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1.  Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909 
Journal of Clinical Oncology  2009;27(36):6101-6108.
Purpose
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.
Results
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%.
Conclusion
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.
doi:10.1200/JCO.2009.22.2554
PMCID: PMC2793032  PMID: 19917845
2.  Detection of Asymptomatic Cardiac Metastasis and Successful Salvage Chemotherapy Comprising a Prednisone, Etoposide, Procarbazine, and Cyclophosphamide Regimen in an Elderly Japanese Patient Suffering from a Delayed Recurrence of Diffuse Large B-Cell Lymphoma 
Case Reports in Oncology  2012;5(1):62-68.
We report a case of facial diffuse large B-cell lymphoma (DLBCL) associated with recurrent metastasis in the heart and other sites in a 76-year-old Japanese woman. Initially, she developed DLBCL in her left upper eyelid that spread into the left orbit (Ann Arbor classification stage I). The lesion went into clinical regression after 4 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by radiotherapy. More than 3 years later, the lymphoma recurred in her facial skin, together with metastases in the mediastinal lymph nodes and the heart; the tumor in the heart was successfully detected by PET/CT and cardiac MRI. To treat the recurrent lesions, we performed a salvage chemotherapy regimen comprising prednisone, etoposide, procarbazine, and cyclophosphamide, which successfully induced tumor regression.
doi:10.1159/000336447
PMCID: PMC3304513  PMID: 22423248
Malignant lymphoma; Diffuse large B-cell lymphoma; Recurrence; Cardiac metastasis; Cardiac MRI; PET/CT; Salvage chemotherapy; Prednisone, etoposide, procarbazine, and cyclophosphamide regimen
3.  Chemotherapy Combinations With Monoclonal Antibodies in Non-Hodgkin’s Lymphoma 
Seminars in hematology  2008;45(2):90-94.
Although the use of monoclonal antibodies as single agents has had a tremendous impact on the care of patients with non-Hodgkin’s lymphoma (NHL), the greatest benefit has been generated by the addition of monoclonal antibodies to conventional cytotoxic chemotherapy. Rituximab is the monoclonal antibody responsible for all clinical improvement noted to date. The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (R-CHOP regimen) improves the response rate, progression-free survival (PFS), and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL). Adding rituximab to CHOP chemotherapy improves response rates and PFS in mantle cell lymphoma (MCL). Finally, the addition of rituximab to a variety of chemotherapy regimens improves the response rates, PFS, and OS in follicular lymphoma (FL). Several other (epratuzumab, bevacizumab, alemtuzumab) monoclonal antibody–chemotherapy combinations are currently under study in NHL. This review will summarize the data supporting the addition of rituximab to chemotherapy in NHL and discuss preliminary data regarding the use of other monoclonal antibodies in combination with chemotherapy.
doi:10.1053/j.seminhematol.2008.02.003
PMCID: PMC2919066  PMID: 18381103
4.  Tackling mantle cell lymphoma (MCL): Potential benefit of allogeneic stem cell transplantation 
Mantle cell lymphoma (MCL) is a type of non-Hodgkins lymphoma (NHL) associated with poor progression-free and overall survival. There is a high relapse rate with conventional cytotoxic chemotherapy. Intensive combination chemotherapy including rituximab, dose intense CHOP- (cyclophosphamide-doxorubicin-vincristine-prednisone) like regimens, high dose cytarabine, and/or consolidation with autologous stem cell transplant (autoSCT) have shown promise in significantly prolonging remissions. Data from phase II studies show that even in patients with chemotherapy refractory MCL, allogeneic stem cell transplant (alloSCT) can lead to long term disease control. Most patients with MCL are not candidates for myeloablative alloSCT due to their age, comorbidities, and performance status. The advent of less toxic reduced intensity conditioning (RIC) regimens, which rely more on the graft-versus-lymphoma (GVL) effect, have expanded the population of patients who would be eligible for alloSCT. RIC regimens alter the balance of toxicity and efficacy favoring its use. Treatment decisions are complicated by introduction of novel agents which are attractive options for older, frail patients. Further studies are needed to determine the role and timing of alloSCT in MCL. Currently, for selected fit patients with chemotherapy resistant MCL or those who progress after autoSCT, alloSCT may provide long term survival.
PMCID: PMC3781733  PMID: 24198514
mantle cell lymphoma; allogeneic SCT; nonmyeloablative; GVL
5.  VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study 
British journal of haematology  2011;155(2):190-197.
Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 days for 6 cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.
doi:10.1111/j.1365-2141.2011.08820.x
PMCID: PMC3188692  PMID: 21848883
bortezomib; chemotherapy; mantle cell lymphoma; non-Hodgkin lymphoma; rituximab
6.  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.
doi:10.1215/15228517-2007-006
PMCID: PMC1907419  PMID: 17452651
angiogenesis; antiangiogenesis; clinical trial; glioblastoma; metronomic chemotherapy
7.  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
8.  Molecular Action of Lenalidomide in Lymphocytes and Hematologic Malignancies 
Advances in Hematology  2012;2012:513702.
The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL). Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK) cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies.
doi:10.1155/2012/513702
PMCID: PMC3409527  PMID: 22888354
9.  Rituximab purging and maintenance therapy combined with autologous stem cell transplantation in patients with diffuse large B-cell lymphoma 
Oncology Letters  2010;1(4):733-738.
The aim of this prospective, single-arm study was to test the efficacy and tolerability of autologous stem cell transplantation (auto-SCT) combined with in vivo rituximab purging and post-transplant rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (DLBCL). This study included 12 DLBCL patients aged 18–65 years with an International Prognostic Index ≥2. The patients received 4–6 cycles of induction therapy consisting of rituximab plus cyclophosphamide, adriamycin, vincristine and prednisone followed by salvage therapy prior to stem cell mobilization. This regimen was followed by rituximab maintenance therapy (375 mg/m2 every three months for two years). Prior to auto-SCT, six patients (50%) achieved complete remission (CR) and six (50%) achieved unconfirmed complete remission (CRu). Three months after transplantation, 11 patients (91.7%) achieved CR and one achieved CRu. After two cycles of rituximab maintenance therapy, all 12 patients achieved CR. Long-term CR was achieved by 10 patients, while two experienced relapse at 14 and 20 months after the end of rituximab maintenance therapy. The median follow-up period was 44 months (range 35–61). Disease-free survival was noted in 10 patients, while two experienced relapse. The three-year overall survival (OS) and progression-free survival (PFS) were 100 and 83%, respectively. Prolonged hypogammaglobulinemia occurred in two patients, although no increase in major infections was observed. Hepatitis B surface antigen was continuously negative in all 12 patients. Our results demonstrated that auto-SCT combined with in vivo rituximab purging and post-transplant rituximab maintenance is safe and effective, and may extend OS and PFS in younger high-risk DLBCL patients.
doi:10.3892/ol_00000128
PMCID: PMC3436212  PMID: 22966371
diffuse large B-cell lymphoma; autologous stem cell transplantation; rituximab purging; rituximab maintenance
10.  Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors 
Procarbazine HCl is a ‘nonclassical’ oral alkylating anticancer agent that was first synthesized in the late 1950s. It has been used in the treatment of many cancers, but its main use is in the treatment of Hodgkin’s lymphoma and brain tumors and, to a lesser extent, Non-Hodgkin’s lymphoma and primary central nervous system lymphoma. Procarbazine is a prodrug that undergoes metabolic transformation into active intermediates that are thought to inhibit DNA, RNA, and protein synthesis. Early use of procarbazine in combination with mechlorethamine, vincristine, and prednisone (MOPP) was effective in the treatment of advanced Hodgkin’s lymphoma, but late toxic effects such as secondary cancer and infertility led to its replacement by other regimens. However, its recent reintroduction in the dose-intensified BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has yielded very promising findings. Procarbazine alone, or more commonly combined in the PCV (procarbazine, lomustine [CCNU], and vincristine) regimen, is also effective in treating gliomas comprising astrocytomas, glioblastomas, and oligodendrogliomas. The most common side effects of procarbazine are gastrointestinal disturbances, myelosuppression, and central nervous system effects. In conclusion, the use of procarbazine in combination with other drugs means that it remains a major anticancer drug in the management of Hodgkin’s lymphoma and gliomas.
