Key words】 mantle cell lymphoma prognosis treatment

    Mantle cell lymphoma is a special clinical pathological manifestations of B-cell non-Hodgkin’s lymphoma, and for the first time in 1992 as an independent type have been proposed [1], accounting for non-Hodgkin’s lymphoma 4% to 6%. Origin of tumor cells in primary follicles or sleeve-shaped zone of secondary follicles naive germinal center cell is composed by a single medium-sized nuclei associated with irregular cleft B lymphocyte population. Immune phenotype characterized by CD5 + and CD23-, CD10-. Most cases exist chromosome t (11; 14) translocation and bcl  heavy row, leading Cyclin D1 protein overexpression, the regulation of cell proliferation disorders.

    1 mantle cell lymphoma prognosis

    Mantle cell lymphoma with poor response to treatment, the median survival time is about 3 to 5 years. Some studies on mantle cell lymphoma cases made Retrospective Analysis of prognostic factors, the following factors are considered and its poor prognosis: age> 60 years, Ⅲ or Ⅳ, poor general condition, lactate dehydrogenase level higher than 450 U / L, there are and extranodal sites involving more than two. These five factors are the basis for the formation of the International Lymphoma Prognostic Index, is a measure of mantle cell lymphoma prognosis is very good indicators. Other factors associated with prognosis include: men, splenomegaly, bone marrow involvement, lymphocytosis, anemia, β2 microglobulin, A the Gianyar sugar adenosine phosphorylase (MTAP) expression in the absence of [2], DNA topoisomerase II a [3], the overexpression of cyclin D1, high mitotic index and p53 mutations. According to these prognostic factors to make a comprehensive evaluation of the disease status of the patient, can help clinicians select appropriate treatment options to improve the patient’s quality of life.

    Treatment of mantle cell lymphoma

    Treatment of mantle cell lymphoma, not a standard treatment program is generally believed that a strong program of treatment can improve the patient’s disease-free survival, but not a therapeutic means to really cure this disease.

    2.1 Traditional chemotherapy

    CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is most commonly used in non-Hodgkin’s lymphoma, is also used for the treatment of mantle cell lymphoma, but previous studies show that its effect is not satisfactory. Joshua [4] in the analysis of a variety of chemotherapy regimens for MCL patients, concluded with CHOP regimen in the treatment of MCL patients, the overall response rate was about 75%, the rate of complete remission (CR) in 20% to 80% , of which the median survival time, median disease-free survival time of between 10 to 16 months to 3 years. Can be seen with CHOP regimen does not affect the patient’s median survival time, improve the survival of patients.

    Hyper  CVAD program is a powerful chemotherapy for leukemia, is in the high-dose cyclophosphamide, vincristine, adriamycin, dexamethasone based on the addition of high-dose cytarabine, methotrexate whisper a program. American MD Anderson Cancer Treatment Center Hyper  CVAD program of treatment for MCL, they will be the treatment of 25 cases the MCL of patients with this scenario, results of the overall response rate was 92% CR rate was 68%, with a median survival time for the 15 months, but there are obvious hematologic toxicity [5]. As can be seen from this study, Hyper  CVAD compared with CHOP higher response rate and CR rate, but toxic, and the lack of a comparison between the large sample, and therefore as the MCL standard treatment options need to be further research.

    Fludarabine main sources of B-cell non-Hodgkin’s lymphoma, Foran [6] reported that fludarabine MCL, lymphoplasmacytic like lymphoma and Waldernstroms, macroglobulinemia early onset among Phase Ⅱ study. The study included 21 cases of MCL patients, and 17 patients efficacy testing. The results show that fludarabine MCL cases efficiency is far lower than other lymphoma patients: 63% and 79%, 41% in MCL and other lymphomas. Among them, two cases of MCL patients achieved a partial response, 5 patients achieved complete remission. MCL cases, the median time of disease progression was 1.1 years, significantly shorter than the other lymphoma this study the median disease-free survival time were evaluated. A phase Ⅱ clinical studies and the same conclusion, Tobinai [7] with the oral formulation of fludarabine treatment of 52 patients with indolent B-cell non-Hodgkin’s lymphoma, including six cases of MCL patients, the results The overall response rate and CR rate MCL group were significantly lower than that of other lymphoma group, the median time to treatment failure (TTF) MCL group was 6.1 months, while other lymphoma group for 12 months. As can be seen from these two studies, fludarabine poor response rate in MCL, MCL treatment as the main drug evidence is not sufficient.

