| Radiotherapy combined with L-Asparaginase-based chemotherapy is recommended for nasal NK/T-cell lymphoma. Agreement has been made on the dose and field of radiotherapy and L-Asp is now recommended by most of the center for the first-line treatment of nasal NK/T-cell lymphoma. While there is still no consensus about which is the best regimen that should be combined with L-Asp.In this study, we reviewed the outcome of nasal NK/T-cell lymphoma patients who received radiotherapy combined with L-Asp-based chemotherapy in our center, as well as the difference in response rate and overall survival between different patient groups. The difference in response rate, overall survival and treatment-related toxicity between L-Asp and PEG-Asp, and among different chemotherapy regimen was further analysed, in order to make reference for clinical practice and clinical trials. We also investigated the first-line treatment of nasal NK/T cell lymphoma associated with hemophagocytic syndrome. We also investigated the anti-lymphoma activity of terpenoid from Compositae and Taxus Cuspidata so as to explore new drug from plants for the treatment of T/NK-cell lymphoma.Part one The response, survival and toxicity of L-Asp-based chemotherapy in nasal NK/T-cell lymphomaObjective: To lea r n the characteristics of nasal NK/T-cell lymphoma in our center and the response rate, survival and toxicity of L-Asp-based chemotherapy.Methods: The clinical data of NK/T-cell lymphoma diagnosed in our center during 2006.6-2014.11 was collected. The patients received L-Asp-based chemotherapy and involved-field radiotherapy. The toxicity during chemotherapy, the CR rate and the survival of the patients were analysed.Results: 1 NK/T-cell lymphoma mainly affected young patients. 80% of the patients felled in limited stage. 68% and 56% of the patients was admitted with B symptom or fever respectively. 90% of the patients were in low or low-middle risk group according to the IPI. 30%, 29% and 25% of the patients were admitted with anemia, hypoalbuminemia or elevated LDH; 2 After L-Asp-based chemotherapy and involved-field radiation, 83.0% of the patients got CR, and 9.1% of the patients got PR. Subgroup analysis showed that the CR rate(90.1%) of the patients with limited stage was significantly higher than that of the patients with advanced stage(52.9%), the CR rate(87.3%) of the patients in low risk and low-middle risk group was significantly higher than that of the patients in high risk and middle-high risk group(44.4%),the CR rate(91.9%) of the patients with normal albumin level was significantly higher than that of the patients with hypoproteinemia(60%), the CR rate(87.7%) of the patients with normal LDH level was significantly higher than that of the patients with elevated LDH level(65%); 3 After a median follow-up of 14 months, the 2-year and 5-year survival of the patients were 73.9% and 61.3% respectively. Subgroup analysis showed that patient in low risk or low-middle risk group according to IPI, patients in limited stage and patients with normal albumin level had a better survival; 4 The incidence of treatment-related toxicity was as follow: leukopenia(76.9%) and grade 3/4 leukopenia(44.1%), thrombocytopenia(25.2%) and grade 3/4 thrombocytopenia(8.5%), anemia(67.0%) and grade 3/4 anemia(13.9%), fever with neutropenia(20.8%), hypofibrinogenemia(40.0%) and 3/4 grade hypofibrinogenemia(5.1%), elevated transaminase(37.0%) and grade 3/4 elevated transaminase(1.6%), hyperbilirubinemia(10.2%) and grade 3/4 hyperbilirubinemia(1.8%), hypoalbuminemia(52.2%) and grade 3/4 hypoalbuminemia(2.1%).Summary: Nasal NK/T-cell lymphoma mainly affected young patients. Most of the patients fell in limited stage. L-Asp-based chemotherapy and involved-field radiation produced a high CR rate and good survival in patients in limited stage or low-risk group. The main treatment-related toxicity was leukopenia, fever with neutropenia, anemia, hypofibrinogenemia and hypoalbuminemia.Part two Analysis of the treatment result of L-Asp/PEG-Asp combined with CHOP/EPOCH/GDP in nasal NK/T-cell lymphomaObjective: To investigate the difference in CR rate, survival and toxicity between L-Asp and PEG-Asp group, or among the regimens group of CHOP, EPOCH, and GDP.Methods: The data of the patients in Part One was analysed further to investigate the difference in response rate, overall survival