ALBERT

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Description: research

Description: DFG, SUB Göttingen

Description: BACKGROUND The phase 3 REACH2 trial (NCT02913261; N = 309) was the first successful randomized study in SR aGVHD, demonstrating that RUX, a JAK1/2 inhibitor, was superior to BAT. At day 28, RUX pts had a significantly higher overall response rate (ORR) than BAT pts (62.3% vs 39.4%; P 〈 .001). RUX also led to a higher durable ORR at day 56 (39.6% vs 21.9%; P 〈 .001) and showed clinically meaningful treatment benefits across pt subgroups of baseline characteristics; failure-free survival was longer with RUX (5.0 vs 1.0 month; HR, 0.46; 95% CI, 0.35 to 0.60) (Zeiser R, et al. NEJM. 2020). The safety profile of RUX was as expected in pts with SR aGVHD, with cytopenias being the most common adverse events (AEs). To further define the safety profile of RUX in SR aGVHD, we report additional safety data up to day 28. METHODS Pts ≥ 12 years old with grade II-IV aGVHD following allogeneic hematopoietic cell transplant (alloHCT) who were refractory to steroids were randomized 1:1 to RUX (starting dose, 10 mg bid) or investigator-selected BAT and stratified by aGVHD grade. Crossover to RUX was allowed in BAT pts who had not responded by day 28 or lost response thereafter. Safety was assessed during the randomized treatment period by monitoring the frequency, duration, and severity of AEs, including AEs of special interest (AESI; ie, cytopenias, infections, bleeding events, other). AEs were assessed according to the Common Terminology Criteria for Adverse Events v4.03. Infections were also assessed by investigators using an infection-specific grading system predictive of mortality that was developed for and validated in alloHCT recipients (Cordonnier C, et al. Transplantation. 2006). Infections were classified by type (viral, bacterial, fungal, unknown, other) and severity (grades 1 to 3). We report AEs up to day 28, when exposure to RUX and BAT was similar. RESULTS A total of 302 pts (RUX, n = 152; BAT, n = 150) received ≥ 1 dose of study drug and were included in this analysis. Most pts experienced ≥ 1 AE up to day 28, with similar rates observed between RUX (96.1% [grade ≥ 3, 78.3%]) and BAT (94.7% [grade ≥ 3, 79.3%]). The most common AEs (all grades [grade ≥ 3]) in RUX vs BAT pts were thrombocytopenia (32.9% [27.0%] vs 18.7% [16.0%]), anemia (30.3% [22.4%] vs 28.0% [18.7%]), and cytomegalovirus (CMV) infection/reactivation (25.7% [7.2%] vs 20.7% [8.0%]). However, AEs led to low rates of discontinuation (RUX, 11.2%; BAT, 4.0%), primarily due to anemia (2.0% vs 0.7%), thrombocytopenia (2.0% vs 0%), and pancytopenia (1.3% vs 0%). Serious AEs occurred in 37.5% of RUX pts and 34.0% of BAT pts. The most commonly reported serious AEs were sepsis (RUX, 5.3%; BAT, 2.0%), diarrhea (3.3%; 0.7%), and CMV infection/reactivation (2.6%; 3.3%), with sepsis leading to death in 3 RUX pts (2.0%) and 2 BAT pts (1.3%). Among AESI, the most common events were infections excluding tuberculosis (RUX, 61.2% [grade ≥ 3, 32.2%] vs BAT, 58.7% [grade ≥ 3, 37.3%]) and thrombocytopenia (50.0% [41.4%] vs 32.7% [29.3%]). The risk of developing an AESI was similar between RUX and BAT pts, except for the risk of thrombocytopenia, which was higher in pts receiving RUX (Figure). A total of 15 deaths in the RUX arm (9.9%) and 21 in the BAT arm (14.0%) occurred up to day 28. The main cause of death in both arms was aGVHD, with higher rates seen in the BAT arm (11.3% vs 5.9% in the RUX arm). When assessed using the grading system developed by Cordonnier et al, infections were reported in 61.2% (grade 3, 22.4%) of RUX pts and 55.3% (grade 3, 18.7%) of BAT pts. Among pts with infection, the median time to first occurrence of infection was 2.1 (range, 0-27.0) weeks with RUX vs 1.9 (range, 0-21.3) weeks with BAT. Main types of infections were viral (RUX, 42.8%; BAT, 33.3%), bacterial (29.6%; 32.7%), and fungal (8.6%; 4.7%). The most common viral infections in RUX vs BAT pts were CMV (grade 3, 4.6% vs 3.3%) and Epstein-Barr virus (no grade 3); the most common bacterial infections were urinary tract (no grade 3), device-related (no grade 3), and sepsis (grade 3, 2.6% vs 2.0%); and the most common fungal infections were bronchopulmonary aspergillosis (grade 3, 2.0% vs 0%) and oral candidiasis (no grade 3). CONCLUSIONS The safety profile of RUX was consistent with what has been previously reported and what is expected in pts with SR aGVHD, including a higher risk of developing thrombocytopenia with RUX. Up to day 28, the risk of developing other AESI was similar between RUX and BAT. No new or unexpected safety findings were observed. Disclosures 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. Wagner:MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Shire: Other: Travel grand; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Novartis: Other: Travel grant for congress; Sanofi: Other: Travel grant for congress. Civriz Bozdag:Novartis: Research Funding. Ayuk:Neovii: Research Funding; Therakos/Mallinckrodt: Honoraria, Research Funding; Kite/Gilead: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Honoraria. Yoon:Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; 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; YuhanPharma: Research Funding. García Gutiérrez:Novartis Pharma AG: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding. Xu:Novartis: Current Employment. Morando:Novartis: Current Employment. Mahuzier:Novartis: Current Employment. Chandraiah:Novartis: Current Employment. Socié:Incyte: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding; Elsalys: Honoraria.