PMCID: PMC1936303  PMID: 18360630
procarbazine; Hodgkin’s lymphoma; non-Hodgkin’s lymphoma; lymphoma; brain tumor; glioma
11.  Rituximab in the treatment of B-cell non-Hodgkin lymphoma, focus on outcomes and comparative effectiveness 
Rituximab is an important and well established component in the treatment of many patients with B-cell non-Hodgkin lymphoma. In this paper we review recent clinical trials investigating the addition of rituximab to standard chemotherapy regimens for treatment of patients with diffuse large B cell lymphoma and follicular lymphoma. This report focuses upon treatment efficacy, quality of life, and safety of rituximab or rituximab-containing regimens. More uniquely, we review economic aspects of lymphoma treatments, including the cost of standard chemotherapy regimens with or without rituximab, cost effectiveness of rituximab in both induction and maintenance treatment, and lymphoma’s impacts on patient’s productivity and their caregivers. We conclude that adding rituximab to standard chemotherapy treatment for patients with B-cell non-Hodgkin lymphoma is safe and cost-effective in numerous settings during both induction and maintenance therapies. Despite extensive review of the literature, many important questions have yet to be answered in the rituximab era and these represent important directions for future study.
PMCID: PMC3169958  PMID: 21935313
rituximab; lymphoma; cost effectiveness; transplant; safety
12.  Novel Therapies for Aggressive B-Cell Lymphoma 
Advances in Hematology  2012;2012:302570.
Aggressive B-cell lymphoma (BCL) comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and mantle cell lymphoma (MCL). DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper.
doi:10.1155/2012/302570
PMCID: PMC3318210  PMID: 22536253
13.  High-dose Cyclophosphamide and Rituximab without Stem Cell Transplantation: a Feasibility Study for Low Grade B cell, Transformed and Mantle Cell Lymphomas 
Leukemia & lymphoma  2011;52(11):2076-2081.
Relapse after autologous stem cell transplantation for low-grade B-cell lymphoma is common secondary to ineffective conditioning and/or tumor autograft contamination. We investigated high-dose cyclophosphamide and rituximab without stem cell rescue as first-line or salvage-therapy in lymphomas. After establishing safety, accrual was increased to evaluate event-free survival (EFS). 81 adults received rituximab [375mg/mm days 1, 4, 8, 11, 45, 52], cyclophosphamide [50mg/kg days 15-18] and pegfilgrastim (day 20). Forty-two patients had low-grade B-cell lymphoma [grade I/II follicular (69%), transformed lymphoma (17%), other (15%)]: 45% were treated without measurable disease. Thirty-nine patients had mantle cell lymphoma: 82% were treated without measurable disease. All achieved hematopoietic recovery; 46% required brief hospitalizations. The 5 year EFS and overall survival (OS) for low-grade B-cell and transformed patients was 40% and 72%, respectively. The 5 year EFS and OS for the MCL patients was 39% and 62%, respectively. This low-toxicity therapeutic approach obviates the need for stem cell products and establishes a platform for future therapies.
doi:10.3109/10428194.2011.594191
PMCID: PMC3390263  PMID: 21756035
Cyclophosphamide; NHL; Mantle Cell Lymphoma
14.  Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP) 
British journal of haematology  2009;148(2):235-244.
Diffuse large B cell lymphoma (DLBCL) is clinically and biologically heterogeneous. In most cases of DLBCL, lymphoma cells coexpress vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, suggesting autocrine in addition to angiogenic effects. We enumerated microvessel density and scored lymphoma cell expression of VEGF, VEGFR1, VEGFR2 and phosphorylated VEGFR2 in 162 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone)-like regimens. VEGFR2 expression correlated with shorter overall survival (OS) independent of International Prognostic Index (IPI) (p=0.0028). Phosphorylated VEGFR2 (detected in 13% of cases) correlated with shorter progression-free survival (PFS, p=0.044) and trended toward shorter OS on univariate analysis. VEGFR1 was not predictive of survival on univariate analysis, but it did correlate with better OS on multivariate analysis with VEGF, VEGFR2, and IPI (p=0.036); in patients with weak VEGFR2, lack of VEGFR1 coexpression was significantly correlated with poor OS independent of IPI (p=0.01). These results are concordant with our prior finding of an association of VEGFR1 with longer OS in DLBCL treated with chemotherapy alone. We postulate that VEGFR1 may oppose autocrine VEGFR2 signaling in DLBCL by competing for VEGF binding. In contrast to our prior results with chemotherapy alone, microvessel density was not prognostic of PFS or OS with R-CHOP-like therapy.
