In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia

We recently reported that rabbit antithymocyte globulin was markedly inferior to horse antithymocyte globulin as a primary treatment for severe aplastic anemia. Here we expand on our findings in this unique cohort of patients. Rabbit antithymocyte globulin was detectable in plasma for longer periods than horse antithymocyte globulin; rabbit antithymocyte globulin in plasma retained functional capacity to bind to lymphocytes for up to 1 month, horse antithymocyte globulin for only about 2 weeks. In the first week after treatment there were much lower numbers of neutrophils in patients treated with rabbit antithymocyte globulin than in patients receiving horse antithymocyte globulin. Both antithymocyte globulins induced a “cytokine storm” in the first 2 days after administration. Compared with horse antithymocyte globulin, rabbit antithymocyte globulin was associated with higher levels of chemokine (C-C motif) ligand 4 during the first 3 weeks. Besides a much lower absolute number and a lower relative frequency of CD4(+) T cells, rabbit antithymocyte globulin induced higher frequencies of CD4(+)CD38(+), CD3(+)CD4(−)CD8(−) T cells, and B cells than did horse antithymocyte globulin. Serum sickness occurred around 2 weeks after infusion of both types of antithymocyte globulin. Human anti-antithymocyte globulin antibodies, especially of the IgM subtype, correlated with serum sickness, which appeared concurrently with clearance of antithymocyte globulin in blood and with the production of cytokines. In conclusion, rabbit and horse antithymocyte globulins have very different pharmacokinetics and effects on neutrophils, lymphocyte subsets, and cytokine release. These differences may be related to their efficacy in suppressing the immune system and restoring hematopoiesis in bone marrow failure. Clinicaltrials.gov identifier: NCT00260689

Translocation (8;21) acute myeloid leukemia presenting as severe aplastic anemia

We report a case of t(8;21) acute myeloid leukemia presenting as severe aplastic anemia. While initial bone marrow biopsy lacked any cytogenetic abnormalities in 20 analyzed metaphases, repeat bone marrow biopsy eight days later demonstrated this translocation. Initial cytogenetic analysis of 20 metaphases was therefore insufficient to make the diagnosis of hypocellular acute myeloid leukemia. We discuss that further complementary molecular tests, such as CGH, would likely provide a more robust diagnosis of hematopoietic diseases

2009

ABSTRACT Method

Consensus minimum hemoglobin level above which patients with myelodysplastic syndromes can safely forgo transfusions

The anemia of MDS often results in decreased quality of life, which is invoked to justify red cell transfusions; however, there are sparse data regarding the minimum hemoglobin (Hb) at which it is safe to forgo transfusions for patients with no evidence of end-organ damage. This issue is even more important in the COVID-19 era, where decreases in blood donations have stressed the blood supply. In March 2018, using a modified Delphi method, we convened a panel of 13 expert MDS clinicians for three iterative rounds to discuss a minimum safe Hb for this population. While the panel was unable to reach the pre-set consensus of 75% for a specific Hb threshold, there was 100% consensus that it be no greater than 7.5 g/dL. Our data suggest that, given no end-organ effects of anemia, patients with MDS can safely forgo transfusions with a Hb of 7.5 g/dL or higher

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors.

BACKGROUND: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors. PATIENTS AND METHODS: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. RESULTS: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67 CONCLUSIONS: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing

Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors

PURPOSE: Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. PATIENTS AND METHODS: In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability. RESULTS: Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1,500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by >100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies. CONCLUSIONS: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated

Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors

Purpose: Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1 K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability. Results: Among the 27 and 31 patients who received MEDI0562 þ durvalumab or MEDI0562 þ tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 þ durvalumab was 7.5 mg MEDI0562 þ 1,500 mg durvalumab; the maximum administered dose of MEDI0562 þ tremelimumab was 22.5 mg MEDI0562 þ 225 mg tremelimumab. Three patients in the MEDI0562 þ durvalumab arm had a partial response. The mean percentage of Ki67 þCD4 þ and Ki67 þCD8 þ memory T cells increased by >100% following the first dose of MEDI0562 þ durvalumab or tremelimumab in all dose cohorts. A decrease in OX40 þFOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies. Conclusions: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated

Safety and tolerability of MEDI0562, an OX40 agonist monoclonal antibody, in combination with durvalumab or tremelimumab in adult patients with advanced solid tumors.

PURPOSE: Combination therapies targeting immunological checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 monoclonal antibody, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. EXPERIMENTAL DESIGN: In this phase 1, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every two weeks (Q2W) in combination with durvalumab (1500 mg) or tremelimumab (75 or 225 mg) Q4W, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed Q8W. The primary objective was to evaluate safety and tolerability. RESULTS: Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment‑emergent AE that led to discontinuation, respectively. The maximum tolerated dose of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by \u3e100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 T regulatory cells was observed in a subset of patients with available paired biopsies. CONCLUSIONS: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated