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1.  Clinical features and treatment outcomes in patients with mantle cell lymphoma in Korea: Study by the Consortium for Improving Survival of Lymphoma 
Blood research  2014;49(1):15-21.
We investigated the clinical features and treatment outcomes of patients with mantle cell lymphoma (MCL) in Korea.
We retrospectively analyzed the clinical characteristics and prognosis of 131 patients diagnosed with MCL between January 2004 and December 2009 at 15 medical centers in Korea; all patients received at least 1 chemotherapeutic regimen for MCL.
The median age for the patients was 63 years (range, 26-78 years), and 77.9% were men. A total of 105 patients (80.1%) had stage III or IV MCL at diagnosis. Fifty-two patients (39.7%) were categorized with high- or high-intermediate risk MCL according to the International Prognostic Index (IPI). Eighteen patients (13.7%) were in the high-risk group according to the simplified MCL-IPI (MIPI). The overall incidence of extranodal involvement was 69.5%. The overall incidence of bone marrow and gastrointestinal involvements at diagnosis was 41.2% and 35.1%, respectively. Cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab were used frequently as the first-line treatment (41.2%). With a median follow-up duration of 20.0 months (range, 0.2-77.0 months), the overall survival (OS) at 2 years was 64.7%, while the event-free survival (EFS) was 39.7%. Multivariate analysis showed that the simplified MIPI was significantly associated with OS. However, the use of a rituximab-containing regimen was not associated with OS and EFS.
Similar to results from Western countries, the current study found that simplified MIPI was an important prognostic factor in Korean patients with MCL.
PMCID: PMC3974951  PMID: 24724062
Mantle cell lymphoma; Epidemiology; Trend; Survival; Chemotherapy; Rituximab
2.  Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial 
The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ≥3, and high tumor burden by modified Groupe d’Etude des Lymphomas Folliculaires [GELF] criteria).
Patients aged ≥18 years with grade 1/2 FL, ≥1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2–5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS.
103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ≥3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%).
High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility.
Trial registration
The phase 3 LYM3001 trial is registered with, with the identifier NCT00312845.
PMCID: PMC3502148  PMID: 23088650
Bortezomib; Follicular; High risk; Lymphoma; Rituximab
3.  The clinical features, therapeutic responses, and prognosis of the patients with mantle cell lymphoma 
Chinese Journal of Cancer  2012;31(7):348-353.
Mantle cell lymphoma (MCL), a special type of non-Hodgkin's lymphoma, is incurable through conventional treatment. This study aimed to analyze the clinical features, therapeutic responses, and prognosis of patients with MCL. Clinical data of 30 patients with MCL treated in our hospital between April 2006 and July 2011 were analyzed. Eighteen patients were treated with CHOP plus rituximab (R-CHOP) regimen, 12 underwent conventional chemotherapy. The median age of the 30 patients was 58 years, 23 were men, all patients had Cyclin D1 overexpression, 29 (96.7%) had advanced disease, 11 (36.7%) had bone marrow involvement, 9 (30.0%) had gastrointestinal involvement, and 15 (50.0%) had splenomegaly. The complete response (CR) rate and overall response rate (ORR) were significantly higher in patients undergoing R-CHOP immunochemotherapy than in those undergoing conventional chemotherapy (38.9% vs. 16.7%, P = 0.187; 72.2% vs. 41.4%, P = 0.098). The difference of 2-year overall survival rate between the two groups was not significant (P = 0.807) due to the short follow-up time. The 2-year progression-free survival (PFS) rate was higher in R-CHOP group than in conventional chemotherapy group (53% vs. 25%, P = 0.083), and was higher in patients with a lower mantle cell lymphoma international prognostic index (MIPI) (51% for MIPI 0-3, 33% for MIPI 4-5, and 0% for MIPI 6-11, P = 0.059). Most patients with MCL were elderly; in an advanced stage; showed a male predominance; and usually had bone marrow involvement, gastrointestinal involvement, or splenomegaly. R-CHOP regimen could improve the CR rate and ORR of MCL patients. MIPI can be a new prognostic index for predicting the prognosis of advanced MCL.
PMCID: PMC3777499  PMID: 22704490
Mantle cell lymphoma; clinical features; therapeutic efficacy; prognosis
Gynecologic oncology  2007;105(2):508-516.
A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy, and to correlate angiogenesis biomarker expression with clinical outcome.
