Advances in the treatment of peripheral T-cell lymphoma

　　Peripheral T-cell lymphoma (PTCL) is a group of malignant neoplasms of the lymphatic system originating from post thymic mature T lymphocytes or natural killer (NK) cells, mainly including: peripheral T-cell lymphoma non-specific (PTCL-NOS), angioimmunoblast T-cell lymphoma (AITL) , NK/T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), ALK(+) mesenchymal large cell lymphoma (ALCL), ALCL with ALK(-), enteropathic T-cell lymphoma (ETTL) and hepatosplenic T-cell lymphoma (HSTCL).　　The low incidence of PTCL disease, large geographical differences, marked heterogeneity in the biological behavior and clinical manifestations of each subtype, and few randomized clinical trials have led to slow progress in research on related treatments. Overall, compared with B-cell lymphoma, PTCL is more aggressive, has a worse prognosis, and lacks a unified standard treatment protocol for treatment, and is therefore becoming the most cutting-edge and challenging research area in lymphoma treatment. In recent years, as the understanding of the biological nature, disease characteristics, and heterogeneity of each subtype of PTCL has improved, new drugs with different mechanisms of action have been developed and applied in the clinic, and the treatment plan and strategy for each subtype have become more and more individualized.　　(i) Limitations of CHOP or CHOP-like regimens It is well known that PTCL, a typical representative of aggressive lymphoma, has been treated with first-line regimens and treatment strategies similar to those for aggressive B-cell lymphoma in previous conventional treatments. Anthracycline-containing chemotherapy regimens such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) or CHOP-like regimens have been considered the logical first choice for the treatment of PTCL. However, several retrospective studies have shown that the efficacy of CHOP or CHOP-like regimens for most PTCL is not satisfactory, and 5-year overall survival (OS) rates often struggle to exceed 30%, with the exception of ALCL, all of which are significantly lower than those for B-cell lymphoma [1,2]. In the International PTCL clinical and pathologic review project, a retrospective analysis of 1153 PTCL cases in 22 countries, except for ALK(+) ALCL, which was found to be more effective, anthracycline-containing regimens were less effective in the treatment of patients with PTCL-NOS and AITL, and there was no significant difference in the efficacy between anthracycline-based and non-anthracycline-based regimens difference [3]. In a retrospective study conducted at the British Columbia Cancer Agency, among PTCL patients treated with CHOP or CHOP-like regimen chemotherapy, the 5-year OS rate was higher in the low-risk group of patients with an International Prognostic Index (IPI) of 0 or 1 (64%) than in the high-risk group with an IPI ≥ 2 (only 22%).The prognosis of ALK-positive ALCL patients was better than that of ALK-negative ALCL patients ( 5-year OS was 58% versus 34%, respectively) [4].　　In conclusion, CHOP or CHOP-like regimens can be considered as first-line treatment options for patients with low-risk PTCL (ALK-positive ALCL and PTCL-NOS patients with 0-1 adverse factors), but there is a strong need to explore new treatment options for patients with intermediate- to high-risk PTCL (ALK-negative ALCL and other non-ALCL patients with more than 1 adverse factor).　　(ii) Exploration of dose-intensity regimens Based on the limitations of CHOP or CHOP-like regimens for the treatment of PTCL, many investigators have attempted to improve the efficacy by increasing the dose-intensity of chemotherapy (by increasing the dose administered, dose intensification, increasing the drug combination, or changing the mode of administration). Most of these studies are from the United States and Europe, and although the specific study designs, case characteristics, and treatment regimens differ, the U.S. studies are mostly negative, whereas the European studies appear to show the feasibility of dose-intensity regimens.　　