Phase II clinical studies of denileukin diftitox diphtheria toxin fusion protein in patients with previously treated chronic lymphocytic leukemia

BACKGROUND: The safety and efficacy of the interleukin-2 diphtheria toxin fusion protein (DAB(389)IL2; denileukin diftitox) directed against the IL-2 receptor (IL-2R) was tested in patients with recurrent or refractory chronic lymphocytic leukemia (CLL). METHODS: Denileukin diftitox was administered as 60-minute intravenous infusions for 5 days every 21 days at a dose of 18 mug/kg per day for up to 8 cycles. In total, 28 patients were treated in 2 multiinstitutional studies with similar eligibility criteria and treatment protocols. Twenty-two patients receive > or = 2 cycles of denileukin diftitox and were evaluable for response. RESULTS: Twelve of 22 patients achieved reductions of peripheral CLL cells, with 5 of 12 patients achieving >80% reductions. Six of 22 patients achieved reductions in the size of lymph node on examination and computed tomography scans, and all 6 of those patients met the criteria for a partial or complete response that lasted > or = 2 months. Bone marrow biopsies before and after treatment confirmed a complete remission that lasted for 1 year in 1 patient. Overall, denileukin diftitox produced complete remission in 1 of 22 patients (4%) and partial remission in 5 of 22 patients (23%) for a total remission rate of 27%. Progression-free intervals in the responders were 2 months in 2 patients and 4 months, 6 months, 7 months, and 12 months in 1 patient each. Toxicities were moderate. No infections associated with immunosuppression were seen. There was no significant correlation of response or toxicities with the numbers of denileukin diftitox cycles received or with CD25 levels. CONCLUSIONS: Follow-up studies will be required to identify predictors of response that may improve the response rate to denileukin diftitox in patients with CLL.     

Denileukin diftitox as novel targeted therapy for lymphoid malignancies

Denileukin diftitox (DAB₃₈₉IL-2; Ontak) is a cytotoxic fusion protein designed to target cells expressing the receptor for interleukin-2 (IL-2). It has been approved for treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor, but more recent data indicate activity in the setting of not only T-cell but also B-cell malignancies. This review will update the experience to date of denileukin diftitox in T- and B-cell malignancies.     

Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma

Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ T(reg) cells while rituximab would deplete malignant B cells. Patients received rituximab 375?mg/m(2) weekly for 4 weeks and denileukin diftitox 18?mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27-69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37-82%). Thirteen patients (57%) experienced grade ≥3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.     

Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.     

Denileukin diftitox: a concise clinical review

Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. This article will review the clinical trials leading to the approval of denileukin diftitox for cutaneous T-cell lymphoma, and discuss the potential future role of this novel drug in patients with both malignant and nonmalignant diseases, including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, solid tumors, psoriasis and graft-versus-host disease.     

Phase II study of denileukin diftitox for previously treated indolent non-Hodgkin lymphoma: final results of E1497

Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with B-cell non-Hodgkin lymphoma (NHL). This phase II trial evaluated response rate (RR) and tolerability of DD in this population. Patients were stratified into two arms: those with NHL expressing > or =20% IL-2R (IL-2R+) or <20% IL-2R (IL-2R-). DD was dosed at 18 microg/kg/day for 5 days every 21 days. Corticosteroid pre-medication was not allowed. Thirty-five patients of a planned 77 accrued due to closure for slow accrual. This report is on 29 patients (18 males) with indolent B-cell NHL (11 IL-2R+ and 18 IL-2R-). Histologic subtypes included small lymphocytic (SLL) (8 patients) and follicular grade I/II lymphoma (21 patients). Patients received a median of three prior regimens, including rituximab in 76%. Three partial responses were observed (RR 10%). The RR for the IL-2R- and IL-2R+ patients was 11% and 9%, respectively. Of 8 patients with SLL, 2 responded. Toxicities were generally grade I - II and transient but 1 patient experienced a fatal thrombo-embolism. Therapy with DD is tolerable and modest efficacy was observed in SLL subtype. Measured IL-2R status did not correlate with efficacy.     

Denileukin diftitox: a concise clinical review

Denileukin diftitox (DAB₃₈₉IL-2; Ontak^®) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. This article will review the clinical trials leading to the approval of denileukin diftitox for cutaneous T-cell lymphoma, and discuss the potential future role of this novel drug in patients with both malignant and nonmalignant diseases, including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, solid tumors, psoriasis and graft-versus-host disease.     