Consenting patients were treated until progression or intolerable toxicity with an oral starting dose of 200 mg thalidomide/day that was to increase by 200 mg every 2 weeks to a target dose of 1000 mg/day. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and soluble endothelial protein C receptor (sEPCR) were analyzed by ELISA in pre and post-treatment specimens.
Twenty-four of 27 patients enrolled in the study were eligible, of whom 2 reached the target dose, 8 progressed before achieving the target dose and 14 refused or had toxicity that prohibited escalation. Two patients (8.3%) remained progression-free ≥ 6 months. There were 3 (12.5%) with partial responses, 2 (8.3%) with stable disease, 15 (62.5%) with increasing disease, and 4 (16.7%) who were inevaluable for response. Median progression-free survival and overall survival were 1.7 months and 6.3 months, respectively. No grade 4 toxicities were observed. Common grade 3 toxicities included hematologic (n=3), cardiovascular (n=3), constitutional (n=3), and neurologic (n=4). Thalidomide did not decrease VEGF or bFGF levels but reduced sEPCR levels in serum. Elevated plasma vascular endothelial growth factor levels were associated with increased risk of progression and death.
Thalidomide demonstrated limited ability to delay progression (as measured by PFS at 6 months), produce objective responses or reduce angiogenic marker levels in chemotherapy refractory endometrial cancer. VEGF level appears to be prognostically significant in such patients, independent of thalidomide treatment.
PMCID: PMC1931832  PMID: 17306350
5.  Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer 
British Journal of Cancer  2000;82(4):812-817.
To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-α) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33–62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P< 0.05) and maintained appetite (P< 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-α and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted. © 2000 Cancer Research Campaign
PMCID: PMC2374399  PMID: 10732751
Thalidomide; TNF-α; renal cell carcinoma
6.  A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma 
British Journal of Haematology  2014;165(6):768-776.
Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.
PMCID: PMC4282031  PMID: 24617454
vorinostat; indolent B-cell non-Hodgkin lymphoma; follicular lymphoma; phase II trial; HAT mutation
7.  Flavopiridol, Fludarabine, and Rituximab in Mantle Cell Lymphoma and Indolent B-Cell Lymphoproliferative Disorders 
Journal of Clinical Oncology  2009;28(3):418-423.
Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.
Patients and Methods
Therapy included fludarabine 25 mg/m2 intravenously (IV) days 1 to 5 and rituximab 375 mg/m2 day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m2 by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m2 30-minute IVB + 20 mg/m2 4-hour IV infusion (n = 3); or 30 mg/m2 + 30 mg/m2 (n = 14).
Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.
FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
PMCID: PMC2815704  PMID: 20008633
8.  Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis 
BMC Cancer  2014;14:153.
Ki-67 is a nuclear protein involved in cell proliferation regulation, and its expression has been widely used as an index to evaluate the proliferative activity of lymphoma. However, its prognostic value for lymphoma is still contradictory and inconclusive.
PubMed and Web of Science databases were searched with identical strategies. The impact of Ki-67 expression on survival with lymphoma and various subtypes of lymphoma was evaluated. The relationship between Ki-67 expression and Diffuse Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) was also investigated after the introduction of a CD-20 monoclonal antibody rituximab. Furthermore, we evaluated the association between Ki-67 expression and the clinical-pathological features of lymphoma.
A total of 27 studies met the inclusion criteria, which comprised 3902 patients. Meta-analysis suggested that high Ki-67 expression was negatively associated with disease free survival (DFS) (HR = 1.727, 95% CI: 1.159-2.571) and overall survival (OS) (HR = 1.7, 95% CI: 1.44-2) for lymphoma patients. Subgroup analysis on the different subtypes of lymphoma suggested that the association between high Ki-67 expression and OS in Hodgkin Lymphoma (HR = 1.511, 95% CI: 0.524-4.358) was absent, while high Ki-67 expression was highly associated with worse OS for Non-Hodgkin Lymphoma (HR = 1.777, 95% CI: 1.463-2.159) and its various subtypes, including NK/T lymphoma (HR = 4.766, 95% CI: 1.917-11.849), DLBCL (HR = 1.457, 95% CI: 1.123-1.891) and MCL (HR = 2.48, 95% CI: 1.61-3.81). Furthermore, the pooled HRs for MCL was 1.981 (95% CI: 1.099-3.569) with rituximab and 3.123 (95% CI: 2.049-4.76) without rituximab, while for DLBCL, the combined HRs for DLBCL with and without rituximab was 1.459 (95% CI: 1.084-2.062) and 1.456 (95% CI: 0.951-2.23) respectively. In addition, there was no correlation between high Ki-67 expression and the clinical-pathological features of lymphoma including the LDH level, B symptoms, tumor stage, extranodal site, performance status and IPI score.
