ABSTRACT
Bcell lymphoma is difficult to cure because of its biological and clinical heterogeneity, and due to native chemoresistance. Immunotherapies that overcome cancerinduced immune evasion have been the center of recent developments in oncology. This is emphasized by the accomplishment of various agents that disrupt programmed cell death protein 1 (PD1)mediated immune suppression in diverse tumors. However, while PD1 blockade has been effective in numerous malignancies, a significant proportion of cancers, including Bcell lymphoma, show certain rates of primary resistance to these therapeutic strategies. Histone deacetylase inhibitors (HDACis) have exhibited anticancer activity though suppressing cell proliferation, inducing differentiation and triggering apoptosis. The present study aimed to explore a therapeutic strategy combining a HDACi (romidepsin) and PD1 blockade (BMS1) in Bcell lymphoma, utilizing a constructed mouse model of Bcell lymphoma. The IC50 of the two inhibitors was confirmed by MTT assay, and their inhibitory effects were revealed to be dose and timedependent. The data demonstrated that the combined treatment of romidepsin and BMS1 synergistically inhibited the growth of Bcell lymphoma. Furthermore, it was revealed that romidepsin and BMS1 synergistically triggered apoptosis in mouse Bcell lymphoma. The synergistic effect of these agents was capable of activating tumorinfiltrating lymphocytes, particularly CD3+CD4+ and CD3+CD8+ T cells. The results of the present study underscore the potential of HDAC inhibition in conjunction with PD1 blockade as a novel therapeutic approach for Bcell lymphoma, highlighting the synergistic effects of these two mechanisms in enhancing antitumor immunity.
Subject(s)
Apoptosis , Depsipeptides , Drug Synergism , Histone Deacetylase Inhibitors , Lymphoma, B-Cell , Programmed Cell Death 1 Receptor , Animals , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Apoptosis/drug effects , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Depsipeptides/administration & dosage , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/pathology , Humans , Cell Line, Tumor , Cell Proliferation/drug effects , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Disease Models, Animal , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Disease Progression , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL. METHODS: Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375). FINDINGS: 86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown). INTERPRETATION: Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial. FUNDING: Bristol-Myers Squibb. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Subject(s)
Azacitidine , Humans , Male , Female , Aged , Middle Aged , Azacitidine/therapeutic use , Azacitidine/adverse effects , Azacitidine/administration & dosage , Administration, Oral , Bendamustine Hydrochloride/therapeutic use , Bendamustine Hydrochloride/administration & dosage , Bendamustine Hydrochloride/adverse effects , Gemcitabine , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/mortality , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Depsipeptides/therapeutic use , Depsipeptides/adverse effects , Depsipeptides/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/administration & dosage , Aged, 80 and overABSTRACT
Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT01947140).
Subject(s)
Aminopterin , Antineoplastic Combined Chemotherapy Protocols , Depsipeptides , Histone Deacetylase Inhibitors , Lymphoma, T-Cell , Humans , Aminopterin/analogs & derivatives , Aminopterin/therapeutic use , Aminopterin/administration & dosage , Aminopterin/adverse effects , Depsipeptides/administration & dosage , Depsipeptides/adverse effects , Depsipeptides/therapeutic use , Male , Middle Aged , Female , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/pathology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/administration & dosage , Treatment Outcome , Folic Acid Antagonists/therapeutic use , Folic Acid Antagonists/adverse effects , Folic Acid Antagonists/administration & dosage , Aged, 80 and overABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Ro-CHOP phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT01796002) established that romidepsin (Ro) plus cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) did not yield an increased efficacy compared with CHOP alone as first-line treatment of peripheral T-cell lymphoma. We report the planned final analysis 5 years after the last patient enrolled. With a median follow-up of 6 years, median progression-free survival (PFS) was 12.0 months compared with 10.2 months (hazard ratio [HR], 0.79 [95% CI, 0.62 to 1.005]; P = .054), while median overall survival was 62.2 months (35.7-86.6 months) and 43.8 months (30.1-70.2 months; HR, 0.88 [95% CI, 0.68 to 1.14]; P = .324) in the Ro-CHOP and CHOP arms, respectively. In an exploratory analysis, the median PFS in the centrally reviewed follicular helper T-cell lymphoma subgroup was significantly longer in the Ro-CHOP arm (19.5 v 10.6 months, HR, 0.703 [95% CI, 0.502 to 0.985]; P = .039). Second-line treatments were given to 251 patients with a median PFS2 and OS2 after relapse or progression of 3.3 months and 11.5 months, respectively. Within the limits of highly heterogeneous second-line treatments, no specific regimen seemed to provide superior disease control. However, a potential benefit was observed with brentuximab vedotin in association with chemotherapy even after excluding anaplastic large-cell lymphoma subtype or after adjusting for histology and international prognostic index in a multivariate model (HR for PFS, 0.431 [95% CI, 0.238 to 0.779]; P = .005).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cyclophosphamide , Depsipeptides , Doxorubicin , Lymphoma, T-Cell, Peripheral , Prednisone , Vincristine , Humans , Lymphoma, T-Cell, Peripheral/drug therapy , Lymphoma, T-Cell, Peripheral/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Vincristine/administration & dosage , Vincristine/therapeutic use , Prednisone/administration & dosage , Prednisone/therapeutic use , Depsipeptides/administration & dosage , Depsipeptides/therapeutic use , Middle Aged , Male , Female , Aged , Adult , Progression-Free SurvivalABSTRACT
Cutaneous T-cell lymphomas are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T-cells. A distinctive clinical feature of cutaneous T-cell lymphomas is their sensitivity to treatment with histone deacetylase inhibitors. However, responses to histone deacetylase inhibitor therapy are universally transient and noncurative, highlighting the need for effective and durable drug combinations. In this study, we demonstrate that the combination of romidepsin, a selective class I histone deacetylase inhibitor, with afatinib, an EGFR family inhibitor, induces strongly synergistic antitumor effects in cutaneous T-cell lymphoma models in vitro and in vivo through abrogation of Jak-signal transducer and activator of transcription signaling. These results support a previously unrecognized potential role for histone deacetylase inhibitor plus afatinib combination in the treatment of cutaneous T-cell lymphomas.