Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02282215.

Conflict of interest statement

Pinkal M. DesaiEmployment: Johnson & Johnson/JanssenHonoraria: Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Bristol Myers Squibb/Celgene, Agios, Kura Oncology, Takeda, SanofiResearch Funding: Janssen Research & Development, Astex PharmaceuticalsPatents, Royalties, Other Intellectual Property: Detection of mutations in blood prior to leukemia Janice BrownConsulting or Advisory Role: Merck, Pfizer, Astellas Pharma, Cidara, Jasper Therapeutics, Cellerant TherapeuticsResearch Funding: Merck, Astellas Pharma, Pfizer, viropharmaPatents, Royalties, Other Intellectual Property: I hold the patent for Use of myeloid progenitors Saar GillStock and Other Ownership Interests: Carisma Therapeutics, Interius BiotherapeuticsHonoraria: Magellan HealthConsulting or Advisory Role: Asher BioResearch Funding: Novartis, Carisma TherapeuticsPatents, Royalties, Other Intellectual Property: Patents for chimeric antigen receptor T cells for acute myeloid leukemia Melham M. SolhSpeakers' Bureau: Bristol Myers Squibb, Amgen, AbbVie, SeagenResearch Funding: Partner therapeutics Luke P. AkardConsulting or Advisory Role: Takeda, Jazz PharmaceuticalsSpeakers' Bureau: AbbVie, Astellas Pharma, Bristol Myers Squibb, Celgene, Novartis, Takeda, Verastem Jack W. HsuConsulting or Advisory Role: Daiichi Sankyo Celalettin UstunHonoraria: Novartis, Blueprint MedicinesSpeakers' Bureau: Novartis Charalambos AndreadisEmployment: GenentechStock and Other Ownership Interests: Roche/GenentechConsulting or Advisory Role: Gilead Sciences, Kite, a Gilead company, Karyopharm Therapeutics, Atara Biotherapeutics, Incyte, TG therapeutics, EpizymeResearch Funding: Novartis, GlaxoSmithKline, Amgen, Juno Therapeutics, Celgene, MerckTravel, Accommodations, Expenses: Gilead Sciences, Kite, a Gilead company Olga FrankfurtConsulting or Advisory Role: Agios, CelgeneSpeakers' Bureau: Agios, Celgene, Jazz Pharmaceuticals James M. ForanConsulting or Advisory Role: Servier, Bristol Myers Squibb/Celgene, Stemline Therapeutics, Taiho Pharmaceutical, Syros Pharmaceuticals, Sanofi, Certara Inc, Novartis, Pfizer, Revolution MedicinesResearch Funding: AbbVie, Actinium Pharmaceuticals, Aprea Therapeutics, Aptose Biosciences, Boehringer Ingelheim, H3 Biomedicine, Kura Oncology, Sellas Life Sciences, Takeda, Trillium Therapeutics, Xencor John ListerConsulting or Advisory Role: Oncology Analytics Gary J. SchillerStock and Other Ownership Interests: Bristol Myers Squibb, Amgen, Johnson & JohnsonConsulting or Advisory Role: Ono Pharmaceutical, Agios, Celgene, Incyte, Jazz Pharmaceuticals, NovartisSpeakers' Bureau: Astellas Pharma, Kite, a Gilead company, Amgen, Jazz Pharmaceuticals, Stemline Therapeutics, Bristol Myers Squibb, SanofiResearch Funding: AbbVie, Actinium Pharmaceuticals, Actuate Therapeutics, Arog, Astellas Pharma, Bristol Myers Squibb/Celgene, Celator, Constellation Pharmaceuticals, Daiichi Sankyo , Deciphera, Delta-Fly Pharma, Forma Therapeutics, Fujifilm, Gamida Cell, Genentech/Roche, Geron, Incyte, Karyopharm Therapeutics, Kite, a Gilead company, Mateon Therapeutics, Onconova Therapeutics, Pfizer, PrECOG, REGiMMUNE, Samus Therapeutics, Sangamo Bioscience, Sellas Life Sciences, Stemline Therapeutics, Takeda, Tolero Pharmaceuticals, Trovagene, Agios, Amgen, Jazz Pharmaceuticals, ElevateBio, Ono Pharmaceutical, Novartis, Sanofi Matthew J. WieduwiltStock and Other Ownership Interests: Reata PharmaceuticalsHonoraria: Gilead SciencesConsulting or Advisory Role: Gilead SciencesResearch Funding: Amgen, Merck, Cantex, ADC Therapeutics, Jazz Pharmaceuticals, Servier, Leadiant Biosciences, NCI, Macrogenics, Moleculin Biotech, Glycomimetics John M. PagelConsulting or Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, BeiGene, Loxo, MEI Pharma, TG Therapeutics, MorphoSys, Epizyme Patrick J. StiffConsulting or Advisory Role: CRSPR Therapeutics AGResearch Funding: Kite, a Gilead company, Seattle Genetics, Gamida Cell, Incyte, Amgen, TG Therapeutics, Macrogenics, Actinium Pharmaceuticals, Atara Biotherapeutics, Takeda Delong LiuConsulting or Advisory Role: Hengrui TherapeuticsSpeakers' Bureau: Incyte, Pharmacyclics, Astellas Pharma, BeiGene, RigelResearch Funding: Janssen, Celgene, Pfizer, De Novo Pharmaceuticals, Acerta PharmaTravel, Accommodations, Expenses: Incyte, Pharmacyclics, Astellas Pharma Irum KhanHonoraria: Takeda, CelgeneConsulting or Advisory Role: IncyteResearch Funding: TakedaTravel, Accommodations, Expenses: Incyte Wendy StockHonoraria: AbbVieConsulting or Advisory Role: Adaptive Biotechnologies, Jazz Pharmaceuticals, Agios, Kite, a Gilead company, Kura Oncology, GlaxoSmithKline, MorphoSys, Pfizer, ServierPatents, Royalties, Other Intellectual Property: Royalties for a chapter in Up to DateTravel, Accommodations, Expenses: Pfizer Martin S. TallmanHonoraria: Jazz Pharmaceuticals, Roche, Novartis, Society for Immunotherapy of Cancer, AbbVie, WebMD, Japanese Society of HematologyConsulting or Advisory Role: AbbVie, Daiichi-Sankyo, Orsenix, Delta-Fly Pharma, Tetraphase Pharma, Jazz Pharmaceuticals, Roche, Novartis, Innate Pharma, Kura Oncology, Syros PharmaceuticalsResearch Funding: AbbVie, Orsenix, Biosight, Glycomimetics, Rafael Pharmaceuticals, AmgenPatents, Royalties, Other Intellectual Property: UpToDate updates John EdwardsSpeakers' Bureau: Jazz Pharmaceuticals, Astellas PharmaResearch Funding: AbbVieTravel, Accommodations, Expenses: Incyte Iskra PusicConsulting or Advisory Role: Kadmon, Incyte, Syndax Hagop M. KantarjianHonoraria: AbbVie, Amgen, ARIAD, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, AbbVie, Agios, Cyclacel, Immunogen, Jazz Pharmaceuticals, Pfizer Richard MamelokConsulting or Advisory Role: Cellerant Alicia WongEmployment: Iovance Biotherapeutics, Cellerant Therapeutics Rodney Van SyocEmployment: PTC Therapeutics, BioElectron Ramkumar MandalamEmployment: Cellerant TherapeuticsLeadership: Cellerant TherapeuticsStock and Other Ownership Interests: Cellerant TherapeuticsPatents, Royalties, Other Intellectual Property: Hold a patent (Cellerant Therapeutics) Camille N. AbboudStock and Other Ownership Interests: AbbVie, Abbott Laboratories, Gilead Sciences, Bristol Myers Squibb, Johnson & JohnsonConsulting or Advisory Role: ArcherDXSpeakers' Bureau: Jazz PharmaceuticalsResearch Funding: Actinium Pharmaceuticals, Selvita, Forty Seven Farhad RavandiHonoraria: Amgen, Pfizer, Astellas Pharma, Orsenix, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: Amgen, Astellas Pharma, Orsenix, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara IncResearch Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, CellerantNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. G-CSF, granulocyte colony-stimulating factor; HiDAC, high-dose cytarabine.