First, the classical clinical study of the Southeast Collaborative Group (SWOG) in the United States (containing some PTCL) showed that third-generation dose-intensity regimens (m-BACOD, ProMACE-CytaBOM, and MACOP-B regimens) did not show a survival advantage compared with CHOP regimens [5]. Second, a retrospective study at the M.D. Anderson Cancer Center in the United States [6] showed that a total of 135 non-ALCL PTCL patients treated with Hyper-CVAD (cyclophosphamide, methotrexate, doxorubicin, vincristine, prednisone, methotrexate, algocytosine), M-BACOS (bleomycin, doxorubicin, cyclophosphamide, vincristine, methyl M-BACOS (bleomycin, doxorubicin, cyclophosphamide, vincristine, methylprednisolone, methotrexate), ASHOP (doxorubicin, methylprednisolone, cytarabine, cisplatin), and MINE (isocyclophosphamide, methotrexate, mitoxantrone, etoposide) were not significantly different from those on the CHOP regimen in terms of complete remission (CR) or significant survival benefit (3-year OS rate of 49% vs. 43 %). However, the GELA trial reported in 2003 compared the efficacy of the ACVBP regimen (cyclophosphamide + doxorubicin + vincristine + bleomycin + prednisone) with the CHOP regimen for the treatment of elderly PTCL and found an improvement in 5-year OS (46% vs. 38%) and Event Free Survival (EFS) (39% vs. 29%) in patients [7]. In the German Study Group on Non-Hodgkin’s Lymphoma (DSHNHL) in the Aggressive PTCL study [4,8], 300 patients with PTCL were randomized into four groups and given CHOP-14, CHOP-21, CHOEP-14 and CHOEP-21 regimens, respectively. The results showed that in older patients, neither OS nor EFS was significantly improved by shortening the chemotherapy interval or increasing etoposide; however, CR rate and EFS were improved in younger patients. In particular, in young ALCL patients with good prognostic factors, the 3-year EFS rate was 71% with the CHOEP regimen compared with 50% with the CHOP regimen (P=0.01). A phase I dose-tolerant clinical trial of CHOEP-21 was conducted at the Cancer Hospital of Chinese Academy of Medical Sciences, and the results showed that the dose of VP-16 in the 3-week CHOEP regimen tolerated by the national population was a total of 200 mg/m2 applied over 3 days based on the dose level of the standard CHOP regimen, and the regimen was safe and feasible with G-CSF support.　　In fact, although the exploration of dose-intensity regimens for PTCL is currently being explored with great caution, it would be inappropriate to beat a stick to death. We should see that the patients analyzed in the relevant studies may themselves have a poor prognosis, and with the lack of randomized large sample studies, it is not surprising that negative results were obtained. Objectively speaking, the exploration of dose-intensity regimens requires longer follow-up high-quality studies.　　(iii) High-dose chemotherapy combined with autologous hematopoietic stem cell transplantation Autologous hematopoietic stem cell transplantation (ASCT)/high-dose chemotherapy (HDC) is currently recommended for first-line consolidation/intensification or second-line salvage therapy in PTCL. Several retrospective and prospective clinical studies have explored the efficacy of ASCT treatment in PTCL patients who achieved CR/PR after induction chemotherapy. The Spanish GEL-TAMO study [9] retrospectively analyzed 115 patients treated in multiple centers over a total of 10 years. 5-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 60%, respectively. The predominant pathological type of patients was PTCL-NOS (62.6%), followed by ALCL (22%). 37 patients (32%) underwent HDT-ASCT in first complete remission (CR1), with 5-year OS and DFS of 80% and 79%, respectively, and none of the patients surviving for more than 2 years relapsed. In the above study, there were no other good prognostic factors for patients in stage CR1 except for the median age of 31 years, and 73% of them had aaIPI scores of 2-3. MD Anderson Cancer Center, USA, reported and retrospectively analyzed a total of 126 patients with PTCL between 1986 and 2009 at the 11th International Conference on Lymphoma (11-ICML) this year (42 cases of PTCL-NOS, 38 cases of ALK-negative ALCL, 9 cases of ALK-positive ALCL, 15 cases of AITL, 6 cases of NK/T-cell lymphoma. (HSTCL 6 cases, other 10 cases) treated with ASCT with a median age of 49 (18-75) years and 65% male. Pre-transplant CR1 accounted for 33%, sensitive relapse for 51%, refractory resistant patients for 16%, and pretreatment was mainly with BEAM or BEAM-like regimens (82%). At a median follow-up of 39 months, actual OS and PFS were 39% and 30%, and treatment-related death was 3%. post-transplant outcomes were best in CR1 patients with 4-year OS and PFS of 87% and 67%, and in sensitive relapsed and refractory patients with 4-year