and toxicity between L-Asp group and PEG-Asp group, or among CHOP group, EPOCH group and GDP group.Results: 1 There was no difference in CR rate between L-Asp and PEG-Asp, but the CR rate of GDP regimen was higher than that of CHOP or EPOCH regimen; 2 Neither the type of Asp nor the type of chemotherapy did not have any significant effect on the survival of the patients; 3 The incidence of grade 3/4 leukopenia during the treatment of CHOP, EPOCH and GDP regimen was 43.6%, 60.1% and 20.5% respectively, with significant difference. The incidence of thrombocytopenia was significantly higher in GDP regimen(44.3%) than that in CHOP regimen(21.0%) or EPOCH regimen(17.6%), and the incidence of grade 3/4 thrombocytopenia was significantly higher in GDP regimen(21.6%) than that in CHOP regimen(5.0%) or EPOCH regimen(4.1%). The incidence of anemia in GDP regimen(75%) was significantly higher than that in EPOCH regimen(58.1%). But there was no significant difference in grade 3/4 anemia among CHOP, EPOCH or GDP regimen(17.7%, 10.1% and 11.4%, respectively). The incidence of hypofibrinogenemia in PEG-Asp group(57.6%) was significantly higher than that in L-Asp group(32.7%), and the incidence of grade 3/4 hypofibrinogenemia in PEG-Asp group(12.2%) was significantly higher than that in L-Asp group(1.8%). The incidence of hypoalbuminemia in PEG-Asp group(80.4%) was significantly higher than that in L-Asp group(38.3%), but there was no significant difference in grade 3/4 hypoalbuminemia between the two groups. The incidence of febrile neutropenia was significantly higher in EPOCH regimen(31.8%) than that in CHOP regimen(19.3%) or GDP regimen(8.0%).Summary: PEG-Asp was not better than L-Asp in CR rate and survival in nasal NK/T-cell lymphoma, but with more incidence of hypoalbuminemia and hypofibrinogenemia. When combined with Asp, CHOP regimen was still effective and safe, while EPOCH regimen no longer had any advantage, but with more incidence of grade 3/4 leukopenia and febrile neutropenia. GDP regimen may produce a higher CR rate, but the treatment-related toxicity such as anemia and thrombocytopenia should be kept in mind.Part three The clinical characteristics and first-line treatment of nasal NK/T-cell lymphoma associated with hemophagocytic syndromeObjective: To investigate the characteristics and first-line treatment of nasal NK/T-cell lymphoma associated with hemophagocytic syndrome.Methods: The clinical data of NK/T-cell lymphoma associated with hemophagocytic syndrome diagnosed in our center during 2006.5-2013.12 was collected. The patients received LOD regimen(L-Asp, vincristine and dexamethasone) or non-LOD regimen(mainly corticosteroids with some combined with vincristine or etoposide). The temperature, blood cell count and liver function during and after the treatment were analysed. And the overall survival between the two groups were compared.Results: 1 Fifteen patients were enrolled in the study with a median age of 32 years old. Most(46.7%) of the patients had poor performance status with ECOG score of 2 or above. 66.7% of the patients were in advanced stage. All of the patients had fever, and splenomegaly was found in 80.0% of the patients. Most of patients(66.7%) were in high risk or high-middle risk group according to the IPI model. Hemophagocytic syndrome were diagnosed in the first visit(33.3%), during radio-chemotherapy(13.3%) or at the time of relapse/progression(53.3%). The incidence of leukopenia, anemia, and thrombocytopenia were 80.0%, 46.7% and 46.7% respectively. Hypofibrinogenemia was found in 53.3% of the patients. Hyperbilirubinemia and hypoalbuminemia could be found in 53.3% and 66.7% of the patients. Hemophagocytosis could be found in the bone marrow of 53.3% of the patients; 2 After LOD chemotherapy, of the 7 patients, 3 patients got CR and 4 patients got PR, the mean survival time of the patients in the LOD group was 405.0 days, while the mean survival time of the patients in the non-LOD group was only 21.8 days, which was too short to get the response rate; 3 In the LOD group, most(6/7) of the patients` temperature got normal in the second day of chemotherapy. Though the blood cell count could decline temporarily after the start of chemotherapy, most of the patients` blood cell count recovered 4 days after chemotherapy, and the median time for the recovery of liver function was the seventh