FIG 2.

Schematic figure of romyelocel-L administration. ANC, absolute neutrophil count; G-CSF, granulocyte colony-stimulating factor.

FIG 3.

Incidence of infection relative to day of infusion or day 9 for control subjects during induction. The figure shows the number of nonminor MDIs or CDIs of a bacterial or fungal cause onset relative to the day of infusion (day 9 for G-CSF alone subjects) for each type of chemotherapy: (A) 7 + 3, (B) HiDAC, and (C) pooled. The vertical lines indicate the infusion day, 6 days after infusion, and 19 days after infusion. CDI, clinically diagnosed infection; G-CSF, granulocyte colony-stimulating factor; HiDAC, high-dose cytarabine; MDI, microbiologically defined infection.

FIG A1.

Classification of incidence of infections in the evaluable population: (A) 7 + 3 arm and (B) HiDAC arm. Each nonminor MDI or CDI in the evaluable population was classified. Infections in the control arm are shown in black, whereas the treatment arm is shown in blue. The onset date of the infection was diagnosed by the IAC and the brackets indicate the time frame of romyelocel-L infusion. A complete listing of all infections is described in the Data Supplement. CDI, clinically diagnosed infection; HiDAC, high-dose cytarabine; IAC, independent, adjudication committee; MDI, microbiologically defined infection; SSTI, skin and soft tissue; UTI, urinary tract infection.