Kooperativer Bibliotheksverbund

In: Annals of Hematology, Springer Science and Business Media LLC

Abstract: Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating disease‑related splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, non‑interventional, phase IV study in MF. Between 2012–2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following RUX treatment, 82.5% of patients experienced rapid (≤ 1 month), significant decreases in palpable spleen size, which remained durable for 24 months (60% patients). Symptom assessment scores improved significantly in Month 1 (median –5.2) up to Month 12 (–6.2). Common adverse events (AEs) were anemia (31.2%) and thrombocytopenia (28.6%). At cutoff, 54.3% of patients had terminated the study due to, death, AEs, or deterioration of health. No new safety signals were observed. Interim analysis of the JAKoMo study confirms RUX safety and efficacy in a representative cohort of real-world, elderly, JAKi-naïve patients with MF. Risk scores were used in less than half of the patients to initiate RUX treatment. Trial registration: NCT05044026; September 14, 2021.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-023-05458-1

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. 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: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5195-5195

Abstract: Background. Thrombembolic (TE) and bleeding (B) events pose a severe risk for patients (pts) with myeloproliferative neoplasms (MPN). Multiple disease-related factors have been identified that contribute to these events, such as the interaction between platelets, leucocytes, and endothelial cells. However, not all pts develop thrombosis or severe bleeding, suggesting that further contributing factors may play a role, including specific comorbidities and cardiovascular risk factors. Aims. The aim of our analysis was to evaluate the association between thromboembolic events, specific comorbidities, and cardiovascular risk factors in MPN pts. Methods. We analyzed clinical data frompts treated at the MPN Center at RWTH Aachen University hospital. All pts were aged ≥18 years and carried a diagnosis of classical BCR-ABL negative MPN (polycythemia vera [PV], essential thrombocythemia [ET] , primary and secondary myelofibrosis [MF]), as defined by WHO criteria (2008). In addition, data about MPN disease complications, age, cardiovascular risk factors (smoking habits, arterial hypertension, diabetes mellitus, obesity, and hyperlipoproteinemia) and MPN subtype were included. Comorbidities were scored using three different comorbidity scales (CIRS, Charlson comorbidity index, and ACE-27). Results. 75 MPN pts were included in this analysis, 25 with PV, 19 ET pts and 31 pts with MF (19 pts with PMF, 9 Post-PV-MF pts and 3 pts with Post-ET-MF). Characterization of pts regarding age, sex, thrombembolic/bleeding events as well as median scores in comorbidity scales are shown in Table 1. In addition, pts were divided into a group with (Group TE+B) or without (Group no TE+B) thromboembolic or severe bleeding events. 