Sustained hematologic and central nervous system remission with single-agent denileukin diftitox in refractory adult T-cell leukemia/lymphoma

Human T-lymphotrophic virus-1-associated adult T-cell leukemia/lymphoma (ATLL) is a rare and often fatal disease. Initial treatment often includes zidovudine/interferon (IFN)-based therapy, although disease remission is typically not complete or durable. This study reports on a 55-year-old man with relapsed/refractory leukemic-phase ATLL including significant central nervous system (CNS) disease with resistance to previous zidovudine/IFN and arsenic trioxide/IFN treatment. The patient experienced a rapid hematologic and CNS clinical response with single-agent denileukin diftitox therapy (18 microg/kg per day for 5 days). He tolerated 8 cycles of denileukin diftitox therapy well and experienced a sustained complete hematologic and CNS remission. The patient subsequently underwent matched sibling reduced-intensity allogeneic transplantation and remains disease free. Further study examining denileukin diftitox in patients with relapsed/refractory ATLL is warranted.     

Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-Cell non-Hodgkin's lymphoma

AIM: Yttrium-90 ((90)Y) ibritumomab tiuxetan (Zevalin) radioimmunotherapy is an effective treatment for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL), with overall response rates ranging from 74% to 82%. This retrospective analysis was conducted to determine the number of patients achieving long-term durable responses with (90)Y ibritumomab tiuxetan treatment. MATERIALS AND METHODS: The medical records of patients (n = 211) with relapsed, refractory, or transformed indolent CD20+ B-cell NHL who were treated with 90Y ibritumomab tiuxetan were reviewed. Time to progression (TTP) of > or =12 months was noted in 78 patients (37%), who were identified as long-term responders and were further characterized. RESULTS: Median age of the long-term responders was 58 years (range, 24-80 years) with 44% over 60 years, and 55% were male. Notably, 59% of patients had received > or =2 prior regimens, 33% had received > or =3 prior regimens, and 37% had failed to respond to immediate prior therapy. Median response duration was 28.1 months (range, 10.5-80.3+ months). Median TTP was 29.3 months (range, 12.1-81.5+ months). In patients with ongoing response, median TTP was 53.9 months (range, 49-82+ months). CONCLUSIONS: (90)Y ibritumomab tiuxetan produces durable long-term responses in patients with relapsed/refractory B-cell NHL. Failure to respond to prior therapy does not preclude achieving a long-term response with 90Y ibritumomab tiuxetan.     

ATT循环方案治疗复发及难治性非霍奇金恶性淋巴瘤

背景与目的:复发性和难治性非霍奇金恶性淋巴瘤(non-Hodgkin's lymphoma,NHL)的治疗一直是临床的难题之一。三联循环方案(alternating triple therapy,ATT)是ASHAP、m-BACOD、MINE3种方案每3周交替使用。本研究的目的是探讨ATT治疗复发及难治性NHL的疗效。方法:回顾性分析用ATT方案治疗的38例复发及难治性NHL患者的临床资料,其中复发性NHL28例,难治性NHL10例。结果:10例(26.3%)患者达到完全缓解,12例(31.6%)达到部分缓解,总有效率为63.2%。B细胞性淋巴瘤总有效率为60.0%(12/20),而T细胞性淋巴瘤总有效率为55.6%(10/18)。≤60岁年龄组总有效率为65.4%(17/26),>60岁组总有效率为41.7%(5/12)。全组中位随访时间11个月,1年总生存率42.1%(16/38),2年总生存率为13.2%(5/38)。毒副作用以骨髓抑制为主。结论:ATT循环方案对于复发及难治性NHL有较好的疗效,毒副反应患者可以耐受,值得在更多病例中进一步研究。     

Toxic epidermal necrolysis associated with denileukin diftitox (DAB389IL-2) administration in a patient with follicular large cell lymphoma

Denileukin diftitox (DAB₃₈₉IL-2 or Ontak®) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.     

Remission of follicular non-Hodgkin's lymphoma with denileukin diftitox (ONTAK) after progression during rituximab,CHOP and fludarabine therapy

Denileukin diftitox (ONTAK) is indicated for the treatment of patients with cutaneous T cell lymphoma. Clinical experience with this drug in other lymphomas is limited. This case report concern a patient with stage IV follicular lymphoma who, relapsing after autologous transplant and having failed multiply systemic therapies, including retuximab and CHOP, achieved a prolonged remission with denileukin diftitox.     

