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  • 1
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    Refining risk stratification in CMML: A comprehensive assessment of the IPSS-M and other molecularly informed models.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 7020-7020
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 7020-7020
    Abstract: 7020 Background: Multiple molecularly-informed models have been designed in hopes of improving prognostication in CMML. More recently the IPSS-M was introduced for MDS and showed improved prognostic accuracy over the IPSS-R. Here we aimed to analyze whether the applicability of the IPSS-M extends to CMML and provide a definitive comparison between all major molecularly-informed models. Methods: A total of 367 pts with CMML treated at Moffitt Cancer Center with annotated clinical and molecular data were analyzed. The mean IPSS-M score was used as reference. Correlative analysis between CPSS-Mol, Mayo Molecular (MMM), GFM and IPSS-M was performed. Time-to-event analyses were estimated using Kaplan–Meier. We used Cox regression for survival endpoints. Model discrimination was evaluated using Harrell’s C concordance index. Results: We identified 987 driver point mutations involving 21 genes across 367 pts. We identified at least 1 mutation in 96% of pts (n = 352). Median follow-up was 4.4 yrs (3.8-5.0). The most prevalent mts were TET2, SRSF2, ASXL1, RUNX1 and NRAS. Using the IPSS-M schema, pts were classified as very low (7%, n = 26), low (29%, n = 108), moderate low (21%, n = 76), moderate high (16%, n = 58), high (18%, n = 65) and very high-risk (9%, n = 34). The IPSS-M identified 6 risk categories with mOS of 5.0, 5.1, 3.9, 2.6, 1.7 and 1.1 yrs, ranging from VL to VH (p 〈 .05) and a 4-yr cumulative incidence of AML evolution of 2%, 14%, 17%, 18%, 25% and 14% respectively (p 〈 .05) CPSS-Mol and IPSS-M equally showed improved OS discrimination over the MMM and GFM as demonstrated by an 11% and 6% increase in c-index respectively (0.71 vs 0.60 and 0.65). Similarly, CPSS-Mol outperformed CPSS by 3% (0.71 vs 0.68), as did IPSS-M relative to IPSS-R (6%, 0.71 vs 0.65) A 4-to-4 mapping between CPSS-Mol and IPSS-M risk groups (by merging VL/L and H/VH into LR and HR), resulted in the restratification of 57% of pts (n = 202). 22% (n = 15) of LR CPSS-Mol pts were upstaged. 30% (n = 23) of HR pts were downstaged 87 pts (23.7%) developed AML: 34 by 1 (9.2%), 60 by 2 (16.3%) and 79 by 4 yrs (21.5%). There was significant segregation between IPSS-M and CPSS-Mol groups and AML risk (p 〈 .05), but not MMM (p = .191). CPSS-Mol showed the highest accuracy, followed by IPSS-M, MMM and GFM (0.66 vs 0.63 vs 0.57 vs 0.52) We then analyzed the predictive value of the models in pts receiving frontline HMA (n = 146). IPSS-M retained its prognostic accuracy with significant segregation between strata (p 〈 .01), as did CPSS-Mol (p 〈 .01) and MMM (p = .01). Conclusions: The IPSS-M can be used reliably in pts with CMML and shows comparable prognostic accuracy to the CPSS-Mol. Both outperformed MMM and GFM. All models retained its predictive value in pts receiving frontline HMA. This carries particular importance in community settings where CMML tends to be misdiagnosed as MDS. In such instances use of the IPSS-M is unlikely to adversely impact outcomes when used to guide treatment decisions.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.7020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Hyperferritinemia as predictive biomarker of poor clinical outcomes in CMML.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7055-7055
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7055-7055
    Abstract: 7055 Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Methods: Retrospective data was collected from a database of CMML pts treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels ( 〈 1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin 〉 1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n = 168) developed hyperferritinemia vs 71% (n = 403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p = 0.001) and harbor a proliferative phenotype (p = 0.01). They presented with higher marrow cellularity (mean 83%, p = 0.08), PLT (mean 177k, p = 0.038), and lower Hb (mean 9.5, p 〈 0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p = 0.007), cytopenias (p 〈 0.05), % peripheral blasts (p 〈 0.05), RBC and PLT transfusion dependence (p 〈 0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p 〈 0.05); and had higher rates of AML transformation (p 〈 0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p 〈 0.05). ASXL1 (p = 0.002), EZH2 (p = 0.003), and SETBP1 (p = 0.019) mutations were more common among pts with hyperferritinemia. Conversely, TET2 (p = 0.001), CBL (p = 0.028) and SRSF2 (p = 0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin 〈 1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p 〈 0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR = 0.69; 95%CI 0.53-0.89; p = 0.005). Conclusions: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and higher rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7055