OS and PFS of 39% and 36%, 24% and 15%, respectively, P<0.05. PTCL-NOS, ALCL, AITL , NK/T, and T-LBL had 4-year PFS of 48%, 38%, 37%, 67%, and 14% for different disease types, respectively. The study concluded that this is the largest sample of single-center data available, confirming the value of ASCT in first-line consolidation/intensive therapy for PTCL. the results of the largest prospective multicenter phase II clinical trial study exploring the effects of first-line ASCT for PTCL were reported in 2009 [10]. Patients enrolled were given DexaBEAM or ESHAP regimens for induction and stem cell collection after 4-6 courses of CHOP. Patients in complete or partial remission received clear-cut radiotherapy and chemotherapy (hyper-segmented systemic radiotherapy and high-dose cyclophosphamide therapy) followed by autologous stem cell transplantation. A total of 83 patients were enrolled in this study, 32 with PTCL-NOS and 27 with AITL. 55 of the 83 patients received transplantation (66%), and the main reason for not receiving transplantation was disease progression. The analysis showed an overall effective rate (ORR) of 66% (56% CR) in patients who received marrow clearing therapy. A median of 43 patients survived after 33 months of follow-up. Patients who achieved complete remission had 3-year OS and 3-year progression-free survival (PFS) rates of 53% and 36%, respectively. The results of this study show definite efficacy of first-line autologous stem cell transplantation, but randomized clinical trials are needed to demonstrate this, and further improvements in pre-transplantation therapy are needed to improve the transplantability rate. From 1990 to 2008, a total of 46 patients with PTCL were treated with ASCT after CR1/PR1, including 30 with PTCL-NOS, 11 with ALCL, and 5 with other pathological types, at the Cancer Hospital of Chinese Academy of Medical Sciences. At a median follow-up of 34.8 months, the 3-year PFS and OS were 53.8% and 60.7%, respectively.　　(iv) Graft-versus-lymphoma effect of allogeneic hematopoietic stem cell transplantation Allogeneic transplantation (Allo-HSCT) is currently considered an effective salvage therapy for refractory/relapsed malignant lymphoma based on the following theories: (i) allogeneic-derived stem cells do not contain tumor cells, thus resulting in a much lower relapse rate of the disease after transplantation; and (ii) graft-versus-lymphoma effect (GVL). Although the relapse rate after allogeneic transplantation is lower than that of autologous stem cell transplantation, its treatment-related mortality rate (TRM) is relatively high. It has been proposed that autologous stem cell transplantation followed by non-cleared marrow Allo-HSCT is expected to reduce TRM while preserving its GVL effect as much as possible.Paolo Corradini et al. conducted a phase II clinical study to evaluate the place of the reduced pretreatment regimen (RIC) in the treatment of PTCL [11].Seventeen patients were resistant or relapsed, eight of whom were autologous stem cell relapsed after transplantation, and a non-clearing pretreatment regimen containing fodarabine was used. At a median follow-up of 28 months, 14 patients were alive (12 CR, 1 PR, 1 stable); 2 patients died of disease progression and 1 died of GVHD-related sepsis. 3-year OS and PFS were 81% and 64%, respectively. 2 patients who developed disease progression after transplantation achieved remission after receiving donor lymphocyte infusion (DLI). Despite the limited number of cases in the above study, the results suggest that RIC-Allo-HSCT is feasible and effective in the treatment of PTCL.11-ICML Conference Update Report DSHNHL-R3 study data, a total of 66 (23 PTCL-NOS, 12 AITL, 11 ALCL, 6 T-LBL, 7 T-PLL, 7 others) relapsed Patients with refractory T-cell lymphoma with allogeneic peripheral blood stem cell transplantation (33 related donors and 33 unrelated donors), pretreated mainly with the FBC-12 (fodarabine + maricylan + cyclophosphamide) regimen, had a group-wide TRM of 29% (19/66) and a median follow-up of 12 months with OS and DFS of 48% and 46%. This study showed that a significant proportion of patients with relapsed refractory T-cell lymphoma achieved longer sustained remission with Allo-HSCT, even though some of the post-transplant relapsed patients were also able to regain remission with immunomodulatory therapy such as DLI (exploiting the GVL effect).　　