DICE方案治疗复发或耐药中高度恶性非霍奇金淋巴瘤

背景与目的:复发或耐药非霍奇金淋巴瘤(non鄄Hodgkin蒺slymphoma,NHL)目前尚无标准的解救化疗方案,DICE、ESHAP、MINE和EPOCH等常见的解救治疗方案缓解率仅为30%～70%。本文旨在观察DICE方案作为解救化疗方案治疗复发或耐药中高度恶性NHL的疗效和安全性。方法:选取35例复发或耐药的中高度恶性NHL患者,其中T细胞和B细胞NHL分别为14和21例,既往接受过以CHOP或CHOP样方案为主中位6周期(2～12个周期)的化疗,采用DICE方案进行解救治疗。结果:35例患者接受了中位4周期(2～7个周期)的DICE方案化疗,所有患者均可评价疗效和不良反应。总的客观有效率为74.3%,完全缓解率为31.4%;中位缓解时间为4个月(1～30个月),中位至治疗失败时间为7个月(2～34个月),中位生存期为14个月(3～51个月),实际2年生存率为33.3%。T细胞和B细胞NHL的有效率分别为85.7%(12/14)和66.7%(14/21),完全缓解率分别为50.0%(7/14)和19.0%(4/21)(P=0.073)。LDH升高和伴有巨大肿块是影响解救治疗疗效的高危因素(P<0.05),DICE解救疗效是复发耐药患者生存期的独立预后因素(P=0.001)。主要不良反应为骨髓抑制,Ⅲ～Ⅳ度粒细胞和血小板减少的发生率分别为71.4%和8.6%。结论:DICE方案是复发或耐药中高度恶性NHL安全有效的解救治疗方案。LDH升高和伴有巨大     

Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with denileukin diftitox (ONTAK)

Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with heavily pretreated advanced and/or recurrent CTCL, the effects of an interleukin-2 receptor-targeted fusion protein, denileukin diftitox (DAB389IL-2, ONTAK), on patient-rated overall quality of life (QOL), skin appearance, and pruritus severity were evaluated. A total of 71 patients with stage IB-IVA CTCL received intravenous denileukin diftitox 9 microg/kg/day or 18 microg/kg/day over 15-60 minutes for 5 consecutive days on an outpatient basis; cycles were planned for every 21 days for a total of 8 cycles over 6 months. Prior to each treatment cycle, patients were evaluated for disease response and were asked to self-rate their overall QOL via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, skin appearance (7-point scale), and pruritus severity (10-cm visual analogue scale). Composite FACT-G and most individual subscale scores (physical, social/family, emotional, and functional well being) in documented responders (n = 21) gradually increased during the study period, generally reaching statistical significance (P < 0.05) by cycle 3, and were significantly (P < or = 0.041) higher than the scores of nonresponders at endpoint. Additionally for responders, assessments of skin severity and pruritus severity showed significant (P < or = 0.05) improvements at study endpoint compared with baseline. Adverse transfusion-related events (eg, hypersensitivity reactions, flu-like syndrome) were common during cycles 1 and 2, and vascular-leak syndrome occurred in 25% of patients. Denileukin diftitox was not associated with any clinically significant myelosuppression. Heavily pretreated patients with advanced and/or recurrent CTCL who responded to denileukin diftitox therapy showed significant improvements in self-rated overall QOL, skin appearance, and pruritus severity.     

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.     

亚砷酸联合吉西他滨和顺铂治疗难治性或复发性非霍奇金淋巴瘤

目的:观察亚砷酸注射液(三氧化二砷,As2O3)联合吉西他滨和顺铂方案治疗难治性或复发性非霍奇金淋巴瘤(NHL)的有效率.方法:18例难治性或复发性NHL患者 ,男性12例,女性6例,中位年龄 51岁.给予As2O3注射液 10mg/d静脉滴注第1-14天,吉西他滨 1000mg/m2,第 1和第8天,顺铂 25mg/m2第 1-3天,21d为 1个周期.结果:18例患者中完全缓解4例,部分缓解7例,有效率 61.1%.肿瘤中位进展时间(TTP)6.5个月,1年生存率 42.3%.不良反应主要为血液学毒性、肝肾功能损害.结论:亚砷酸注射液联合吉西他滨和顺铂方案是治疗复发或难治性非霍奇金淋巴瘤较为安全、有效的化疗方案.     

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma

Background: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma. A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m² of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) was well tolerated and had significant clinical activity.Patients and methods: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m² Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated.Results: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively.Conclusions: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with that seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.     

Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease.

