Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL Journal Article
| Authors: | Ruan, J.; Moskowitz, A.; Mehta-Shah, N.; Sokol, L.; Chen, Z.; Kotlov, N.; Nos, G.; Sorokina, M.; Maksimov, V.; Sboner, A.; Sigouros, M.; van Besien, K.; Horwitz, S.; Rutherford, S. C.; Mulvey, E.; Revuelta, M. V.; Xiang, J.; Alonso, A.; Melnick, A.; Elemento, O.; Inghirami, G.; Leonard, J. P.; Cerchietti, L.; Martin, P. |
| Article Title: | Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL |
| 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. © 2023 The American Society of Hematology |
| Keywords: | immunohistochemistry; adult; cancer survival; clinical article; controlled study; treatment response; overall survival; promoter region; prednisone; clinical trial; constipation; fatigue; neutropenia; doxorubicin; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; methotrexate; cancer staging; follow up; antineoplastic agent; cancer grading; anorexia; ki 67 antigen; antigen expression; cell proliferation; phenotype; interleukin 2; edema; progression free survival; phase 2 clinical trial; gene expression; neuropathy; thrombocytopenia; antineoplastic combined chemotherapy protocols; myalgia; genetic association; cyclophosphamide; vincristine; cell differentiation; pathology; dna methylation; abdominal pain; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; coughing; dizziness; febrile neutropenia; fever; hyperglycemia; pneumonia; pruritus; rash; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; chemotherapy induced emesis; hypoalbuminemia; hyponatremia; hypotension; t lymphocyte receptor; peripheral t cell lymphoma; bone marrow biopsy; cpg island; multicenter study; remission; rhoa guanine nucleotide binding protein; world health organization; lactate dehydrogenase; alkaline phosphatase blood level; upregulation; headache; protein bcl 6; immunologic factors; point mutation; alopecia; good clinical practice; granulocyte colony stimulating factor; disease exacerbation; lactate dehydrogenase blood level; cd30 ligand; azacitidine; immunologic factor; creatinine clearance; dysgeusia; hypocalcemia; tumor necrosis factor; cellulitis; common acute lymphoblastic leukemia antigen; dna methyltransferase 3a; international prognostic index; tumor microenvironment; lymphoma, t-cell, peripheral; rna methylation; pegfilgrastim; macrophage activation; chemokine receptor ccr5; b lymphocyte activation; influenza a; isocitrate dehydrogenase 2; chemotherapy induced anemia; humans; human; male; female; article; rna sequencing; whole exome sequencing; cxcl13 chemokine; positron emission tomography-computed tomography; tumor necrosis factor receptor superfamily member 8; cc-486; chemotherapy induced nausea; coronavirus disease 2019; strongyloides hyperinfection syndrome |
| Journal Title: | Blood |
| Volume: | 141 |
| Issue: | 18 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2023-05-04 |
| Start Page: | 2194 |
| End Page: | 2205 |
| Language: | English |
| DOI: | 10.1182/blood.2022018254 |
| PUBMED: | 36796016 |
| PROVIDER: | scopus |
| PMCID: | PMC10356559 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in PubMed and PDF -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work