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Outcomes of IDH1/2 mutant AML patients treated with IDH1/2 inhibitors: A single institutional experience.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e19010-e19010
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e19010-e19010
    Abstract: e19010 Background: Recent studies showed that IDH1/2 are frequently mutated in AML and that aberrant 2-HG elevation driven by the mutant IDH1/2 proteins plays a pivotal role in AML development. Subsequent clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2 mut AML patients. In this single institutional retrospective study, we explored the efficacy and safety outcomes of IDH1/2 mut AML patients treated with Ivosidenib or Enasidenib. Methods: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Results: A total of 43 ( IDH1 mut , n = 12; IDH2 mut , n = 33; both IDH1/2 mut , n = 2) patients were included in the study. Median age at AML diagnosis was 67.6 (24.2-83.3) years and 24 (55.8%) patients were male. Eighteen (42%) patients had secondary AML and 13 (34.2%), 17 (44.7%), and 8 (21.1%) patients had favorable, intermediate, and adverse risk, respectively. A total of 23 (53.5%) and 9 (20.9%) patients received intensive chemotherapy and hypomethylating agents as their 1 st line therapy. One patient received Enasidenib as the 1 st line therapy and the rest of the patients had relapsed/refractory disease prior to IDH1/2 inhibitor therapy. Median number of treatment prior to IDH1/2 inhibitors was 4 (0-8). The median duration of IDH1/2 inhibitor treatment was 3.2 (0.2-31.6) months ( IDH1 mut , 2.5 [0.7-13.5]; IDH2 mut , 3.4 [0.2-31.6]). Treatment response was assessed in 38 patients and 18 had overall response (CR, n = 7 [18.4%] ; PR, n = 11 [28.9%]). Among these, 13 patients had concurrent somatic mutations in FLT3, KRAS, NRAS, or PTPN11. The overall response rate in these patients was not statistically different compared to patients who did not have these mutations (38.5% vs. 40%, p 〉 0.05). The median PFS was 3.9 (0.4-14.7) months ( IDH1 mut , 5.6 [1.7-11.5] vs. IDH2 mut , 3.7 [0.4-14.7], p 〉 0.05) and median OS was 7.6 (0.4-44.1) months. The most common reason for IDH1/2 inhibitor discontinuation was disease progression (n = 21) followed by adverse events (n = 3) and allogeneic transplant (n = 2). The adverse events were assessed in 41 patients and the most common adverse events were differentiation syndrome ( IDH1 mut , n = 3; IDH2 mut , n = 5) and leukocytosis ( IDH1 mut , n = 4; IDH2 mut , n = 4) followed by hepatic toxicity ( IDH2 mut n = 7), and QTc prolongation ( IDH1 mut , n = 3). Conclusions: Our study indicates that IDH1/2 inhibitors remain a reasonable option for the refractory/relapsed IDH1/2 mut AML. However, significant number of patients failed to show any response and many of the patients who showed initial response had short response duration. These findings warrant further studies to identify underlying resistance mechanisms of IDH1/2 inhibitors and the optimal combination therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e19010
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 4
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    Clinical outcomes associated with azacitidine (AZA) monotherapy for treatment-naïve, higher-risk myelodysplastic syndrome (HR-MDS): A systematic literature review and meta-analysis.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e19062-e19062
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e19062-e19062
    Abstract: e19062 Background: AZA is a standard of care for patients who have HR-MDS. Given the limited availability of large datasets describing outcomes in the current treatment paradigm of HR-MDS, this analysis aimed to aggregate clinical outcomes associated with AZA monotherapy for treatment-naïve HR-MDS. Methods: CENTRAL, EMBASE, and MEDLINE were searched to identify interventional, prospective, and retrospective observational studies in treatment-naïve HR-MDS (defined as intermediate-2 or high risk by IPSS or intermediate to very high risk by IPSS-R) using AZA monotherapy. Inclusion of observational studies was limited to those with n 〉 20 in the AZA arm. Responses according to IWG 2000 or IWG 2006 including complete remission (CR) rate, overall response rate (ORR; defined as CR, marrow CR [mCR], partial response, and hematologic improvement), overall survival (OS), duration of response (DOR), and time to response (TTR) were extracted. Response rates were synthesized using random-effects models; median of medians was used for OS, DOR, and TTR. Results: Of 3250 abstracts identified, 34 publications describing 16 studies met inclusion criteria: 5 randomized controlled trials (RCTs), 3 prospective studies, and 8 retrospective studies. None of the response endpoints were reported in all studies (see Table). The pooled ORR ranged from 44% to 55% across RCTs, prospective, and retrospective studies. The pooled CR rates, reported in 2 RCTs (n=55), 1 prospective study (n=27), and 3 retrospective studies (n=509), were 14%, 11%, and 16%, respectively. The pooled CR rate across all studies (n=591) was 16% (95% CI: 13%, 19%). Pooled median OS (mOS) was 16.7 months (mo) in the 3 RCTs (n=161), 16.5 mo in a single prospective study (n=34), and 14.4 mo in the 5 retrospective studies (n=1472). Pooled mOS across all studies (n=1667) was 16.4 mo (95% CI: 12.0, 17.3). The pooled median DOR was 10.1 mo (95% CI: 9.1, 11.0), and the median TTR was 4.6 mo (95% CI: 3.0, 9.0). Conclusions: These findings provide evidence th at benefit from AZA monotherapy in treatment-naïve HR-MDS patients is limited. Opportunity exists for novel therapies to increase response rates, improve the duration of responses, and prolong survival. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e19062
