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PURPOSE Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Summary While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

7043Background: Induction chemotherapy for AML results in prolonged neutropenia and a high risk of infection. CLT-008 is a human off-the-shelf allogeneic MPC preparation manufactured by ex vivo cul...

Background: Current management of chemotherapy and radiation-induced neutropenia is unsatisfactory with frequent infection-related deaths. A novel allogeneic human myeloid progenitor cell product, CLT-008, that is culture-derived from G-CSF mobilized HSCs, can be cryopreserved and infused without HLA matching. Cells are intended to engraft transiently and produce mature myeloid effector cells that migrate to tissues and may mitigate the risk of bacterial or fungal infection for weeks, as has been demonstrated in murine models. Methods: To evaluate the safety of CLT-008, a phase 1 dose escalation study was conducted in subjects with AML, MDS or ALL during consolidation (n=18) or with AML or tAML during first or subsequent induction (n=31). Eligible subjects were age 18 or older and treated with a high-dose or standard-dose cytarabine-based regimen. All 18 consolidation subjects and 23 induction subjects received CLT-008. Subjects received CLT-008 on study day 6 (consolidation 106 or 107cells/kg) or on study day 9 (induction 107 or 3x107 cells/kg). G-CSF was given at 5 µg/kg daily from the day of CLT-008 until the ANC was 500/µL. During induction, 8 non-randomly selected controls received G-CSF without CLT-008. Dose limiting toxicities (DLT) were defined as any grade 3-5 infusion reaction, grade 4-5 organ toxicity (not due to the primary malignancy, infection, pre-existing condition, or initiation of new chemotherapy), any Grade III to IV GVHD, or failure of autologous neutrophil recovery at Day 42 not clearly attributable to another cause. All subjects were followed for 49 days and status was assessed at 6 months. Results: Among 41 currently evaluable subjects, 1 experienced a DLT of grade 3 allergic infusion-related reaction which resolved promptly with steroids and antihistamine. There were no other DLTs and no GVHD of any grade. Treatment-emergent adverse events occurring in 3 or more subjects included febrile neutropenia, infection, mucosal inflammation, fatigue, diarrhea, tachycardia and nausea but were not judged related to the product. Among the 23 induction subjects receiving CLT-008 with G-CSF, there was a reduction in mucositis (WHO grade 2 or greater) and in duration of febrile episodes when compared to the 8 control subjects. CLT-008-derived cells were detectable in the peripheral blood for 6 of 23 induction subjects at 2-10% of nucleated cells using STR-PCR; there was no clear effect on ANC from this chimerism. To date, 8 of 23 induction subjects went on to subsequent HSC transplant. Seven engrafted while one died on post-transplant day 10 from an unrelated cause. Conclusions: CLT-008 was safe and well tolerated in this phase 1 study. Only 1 DLT occurred and the pattern of AEs was as expected for this population. Among the induction subjects treated at 3x107 cells/kg, efficacy signals with respect to mucositis and duration of fever were found in the absence of high-level peripheral blood CLT-008 chimerism. These observations suggest that CLT-008-derived myeloid effector cells preferentially migrate to chemotherapy-damaged mucosal tissues where they could function to mitigate infection risk. Further clinical development is planned in a randomized phase 2 study using an enhanced potency iteration of CLT-008, assessment of tissue-level chimerism, and specific ascertainment of outcomes related to infection and chemotherapy sequellae. Figure 1 Figure 1. Disclosures Wieduwilt: Cellerant Therapeutics: Honoraria, Research Funding. Cerny:Cellerant Therapeutics: Honoraria, Research Funding. Akard:Cellerant Therapeutics: Research Funding. Ustun:Cellerant Therapeutics: Honoraria, Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. Rossetti:Cellerant Therapeutics: Research Funding. Hill:Cellerant Therapeutics: Honoraria, Research Funding. Brown:Cellerant Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Kellerman:Cellerant Therapeutics: Employment, Equity Ownership. Van Syoc:Cellerant Therapeutics: Employment, Equity Ownership. Reed:Cellerant Therapeutics: Employment, Equity Ownership. Andreadis:Cellerant Therapeutics: Research Funding.