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Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.
PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.
AML-399 A Phase 2, Open-Label, Multiarm, Multicenter Study to Evaluate Magrolimab Combined With Antileukemia Therapies for First-Line, Relapsed/Refractory, or Maintenance Treatment of Acute Myeloid Leukemia (AML)
Context: Patients with newly diagnosed AML who are ineligible for intensive chemotherapy (IC) are incurable, despite progress with azacitidine + venetoclax, whereas patients with relapsed/refractory disease continue to have a poor prognosis. Furthermore, relapse remains frequent for patients in remission receiving oral azacitidine. Magrolimab is a blocking antibody against CD47, a “don't eat me” signal overexpressed on cancer cells. This blockade induces tumor phagocytosis and is synergistic with chemotherapy and hypomethylating agents. Magrolimab + azacitidine has demonstrated encouraging efficacy in newly diagnosed AML (objective response rate [ORR], 63%; complete remission [CR], 42%). Objective: To evaluate the safety/tolerability and efficacy of magrolimab combined with antileukemia therapies in patients with newly diagnosed or relapsed/refractory AML or with AML in maintenance post-IC. Design: This open-label, multi-arm, multicenter study includes 3 safety run-ins with corresponding expansion cohorts (NCT04778410). Safety run-in cohorts will enroll 6 patients for 28 days to determine dose-limiting toxicities and the recommended phase 2 dose prior to enrollment of phase 2 cohorts. Patients: Patients must be aged ≥75 or 18–74 years with comorbidities precluding IC (cohort [C]1), have relapsed/primary refractory disease post-IC (C2), or have CR/CR with incomplete hematologic recovery and measurable residual disease (MRD) post-IC (C3). Interventions: Patients will receive magrolimab + venetoclax + azacitidine (C1), magrolimab + mitoxantrone + etoposide + cytarabine (MEC; C2), or magrolimab + CC-486 (C3). In all cohorts, magrolimab will be administered intravenously with priming and ramp-up doses of 1 (day [D]1, D4), 15 (D8), and 30 mg/kg (D11, D15, then QW [x5], followed by Q2W). Azacitidine, venetoclax, MEC, and CC-486 will be administered per label indications. After completion of the safety run-ins, additional patients will be enrolled into the phase 2 study (C1, n=40; C2, n=30; C3, n=40). Study treatments will follow the dosing schedule until disease progression, unacceptable toxicity, or loss of clinical benefit (C1/C3) or for 2 to 3 cycles for MEC with a maximum 12 months of magrolimab (C2). Main Outcome Measures: Primary efficacy endpoints are CR rate (C1/C2) and MRD-negative CR rate (C3). Secondary endpoints include overall survival, ORR, and MRD negativity (C1/C2).
AML-348 A Phase Ib/II Study of Ivosidenib With Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies
Context: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1–14), with or without azacitidine (AZA; 75 mg/m2 D1–7) every 28 days. Objectives: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Design: A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Participants: Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. Results: Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44–84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2–DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease–negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) occurred in 64% of patients following cycle 5. Grade 3–5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55–91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.
AML-262 Pivekimab Sunirine (PVEK, IMGN632) Triplet With Azacitidine and Venetoclax Shows Broad Activity in Adverse Genetic Subsets of Relapsed/Refractory Acute Myeloid Leukemia and Reduced Infusion-Related Reactions
Context: Pivekimab sunirine (PVEK, IMGN632) is a first-in-class ADC comprising a CD123 high-affinity antibody, a cleavable linker, and an IGN (indolinobenzodiazepine pseudodimer) payload. PVEK with azacitidine (AZA) and venetoclax (VEN) is a novel triplet that has demonstrated anti-leukemia activity in relapsed/refractory AML patients. Objective: Evaluate the anti-leukemia activity in genetic subgroups of AML and safety of the triplet. Intervention: Patients with relapsed/refractory AML received PVEK+AZA+VEN in a three-drug escalation over a 28-day cycle: PVEK 0.015 or 0.045 mg/kg day 7, AZA 50 or 75 mg/m2 days 1–7, and VEN 400 mg for 8, 14, or 21 days. Results: Twenty-nine patients (median age 67 y, ELN adverse 62%, prior VEN 48%) were in higher-intensity cohorts (PVEK 0.045 mg/kg and/or VEN for 14 or 21 days). The overall response rate (ORR) was 59% (4 CR, 6 CRh, 1 CRp, 6 MLFS) and the composite complete remission rate (CCR, CR+CRh+CRp+CRi) was 38%. Higher rates are seen in patients with FLT3-ITD (n=9, ORR 89%, CCR 78%), IDH2 (n=4, ORR 75%, CCR 75%), and WT1 (n=7, ORR 57%, CCR 43%) mutations. Lower rates are seen in patients with monosomy 7/abn7q (n=6, ORR 17%, CCR 17%), TP53 (n=4, ORR 25%, CCR 25%), and ASXL1 (n=6, ORR 67%, CCR 17%) deletions or mutations. The safety profile for the PVEK triplet is similar to AZA+VEN. No VOD, TLS, or CRS was reported. IRRs were reported in 33% (n=17, one grade 4) of patients given 1 dose of dexamethasone (8 mg) as premedication (n=51); these IRRs were most frequently tachycardia and chills, with no anaphylactic reactions reported. Following the data cut-off, there was a second grade 4 IRR, and the prophylactic regimen was increased with two additional doses of dexamethasone on the day prior to the PVEK dose. The IRR rate has dropped to 8% (3 of 38), with no grade 3+; all were grades 1–2 that resolved with limited intervention (P<0.01). Conclusions: The PVEK triplet with AZA+VEN demonstrates anti-leukemic activity across multiple high-risk genetic subsets of relapsed/refractory AML. Prophylactic steroids added on day –1 have significantly reduced IRRs. Expansion cohorts are now enrolling for untreated and relapsed AML patients (NCT04086264).
AML-464 Tolerability and Efficacy of the First-In-Class Anti-CD47 Antibody Magrolimab Combined With Azacitidine in Frontline Patients With TP53-Mutated Acute Myeloid Leukemia (AML): Phase 1b Results
Context: Patients with TP53-mutated AML have a poor prognosis. Magrolimab is an antibody blocking CD47, a “don't eat me” signal on cancer cells, which induces tumor phagocytosis and is synergistic with azacitidine. Objective: Report final tolerability and efficacy data. Design: Ph1b single-arm trial of magrolimab+azacitidine (NCT03248479). Patients: 72 frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. Interventions: Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle). Main Outcome Measures: Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: Common treatment-emergent adverse events (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%). Common grade (G)≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; G3, 26.4%; G4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). G3 hemolysis was reported in 1 patient; no G4 hemolysis was reported. Objective response rate was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). 16.7% and 5.6% of patients had stable disease and progressive disease (PD), respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in 4.2% (discontinued due to AEs) and 6.9% (other) of patients prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2) and CR was 3.0 months (range, 1.8-9.6); 14/31 (45.2%) evaluable patients with CR/CRi/CRh/MLFS achieved negative MRD. 8/24 patients with CR had a longitudinal TP53 variant-allele-frequency (VAF) assessment; 5/8 (63%) had ≤5% VAF. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), or other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 (95% CI, 4.7-10.9) and 8.7 (95% CI, 5.3-10.9) months, respectively. Median overall survival was 10.8 months (95% CI, 6.8-12.8; 8.3-month median follow-up). Conclusions: Magrolimab+azacitidine showed durable responses and encouraging overall survival in frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. A Ph3 trial of magrolimab+azacitidine vs standard-of-care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.
AML-432 Overall Survival (OS) by IDH2 Mutant Allele (R140 or R172) in Patients With Late-Stage, Mutant-IDH2 Relapsed/Refractory Acute Myeloid Leukemia (AML) Treated With Enasidenib or Conventional Care Regimens (CCR) in the Randomized, Open-Label, Phase 3 IDHENTIFY Trial
Context: IDH2 mutations (mIDH2) occur in ~8%-19% of patients with AML, typically as R140Q (~75%) or R172K (~25%) point mutations, which have distinct functional effects and prognostic relevance. In the phase 3 IDHENTIFY trial, enasidenib did not significantly improve OS vs CCR in older patients with mIDH2 relapsed/refractory AML, but a trend for improved OS with enasidenib was detected in patients with IDH2-R172. Objective: Investigate molecular profiles and OS in mIDH2 variant subgroups (R140/R172). Methods: IDHENTIFY (NCT02577406) enrolled patients aged ≥60 years who had received 2-3 prior AML-directed therapies. Patients were randomized 1:1 to enasidenib 100-mg/day or CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care). Co-occurring mutations were identified by targeted NGS of BMMC DNA. Total 2-hydroxyglutarate was determined by LC/MS. Results: Of 319 patients enrolled, 88 (28%; 43 enasidenib, 45 CCR) had mIDH2-R172 and 229 (72%; 115 enasidenib, 114 CCR) had mIDH2-R140. Median baseline 2-hydroxyglutarate level and IDH2 VAF were similar between arms and mIDH2 subgroups. Patients with mIDH2-R172 had fewer baseline mutations (median 4 [range 2-8]) than those with mIDH2-R140 (5 [1-11]) (P<0.0001). Common co-mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with R172, R140 was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2, whereas DNMT3A and TP53 were more common with R172. In Cox multivariate analysis including mIDH2 variant, DNMT3A status, and number of baseline mutations, mIDH2-R172 was significantly correlated with improved OS (P=0.04 vs R140) in the enasidenib arm, and number of baseline mutations was significantly (P<0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 months with enasidenib vs 7.8 months with CCR (HR, 0.59 [95%CI 0.35-0.98]; P=0.039); 1-year survival rates were 62% and 30%. In the R140 subgroup, median OS was 5.7 months in both arms (0.93 [0.70-1.24]; P=0.61), and 1-year survival rates were 29% and 25% with enasidenib and CCR. Conclusions: Mutational burden and co-mutational profiles differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR.