The development and application of new drugs (i) New chemotherapeutic agents and their combination regimens 1. Gemcitabine Gemcitabine (gemcitabin) is a less toxic pyrimidine analogue that inhibits ribonucleotide reductase and DNA synthesis by competing with natural cytosine. Several studies have shown that gemcitabine has shown good efficacy both as monotherapy and in combination, both as first-line treatment and for patients with relapsed and refractory PTCL [12-14]. The overall effective rate (ORR) regarding gemcitabine monotherapy in relapsed/refractory PTCL ranged from 60% to 69%, with a CR rate of 8% to 20%. The main gemcitabine-containing combination chemotherapy regimens that have been investigated in recent years for the treatment of primary/relapsed PTCL include GEM-P (gemcitabine, cisplatin, methylprednisolone), VGF (gemcitabine, vincristine, filgrastim), CHOP-EG (cyclophosphamide, adriamycin, vincristine, prednisone, pegylated glycosides and gemcitabine), PEGS (cisplatin, pegylated glycosides, gemcitabine and methylprednisolone), and PEGS (cisplatin, pegylated glycosides, gemcitabine and methylprednisolone). and methylprednisolone) regimens, etc., were mainly small sample studies with an ORR of about 70% and a CR rate of about 20%. Therefore, gemcitabine-based combination regimens are expected to be a new strategy for the treatment of PTCL, but they must be confirmed in multicenter randomized controlled studies.　　2. Pralatrexate Pralatrexate is a new folic acid antagonist that increases tyrosine multimerization, increases cellular drug uptake and prolongs the duration of drug action in tumor cells due to its high affinity for reduced folic acid type 1 carrier (RFC-1) protein, thus increasing drug concentrations in tumor cells [15]. In a phase I/II clinical study Pralatrexate was used to treat multiple types of relapsed and drug-resistant NHL [16], enrolling a total of 54 patients. Its overall objective remission in 22 T-cell NHL was 45%, 6 CR, and 4 PR, whereas in B-cell NHL, the ORR was only 10%. In a larger clinical study [17], 109 patients with relapsed and resistant PTCL with evaluable efficacy, pathological types included 53% PTCL-NOS, 15% ALCL, 12% AITL, 11% transformed MF and 7% others. The results obtained 27% ORR (11% CR) with a mean duration of efficacy of 287 days (9.4 months). The main adverse effects were mucositis (21%) and thrombocytopenia (33%), and most stomatitis was relieved by folic acid and vitamin B12 supplementation. A recent non-randomized, open, multicenter study showed that Pralatrexate treated 65 patients with relapsed refractory T-cell lymphoma, 29 of whom achieved remission. Considering that preclinical studies have found synergistic effects of Pralatrexate and gemcitabine in vitro, encouraging results are expected from clinical trials using the combination of Pralatrexate and gemcitabine in relapsed refractory NHL, including T-cell lymphoma [14].　　3. Bendamustine Bendamustine has received much attention in recent years due to its highly significant efficacy in the treatment of inert lymphomas, and preclinical studies have shown that it also has considerable antitumor activity in T-cell lymphomas. The French BENTLY study at the 11-ICML meeting recently reported its therapeutic efficacy against relapsed drug-resistant PTCL in 47 patients (17 PTCL-NOS, 24 AITL, 4 ALCL, 1 EATL, 1 MF) with a median age of 64 (38-87) years, 87% stage III/IV patients, 76% extra-nodal involvement, and a median prior treatment regimen was 2 (1-3), 7 patients had recurrence after ASCT, and 83% of patients had received previous treatment with CHOP or CHOP-like regimen. The study protocol was bendamustine 120 mg/m2 x 2 days (1 hour IV infusion) every 21 days, with efficacy evaluated every 3 cycles, and CR/PR/SD patients could continue to receive up to 6 cycles. 28 patients completed ≥3 cycles of treatment. The ORR was 42% (23% CR, 19% PR) for the whole group, 50% (25% CR, 25% PR) for AITL patients, 35% (23% CR, 12% PR) for PTCL-NOS patients, and a median duration of efficacy (DOR) of 11.9 months for CR/PR patients; the main hematologic toxicities of degree 3/4 were neutrophil The 3/4 degree hematologic toxicity was mainly neutrophil reduction by 49% and platelet reduction by 36%, and the 3/4 degree non-hematologic toxicity was mainly 34% infection, 11% skin toxicity, 6% cardiac toxicity, and 6% mucositis. This study showed that bendamustine is a proven therapeutic agent for relapse-resistant PTCL with acceptable toxicity, and the combination with other drugs is expected.　　