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Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red ...blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q).
Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg.
Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia 49.3% vs 73.7% for non-del(5q) vs del(5q), respectively, thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia 45.2% vs 72.0% for non-del(5q) and del(5q), respectively, thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%.
Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies.
Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable.
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Almeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.
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Background: Barasertib is the pro-drug to barasertib-hQPA, a selective Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II study (Löwenberg et al. Blood ...2011;118:6030). Methods: AML pts aged ≥60 y considered unsuitable for intensive chemotherapy were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary endpoint was improved objective complete response rate (OCRR: CR + CRi Cheson criteria, but requiring CRi confirmation ≥21 days after first appearance, with partial recovery of platelets and neutrophils). Secondary endpoints included duration of response (DoR), overall survival (OS) and safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and all completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% 17/48 vs 11.5% 3/26; difference, 23.9% 95% CI, 2.7-39.9; P<0.05); barasertib responses were seen in all cytogenetic risk groups and appeared to be durable (median DoR range, 82 28-321 days; vs LDAC 30-85 days). Although not formally sized to compare OS data, a trend favoring barasertib was observed (HR=0.88, 95% CI, 0.49-1.58; P=0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile neutropenia were the most common adverse events (AEs) in the barasertib arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%, respectively). Grade ≥3 AEs with a greater incidence in the barasertib arm were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and pneumonia (25% vs 8%); grade ≥3 infection rates were also higher with barasertib (40% vs 23%). For both arms, there were similar discontinuation rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs (12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative toxicities were not observed with barasertib treatment. Conclusions: In this population with poor prognosis using standard chemotherapy, barasertib showed a significant improvement in OCRR vs LDAC, and a safety profile that was manageable and consistent with previous studies.
Introduction:
CA-4948 is a novel small molecule oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and ...interleukin-1 receptor (IL-1R) signaling pathways These pathways are frequently dysregulated in Non-Hodgkin Lymphomas (NHL) and AML/MDS. 1 Oncogenic IRAK4-L, which is driven by spliceosome mutation (including SF3B1 and U2AF1), is preferentially expressed in >50% of AML/MDS patients 2,3. Recently, activated IRAK4 has been identified as a driver of adaptive resistance in AML and other tumors 4. CA-4948 not only strongly inhibits IRAK4, but also FLT3-ITD AML in vitro and in-vivo models. It has shown safety and activity in patients with relapsed or refractory NHL and will now be evaluated in patients with high-risk MDS and AML.
Study Design and Methods:
This is a multicenter, open-label, single arm Phase 1 dose escalation study of orally administered CA-4948 monotherapy in adult patients with AML or high risk MDS (NCT04278768). This study will be conducted in 2 parts: an initial dose escalation and dose expansion phase. The starting dose level is 200 mg BID which was determined to be safe, capable of achieving relevant levels of drug exposure and has demonstrated signs of biologic activity and clinical efficacy in an ongoing NHL study CA-4948-101. Three patients with AML or MDS will be enrolled at the starting dose. If none of the first 3 patients experience a DLT during the first cycle, patients may be enrolled into the next higher dose level of 300 mg BID.
Dose escalation is expected to enroll approximately 18 patients to establish the initial RP2D. The safety population will include all patients in the study who received any dose of CA-4948, and the efficacy population will include patients who have a valid baseline and post-baseline disease assessment and received at least one dose of the study drug. Each treatment cycle of CA-4948 will be 28 days in length and repeated in the absence of unacceptable toxicity or disease progression.
The major study inclusion and exclusion criteria are as follows: Relapsed or refractory AML (primary or secondary, including treatment-related) after at least one standard treatment (including chemotherapy, re-induction therapy or stem cell transplantation) based on the assessment of the investigator or high/very high risk relapsed/refractory MDS (IPSS-R criteria), following at least 6 cycles of hypomethylating agents HMA or evidence of early progression. Patients diagnosed with acute promyelocytic leukemia (APL, M3), blast phase of CML, allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to start of CA-4948 are excluded.
The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for CA-4948 based on the safety and tolerability, DLTs and PK/PD findings. Secondary objective is characterization of the pharmacokinetic (PK) parameters and preliminary efficacy. Exploratory objective (1)is to assess the potential association between target-related biomarkers (including IRAK4-L and downstream signaling parameters), selected genetic mutations (including spliceosome mutations), gene expression signatures, cell of origin, or other molecular classification subtypes and anti-leukemic activity (including central morphology review), and (2) to assess the pharmacodynamic effects of CA-4948 on selected biomarkers in peripheral blood and bone marrow.
As of 03 August 2020, the trial has enrolled 3 patients in Cohort 1. Clinical updates will be later reported. After the RP2D has been determined, it may be subsequently amended including patient selection and combination therapy in a controlled design.
References:1.Rhyasen, GW, Starczynowski DT, 2015. Brit J Cancer 112, 232-2.Smith MA. et al., 2019 Nat Cell Biol. 21(5): 640-6503.Choudhary G et al.2019. Blood 134 (Suppl 1): 4224.4.Booher R. et al.: 2019: EHA Annual Meeting, Abstr. PS9915.Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828
Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Talati:Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Speakers Bureau; Pfizer: Honoraria; AbbVie: Honoraria. Götze:Celgene: Research Funding.
páttasyrpa ist eine ,Serie' von über 30 Beiträgen zu den mittelalterlichen und neuzeitlichen Literaturen, Kulturen und Sprachen Nordeuropas zu Ehren von Stefanie Gropper, die über zweieinhalb ...Jahrzehnte die Professur für Nordische Philologie an der Universität Tübingen innehatte. Ihre Forschung zu thaettir (,Erzählsträngen' oder kurzen Erzählungen) und Sagaliteratur, Narratologie, Übersetzung und Kulturwissenschaft haben das Feld der Altnordistik nachhaltig geprägt. In Anlehnung an diese Forschungsinteressen versteht sich die Festschrift ebenfalls als eine Sammlung von thaettir, kurzen Beiträgen zu einer ähnlichen Vielfalt von Themen wie Autorschaft und Dichtung, Ästhetik und Erzählwelten, kulturellen Kontakten und Rezeptionsforschung. Zudem reflektiert der Band, zu welchem Freund:innen und Kolleg:innen aus Ländern in ganz Europa und Nordamerika beigetragen haben, Stefanie Groppers weitverzweigte internationale Kooperationen und Beziehungen.
The CRC research project Different Aesthetics aims to change perspectives in aesthetic discussions by directing attention to the 2000-year history of European art and culture before the 18th century.
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