doi:10.1111/j.1365-2141.2009.07942.x
PMCID: PMC2809124  PMID: 19821819
Non-Hodgkin lymphoma; VEGF; angiogenesis; tumour biology; prognostic factors
15.  Management of mantle cell lymphoma in the elderly patient 
Mantle cell lymphoma is a relatively rare B-cell lymphoma with a specific genetic lesion and a typical immunophenotypic profile. The median age is 65 years. There is no curative treatment, except allogeneic stem cell transplantation for a selected group of patients. For the majority of patients, especially the elderly, the aim of therapy should therefore be a long progression-free survival. Age and comorbidity may hamper the use of the most active treatment regimen, such as high dose cytarabine and autologous stem cell transplantation. Therefore, it is a challenge to select the most appropriate therapy for an elderly patient. Studies specifically designed for elderly patients are rare. A recently performed large randomized study for elderly patients, however, has shown that R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by maintenance rituximab can result in a long progression-free survival. For patients too frail for R-CHOP chemotherapy, a treatment should be offered that benefits the patient in reducing the symptoms of the disease without causing too many side effects. Progression or relapse will occur in all patients sooner or later. Second-line treatment should again be carefully selected. Several options are mentioned. New drugs are being developed, and new combinations are investigated. Further improvement in the outcome of patients with mantle cell lymphoma is expected. Participation in well-designed clinical trials, also by elderly patients, is important to find the real benefit that can be achieved, and to get information on the tolerability of these treatments in this age group.
doi:10.2147/CIA.S35082
PMCID: PMC3783516  PMID: 24072968
treatment; chemotherapy; malignant lymphoma; mantle cell lymphoma; elderly; MCL
16.  Ongoing trials in low-grade lymphoma 
Hematology Reports  2011;3(3 Suppl):e5.
There are many therapies available for the management of low-grade lymphoma. With follicular lymphoma, for example, combination of chemotherapy and rituximab (immuno-chemotherapy) and consecutive maintenance therapy for 2 years is the current standard of care. To date, the most widely used regimen seems to be rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Substitution of liposomal doxorubicin in place of conventional doxorubicin may improve outcomes in this indication, although evidence for its use in low-grade lymphoma is not as relevant as in aggressive lymphoma. Bendamustine, in combination with rituximab, has shown very good efficacy and tolerability in several lymphoma types, particularly follicular lymphoma and other low-grade lymphomas. Other combinations, such as those including bortezomib and lenalidomide, are under investigation in low-grade lymphoma, and the duration of rituximab maintenance therapy following bendamustine-rituximab-containing induction is being researched by the German Study Group for Indolent Lymphoma (StiL).
doi:10.4081/hr.2011.s3.e5
PMCID: PMC3269212  PMID: 22586513
low-grade lymphoma; treatment; rituximab; non-pegylated liposomal doxorubicin; bendamustine.
17.  A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma 
Current Oncology  2012;19(3):160-168.
Despite the success of standard treatments in chronic lymphocytic leukemia (cll) and non-Hodgkin lymphoma (nhl), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated cll, bendamustine has demonstrated rates of response and progression-free survival (pfs) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine–rituximab (br) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent nhl and mantle cell lymphoma, br has demonstrated a pfs significantly longer than that achieved with r-chop (rituximab–cyclophosphamide–doxorubicin–vincristine–prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and pfs superior to those with fludarabine–rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of cll and indolent nhl; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with nhl and cll.
doi:10.3747/co.19.1064
PMCID: PMC3364766  PMID: 22670095
Bendamustine; chronic lymphocytic leukemia; non-Hodgkin lymphoma; follicular lymphoma
18.  Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90–Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499 
Journal of Clinical Oncology  2012;30(25):3119-3126.
Purpose
To test the hypothesis that consolidation therapy with yttrium-90 (90Y) –ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data.
Patients and Methods
Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received 90Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP.
Results
With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response–unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients > age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities.
Conclusion
R-CHOP given for four cycles followed by 90Y–ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.
doi:10.1200/JCO.2012.42.2444
PMCID: PMC3732008  PMID: 22851557
19.  Rituximab retherapy in patients with relapsed aggressive B cell and mantle cell lymphoma 
Annals of Hematology  2009;89(3):283-289.
Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pre-treated patients with relapsing aggressive lymphoma. We report here a single-centre retrospective outcome analysis of second-line immunochemotherapy with rituximab. In 28 patients with relapsed or refractory diffuse large B cell lymphomas, first-line immunochemotherapy had induced objective responses in 18 patients. Nine of 28 patients responded to rituximab containing salvage therapy, leading to a median overall survival of 243 days after start of second immunochemotherapy. Long-term disease free survivors (1,260 and 949 days) were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy. In 21 patients with relapsed mantle cell lymphomas (MCL), 19 patients had reached remissions with first-line therapy. Of those, 16 patients experienced responses to salvage therapy with a median overall survival of 226 days. Noteworthy, none of patients with initial non-responding disease reached a remission with second immunochemotherapy. Seven patients with MCL stayed free from progression after high-dose therapy with autologous or allogeneic stem cell transplantation in two and five cases, respectively. In summary, responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma, respectively, but not in primarily refractory disease. Lasting remissions were achieved only by high-dose chemotherapy with stem cell transplantation.
doi:10.1007/s00277-009-0820-9
PMCID: PMC2808532  PMID: 19727725
Lymphoma; Relapse; Rituximab
20.  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.
Summary
Background
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.
Methods
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 ClinicalTrials.gov, number NCT00109967.
Findings
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%).
Interpretation
mTOR inhibitors in combination with rituximab could have a role in the treatment of patients with relapsed and refractory MCL.
doi:10.1016/S1470-2045(11)70062-6
PMCID: PMC3106222  PMID: 21440503
Mantle Cell Lymphoma; mTOR Inhibitor; Rituximab; Phase 2 Trial
21.  Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: long-term follow-up of a pilot study from the Wisconsin Oncology Network 
Leukemia & lymphoma  2011;52(9):1675-1680.
Mantle cell lymphoma (MCL) is challenging to manage, with a median survival of 3–5 years. While intensive strategies are often appropriate for younger patients, these approaches are often not appropriate for older patients. In 2006, we reported our initial results using modified R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with maintenance rituximab. The complete response rate was 64%, and median progression-free survival (PFS) 37 months. Herein, we update our results, now with a median follow-up of 62 months. The median PFS is unchanged and the median overall survival (OS) is 70 months. The proportion of patients surviving at 5 years is 62%, comparable to studies using intensive strategies in similar patient populations. No late toxicities were noted in our cohort. These long-term results suggest that the modified R-hyperCVAD regimen with maintenance rituximab is an excellent option for older patients with newly diagnosed mantle cell lymphoma.
doi:10.3109/10428194.2011.580404
PMCID: PMC3489168  PMID: 21864042
Mantle cell lymphoma; non-Hodgkin’s lymphoma; rituximab maintenance; modified R-hyperCVAD
22.  In vivo regulatory phosphorylation of the phosphoenolpyruvate carboxylase AtPPC1 in phosphate-starved Arabidopsis thaliana 
Biochemical Journal  2009;420(Pt 1):57-65.
PEPC [PEP(phosphoenolpyruvate) carboxylase] is a tightly controlled cytosolic enzyme situated at a major branchpoint in plant metabolism. Accumulating evidence indicates important functions for PEPC and PPCK (PEPC kinase) in plant acclimation to nutritional Pi deprivation. However, little is known about the genetic origin or phosphorylation status of native PEPCs from −Pi (Pi-deficient) plants. The transfer of Arabidopsis suspension cells or seedlings to −Pi growth media resulted in: (i) the marked transcriptional upregulation of genes encoding the PEPC isoenzyme AtPPC1 (Arabidopsis thaliana PEPC1), and PPCK isoenzymes AtPPCK1 and AtPPCK2; (ii) >2-fold increases in PEPC specific activity and in the amount of an immunoreactive 107-kDa PEPC polypeptide (p107); and (iii) In vivo p107 phosphorylation as revealed by immunoblotting of clarified extracts with phosphosite-specific antibodies to Ser-11 (which could be reversed following Pi resupply). Approx. 1.3 mg of PEPC was purified 660-fold from −Pi suspension cells to apparent homogeneity with a specific activity of 22.3 units · mg−1 of protein. Gel filtration, SDS/PAGE and immunoblotting demonstrated that purified PEPC exists as a 440-kDa homotetramer composed of identical p107 subunits. Sequencing of p107 tryptic and Asp-N peptides by tandem MS established that this PEPC is encoded by AtPPC1. Pi-affinity PAGE coupled with immunoblotting indicated stoichiometric phosphorylation of the p107 subunits of AtPPC1 at its conserved Ser-11 phosphorylation site. Phosphorylation activated AtPPC1 at pH 7.3 by lowering its Km(PEP) and its sensitivity to inhibition by L-malate and L-aspartate, while enhancing activation by glucose 6-phosphate. Our results indicate that the simultaneous induction and In vivo phosphorylation activation of AtPPC1 contribute to the metabolic adaptations of −Pi Arabidopsis.