(ii) Histone deacetylase inhibitors (HDACi) Histone deacetylase inhibitors (HDACi), a new class of antitumor agents, can induce cell differentiation, apoptosis and reduce cell proliferation by increasing the acetylation of histones.Vorinostat, Romidepsin and Vorinostat was the first HDACi approved by the US FDA for the treatment of refractory cutaneous T-cell lymphoma (CTCL).In a number of phase IIb multicenter trials of relapsed and refractory CTCL, patients were treated orally with Vorinostat, Romidepsin and Belinostat. The most common toxicities were gastrointestinal adverse effects and thrombocytopenia. Romidepsin 14 mg/m2 (d1, 8, 15, 28-day cycles) showed an ORR of 31% with a median DOR of 9 months; 4 CRs (median DOR of 34 months), 11 PRs, and 7 stable diseasse (SD). The most common toxic reactions were bone marrow suppression, fatigue, nausea and loss of appetite. In addition, another HDACi, Belinostat (PXD101), is currently in clinical studies in CTCL and PTCL, and phase I clinical trials have shown that Belinostat is well tolerated by patients. The interim results of an ongoing phase II clinical trial showed that 2 of 11 patients with PTCL (both PTCL-NOS subtypes) had CR and 5 had SD. It is worth noting that HDACi can cause prolongation of the QT interval and has potential cardiotoxicity, but the incidence of this adverse effect is less than 5% with respect to the results of published clinical trials so far. Selective HDAC inhibitors are still under development.　　(In T-cell NHL, a variety of surface molecules have been identified as therapeutic targets for monoclonal antibodies, including: CCR4, CD2, CD4, CD5, CD7, CD25, CD30 and CD52. With the exception of CD52, the expression of other surface antigen molecules can vary significantly across PTCL subtypes, making the treatment with monoclonal antibodies against these targets more selective and less toxic.　　CD52 is a cell surface glycoprotein that is expressed on the surface of almost all lymphocytes, including T cells, B cells, and natural killer cells, as well as monocytes and sperm cells. Alemtuzumab (Alemtuzumab), a humanized anti-CD52 monoclonal antibody, has a potent killing effect on CD52-expressing positive cells, so alemtuzumab can cause a general deficiency of T cells, B cells, and monocytes, inducing severe immunosuppression. The efficacy of alemtuzumab in lymphatic system tumors was first demonstrated in B-cell chronic lymphocytic leukemia (B-CLL) and has since been reported to have activity in CTCL, T-cell leukemia, and PTCL as well. In one of the first global clinical studies conducted in Europe [22], alemtuzumab monotherapy resulted in a 36% remission rate in relapsed and resistant PTCL after multiple treatments, but was associated with severe hematologic toxicity and infections. Alemtuzumab in combination with CHOP regimens is recently being used in the treatment of patients with PTCL and has shown significant efficacy. However, immunosuppression becomes a concern with the addition of alemtuzumab to cytotoxic chemotherapy regimens, with lymphopenia and neutropenia being the most common treatment adverse effects and severe infections difficult to avoid even with prophylaxis. The most common infections include polyomavirus reactivation, Aspergillus, staphylococcal sepsis, pneumonia, and cytomegalovirus reactivation. In a prospective multicenter clinical study [23], 24 patients with PTCL treated with a CHOP regimen combined with alemtuzumab (30 mg subcutaneously, d1) had a CR rate of 71% and an expected 2-year failure-free survival rate of 48%, but a high rate of infectious complications.An ongoing study at the NCI treating alemtuzumab combined with an adjusted-dose EPOCH regimen with CD52-positive PTCL patients, and early results of this study showed a high treatment response rate [24]. However, with the increase of the therapeutic effect of this treatment, its immunosuppressive effect was presented, which in turn led to the emergence of some rare or opportunistic infections. Moreover, when the dose of alemtuzumab was increased, severe bone marrow hematopoietic dysfunction was also observed, with grade 4 neutropenia in all patients. Thus, alemtuzumab in combination with chemotherapy may improve the efficacy, but the toxicity should not be neglected.　　