This study showed that the prognostic significance of Ki-67 expression varied in different subtypes of lymphoma and in DLBCL and MCL after the introduction of rituximab, which was valuable for clinical decision-making and individual prognostic evaluation.
PMCID: PMC3995999  PMID: 24597851
Ki-67; Prognostic value; Lymphoma; Meta-analysis
9.  The Emerging Role of Lenalidomide in the Management of Lymphoid Malignancies 
Lenalidomide, a novel immunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell lymphomas. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on preclinical models and early correlative studies conducted in parallel to clinical trials, lenalidomide has been found to enhance natural killer (NK)- and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and, to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all of these biological effects appear to play a role in the activity observed in CLL or lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the antitumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory CLL, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) treated with lenalidomide single agent. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated CLL or CLL/lymphoma patients with bulky adenopathy. Correlative studies and/or retrospective analysis of lenalidomide-treated patients had identified several biomarkers associated with clinical endpoints in CLL (i.e. changes in tumor necrosis factor alpha [TNF-α] or vascular endothelial growth factor [VEGF] levels) or DLBCL (non-GCB phenotype) patients, but need to be validated. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with rituximab in previously untreated indolent lymphoma are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting or in combination with other target-specific agents (i.e. proteasome inhibitors) in aggressive lymphomas is being addressed in ongoing clinical trials. In summary, lenalidomide is emerging as a biologically active and novel agent in the treatment of B-cell neoplasms. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory CLL or B-cell lymphomas and identify the subset of patients most likely to gain clinical benefit.
PMCID: PMC3573391  PMID: 23556075
B-cell lymphoma; chronic lymphocytic leukemia; immunomodulatory drug; lenalidomide
10.  Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study 
Annals of Oncology  2013;24(11):2892-2897.
Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphoma
Lenalidomide was administered orally 25 mg daily on days 1–21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR).
Fifty-seven patients with relapsed/refractory, advanced-stage MCL had a median of three prior therapies. The ORR was 35% [complete response (CR)/CR unconfirmed (CRu) 12%], with a median duration of response (DOR) of 16.3 months (not yet reached in patients with CR/CRu) by blinded independent central review. The median time to first response was 1.9 months. Median progression-free survival was 8.8 months, and overall survival had not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), and anemia (13%).
These results show the activity of lenalidomide in heavily pretreated, relapsed/refractory MCL. Responders had a durable response with manageable side-effects. Clinical trial number posted on NCT00413036.
PMCID: PMC3811905  PMID: 24030098
lenalidomide; mantle cell lymphoma; non-Hodgkin lymphoma
11.  The treatment of advanced renal cell cancer with high-dose oral thalidomide 
British Journal of Cancer  2001;85(7):953-958.
Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-α, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34–76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1–29), 7 (32%; 95% CI: 14–55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8–45) had stable disease for between 3 and 6 months. We also measured levels of TNF-α, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD ≥ 3 months or an objective response, a statistically significant decrease in serum TNF-α levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (≥ grade II, 10 patients), constipation (≥ grade II, 11 patients) and neuropathy (≥ grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies. © 2001 Cancer Research Campaign
PMCID: PMC2375104  PMID: 11592764
thalidomide; renal cell carcinoma
12.  Thalidomide plus chemotherapy exhibit enhanced efficacy in the clinical treatment of T-cell non-Hodgkin’s lymphoma: A prospective study of 46 cases 
Molecular and Clinical Oncology  2014;2(5):695-700.