MDS-445 Magrolimab In Combination With Azacitidine for Patients With Untreated Higher-Risk Myelodysplastic Syndromes (HR MDS): 5F9005 Phase 1b Study Results
Context: Magrolimab is a monoclonal antibody blocking CD47, a “don't eat me” signal overexpressed on cancer cells, which leads to tumor phagocytosis and is synergistic with azacitidine. A high unmet need exists to build on current standard-of-care azacitidine in patients with HR MDS. Objective: Report final safety/tolerability and efficacy data. Design: Ph1b trial of magrolimab+azacitidine (NCT03248479). Patients: 95 patients with untreated HR MDS (intermediate, high, or very-high risk per the Revised International Prognostic Scoring System [IPSS-R]). Interventions: Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle). Main Outcome Measures: Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: Median age was 69y [range, 28-91y]). IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21% of patients, respectively. Therapy-related MDS, TP53 mutation, and poor-risk cytogenetics were reported in 22%, 26%, and 62% of patients, respectively. Median number of cycles was 6 (range, 1-27). The most common treatment-emergent adverse events (TEAEs) included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (43%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and white blood cell count decreased (30%). Six patients discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline at first post dose sample was -0.7 g/dL (range, -3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%; 31% of OR-evaluable patients with baseline abnormal cytogenetics had cytogenetic CR. Median time to first OR, duration of CR, duration of OR, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. 12- and 24-month overall survival (OS) rates were 75% and 52%, respectively; median OS was not reached with 17.1 months of follow-up. Favorable outcomes were observed in patients with TP53 mutation (n=25; CR rate, 40%; median OS, 16.3 months) and wild-type TP53 (n=61; CR rate, 31%; median OS, not reached). Conclusions: Magrolimab+azacitidine was well tolerated, with promising efficacy in patients with untreated HR MDS, including those with TP53-mutated and –wild-type disease. A Ph3 trial of magrolimab/placebo+azacitidine (ENHANCE; NCT04313881) is ongoing.
MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS).
CONTEXT: Magrolimab is an antibody blocking CD47, a "don't eat me" signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Preclinical studies found that CD47 is critical to RBC homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD47 agents. Several clinical trials demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower "priming" dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at higher maintenance doses. However, the underlying mechanism has not been fully defined. OBJECTIVE: To describe manageable anemia in magrolimab-treated patients and further investigate the underlying mechanisms in preclinical models. DESIGN: Prospective analysis from a ph1 trial of magrolimab+azacitidine (NCT03248479). Complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected from patients at prespecified time points. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for CD47 expression on RBCs and white blood cells (WBCs). Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice. PATIENTS: 57 patients with HR MDS. INTERVENTIONS: Magrolimab IV 1 mg/kg (priming) then 30 mg/kg QW, then Q2W (maintenance). Azacitidine 75 mg/m2 days 1-7 (each 28-day cycle). RESULTS: Treatment with magrolimab+azacitidine resulted in tolerable anemia that correlated with rapid, near-complete loss of CD47 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for CD47 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab+rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 cross-linking between RBCs and non-RBCs. CONCLUSIONS: These results support the idea that on-target magrolimab-mediated anemia is mitigated by a near-complete loss of RBC CD47. Patients with HR MDS treated with magrolimab+azacitidine had tolerable anemia with priming and maintenance doses.
Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy.
Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.
A randomised evaluation of low-dose cytosine arabinoside (ara-C) plus tosedostat versus low-dose ara-C in older patients with acute myeloid leukaemia: results of the LI-1 trial.
Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low-dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC-T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick-a-Winner' LI-1 trial. There was a statistically non-significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC-T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30-1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37-1·27; P = 0·22). However, overall survival (OS) showed no difference (2-year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73-1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019.
Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study.
PURPOSE: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).
Structures of the human adult muscle-type nicotinic receptor in resting and desensitized states.
Muscle-type nicotinic acetylcholine receptor (AChR) is the key signaling molecule in neuromuscular junctions. Here, we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states and ACh-bound desensitized states. In addition to identifying the conformational changes during recovery from desensitization, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in patients with congenital myasthenic syndrome (CMS), revealing they cause either slow- or fast-channel CMS characterized by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both the AChR state transition and the pathogenic mechanisms of disease variants.
CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade
Abstract Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV− patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10−5), with lower incidence of colitis (P = 7.8 × 10−4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10−4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV− patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10−4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.