Because CD30 is highly expressed in ALCL and certain PTCL-U and weakly expressed in normal cells, CD30 is a promising therapeutic target. Several anti-CD30 monoclonal antibodies have been developed or used for the treatment of PTCL: for example, MDX-060 (humanized anti-CD30 monoclonal antibody), MDX-1401 (humanized anti-CD30 monoclonal antibody), SGN-30 (human-mouse chimeric anti-CD30 antibody), SGN-35 (SGN-30-conjugated MMAE-conjugated monoclonal antibody), etc. Preliminary studies have shown that anti CD30 monoclonal antibodies have low treatment-related toxicity and good clinical tolerability. Two phase II clinical studies on SGN-30 [25,26] showed that treatment of CD30+ relapsed and resistant ALCL was effective in 20% of patients, including 2 CRs and 5 PRs, and treatment of CD30+ cutaneous T-cell lymphoma was effective in 70% of patients. SGN-35 is a second-generation or improved anti-CD30 monoclonal antibody to SGN-30, targeting CD30+ Hodgkin's lymphoma and ALCL, which binds, endocytoses, and releases the anti-microtubule cytotoxic drug MMAE (monomethyauristatin E) through SGN-30 to exert immune chemotherapeutic effect. Phase I clinical study [27] showed that SGN-35 treatment of relapsed resistant Hodgkin's lymphoma and ALCL achieved CR in 7 out of 17 patients, and there was no grade 3/4 toxicity except for one case with grade 3 diarrhea. The results of its phase II clinical study for relapsed resistant ALCL were reported at this year's 11-ICML meeting, with 58 patients (72% ALK negative) achieving an ORR of 86% (50/58) and 53% (31/58) achieving CR. 7 patients who achieved remission with SGN-35 received additional allogeneic or autologous hematopoietic stem cell therapy, respectively. Seven patients who achieved remission with SGN-35 each received additional allogeneic or autologous HSCT. Treatment-related adverse effects included mainly peripheral neurotoxicity (36%), nausea (24%), malaise (22%), diarrhea (19%), and neutropenia (21%); grade 3/4 toxicity included mainly neutropenia (17%), thrombocytopenia (14%), and peripheral neurotoxicity (10%); there were no treatment-related deaths.　　Several new monoclonal antibodies have also shown some activity in the treatment of PTCL, such as those targeting CD2, CD4, and CCR4. zanolimumab is a fully humanized anti-CD4 monoclonal antibody. In a phase II study, 47 patients with MF/SS (Sezary syndrome) were treated and showed that Zanolimumab was well tolerated with an ORR of 36% and was more effective than SS in patients with MF. Approximately 50% of non-cutaneous primary T-cell lymphomas express CD4, and a phase II clinical study treating relapsed and resistant non-cutaneous primary CD4+ T-cell lymphomas [28] resulted in 2 CRs and 2 PRs in 15 patients with no significant serious adverse effects.Siplizumab is an anti-human CD2 monoclonal antibody, and a study on siplizumab for the treatment of CD2 positive T-cell leukemia and lymphoma, preliminary results from a phase I clinical trial [29] showed a complete response in 1 of 9 patients with PTCL. Chemokine receptor 4 (CCR4) is another T-cell surface marker with potential therapeutic target value, and CCR4 expression is detected in approximately 88% of adult T-cell leukemia/lymphoma (ATL) patients and in approximately 38% of PTCL patients, and its expression is associated with poor prognosis in PTCL. Currently, anti-human CCR4 monoclonal antibody (KW-0761) is in early clinical studies for the treatment of ATL and PTCL. A phase I clinical study [30] showed that KW-0761 treated 15 cases of ATL and PTCL without achieving MTD, of which 31% achieved remission (2 CR, 3 PR). The results of its phase II clinical study for the treatment of 28 cases of relapsed drug-resistant ATL with CCR+ were reported by Japanese scholars at the 11-ICML meeting this year; 27 cases were evaluable for adverse effects, common controllable infusion-related adverse effects, grade 3 Steven-Johnson syndrome in 1 case, and grade 3 skin toxicity in 5 cases, and these were remitted with hormones; 26 cases were evaluable for efficacy, with ORR was 50% (8 CR, 5 PR), with median PFS and OS of 5 and 14 months. As a result, a multicenter randomized study in combination with chemotherapy is underway.　　