The treatment of T-cell non-Hodgkin’s lymphoma (T-NHL) remains challenging. There is currently no standard regimen for the treatment of T-NHL in the first- or second-line setting. Thalidomide was previously shown to exert antitumor effects through inhibiting angiogenesis, promoting apoptosis and immunomodulatory activity. However, all the previous studies on the treatment of lymphoma with thalidomide included patient samples of limited size. In the present study, 46 cases of eligible T-NHL patients were randomized into i) the control group (conventional combined chemotherapy, n=22) and ii) the thalidomide group (thalidomide plus combined chemotherapy, n=24). The median dose of thalidomide was 200 mg (range, 150–400 mg) every night, without reported severe side effects. The clinical response to treatment was as follows: Complete response (CR) in 12 cases, partial response (PR) in 7, stable disease (SD) in 1 and progressive disease (PD) in 4 cases in the thalidomide group; and CR in 8 cases, PR in 6, SD in 3 and PD in 5 cases in the control group. The CR rate was 50.0 and 36.4% in the thalidomide and the control groups, respectively (P<0.05). The median progression-free and overall survival were 12 and undefined months, respectively, in the thalidomide group and 6 and 17 months, respectively, in the control group. The toxicity profile was considered acceptable in both groups. Our results indicated that thalidomide plus combined chemotherapy may exhibit enhanced efficacy in the clinical treatment of T-NHL. In addition, this type of treatment may reduce the frequency of adverse gastrointestinal reactions and help alleviate fear of chemotherapy. Therefore, thalidomide plus combined chemotherapy may be a viable option for the clinical treatment of T-NHL.
PMCID: PMC4106729  PMID: 25054032
non-Hodgkin’s lymphoma; T-cell non-Hodgkin’s lymphoma; thalidomide; chemotherapy; treatment
13.  Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909 
Journal of Clinical Oncology  2009;27(36):6101-6108.
Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL.
Patients and Methods
The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab.
There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%.
The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.
PMCID: PMC2793032  PMID: 19917845
14.  Temsirolimus and Rituximab in Patients with Relapsed or Refractory Mantle Cell Lymphoma: a multi-center Phase 2 Study 
The lancet oncology  2011;12(4):361-368.
Temsirolimus is an mTOR inhibitor with single-agent antitumor activity in patients with mantle cell lymphoma (MCL). We therefore tested the efficacy and toxicity of temsirolimus in combination with rituximab in patients with relapsed or refractory MCL.
Patients received temsirolimus 25 mg intravenously weekly while on study. Four weekly doses of rituximab 375mg/m2 were given during the first cycle followed by a single dose of rituximab every other 28-day cycle thereafter. Responding patients after six cycles could continue treatment for a total of 12 cycles and were then observed without additional maintenance therapy. The primary endpoint was the proportion of patients with either rituximab-sensitive or rituximab-refractory disease who had a partial response or better. The analyses were done on all patients who received treatment. The study was registered with, number NCT00109967.
Seventy-one patients were enrolled between May 2005 and March 2009. Sixty-nine patients are evaluable and are included in the final analysis. Patients had received a median of two prior therapies (range, 1-9), 30·4% (21/69) had received a prior stem cell transplant and 30·4% (21/69) were rituximab-refractory. The overall response rate (ORR) was 59·4% (41/69 patients) with 18·8% (13/69) complete responses and 40·6% (28/69) partial responses. The ORR for rituximab-sensitive patients was 62·5% (30/48; 95% CI 47·4-76·1%) and 52·4% (11/21; 95% CI 29·8 – 74·3%) for rituximab-refractory patients. The most common treatment-related grade 3-4 adverse events were thrombocytopenia in 16 patients (23·2%), neutropenia in 15 (21·7%), fatigue in 10 (14·5%), pneumonia in 7 (10·1%), lymphopenia in 7 (10·1%), pneumonitis in 5 (7·2%), dyspnea in 5 (7·2%) and hypertriglyceridemia in 5 (7·2%).
mTOR inhibitors in combination with rituximab could have a role in the treatment of patients with relapsed and refractory MCL.
PMCID: PMC3106222  PMID: 21440503
Mantle Cell Lymphoma; mTOR Inhibitor; Rituximab; Phase 2 Trial
15.  SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study 
British Journal of Haematology  2014;166(1):98-108.
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.
PMCID: PMC4282019  PMID: 24684350
lymphoid malignancies; molecular diagnostics; prognostic factors
16.  Long-term Results of the Treatment of Patients With Mantle Cell Lymphoma With Cladribine (2-CDA) Alone (95-80-53) or 2-CDA and Rituximab (N0189) in the North Central Cancer Treatment Group 
Cancer  2008;113(1):108-116.
The objective of this study was to test cladribine (2-CDA) alone and in combination with rituximab in patients with mantle cell lymphoma (MCL).