40 patients (53.3%) had previously experienced a thrombembolic or bleeding event. These pts showed significantly higher median comorbidity scores (CIRS of 6.5 vs. 2.0, p 〈 0,001, Charlson score of 1 vs. 0, p 〈 0,001, and median ACE-27 of 2 vs. 0, p 〈 0,001). Presence of classic cardiovascular risk factors among groups TE+B vs. no TE+B was heterogeneous (10 vs. 11 (ex-)smokers; 18 vs. 9 pts with arterial hypertension; 9 vs. 14 pts with a BMI 〉 25; 4 vs. 1 pts with diabetes mellitus; 4 vs. 0 pts with hyperlipoproteinemia). TE+B pts had high scores in certain CIRS categories (each category includes a scale of 0-4) especially in categories regarding cardiac diseases, hypertension, vascular disease & endocrinological disease (see Table 2). Furthermore, more than one third of the TE+B pts had also neurological (16/40 pts. (40%) vs. 3/35 (8.6%) in the no TE+B group) and upper-GI-disease (13/40 pts (32.5%) vs. 8/35 (22.9%) in the no TE+B group). Summary and Conclusions. Given the obvious limitations of this analysis due to small sample numbers, this analysis provides an indication that classic cardiovascular risk factors (especially diabetes mellitus, arterial hypertension, and hyperlipoproteinemia) and additional comorbidities contribute to the risk of thromboembolic and bleeding events in pts with classical MPN. Clinical trials should address whether the improvement of such risk factors in addition to anti-MPN treatment can minimize the risk of such events. Table 1. Characterization of pts Subtype of MPN Number of patients Median age at diagnosis (range) Number of patients that developed thromboembolic events (TE) or bleeding (B)* Number of patients without thromboembolic/bleeding events Median CIRS score(Range 0-56) Median Charlson comorbidity index(Range 0-37) Median ACE-27 score(Range 0-3) Polycythemia vera 25(11m/14f) 58 (31-77) 15 (15 TE, 2 B) 10 6 1 1 Essential Thrombo-cythemia 19(10m/9f) 54 (23-64) 6 (5 TE, 1 B) 13 4 0 1 All Myelofibrosis 31(22m/9f) 63 (29-77) 19 (16 TE, 7 B) 12 5 0 1 Myelofibrosis PMF 19(16m/3f) 61 (29-77) 11 (9 TE, 4 B) 8 4 0 1 Post-PV-MF 9(3m/6f) 63 (42-73) 7 (6 TE, 3 B) 2 8 1 1 Post-ET-MF 3(3m/no f) 68 (68-73) 1 (1 TE) 2 13 2 2 · Few Pts had suffered from both thromboembolic and bleeding events Table 2. Number of pts in the TE+B group in comparison to the no TE+B group in certain CIRS categories subdivided according to score CIRS category (TE+B pts vs. no TE+B pts) Score of 0 per category Score of 1 per category Score of 2 per category Score of 3 per category Score of 4 per category Cardiac disease 20 vs. 30 6 vs. 2 5 vs. 3 9 vs. 0 0 vs. 0 Hypertension 22 vs. 26 2 vs. 0 4 vs. 6 12 vs. 3 0 vs. 0 Vascular disease 21 vs. 32 3 vs. 1 12 vs. 0 3 vs. 1 1 vs. 1 Endocrinological disease 21 vs. 26 0 vs.1 19 vs.7 0 vs.1 0 vs.0 Disclosures Isfort: Pfizer: Honoraria; BMS: Honoraria; Mundipharma: Other: Travel & Accomodation; Roche: Other: Travel & Accomodation; Novartis: Other: Travel & Accomodation; Amgen: Other: Travel & Accomodation; Hexal: Other: Travel & Accomodation. Bruemmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences, Research Funding; Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences; Janssen Cilag: Other: Travel reimbursement for scientific conferences.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.5195.5195