The IL-2 receptor (IL-2R) is a marker of T-cell differentiation, and three structural forms of human IL-2R exist, a low-affinity receptor (CD25), a medium-affinity (CD122/CD132), and a high-affinity (CD25/CD122/CD132) receptor. CD25, a subunit of IL-2R, is found in some T-cell lymphomas and leukemias, including cutaneous T-cell lymphomas, PTCL-U and CD30+ ALCL. denileukin diftitox, a fusion protein of diphtheria toxin and IL-2, directly and selectively causes diphtheria toxin killing of target cells. It has been approved for CTCL treatment. In a phase II clinical trial [31], 27 patients with relapsed/refractory PTCL were treated with denibulin and had ORR, CR and SD rates of 48%, 22% and 29%, respectively, with higher treatment efficiency in CD25-positive patients than in CD25-negative patients (61% vs. 45%) and a median PFS of 6 months. Side effects were mild and short-lived, most commonly hypoproteinemia, elevated transaminases, edema and skin reactions. Since there is no significant myelosuppression or immunosuppression, it can be used in combination with chemotherapy or other targeted therapeutic agents. In a recent phase II clinical trial of denibulin in combination with CHOP regimen [32], 49 patients with PTCL were enrolled and 37 were evaluable, with CR and PR rates of 75.7% and 10%, respectively, and ORR of 86.5% after 2 cycles of treatment, with no opportunistic infections. Although denileukin has shown some efficacy in the treatment of PTCL, its significant toxic side effects have attracted attention, and its common adverse effects include hypersensitivity reactions, peripheral edema, and albumin reduction.　　(iv) Other biologically targeted drugs Proteasome inhibitors, especially bortezomib, have clear antitumor effects in many types of tumors. The antitumor effect of bortezomib may be achieved by inhibiting NF-κB pathway, and there are various genes related to dysregulation of NF-κB signaling pathway in PTCL-NOS, so it has been studied for the treatment of PTCL-NOS in recent years. A recently reported phase II clinical study [33] showed that 12 patients with relapsed CTCL or PTCL (mainly isolated recurrent skin lesions) treated with bortezomib (1.3 g/m2 iv, d1, 4, 8, 11, 21-day cycles) had an ORR of 67% (1 PTCL treatment CR).A phase II clinical trial by GELA ( LNH05-ET) comparing the efficacy of ACVBP in combination with bortezomib versus an ACVBP regimen alone in the treatment of primary PTCL [34] showed that the combination bortezomib regimen did not appear to improve treatment efficiency.　　Many kinase inhibitors have been used in studies of targeted therapy for lymphoma, with several ongoing clinical trials enrolling patients with PTCL. Inhibitors of protein kinase C (PKC), phosphatidylinositol 3 protein kinase (PI3K), AKT, mTOR, cytokinin-dependent protein kinase (CDK), Aurora kinase, and various tyrosine protein kinases are currently in early clinical trials.　　With the progress of cytopathology, cytogenetics and molecular biology, the understanding of the biological nature, disease characteristics and heterogeneity of disease regression of each subtype of PTCL has become more and more comprehensive and in-depth, and the distinctive treatments for different subtypes have been studied and developed. From the background of related research, the characteristic therapies are mainly based on the intervention of etiology and its pathogenesis, the disruption of tumor microenvironment, and the treatment of specific molecular targets of tumor cells themselves. These have been reflected to varying degrees in recent years in special studies of different subtypes of PTCL and in the development and utilization of various new drugs, and have been particularly comprehensively reflected in the therapeutic studies of AITL (not detailed here due to the length of the article) [35]. In conclusion, the characteristic treatment of relatively different subtypes is a significant development of the treatment strategy of PTCL in recent years, and is also its inevitable development trend.　　IV. Summary In summary, although people still have a foggy feeling about the treatment of peripheral T-cell lymphoma, a breakthrough is coming after years of accumulation and development. Firstly, in terms of treatment strategies, conventional strategies to avoid and overcome drug resistance are still worthy of continued exploration, and characteristic treatments for different subtypes may bring breakthroughs; secondly, in terms of therapeutic means, the clinical application of new drugs with different mechanisms of action, especially highly efficient and low-toxic biologically targeted drugs, brings new hopes and breakthroughs for the treatment of PTCL. Therefore, it can be said that the treatment of peripheral T-cell lymphoma is already on the way.