Patients with MCL were treated on 2 sequential trials. In Trial 95-80-53, patients received 2-CDA as initial therapy or at relapse. In Trial N0189, patients received combination 2-CDA and rituximab as initial therapy. In both trials, 2-CDA was administered at a dose of 5 mg/m2 intravenously on Days 1 through 5 every 4 weeks for 2 to 6 cycles, depending on response. In Trial N0189, rituximab 375 mg/m2 was administered on Day 1 of each cycle.
Results were reported for 80 patients. Twenty-six previously untreated patients and 25 patients who had recurrent disease with a median age of 68 years received single-agent 2-CDA. The overall response rate (ORR) was 81% with 42% complete responses (CRs) in the previously untreated group. The median progression-free survival (PFS) was 13.6 months (95% confidence interval [95% CI], 7.2–22.1 months), and 81% of patients remained alive at 2 years. The ORR was 46% with a 21% CR rate in the recurrent disease group. The median PFS was 5.4 months (95% CI, 4.6–13.1 months), and 36% of patients remained alive at 2 years. Twenty-nine eligible patients with a median age of 70 years received 2-CDA plus rituximab. The ORR was 66% (19 of 29 patient), and the CR rate was 52% (15 of 29 patients). The median duration of response for patients who achieved a CR had not been reached at the time of the current report, and only 3 of the patients who achieved a CR developed recurrent disease at a median follow-up of 21.5 months.
2-CDA had substantial single-agent activity in both recurrent and untreated MCL, and the results indicated that it may be administered safely to elderly patients. The addition of rituximab to 2-CDA may increase the duration of response.
PMCID: PMC3465670  PMID: 18470909
mantle cell lymphoma; cladribine; response duration; rituximab
17.  A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213 
Annals of Oncology  2013;24(6):1587-1593.
Rituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.
Patients and methods
Forty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35–69.8 years).
Nineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤65 years) and the median overall survival (OS) was 6.8 years.
Although this regimen is toxic, it is active for patients ≤65 years of age and can be given both at academic centers and in experienced community centers.
PMCID: PMC3660082  PMID: 23504948
dose-intensive; mantle cell; rituximab
18.  Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents 
Molecular Cancer  2014;13:159.
Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive.
Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies.
Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts.
Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.
PMCID: PMC4094598  PMID: 24972933
Mantle cell lymphoma (MCL); Cytarabine; Drug resistance; Nucleotide salvage pathway; Proteomics; Mass spectrometry
19.  Angiogenesis in nodal B cell lymphomas: a high throughput study 
Journal of Clinical Pathology  2006;60(5):476-482.
To assess the biological significance of vascular endothelial growth factor (VEGF) A, VEGF receptor (Flk‐1) and cyclooxygenase 2 (COX2) expression with respect to microvessel density (MVD), proliferative activity (Ki‐67), expression of p53 and clinical presentation in a large cohort of nodal B cell lymphomas.
An immunohistochemical and morphometric study was performed on a validated tissue microarray containing 271 B cell lymphoma specimens, 197 of which included follow‐up data. Statistical assessment was done by Pearson's χ2 test, Spearman's rank correlation coefficient, analysis of variance and survival analysis.
266 (98%) cases were evaluable. Strong VEGF expression was observed in only 20 diffuse large B cell lymphomas (DLBCLs). Flk‐1 and COX2 were expressed in 53 and 21 cases, respectively, mainly in DLBCLs, follicular lymphoma (FL) grade 3 and mantle cell lymphomas (MCLs), in a low proportion of cells. MVD decreased in the following order: DLBCLs, FLs, MCLs and small lymphocytic lymphomas/chronic lymphocytic leukaemia (SLL/CLLs). VEGF expression correlated with Ki‐67, p53 and COX2 expression in the whole cohort and in DLBCLs. Flk‐1 expression correlated with Ki‐67 in the cohort and in SLL/CLL and FL grade 1 and 2. COX2 expression correlated with Ki‐67 and p53. The analysed angiogenesis parameters did not correlate with clinical parameters or survival.
Angiogenesis plays a differential role in various B cell lymphomas. Aggressive lymphomas express the potential molecular therapeutic targets VEGF and COX2, and have higher MVD. In a few low proliferation‐fraction lymphomas, Flk‐1 might have a role in proliferative advantage. Therapeutic strategies aimed at angiogenesis should take into account lymphoma heterogeneity.
PMCID: PMC1994554  PMID: 16790692
20.  Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma 
Journal of Clinical Oncology  2012;30(36):4462-4469.
The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known.