days of chemotherapy.Summary: Hemophagocytic syndrome most probably developed in patient with nasal NK/T-cell lymphoma in advanced stage or in status of relapsed or refractory disease. Hemophagocytic syndrome should be take into account when a patient has unexplained fever, pancytopenia, abnormal liver function and hypofibrinogenemia. Compared with the treatment with corticosteroids, the LOD regimen consisting of L-Asp, vincristine and dexamethasone could significantly prolong the survival of patients, with less adverse reactions and good tolerance.Part four Anti-lymphoma activity of terpenoid compounds from plants and the related mechanismObjective: To investigate the anti-lymphoma activity of terpenoid compounds from Compositae, Taxus Cuspidata and Achillea millefolium and to explore the related anti-tumor mechanism, so as to develop new drug from plants for the treatment of T/NK-cell lymphoma.Methods: Thirty-nine kinds of sesquiterpene lactones from Compositae and thirteen kinds of diterpene compounds from Taxus Cuspidata were dectected for anti-lymphoma activity by MTT colorimetric assay. For the terpenoid compounds with inhibitary rate of 80% or more in the concentration of 100μmol/L, the IC50 of the compounds on HUT78/SNK6 cell were further determined. Apoptosis and expression of p53, Bax, caspase-3 of tumor cell treated by compound was detected by FCM and Western blot to explore the related mechanism of anti-tumor activity.Results: Compounds Eupatolid(6),4-dehydroxy-1,10- epoxy-Achillinin A(34), Millifolide B(39) from Compositae and compounds 9,10-deacethyltaxinine(42), taxagifine(52) from Taxus Cuspidata presented obviously anti-lymphoma activity at the concentration of 100 μmol/L, with an inhibitory rate of 80% or more on HUT78/SNK6 cell. The IC50 of compound(6),(34),(39),(42) on HUT78 cells was 25.01μmol/L, 19.10μmol/L, 21.80μmol/L and 18.45μmol/L respectively, which was lower than that of cisplatin(29.08μmol/L). The IC50 of compound(6),(34),(39),(42),(52) on SNK6 cells was 21.57μmol/L, 12.77μmol/L, 33.69μmol/L, 27.63μmol/L and 4.89μmol/L respectively, which was lower than that of cisplatin(48.02μmol/L).The compound(42) may induce expression of p53, Bax, caspase-3 and apoptosis of tumor cell to play anti-tumor activity.Summary: Three sesquiterpene lactone compounds from Compositae and two diterpene compounds from Taxus Cuspidata presented obviously inhibitory activity on HUT78/SNK6 cell, with some of which were stronger than that of cisplatin. The compounds may induce expression of p53, Bax, caspase-3 and apoptosis of tumor cell to play anti-tumor activity.Conclusions:1 Nasal NK/T-cell lymphoma mainly affected young patients. Most of the patients fell in limited stage. L-Asp-based chemotherapy and involved-field radiation produced a high CR rate and good survival in patients in limited stage or in low-risk group. The main treatment-related toxicity was leukopenia,fever with neutropenia, anemia, hypofibrinogenemia and hypoalbuminemia. 2 PEG-Asp was not better than L-Asp in CR rate and survival in nasal NK/T-cell lymphoma, but with more incidence of hypoalbuminemia and hypofibrinogenemia. When combined with Asp, CHOP regimen was still effective and safe, while EPOCH regimen no longer had any advantage, but with more incidence of grade 3/4 leukopenia and febrile neutropenia. GDP regimen may produce a higher CR rate, but the treatment-related toxicity such as anemia and thrombocytopenia should be kept in mind. 3 Hemophagocytic syndrome most probably developed in patient with nasal NK/T-cell lymphoma in advanced stage or in status of relapsed or refractory. Hemophagocytic syndrome should be take into account when a patient has unexplained fever, pancytopenia, abnormal liver function and hypofibrinogenemia. Compared with the treatment with corticosteroids, the LOD regimen consisting of L-Asp, vincristine and dexamethasone could significantly prolong the survival of patients, with less adverse reactions and good tolerance. 4 Three sesquiterpene lactone compounds from Compositae and two diterpene compounds from Taxus Cuspidata presented obviously inhibitory activity on HUT78/SNK6 cell, with some of which were stronger than that of cisplatin. The compounds may induce expression of p53, Bax, caspase-3 and apoptosis of tumor cell to play anti-tumor activity. |
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