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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. 1130-1130

Abstract: Introduction: Telomere biology disorders (TBD) are caused by mutations affecting proper telomere maintenance resulting in premature telomere shortening. Telomere length (TL) assessment is currently being used for screening and diagnosis of TBD of which Dyskeratosis congenita (DKC) is the most prominent TBD subtype typically found in children and adolescents. In adults, TBDs are characterized by a broad spectrum of more "cryptic" diverging mono- or oligosymptomatic clinical manifestations such as bone marrow failure (BMF), hepatopathy or interstitial lung disease (ILD). However, despite growing general clinical awareness and exertion of improved TL screening strategies, insufficient data are available about the clinical course of adult, late-onset TBDs. Here, we present a series of 41 consecutive adult TBD cases from 2014 to 2021 identified through the Aachen Telomeropathy registry. Methods and Patients: Median follow-up of the cohort was 2.0 (range 0-6.2) years. In 39/41 patients TBD diagnosis was established based on coexistence of the following three criteria: 1.) Identification of pathogenic variant in a known TBD-related gene via next-generation panel sequencing (NGS) or sequential whole exome sequencing (WES). 2.) The presence of prematurely shortened TL below the 1% percentile (39/41) or 5% percentile (2/41) in the lymphocyte gate detected by flow-FISH and 3.) the presence of BMF or ILD as predominant clinical manifestation. In 2 out of 41 cases, WES did not identify a definitive pathogenic variant. Here, diagnosis of TBD was established due to short telomere below the 1% percentile, BMF and the presence of typical DKC stigmata, other TBD symptoms and a positive family history. Results: Mean age of our cohort was 35.9 ± 17.6 years. 49% (n=20) of patients were females. Results of the genetic screening revealed heterozygous pathogenic variants in TERC (n=14) and TERT (n=11) as the most frequent variants, followed by RTEL1 (n=6), TIN2 (n=1), CTC1 (n=1) and DKC1 (n=1). Homozygous or compound heterozygous pathogenic variants were found for CTC1 (n=2), NHP2 (n=2) or TCAB1 (n=1). 46% (n=19) of patients had a positive family history. BMF was the most frequent symptom with 93% (n=38) presenting with leukopenia, 78% (n=32) with anemia and 76% (n=31) with thrombocytopenia. ILD was suspected/confirmed clinically in 44% (n=18), hepatopathies in 29% (n=12) and cancer in 12% of the patients in past medical history (n=5, liposarcoma, breast cancer, Hodgkin lymphoma, diffuse large B-cell lymphoma, endometrial cancer). Symptoms of the typical DKC triad (leukoplakia, nail dystrophy, abnormal skin pigmentation) were observed in 41% (n=17). Of those, 76% (13/17) presented with only one or two clinical signs. Based on past medical history, the onset of first TBD manifestation was observed at a mean age of 26.9 ± 18.3 years. Time from first symptom observed to the diagnosis of TBD was 8.2 ± 9.5 years. 22% (n=9) patients died during follow-up with mean time of 11.7 ± 10.1 years from first manifestation of TBD to death. Regarding treatment, 39% (n=16) were listed for allogeneic stem cell transplantation (allo Tx), but only 38% (6/16) of these eventually received allo Tx. Immunosuppressive therapy with ATG and CSA was carried out in 12% (n=5) of the patients with no patient responding to treatment. Eltrombopag was given in 5% of cases (n=2) without response. 15% (n=6) received androgen treatment with danazol as the most frequently used drug in five of the six reported cases. All patients showed a response at least in one hematological lineage. Conclusions: Our data support the notion that despite the recent progress in screening and genetic diagnostics, late-onset TBD is still frequently underdiagnosed with several years from first manifestation of disease to diagnosis. Implementation of routine screening for TBD might improve the rate of correct TBD diagnosis and could help to avoid ineffective treatments. Disclosures Beier: Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Other: Travel reembursement; Alexion: Speakers Bureau. Roeth: Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Kira: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. Platzbecker: AbbVie: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Geron: Honoraria. Radsak: Novartis: Consultancy, Honoraria, Other: e.g. travel support; JAZZ: Other: e.g. travel support; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Other: e.g. travel support; Daiichi Sankyo: Consultancy, Honoraria, Other: e.g. travel support; Astellas: Other: e.g. travel support; Incyte: Consultancy, Honoraria; Corat: Consultancy, Honoraria; Cogent Biosciences: Consultancy, Honoraria; TEVA: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Amgen: Other: e.g. travel support; Abbvie: Other: e.g. travel support. Schafhausen: Blueprint Medicines: 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; MSD: 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; 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. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Heuser: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; Karyopharm: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees. Koschmieder: Incyte: 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); Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Karthos: Other: Travel support; Shire: Honoraria, Other; CTI: Membership on an entity's Board of Directors or advisory committees, Other; 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; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Alexion: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Other: Travel support; Image Biosciences: Other: Travel support; 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. Panse: Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Grunenthal: 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; Apellis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Isfort: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Ariad: 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; BMS: Honoraria; Hexal: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Brummendorf: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153630