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): The phase 3, randomized, ENHANCE study.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS7055-TPS7055
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS7055-TPS7055
    Abstract: TPS7055 Background: MDS is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. The median age of diagnosis is approximately 70 yrs of age and prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high and very high risk MDS (HR-MDS) have a median overall survival (OS) of 0.8 to 3.7 years. Despite the high unmet need in this patient population, azacitidine (AZA) is the only approved therapy for HR-MDS which has improved overall survival in clinical trials to date. However, these agents lead to low complete response (CR) rates (10-17%) with limited OS ( = 2 years), indicating a need for alternative therapy. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of tumor cells. AZA increases expression of prophagocytic “eat me” signals, facilitating synergy with magrolimab. In an ongoing phase 1b study, the combination of magrolimab + AZA led to high response rates (ORR 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. ENHANCE (NCT04313881) is a phase 3 trial comparing the efficacy and safety of magrolimab + AZA with that of AZA + placebo (PBO) in previously untreated patients with HR-MDS. Methods: Patients ≥18 years old with previously untreated intermediate to very high risk MDS by IPSS-R are eligible for ENHANCE. Randomization is 1:1 to magrolimab + AZA or AZA + PBO with no crossover allowed. Magrolimab or placebo is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on target anemia. An intrapatient dose escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, with 30 mg/kg Q2W dosing occurring in Cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. Two primary efficacy endpoints are CR rate and OS. For patients undergoing allogeneic stem cell transplantation (ASCT), data for the CR rate will be censored at the time of ASCT and OS will be censored at the last known alive date. Secondary efficacy endpoints include RBC transfusion independence rate, event-free survival, minimal residual disease-negative rate, time to AML transformation, and patient-reported Functional Assessment of Cancer Therapy (FACT)-Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of magrolimab will also be explored. Planned enrollment is approximately 520 patients globally, which began in September 2020. Accrual is ongoing. Clinical trial information: NCT04313881.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.TPS7055
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Phase 1/2a study of the IRAK4 inhibitor CA-4948 as monotherapy or in combination with azacitidine or venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia or lyelodysplastic syndrome.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7016-7016
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7016-7016
    Abstract: 7016 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with CA-4948 monotherapy. Phase 1b includes 2 arms of combination therapy: CA-4948 + azacitidine (AZA) and CA-4948 + venetoclax (VEN). The primary objectives of this study are to assess the safety, clinical activity, and identify the Recommended Phase 2 Dose (RP2D) of CA-4948 as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for CA-4948 monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16 th , 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30 th , allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of CA-4948 were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30 th , 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration 〉 6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to CA-4948. Conclusions: CA-4948 is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting CA-4948 may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing. Clinical trial information: 04278768.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7016
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Influence of variant allele frequency (VAF) on the phenotypic penetrance of TP53 mutations in myeloid malignancies.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 7091-7091
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 7091-7091
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.7091
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 8
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    A phase I study of AMV564 in patients with intermediate or high-risk myelodysplastic syndromes.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS7071-TPS7071
