)) and efficacious as 2 nd and 3 rd line therapy after failure of previous 2G-TKI therapy whereas an advantage of run-in dosing regimens remains to be proven. Figure 1 Figure 1. Disclosures Isfort: Mundipharma: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hexal: Other: Travel reimbursement; Alexion: Other: Travel reimbursement; BMS: Honoraria; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Teichmann: Pfizer: Membership on an entity's Board of Directors or advisory committees. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Saussele: Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria. Kiani: Novartis Pharma GmbH: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Göthert: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel reimbursement; Incyte: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Proteros Biostructures: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel reimbursement; zr pharma & : Honoraria. Schafhausen: Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Brümmendorf: Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151240

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 10 ( 2023-10), p. 2741-2752

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.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-023-05394-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1458429-3

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 12194-12196

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-164607

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 2, No. 13 ( 2018-07-10), p. 1572-1579

Abstract: TL in LSCs is significantly shortened at diagnosis of CML and correlates with LSC burden. TL in nonleukemic myeloid cells in deep molecular remission is unaffected by long-term TKI treatment.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2018017772

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 2876449-3

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 7 ( 2020-07-01), p. 1949-1953

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0890-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1790-1793

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157265

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 2 ( 2023-02), p. 349-358

Abstract: Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-022-05080-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1458429-3

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 11 ( 2020-11), p. 3106-3106

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0970-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 672-672

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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127859

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4637-4637

Abstract: Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a more precised assessment of prognosis. For instance, CALR mutated MF is associated with favorable prognosis, while mutations in distinct high molecular-risk (HMR) genes are considered adverse. Our multicenter phase-Ib/II MPNSG-0212 trial (NCT01644110) investigating ruxolitinib plus pomalidomide in a total cohort of 92 patients with advanced MF and anemia provides an ideal basis for investigating the genomic landscape and molecular risk in a well-defined study population. Aims & Methods: To assess the genomic landscape in MF patients treated within the MPNSG-0212 trial and to correlate the results with clinical parameters and overall survival (OS). So far, targeted next generation sequencing (NGS) of 269 candidate genes was performed in peripheral blood or bone marrow from 81/92 patients using libraries prepared with SureSelectXT HS (Agilent, Santa Clara, USA). NGS was carried out on a NextSeq550 (Illumina, San Diego, USA). Results: At study entry, median age of the 81 patients was 71 years (range 52-86), median Hb 8.6 g/dL (range 5.4-11.7 g/dl); 30% of patients were RBC transfusion-dependent; 67% had primary MF (PMF) and 33% secondary MF (SMF), respectively. According to DIPSS, the vast majority of the patients were categorized as intermediate-2 (63%) or high-risk (26%) MF; 11% were low- and intermediate-1 risk patients. Overall, 315 muts were identified in 80/81 (99%) patients with a median of 3 muts/patient (range 0-9). Recurrent muts (≥5%) were identified in JAK2 (60%), ASXL1 (30%), SRSF2 (21%), CALR (20%; type-1: 75% [n=12], type-2 and non-type-1/2: 12.5% [n=2] each), MPL (19%), SF3B1 (19%), TET2 (16%), U2AF1 (15%), CBL and EZH2 (10% each), IDH2 and DNMT3A (7% each), PHF6, ZRSR2, and CUX1 (5% each). The majority of the patients (95%) was characterized by the presence of a driver mut in JAK2, CALR, or MPL; 4/81 patients (5%) were triple negative (Figure 1). JAK2mut was associated with TET2mut (p=.047), whereas muts in CALR and TET2 were mutually exclusive (p=.05). CALRmut patients had less co-muts than patients with JAK2/MPL muts (mean 2.5 vs. 4.1, p=.007) and were mutually exclusive with muts in the spliceosome regulating genes SRSF2, SF3B1, U2AF1, and ZRSR2 (p=.009). Compared to MF with mutated JAK2 or MPL, MF patients with mutated CALR had a longer median OS (not reached vs. 3.1 years; p=.04). With regard to high molecular risk (HMR) muts, n=56 were detected in 38 patients (47%), with 40% (15/38) of the patients harboring ≥2 HMR muts. The most commonly mutated HMR genes were ASXL1 (43%; 24/56), followed by SRSF2 (30%), EZH2 (14%), IDH2 (11%), and IDH1 (2%). MPLmut but not JAK2mut or CALRmut were significantly associated with HMR mut (p=.023). HMR mut patients harbored more co-muts than HMR wt patients (median 5 vs. 3; p & lt;.0001). There were no significant differences in the variables age, sex, WBC, Hb, PLT, or LDH level between patients with HMR mut and HMR wt MF. In univariate analysis, patients with HMR mut MF had shorter median OS (2.3 vs 3.7 years, p=.007). In multivariate analysis (HMR mut, age, DIPSS-category, SMF vs. PMF) a higher DIPSS-score (HR, 3.2; 95% CI, 1.5-7.0; p=.004) and muts in HMR genes (HR, 3.5; 95% CI, 1.5-8.1; p=.003) were significant adverse prognostic factors for OS. Conclusions: Our NGS data underline the genomic complexity of advanced MF. CALR mutations were only found in 20% of the patients that were characterized by less co-mutations, mutual exclusivity with spliceosome mutations, and with more favorable outcome suggesting a distinct disease biology. Almost 50% of patients showed mutations in HMR genes which were associated with an inferior OS in univariate and multivariate analyses. §Frank Stegelmann and Konstanze Döhner contributed equally to this work. Figure 1 Figure 1. Disclosures Koschmieder: Shire: Honoraria, Other; Alexion: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Celgene: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Image Biosciences: Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karthos: Other: Travel support. Heidel: Incyte: Consultancy, 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; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hebart: AbbVie: Honoraria; AstraZeneca: Honoraria; BMS: Honoraria; Janssen: Honoraria; Roche: Honoraria. Isfort: Alexion: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Hexal: Other: Travel reimbursement; BMS: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement. Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Waller: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Mylan: Consultancy; Alvotech: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Chugai: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Membership on an entity's Board of Directors or advisory committees; IPSEN: Other: travel grant. Scheid: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goethert: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; zr pharma & : Honoraria; BMS: Consultancy, Honoraria, Other: Travel support; AOP Orphan Pharmaceuticals: Honoraria, Other: travel support; Proteros Biostructures: Consultancy. Schafhausen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Radsak: Otsuka: Consultancy, Honoraria; Abbvie: Other: e.g. travel support; Astellas: Other: e.g. travel support; TEVA: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: e.g. travel support; Daiichi Sankyo: Consultancy, Honoraria, Other: e.g. travel support; Celgene/BMS: Consultancy, Honoraria, Other: e.g. travel support; Amgen: Other: e.g. travel support; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Corat: Consultancy, Honoraria; Cogent Biosciences: Consultancy, Honoraria; JAZZ: Other: e.g. travel support. Gattermann: Takeda: Research Funding; Novartis: Honoraria; Celgene: Honoraria. von Bubnoff: Novartis: Honoraria; Takeda: Honoraria. Brümmendorf: Bristol Myers: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria. Döhner: Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding; GEMoaB: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Roche: Honoraria; Pfizer: Research Funding. Griesshammer: Amgen: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Stegelmann: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Jazz Roche: Consultancy, Honoraria; Daiichi Sankyo: Honoraria, Other: Advisory Board; Astellas: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Agios and Astex: Research Funding. OffLabel Disclosure: Pomalidomide was shown to be active in patients with myelofibrosis in particular in the treatment of anemia (Tefferi et al 2009, Begna et al 2011, Mesa et al 2010)

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150361

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7