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1.  Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma 
American journal of hematology  2015;90(6):E111-E116.
A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naïve patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the mantle cell lymphoma International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33% – 68%) and the 5-year OS was 85% (95% CI 73% – 97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL.
PMCID: PMC4439262  PMID: 25737247
2.  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
3.  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
4.  Longer‐term follow‐up and outcome by tumour cell proliferation rate (Ki‐67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL‐001(EMERGE) pivotal trial 
British Journal of Haematology  2015;170(4):496-503.
Patients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.
PMCID: PMC5029780  PMID: 25921098
efficacy; Ki‐67; lenalidomide; mantle cell lymphoma; safety
5.  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
7.  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
8.  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
9.  Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats 
PLoS ONE  2016;11(1):e0147212.
Background and Aims
By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation.
Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment.
In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release.
The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis.
PMCID: PMC4731147  PMID: 26820153
10.  Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults 
Neuro-Oncology  2007;9(3):354-363.
Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33–74 years), and median KPS was 70 (range, 60–100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted.
PMCID: PMC1907419  PMID: 17452651
angiogenesis; antiangiogenesis; clinical trial; glioblastoma; metronomic chemotherapy
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma 
The New England journal of medicine  2015;373(19):1835-1844.
Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy.
We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life.
A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome (“tumor flare”) (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life.
Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; number, NCT01472562.)
PMCID: PMC4710541  PMID: 26535512
17.  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
18.  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
19.  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
20.  Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study 
Oncotarget  2016;7(22):33331-33339.
Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P <0.05). At a median follow-up of 96 months, median PFS for T-CHOP group was still not reached yet, and in CHOP group it was 22.9 months (95% CI [0-50.4]). (P=0.163). Median overall survival (OS) for T-CHOP group was also not reached, and the estimated median OS for CHOP group was 83.5 months, the difference of OS between the two groups is not significant (p=0.263). But, in patients with Bcl-2 positive and Bcl-6 negative, the median PFS in T-CHOP group was longer than that in CHOP group (111.0 vs 8.5 months (P=0.017). In addition, thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity.
PMCID: PMC5078098  PMID: 27129176
thalidomide; chop; diffuse large B-cell lymphoma
21.  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
22.  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
23.  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
24.  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
25.  Effect of prognostic classification on temsirolimus efficacy and safety in patients with relapsed or refractory mantle cell lymphoma: a retrospective analysis 
Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator’s choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL).
This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category.
Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069).
This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis.
Trial registration NCT00117598.
Electronic supplementary material
The online version of this article (doi:10.1186/s40164-015-0006-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4416347  PMID: 25938001
Mantle cell lymphoma; Prognostic; Risk; Temsirolimus; Efficacy; Safety

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