doi:10.1042/BJ20082397
PMCID: PMC2677216  PMID: 19228119
Arabidopsis; gene expression; Pi starvation; mass spectrometry; phosphoenolpyruvate carboxylase kinase (PPCK); protein phosphorylation; Ab, antibody; anti-RcPEPC IgG, anti-(Ricinus communis PEPC) IgG; AtPPC1, Arabidopsis thaliana PEPC1; CAM, crassulacean acid metabolism; DTT, dithiothreitol; Glc-6-P, glucose 6-phosphate; MALDI, matrix-assisted laser-desorption ionization; MS medium, Murashige and Skoog medium; MS/MS, tandem MS; p107, 107-kDa PEPC polypeptide; oMALDI 2, orthogonal MALDI 2; PEP, phosphoenolpyruvate; PEPC, PEP carboxylase; +Pi, Pi-sufficient; −Pi, Pi-deficient; PP2A, protein phosphatase type-2A; PPCK, PEPC kinase; Q-TOF, quadrupole time-of-flight; QqTOF, quadrupole/quadrupole TOF; RT, reverse transcription
23.  CD20-targeted measles virus shows high oncolytic specificity in clinical samples from lymphoma patients independent of prior rituximab therapy 
Gene therapy  2010;18(3):313-317.
New therapeutic modalities for B-cell non-Hodgkin’s lymphomas (B-NHL) are needed, especially for relapsing and aggressive subtypes. Toward this end, we previously generated a fully CD20-targeted and armed measles virus, and tested its efficacy in a xenograft model of mantle cell lymphoma (MCL). Here, we quantify its spread in peripheral blood mononuclear cells and/or tissue of patients with different histological subtypes of B-NHL, including splenic marginal zone lymphoma (SMZL). CD20-targeted MV efficiently infects lymphoma cells from SMZL and MCL while sparing most cells in the CD20-negative population, in contrast to the parental vaccine-lineage MV, which infects CD20-positive and CD20-negative cells equally. Rituximab therapy (4–8 months before relapse) did not interfere with the infectivity and specificity of MVgreenHblindantiCD20 in patient lymphoma samples. Thus, CD20-targeted oncolytic virotherapy is likely to be effective after previous antiCD20 therapy.
doi:10.1038/gt.2010.150
PMCID: PMC3896318  PMID: 21068781
CD-20; lymphoma; oncolytic virotherapy
24.  Rituximab and new regimens for indolent lymphoma: a brief update from 2012 ASCO Annual Meeting 
Indolent lymphoma (IL), the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard frontline regimen for diffuse Large B –cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab) has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial, R-CHOP was compared with R-CVP (cyclophosphamide, vincristine, prednisone) and R-FM (fludarabine, mitoxantrone). The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab) has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.
doi:10.1186/1475-2867-12-38
PMCID: PMC3480919  PMID: 22913602
25.  Light-regulated and cell-specific methylation of the maize PEPC promoter 
Journal of Experimental Botany  2011;63(3):1381-1390.
The molecular mechanisms governing PEPC expression in maize remain to be fully defined. Differential methylation of a region in the PEPC promoter has been shown to correlate with transcript accumulation, however, to date, investigations into the role of DNA methylation in maize PEPC expression have relied on the use of methylation-sensitive restriction enzymes. Bisulphite sequencing was used here to provide a single-base resolution methylation map of the maize PEPC promoter. It is shown that four cytosine residues in the PEPC promoter are heavily methylated in maize root tissue. In leaves, de-methylation of these cytosines is dependent on illumination and is coincident with elevated PEPC expression. Furthermore, light-regulated de-methylation of these cytosines occurs only in mesophyll cells. No methylation was discovered in the 0.6 kb promoter required for mesophyll-specific expression indicating that cytosine methylation is not required to direct the cell-specificity of PEPC expression. This raises interesting questions regarding the function of the cell-specific cytosine de-methylation observed in the upstream region of the PEPC promoter.
doi:10.1093/jxb/err367
PMCID: PMC3276097  PMID: 22143916
Bundle sheath; C4 photosynthesis; maize; mesophyll; methylation; PEPC

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