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Clinical Trial
. 2023 May 4;141(18):2194-2205.
doi: 10.1182/blood.2022018254.

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL

Jia Ruan  1 , Alison Moskowitz  2 , Neha Mehta-Shah  3 , Lubomir Sokol  4 , Zhengming Chen  1 , Nikita Kotlov  5 , Grigorii Nos  5 , Maria Sorokina  5 , Vladislav Maksimov  5 , Andrea Sboner  1 , Michael Sigouros  1 , Koen van Besien  1 , Steven Horwitz  2 , Sarah C Rutherford  1 , Erin Mulvey  1 , Maria V Revuelta  1 , Jenny Xiang  1 , Alicia Alonso  1 , Ari Melnick  1 , Olivier Elemento  1 , Giorgio Inghirami  1 , John P Leonard  1 , Leandro Cerchietti  1 , Peter Martin  1
Affiliations
Clinical Trial

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL

Jia Ruan et al. Blood. .

Abstract

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (OS) was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5%, and 23.5%, respectively, with TET2 mutations significantly associated with CR (P = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266.

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Conflict of interest statement

Conflict-of-interest disclosure: J.R. has received research support from BMS/Celgene, AstraZeneca, Genentech, Daiichi Sankyo, Pharmacyclics, and Seattle Genetics, as well as honorarium for service as a consultant for BMS/Celgene, Seattle Genetics, Secura Bio, Daiichi Sankyo, AstraZeneca, and Kite Pharma. A.M. has received research support from ADC Therapeutics, BeiGene, Miragen, Seattle Genetics, Merck, Bristol-Myers Squibb, Incyte, and SecuraBio, as well as honorarium for service as a consultant for Affimed, Imbrium Therapeutics L.P./Purdue, Janpix Ltd, Merck, Seattle Genetics, and Takeda. N.M.-S. has received research support from AstraZeneca, Bristol-Myers Squibb, Celgene, C4 Therapeutics, Corvus Pharmaceuticals, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Secura Bio/Verastem, as well as honorarium for service as a consultant for Secura Bio/Verastem, Daiichi Sankyo, C4 Therapeutics, Genentech, Karyopharm Therapeutics, Kyowa Hakko Kirin, and Ono pharmaceuticals. L.S. has received research support from Kyowa-Kirin, and EUSA Pharma, as well as honorarium for service as a consultant for Kyowa-Kirin, Daiichi Sankyo, Dren-Bio, and Secura Bio. S.H. has received research support from ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, C4, and Verastem/SecuraBio, as well as honorarium for service as a consultant for Affimed, Abcuro, Cimieo Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, ONO Pharmaceuticals, SecuraBio, Shoreline Biosciences, Inc, Takeda, Yingli Pharma Limited, Auxilius Pharma, Myeloid Therapeutics, Acrotech, and Tubulis. S.C.R. has received research support from Genentech and Karyopharm, as well as honorarium for service as a consultant for ADC Therapeutics, Genmab, Karyopharm, Kite, and Seagen. P.M. has served as a consultant for AstraZeneca, BeiGene, BMS/Celgene, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, and Takeda. J.P.L. has received research support from Janssen, Genentech, Epizyme, the Leukemia and Lymphoma Society, as well as honorarium for service as a consult for AbbVie, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Calithera, Constellation, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Janssen, Karyopharm, Merck, Mustang Bio, Pfizer, Roche/Genentech, Second Genome, Sutro, and Caribou Biosciences. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study treatment schema and flowchart. (A) The study schema. Treatment consisted of standard dose CHOP given on day 1 of each cycle for 6 cycles. Oral azacitidine (CC-486) at 300 mg daily was administered for 7 days before cycle 1 of CHOP, and for 14 days before CHOP cycles 2 to 6. Growth factor such as pegfilgrastim was mandatory after CHOP. (B) The study flowchart. Of the 21 patients enrolled, 20 completed 3 cycles of study treatment, and 18 completed 6 cycles. Ten patients received consolidative SCT. EOT, end of treatment.
Figure 2.
Figure 2.
Treatment responses. (A) Cutaneous response after 7-day CC-486 priming before CHOP chemotherapy in a study subject with biopsy-proven skin involvement by AITL. (B) PET/CT response at interim assessment after treatment with 3 cycles of CC-486 plus CHOP in a study subject. (C) Waterfall plot of interim and end-of-treatment response assessment in 20 evaluable subjects. PET/CT, positron emission tomography/computed tomography.
Figure 3.
Figure 3.
Kaplan-Meier survival curves. (A-B) OS for all patients (A) and PTCL-TFH subset (B). (C-D) PFS for all patients (C) and PTCL-TFH subset (D).
Figure 4.
Figure 4.
Genomic and transcriptomic analyses. (A) Oncoprint plot with driver mutations landscape in PTCL cohort. Each sample is shown on the x-axis, with 4 major driver mutations on the y-axis. Different colors depict different types of mutations. (B) Lollipop plots representing distribution of 4 major driver genes. All amino acid positions are depicted on the x-axis, with colored blocks representing protein domains. (C) Clonal evolution analysis of longitudinal biopsy samples from patient with relapsed disease. x-axis denotes putative time points of mutation emergence, and real time points of the biopsies. Main clone is colored with green, 2 subclones with red and yellow. (D) Volcano plot of differential gene expression in paired tumor specimens before (C1D-6) and after Aza priming (C1D1) by RNA sequencing analysis. (E) Waterfall plot with differentially expressed gene set terms. Each bar represents a gene set, red stands for upregulated gene set, and blue stands for downregulated gene set. Upregulated and downregulated genes were subjected to gene set enrichment analysis. Top DEG with bonferroni-adjusted P value < .05 and absolute log2FC higher than 1.
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