Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Untreated Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a rare and highly heterogeneous group of hematologic malignancies, belonging to the T-cell tumor category of non-Hodgkin lymphoma (NHL). Compared to B-cell tumors, current understanding of T-cell leukemia and lymphoma remains relatively underdeveloped, and a significant proportion of patients are diagnosed at an advanced stage. Therefore, PTCL patients have not experienced the same level of prognostic improvement over the past 20 to 30 years. In recent years, however, with a deeper understanding of the molecular pathogenesis of PTCLs and the approval of numerous new drugs (including various epigenetic modifiers and biologics), the prognosis for T-cell lymphoma patients may be further improved.

Although histone deacetylase inhibitors (HDACi), PD-1/PD-L1 inhibitors, EZH2 inhibitors, and demethylating agents have made some progress in clinical research on PTCLs, their clinical application still relies heavily on CHOP-based chemotherapy regimens. A study of 239 patients with localized nodular PTCL showed that among patients receiving CHOP-like therapy ± radiotherapy, the 5-year overall survival (OS) was 58%, and the 5-year progression-free survival (PFS) was 53%. Multivariate analysis indicated that age ≥60 years and presence of B symptoms at onset were poor prognostic factors, while ALK-positive anaplastic large T-cell lymphoma had a better prognosis. Therefore, for elderly PTCL patients, there is an urgent need to find a low-toxicity, tolerable, and effective basic chemotherapy regimen.

Aclarubicin (Acla) is an anthracycline anticancer drug. In vitro, Acla has demonstrated potent cytotoxicity against various lymphoma and T-lymphocytic leukemia cell lines. Mechanistic studies of anthracyclines have revealed that doxorubicin, epirubicin, daunorubicin, and idarubicin all induce tumor cell apoptosis through two mechanisms: 1. DNA damage: through inhibition of topoisomerase II (Topo II), leading to DNA double-strand breaks (DSBs); and 2. Chromatin damage: through histone removal, causing chromatin alterations at specific genomic loci. However, these dual mechanisms also lead to dose-dependent, irreversible cardiotoxicity. Compared with classic anthracyclines (such as doxorubicin and daunorubicin), Acla does not cause DNA damage and accumulates significantly in lymphoid tissues (spleen, thymus, and lymph nodes), with poor distribution to other tissues. Consequently, its cardiotoxicity is significantly reduced. Even at high cumulative doses, it is less likely to cause cardiac dysfunction. Therefore, Acla may offer a safer option for elderly patients or those with concomitant heart disease. Previous studies have shown that the combination of Acla and cytarabine (such as the CAG regimen) has some efficacy and is well tolerated in relapsed/refractory and elderly patients with acute myeloid leukemia. In the 1980s and 1990s, studies explored the use of Acla in chemotherapy regimens for non-Hodgkin's lymphoma and Hodgkin's lymphoma, demonstrating some activity. Small studies have shown that Acla monotherapy can achieve a response rate of approximately 30% in patients with advanced non-hedging lymphoma, without compromising cardiac function. Japanese researchers have found that combination chemotherapy regimens containing Acla in T-cell lymphomas exhibit superior efficacy.

In this study, the investigators will replace doxorubicin in the traditional CHOP regimen with aclarubicin, which has good efficacy and low cardiotoxicity, to create a novel CAOP (aclarubicin, cyclophosphamide, vincristine, and prednisone) regimen for elderly patients newly diagnosed with PTCL. This combination chemotherapy regimen may improve efficacy while also considering tolerability and safety, providing a new treatment option for elderly patients with PTCLs.