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1679-1679

Abstract: Introduction: Interferon alpha (IFNa) is a cytokine with anti-viral and anti-tumoral properties which, either in its unmodified or pegylated form, is successfully used in the treatment of patients with myeloproliferative neoplasms (MPN), including polycythemia (PV), essential thrombocythemia (ET) and early primary myelofibrosis (PMF). Despite its efficacy including molecular responses and thus its potential disease modifying capabilities, IFNa carries the risk of significant adverse events, including liver toxicity, autoimmunity, and depression. This has prompted the development of interferons with improved features including better tolerability. However, biomarkers for response have been lacking, mostly due to the heterogeneity of cells analyzed and the difficulty in obtaining them from the bone marrow. Methods: Therefore, we have set up a clonogenic assay from Ficoll-isolated mononuclear cells of the peripheral blood of patients (PBMC) with MPN (n=51, including 17 PV, 14 ET, and 14 PMF, 1 MDS/MPN, 2 Post-PV-MF, 2 Post-ET-MF, 1 MPNu) to analyze the in vitro IFNa response (either using 0.5 µg/ml ropeginterferon alfa-2b [ropegIFNa] or 500 U/ml recombinant human IFN-alpha2b [hIFNa] or no treatment control) in the cells that drive malignant clonogenic growth in the patients. After 10-14 days, the number of colonies was assessed. For each patient and condition, twenty-five of the resulting colonies were then genotyped for zygosity of JAK2V617F and three colonies per condition were analyzed for STAT1 RNA expression using RT-qPCR, an important transcriptionally induced IFNa target gene. The number of mutated alleles was determined (zero for wildtype, one for heterozygous, two for homozygous colonies), and, based upon the change in mutant alleles after in vitro hIFNa treatment, samples were categorized into responders (mutant alleles decreased) and non-responders (mutant alleles unchanged or increased). All patients provided written informed consent, and the study was approved by the local ethics committee. Results: To assess potential differences between the two interferons used, a 14-day proliferation assay was performed in Set-2 cells, showing more sustained inhibition of proliferation by ropegIFNa than hIFNa (p=0.007), confirming the longer half-life of ropegIFNa. In the clonogenic assay, different colonies were observed depending on the MPN subtype, ranging from exclusive CFU-E (PV) to exclusive CFU-G and CFU-M (PMF) types of colonies. Both hIFNa and ropegIFNa significantly inhibited colony growth as compared to the control and reduced the colony number to 72.7 % (hIFNa) and 58.5% (ropegIFNa) of the untreated control, with ropegIFNa showing significantly stronger effects than hIFNa (p=0.0137). Interestingly, there were marked differences in the amount of JAK2 alleles in the colonies between the patients (n=24 analyzed), with 16 patients showing a reduction of up to 22% of the allele burden upon in vitro treatment with hIFNa (responders), while 8 patients showed no reduction or even an increase of up to 15% (non-responders) (p=0.0001). Basal STAT1 expression in the colonies (three colonies per patient and treatment) was significantly lower in responders than non-responders (p=0.0200). After treatment with hIFNa, STAT1 expression was induced to similar levels in both responders and non-responders (p=0.6620). As a result, STAT1 fold induction was significantly higher in responders than non-responders (p=0.0013). Interestingly, there was no correlation of the responses with current clinical treatment of the patients (previous interferon exposure did not prevent responses) or with the MPN subtype, confirming clinical reports that patients with myelofibrosis can respond to interferon. Conclusion: In conclusion, clonogenic cells from the peripheral blood of MPN patients can be used to assess their molecular response to IFNa. In vitro, ropegIFNa induced stronger effects than non-pegylated IFNa. The responses were heterogeneous at the molecular level, but, when combined with RNA expression analysis, we were able to dissect molecular responders from non-responders. The mechanisms for these differences and their clinical impact are currently being studied. Disclosures Gezer: AMGEM: Membership on an entity's Board of Directors or advisory committees. Isfort:Mundipharma: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Hexal: Other: Travel reimbursement; BMS: Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Brümmendorf:Ariad: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Novartis: Consultancy, Research Funding; Merck: Consultancy. Koschmieder:Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Foundation: Research Funding; Bayer: 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; AOP Pharma: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122676

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 98, No. 12 ( 2019-12), p. 2703-2709

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-019-03836-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 1458429-3

In: Drug Delivery and Translational Research, Springer Science and Business Media LLC, Vol. 13, No. 4 ( 2023-04), p. 915-923

Abstract: Despite the introduction of multiple new drugs and combination therapies, conventional dexamethasone remains a cornerstone in the treatment of multiple myeloma (MM). Its application is, however, limited by frequent adverse effects of which the increased infection rate may have the strongest clinical impact. The efficacy-safety ratio of dexamethasone in MM may be increased by encapsulation in long-circulating PEG-liposomes, thereby both enhancing drug delivery to MM lesions and reducing systemic corticosteroid exposure. We evaluated the preliminary safety and feasibility of a single intravenous (i.v.) infusion of pegylated liposomal dexamethasone phosphate (Dex-PL) in heavily pretreated relapsing or progressive symptomatic MM patients within a phase I open-label non-comparative interventional trial at two dose levels. In the 7 patients that were enrolled (prior to having to close the study prematurely due to slow recruitment), Dex-PL was found to be well tolerated and, as compared to conventional dexamethasone, no new or unexpected adverse events were detected. Pharmacokinetic analysis showed high and persisting concentrations of dexamethasone in the circulation for over a week after i.v. administration, likely caused by the long-circulation half-life of the liposomes that retain dexamethasone as the inactive phosphate prodrug form, something which could significantly limit systemic exposure to the active parent drug. Thus, despite the limitations of this small first-in-man trial, Dex-PL seems safe and well tolerated without severe side effects. Follow-up studies are needed to confirm this in a larger patient cohort and to evaluate if i.v. Dex-PL can provide a safer and more efficacious dexamethasone treatment option for MM. Graphical Abstract

Type of Medium: Online Resource

ISSN: 2190-393X , 2190-3948

URL: Article

DOI: 10.1007/s13346-022-01268-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2590155-2

SSG: 15,3