Description: 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

Description: BACKGROUND aGVHD, a common complication of allogeneic stem cell transplant (alloSCT), is driven by proinflammatory cytokines and chemokines that activate the immune system, resulting in end-organ damage. Steroids are first-line treatment but up to 50% of pts are steroid refractory (SR), resulting in high mortality and morbidity. RUX, a JAK1/JAK2 inhibitor, inhibits cytokine-dependent activation of the JAK-STAT pathway and cell proliferation and differentiation, which prevents worsening of aGVHD and allows recovery. JAK pathway inhibition by RUX may also lead to modulation of proinflammatory cytokines and prognostic GVHD biomarkers. The phase 3 randomized REACH2 trial (NCT02913261) in SR aGVHD demonstrated superiority of RUX vs BAT, with a significantly higher overall response rate (ORR; complete [CR] + partial response [PR]) at D28 (62% vs 39%; P 〈 .001) and higher durable ORR at D56 (40% vs 22%; P 〈 .001) (Zeiser R, et al. N Engl J Med. 2020). In this exploratory analysis of REACH2, we assessed whether baseline (BL) levels of proinflammatory cytokines and GVHD markers were prognostic for response and how this changed over time related to treatment. METHODS Pts (N = 309; ≥ 12 y old with grade II-IV SR aGVHD after alloSCT) were randomized 1:1 to RUX (starting at 10 mg bid) or investigator-selected BAT and stratified by aGVHD grade; 295 pts had valid biomarker levels. Serum samples were collected at BL, D14, and D28 and biomarkers, including inflammatory cytokines, soluble receptors of cytokines, chemokines, and tissue-specific markers for gastrointestinal (GI), liver, and skin GVHD, were assessed (Table). Biomarker levels at BL were stratified by response (CR, PR, none [NR]) at D28 for each treatment arm; those that differed by response were analyzed by logistic regression (LR) to assess the association (CR+PR vs NR), adjusting for treatment. The analysis was repeated, adjusting for key covariates that had significant impact on the biomarker-response relationship. Change in biomarkers over time (BL to D28) was assessed via geometric mean values at each visit, along with fold change from BL for each treatment arm. RESULTS Of 22 GVHD biomarkers assessed, 17 (77%) were evaluable (Table). Higher median BL levels of proinflammatory cytokines (IL-6, IL-8, TNF-α), soluble cytokine receptors (IL2RA, TNFRSF1A, ST2) and tissue-specific GVHD markers (REG3A, HGF) were generally observed in NR vs CR pts (Table) and were further analyzed. Higher BL levels of these markers were significantly associated with a lower probability of OR (P[OR]) in the LR analysis (Figure). An interaction term was investigated to assess whether there was a differing biomarker effect within treatment groups; however, this was insignificant and not retained. The addition of skin involvement to the LR for all biomarkers had an impact on P(OR), with increased P(OR) for pts with skin involvement at BL. Liver involvement at BL was added to the LR for HGF, IL6, REG3A, TNFα, and TNFRSF1A. The LR models showed a significant decrease in P(OR) for pts with liver involvement at BL. GI involvement did not have a significant impact for any biomarker. Geometric mean levels of TNFα, TNFRSF1A, IL2RA, REG3A, and ST2 decreased from BL to D14 in CR pts in the RUX arm but increased with BAT. NR pts had increases in these biomarkers regardless of treatment; however, longer follow-up is needed. Treatment had an underlying impact on P(OR) but no further impact on the effect of biomarkers on P(OR). Maximum change from BL was observed at D14; a slight return to BL levels was observed at D28 in CR pts. Surprisingly, IL6 levels increased with RUX regardless of response. IL6, like TNFα, is directly modulated by the JAK-STAT pathway and was therefore expected to decrease with RUX. CONCLUSIONS This is the first biomarker study in a phase 3 trial in GVHD. BL levels of IL6, IL8, TNFα, IL2RA, TNFRSF1A, ST2, REG3A, and HGF tended to be higher in NR vs CR pts; higher levels were associated with lower P(OR) when adjusted for treatment arm. Skin and liver involvement also had an impact on response. Skin involvement was associated with higher P(OR), regardless of biomarker BL levels, possibly because no skin involvement implied other organ involvement and tended to be associated with a higher overall severity grade at BL. CR pts in the RUX group had lower BL levels of TNFα and showed trends toward decreases from BL to D14 in the soluble cytokine receptors ST2, TNFRSF1A, and IL2RA and tissue-specific marker REG3A. Disclosures Socié: Elsalys: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Niederwieser:Amgen: Speakers Bureau; Daiichi: Research Funding; Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees. 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. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Szer:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Or:Hadassah Hebrew University Medical Center: Consultancy, Current Employment. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Shire: Other: Travel grand. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Sanofi: Other: Travel grant for congress; Novartis: Other: Travel grant for congress. Civriz Bozdag:Novartis: Research Funding. Chaturvedi:Novartis: Current Employment. Wilke:Novartis Pharma AG: Current Employment, Other: Stock owner. Zeiser:Novartis: Honoraria; Incyte: Honoraria; Malinckrodt: Honoraria.