PURPOSE: The purpose of this study was to evaluate the clinical activity and toxicity of recombinant human Interleukin (IL)-12 in patients with relapsed and refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). EXPERIMENTAL DESIGN: Forty-two previously treated patients (32 patients with NHL and 10 patients with HD) were enrolled on the study. Patients were treated with either intravenous (n = 11) or subcutaneous (n = 31) administration of IL-12. The patients had received a median of three prior treatment regimens, and 16 patients had undergone prior autologous stem cell transplantation. RESULTS: All patients were assessable for toxicity, and 39 of 42 (93%) patients were assessable for response. Six of 29 (21%) patients with NHL had a partial or complete response, whereas none of the 10 patients with HD responded. Furthermore, 15 patients had stable disease that lasted for up to 54 months. Progression-free survival in patients with indolent NHL, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Treatment was well tolerated, and the most common toxicity was flu-like symptoms. Reversible grade 3 hepatic toxicity was observed in three patients requiring dose reduction. IL-12 therapy increased the median number of peripheral blood CD8 T lymphocytes from 423/microl to 576/microl (P = 0.0019). Furthermore, IL-12 therapy decreased serum vascular endothelial growth factor and basic fibroblast growth factor concentrations in 37% of the patients. CONCLUSIONS: The ability of recombinant human IL-12 therapy to increase the number of circulating CD8+ cells and induce clinical remissions in patients with relapsed NHL warrants further investigation of the drug.     

含美罗华联合方案治疗复发耐药B细胞性非霍奇金淋巴瘤

Objective： The prognosis of relapsed or refractory B-cell lymphoma is poor, with a short-term survival after conventional second-line chemotherapy, Rituximab, a chimeric anti-CD20 antigen, in combination with CHOP or CHOP-like chemotherapy may improve both disease free survival （DFS） and overall survival （OS） of naive patients, but its role in the second-line therapy for relapsed non-Hodgkin＇s Lymphoma （NHL） remains to be defined, This study aimed to evaluate the efficacy of rituximab-containing salvage regimens for relapsed or refractory NHL, and observe the toxicities. Methods： The clinical data of 54 patients, who were with relapsed or refractory NHL and treated in the Cancer Center of Sun Yat-sen University, were analyzed retrospectively, Of the 54 patients, 29 were man, 25 were women, with a median age of 52.5 years old （range 18 to 75）; 50 patients （92.6%） scored 0-1 for the ECOG performance status; for second-line international prognostic index （slPI）, 21 （38.9%） scored 0-1,30 （55.6%） scored 2 to 3, and 3 （5.6%） scored 4-5; 40 cases were diffuse large B-cell lymphoma （DLBCL）, accounting for 74.1% of all subtypes, Rituximab was administered intravenously at a dose of 375 mg/m^2 at the day before each chemotherapy cycle, The second or third-line salvage regimens included EPOCH, CHOP, DHAP, DICE, IVAC, IMVP-16 and FND, Results： Of the 54 patients, 49 received retuximab-containing salvage regimens, The objective response rate of the 45 evaluable cases was 68,8%, with a complete remission （CR） rate of 37.7%; 3 patients achieved CR after radiotherapy following rituximab-based regimens and 3 achieved CR after autologous hematopoietic stem cell transplantation, The most frequent adverse events were leucopenia, nausea and alopecia. The addition of rituximab to chemotherapy only elevated the occurrence of mild infusion-related reactions, such as chills, fever and pruritus. The median follow-up time was 18 months （range 2-86 months）; 5 patients were lost, 24 were dead （23 died of lymphoma, and 1 died of severe hepatitis）, the other patients remained alive. The median survival time was 32 months （range 2-86 months, 95% confidential interval 16-48 months）. The 1-, 2- and 3-year OS rates were 70.6%, 53,6% and 41,5%, respectively, The median TTP was 6 months （range 0-52 months）, The median PFS was 10 months （range 0-47 months, 95% CI 0-26 months）, The 1- and 2-year PFS were 49,3% and 41,3%. Conclusion： Rituximab-containing salvage regimens are effective and well tolerated therapy for patients with relapsed or refractory B-cell NHL, even those were extensively treated.     

外周T/NK细胞淋巴瘤治疗的进展

 外周T细胞淋巴瘤（PTCL）是一组异质性非常明显的淋巴瘤,起源于成熟T淋巴细胞,对传统化疗反应不佳,大部分患者预后差。对复发难治患者的治疗选择尚未达成共识。目前正在进行一些新的临床试验,探讨一些新的治疗方法和药物,如第一次缓解后采用自体干细胞移植进行巩固治疗的前瞻性临床研究,以及denileukin diftitox或者CD52单抗（alemtuzumab）等靶向治疗药物与化疗的联合等。文章对外周T／NK细胞淋巴瘤的流行病学、预后因子和目前的治疗进行了探讨。