    2.2 rituximab single-agent chemotherapy

    MCL belong to the B-cell malignancies, expression of mature B cell surface markers CD19, CD20, CD22, and CD79a. Rituximab is a monoclonal anti-CD20 antibody, is mainly used for malignant lymphoma of the B-cell origin. Foran et al [8] with rituximab treatment of 131 patients with B-cell malignancies, including 74 cases of MCL patients, the use of rituximab weekly 375 mg/m2, once every four weeks, can be used to assess the results of 120 patients. The results show that rituximab in MCL patients, the response rate was 38% complete remission (CR) rate was 13.5%. Another study from Swiss Clinical Cancer Research Group (SAKK), application rituximab treatment of 88 cases of MCL patients, use ibid results reported response rate was 27% CR rate was only 2% [9] . As can be seen above, single-agent rituximab treatment MCL limited efficacy, are commonly used in combination therapy with other programs.

    2.3 rituximab combined with chemotherapy

    2.3.1 rituximab rituximab + CHOP (R + CHOP) Lenz et al [10] compared 122 patients with previously untreated MCL patients randomized to CHOP and R  CHOP regimen, results of CHOP and of R  CHOP program overall response rate 75% and 94% CR rate of 7% and 34%, respectively, with a median time to treatment failure (TTF), respectively, for the 14 months and 21 months, but the median progression-free survival time (PFS) and overall survival (OS) was no significant difference between the two. Another phase Ⅱ clinical study obtained the same results and the former, R  CHOP program for MCL total efficiency is 96% CR rate was 48%, median PFS time was 16.6 months in CR and not the between patients achieved CR, the median PFS time difference was not statistically significant [11]. As can be seen from the above two studies, the of R  CHOP regimen in MCL efficiency and CR rates than CHOP alone program has significantly improved, but whether it can prolong the the MCL patient’s median survival time requires further study.

    2.3.2 rituximab + Hyper  CVAD (R + Hyper  CVAD) in a phase Ⅱ clinical study, Romaguera [12] 100 cases of MCL patients treated with R  Hyper  CVAD program for 6 to 8 cycle, with an average follow-up time of 40 months in the 97 patients evaluable patients, the total efficiency is 97%, including 87% of the patients achieved a CR and 3-year disease-free survival and 3-year overall survival rates were 64% ≤ 65 years of age and> 65-year-old group CR rates were 89% and 84% and 82% in the subgroup analysis (the difference was not statistically significant), but the three-year failure-free survival (FFS) and OS rates were 73 and 50% and 86% of 74% (statistically significant difference), and> 65-year-old group was significantly higher incidence of adverse reactions, so this program a higher CR rate and longer survival time, but Unfortunately, the chemotherapy caused adverse reactions of the blood system is significantly increased, especially in patients age> 65 years, especially the performance, so this program is not suitable as a standard program of elderly patients with MCL. Brad [13] for the side effects of this program, Hyper  CVAD program in group B program exclude that without methotrexate and cytarabine, only with cyclophosphamide, doxorubicin, Changchun new alkali and dexamethasone joint US-rituximab chemotherapy, the formation of a modified Hyer  CVAD + R in the treatment of 22 cases of MCL patients, the results of chemotherapy toxicity after some relief, and for age> 60-year-old patient also showed good resistance by the R + CHOP program still has a higher CR rate and longer disease-free survival time.

    Although the above two studies reflect the advantage of R + Hyper  CVAD program in MCL treatment, but more serious side effects limit its extensive application in MCL patients need a large multi-center clinical trials and longer The follow-up to prove that this program is to improve the the MCL patient’s long-term survival rate.

    2.3.3 MabThera + fludarabine joint program Thomas [14] 16 patients had received CHOP chemotherapy MCL patients with fludarabine, cyclophosphamide + US rituximab combined with chemotherapy (R + FC program) The overall response rate was 75%, CR rate was 56%, median disease-free survival time was 11 months, compared with CHOP alone program to obtain a higher response rate and CR rate. Obtained the same results and previous research in the study of of Forstpointer [15], his US-Luo Hua (R), the fludarabine Bin (F), cyclophosphamide (C), methotrexate (M) joint chemotherapy (R + FCM program) in the treatment of 147 cases of lymphoma patients, including 72 patients with follicular lymphoma (FL) patients and 52 patients with MCL patients, they were randomly divided into two groups, one group of patients alone FCM program, group of patients with R + FCM program, including 48 cases of MCL patients evaluable R + FCM program compared with the FCM program, higher overall response rate, CR rate and the PR rate, including two programs in MCL patients in overall response rate of 58% and 46%, respectively, at the same time observed R + the FCM regimen MCL patients have a higher overall survival.

    As can be seen, rituximab in combination with traditional chemotherapy significantly improved CR rate and OS rate of MCL patients, and even expected to improve survival.