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS7071-TPS7071
    Abstract: TPS7071 Background: The CD33 antigen is expressed on myeloblasts in approximately 75% of patients with myelodysplastic syndromes (MDS) and is also expressed on immunosuppressive myeloid-derived suppressor cells (MDSCs) that are prevalent in MDS. AMV564 is a novel bivalent, bispecific (2:2) T-cell engager that binds both CD33 and the invariant CD3ε on T-cells with strong avidity. AMV564 has significant cytotoxic activity against CD33-postive cells, including MDSCs, in animal models, in vitro studies, and in patients (Reusch et al. Clin Can Res 2016 and List et al. ASH 2017). Preliminary results from the phase 1 acute myeloid leukemia (AML) trial have demonstrated safety and activity in patients with AML arising from prior MDS (Westervelt et al. ASH 2018). Methods: AMV564-201 is an open label, phase 1, multicenter, dose-escalation with expansion trial of AMV564 in patients with intermediate-2 or high-risk MDS who are refractory to or relapsed from hypomethylating agents (HMAs) or intensive chemotherapy. The key objectives of the dose-escalation stage of the study are to characterize the safety and tolerability of AMV564, identify a maximum tolerated dose and/or a dose-schedule to evaluate in the dose expansion portion of the study. In the dose expansion stage of the study, the safety and tolerability of AMV564 will be further characterized in addition to a preliminary assessment of efficacy. Other objectives include characterization of AMV564 pharmacokinetics, pharmacodynamics, and immunogenic potential. Approximately 80 patients with intermediate-2 or high-risk MDS will be enrolled. The Dose Escalation Stage will include up to approximately 30 patients, depending on the dose at which the MTD is determined for each schedule, and approximately 50 additional patients will be enrolled in the Expansion Stage. AMV564 will be administered daily as a continuous intravenous (CIV) infusion over a period of 24 hours for 14 days in each cycle. Each cycle will be approximately 4 weeks. A lead-in dose regimen will be utilized for all patients treated at dose levels at or above 50 mcg/day. Patients will receive up to 4 cycles of AMV564 treatment at the assigned dose level. Clinical trial information: NCT03516591.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.TPS7071
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Magrolimab in combination with azacitidine for untreated higher-risk myelodysplastic syndromes (HR-MDS): 5F9005 phase 1b study results.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7017-7017
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7017-7017
    Abstract: 7017 Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal overexpressed on cancer cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. Here we report final Phase 1b data in patients (pts) with untreated HR-MDS (NCT03248479). Methods: Pts with previously untreated intermediate-/high-/very high-risk MDS per IPSS-R received magrolimab IV as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg weekly or Q2W maintenance dose. AZA 75 mg/m 2 was administered IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: 95 pts (median age 69 years [range 28, 91]) were treated. IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21%, respectively. MDS was therapy-related in 22%; 26% (n=25) had a TP53 mutation and 62% had poor-risk cytogenetics (27% complex). Median (range) number of cycles was 6 (1, 27). The most common TEAEs included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (44%). The most common Grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and WBC count decreased (30%). 6 pts discontinued treatment due to AEs. 60-day mortality was 2%. Median Hb change from baseline (BL) at first post-dose sample was –0.7 g/dL (range –3.1, +2.4). CR and objective response (OR) rates were 33% and 75% with 31% of evaluable OR pts with abnormal cytogenetics at BL having cytogenetic CR. Median time to first OR, duration of CR (DCR), duration of OR, and PFS were 1.9, 11.1, 9.8, and 11.6 mos. OS rates at 12 and 24 mos were 75% and 52%, respectively (median NR with 17.1 mos follow-up for OS). For patients evaluated with sequential WES with a VAF cutoff of 5%, 3 of 3 pts with TP53 mutation who achieved CR had TP53 VAF 〈 5% by C5D1. Favorable outcomes were observed in both TP53 mutant (40% CR, median OS 16.3 months) and wildtype pts (31% CR, median OS NR; Table). Conclusions: Magrolimab+AZA was well tolerated with promising efficacy in pts with untreated HR-MDS including those with TP53-mut and TP53-wt disease. A Phase 3 trial of magrolimab/placebo+AZA (ENHANCE: NCT04313881) is ongoing. Clinical trial information: NCT03248479. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7017
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7020-7020
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7020-7020
    Abstract: 7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m 2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh] , 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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