Patients and Methods
In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation.
After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01).
In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.
PMCID: PMC3646314  PMID: 23091101
21.  Autologous stem cell transplantation for mantle cell lymphoma – single centre experience 
Contemporary Oncology  2013;17(5):456-459.
Aim of the study
Mantle cell lymphoma (MCL) is a B-cell neoplasm showing resistance to conventional chemotherapy. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may result in higher progression-free (PFS) and overall survival (OS) when used as a consolidation for younger and fit patients.
Material and methods
We retrospectively evaluated the results of ASCT for MCL. Patients were transplanted after achieving first or subsequent complete or partial response after conventional chemotherapy.
Twenty patients (7 male and 13 female) at median age of 59 years (range 41–68) were included. 90% of transplanted patients had stage III/IV disease at diagnosis and low, intermediate and high MIPI scores occurred in 5, 9 and 6 patients respectively. Induction chemotherapy consisted of the R-CHOP regimen in all patients except one who received R-CVAD. The disease status at transplant was as follows: first complete response (n = 13); second complete response (n = 4) and partial response (n = 3). The conditioning regimen prior to ASCT consisted of CBV and BEAM for 18 and 2 patients, respectively. The transplant-related mortality was 0% at day 100. Median OS and PFS were 48 and 29.8 months, respectively. The estimated 5-year OS and PFS were found to be 52% and 35%, respectively. After median follow-up after ASCT of 36 months (range 11–73), 10 patients were alive with 8 remaining in complete remission (CR) whereas 2 relapsed and received salvage chemotherapy. Ten patients died from disease recurrence and subsequent chemoresistance.
ASCT as a consolidation for MCL patients is found to be an effective and safe procedure.
PMCID: PMC3934030  PMID: 24596536
mantle cell lymphoma; autologous stem cell transplantation; results
22.  A phase II trial of thalidomide and procarbazine in adult patients with recurrent or progressive malignant gliomas 
Journal of neuro-oncology  2011;106(3):611-617.
Thalidomide and procarbazine have demonstrated single agent activity against malignant gliomas (MG). We evaluated the combination of thalidomide and procarbazine with a single arm phase II trial in adults with recurrent or progressive MG. Procarbazine was given at a dose of 250 mg/m2/d × 5day q 28 days. Thalidomide was administered at a dose of 200 mg/day continuously. Intrapatient dose escalation of thalidomide was attempted (increase by 100 mg/day weekly as tolerated) to a maximum of 800 mg/day. The primary outcome was tumor response, assessed by MRI and CT. Secondary outcomes were progression free survival (PFS), overall survival (OS) and toxicity. In addition, quality of life questionnaires were performed at baseline and prior to each odd cycle in all treated patients. Eighteen patients (median age of 50) were accrued and received a total of 36 cycles (median 2) of therapy. The median maximum thalidomide dose achieved was 400 mg (range 0–800). No complete or partial responses were seen. One patient (6%) experienced stable disease, fourteen (78%) progressed as best response and three (17%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5–2.5). Seventeen patients have died (one patient lost to follow-up after progression); median survival from enrollment was 7.6 months (95% CI, 3.5–9.4). Grade 3/4 drug related toxicity was minimal. Quality of life diminished over time. The combination of thalidomide and procarbazine demonstrated no efficacy in this trial.
PMCID: PMC3780974  PMID: 21870118
Chemotherapy; Clinical trial; High grade astrocytoma; Glioblastoma multiforme; Thalidomide; Procarbazine
23.  Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation 
Journal of Clinical Oncology  2011;29(22):3023-3029.
High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown.
Patients and Methods
To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.
The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.
An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.
PMCID: PMC3157964  PMID: 21730271
24.  Phase I trial of metastatic renal cell carcinoma with oral capecitabine and thalidomide 
Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF). Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment.
Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm2 twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment.
Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%), a stable disease in 4/12 patients (33%) and progression was seen in 7 patients (58%). The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months.
Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.
PMCID: PMC2716555  PMID: 19675744
metastasized renal cell carcinoma; 5-FU; thalidomide; phase I trial
25.  Combination bortezomib and rituximab treatment affects multiple survival and death pathways to promote apoptosis in mantle cell lymphoma 
mAbs  2009;1(1):31-40.
Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFκB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFκB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
PMCID: PMC2715189  PMID: 20046572
mantle cell lymphoma; proteasome inhibition; CD20; survival and death pathways; apoptosis

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