    2.4 autologous stem cell transplantation (ASCT)

    Currently, autologous stem cell transplantation in MCL application has many clinical studies. Recent the European MCL collaboration group to do a randomized controlled trial, they will be 122 patients achieved CR or PR after CHOP regimen MCL patients were randomly divided into two groups, one with ASCT treatment control group treated with interferon  α results of the the ASCT group of median disease-free survival was significantly longer than the control group for 39 months and 17 months, respectively (P = 0.0108), but no significant difference in the 3-year survival rates, respectively, 83% and 77% (P = 0.18 ) [16]. Mangel [17] such as the study, 20 cases accepted ASCT + rituximab treatment of MCL patients compared with 40 cases receiving traditional chemotherapy (CHOP program) MCL patients, their 3-year disease-free survival rates, respectively, for 89% and 29% ( P <0.00001), 3-year overall survival rates were 88% and 65% (P = 0.052).

    Above studies have shown that, after ASCT treatment of patients with longer disease-free survival time and a higher survival rate, but due to the limited follow-up time, the relatively small sample size, and the lack of a large multi-center randomized controlled trial comparing Therefore ASCT whether it can really change the MCL adverse prognostic further research is needed.

    2.5 radiotherapy and radioimmunotherapy (RIT)

    MCL is a systemic disease, radiotherapy is rarely used in the treatment of MCL. Rosenbluth et al [18] reported a retrospective analysis of 21 MCL patients receiving local regional radiation therapy, these patients are once received chemotherapy for advanced or recurrent patients, and the results show the partial response rate was 100%, local CR rate of 64%, the local PR rate of 36%, and did not see in the course of treatment Ⅲ degree of toxicity, this study only showed that radiotherapy can improve local control rates, but whether it can improve long-term survival more research is needed to confirm.

    Radioimmunotherapy (RIT), radionuclides (131I, 90Y) in combination with anti-CD20 monoclonal antibody alone, radiotherapy selectively concentrated in the tumor cell killing tumor cells while reducing radiation damage to normal tissue a method of treatment [19]. Gopal et al [20] rituximab with radioactive 131I bind to form a both a targeting radioactive drugs bound 131I 20 ~ 25Gy radiation dose, they will this drug for 16 MCL patients, the plus after treatment with autologous stem cell transplantation, the results of the total response rate of 100%, in the course of treatment, no treatment-related deaths occurred, 12 patients, 3-year disease-free survival rate of approximately 61% The survival rate was 93% after 3 years. Sankaran et al [21], 13 patients with relapsed or refractory MCL patients treated with RIT results in 12 patients evaluable patients, only 3 patients achieved CR, 3 PR, 6 patients invalid patients achieved CR only two cases of progression-free survival time of 1, and the remaining patients were in relapse within 4 months. Thus, RIT is a new treatment, but its efficacy in MCL also temporarily can not be sure, despite the from above first study found RIT + ASCT achieved some exciting results, but still in clinical trials, but also not as the MCL conventional treatment.

    2.6 new drugs in the MCL

    Boron is approved by the FDA in 2003 for relapsed multiple myeloma drug bortezomib (Chinese trade name: Velcade) is a proteasome inhibitor, its mechanism of action is the inhibition of tumor cell 26S proteasome, the impact of multi-level cells signal series, resulting in disorders of the intracellular environment, and ultimately lead to cell death. Goy et al [22] 33 patients with refractory MCL patients relapse with boron bortezomib treatment, boron bortezomib 1.5 mg/m2, days 1,4,8,11, one cycle every 21 days, up to six courses results in 29 patients were evaluable for efficacy, the overall response rate was 41%, 6 cases (20.7%) reached CR, 6 PR 6-month PFS rate was 42%. Another study obtained the same results, Connor et al [23] with bortezomib in the treatment of 11 cases of MCL patients, the results of the overall response rate was 46%, including one case up to CR, 4 PR, 4 cases of stable disease. Visible bortezomib in clinical trials show preliminary efficacy of currently need more clinical studies are needed to further confirmed its role in the treatment of MCL.

    The anti-tumor effect of thalidomide has been proven in many clinical and basic tests Kaufmann et al [24] with thalidomide plus Rituximab treatment of 16 patients with relapsed, refractory MCL patients, results overall response rate was 81% CR rate was 31%, 3-year disease-free survival time was 20.4 months, 3-year survival rate was 75%, compared to this program with traditional chemotherapy in CR rate, 3-year disease-free survival time, 3 years survival rates have significantly improved, and the toxic side effects is small.

    3 Prospects

    Although most people think that mantle cell lymphoma, intermediate grade lymphoma, but its long-term survival rate is very low, although a lot of new treatments and new drugs improve the the MCL patient’s CR rate, but still can not improve long-term survival of patients. Therefore need to develop new treatment options, and evaluate them with the science of clinical research methods, try a real change in the prognosis of MCL patients, and toxic side effects of chemotherapy. We look forward to more new drugs to change the embarrassing situation of the MCL treatment, but also hope that the large sample of clinical trials to evaluate existing programs and to establish MCL treatment of first-line program, a unified understanding of the MCL treatment.