Curr Oncol Rep (2010) 12:395401 DOI 10.

1007/s11912-010-0128-x

Maintenance and Consolidation Strategies in Non-Hodgkins Lymphoma: A Review of the Data

Fredrick B. Hagemeister

Published online: 4 September 2010 # Springer Science+Business Media, LLC 2010

Abstract Results of treatment for patients with nonHodgkins lymphomas have significantly improved over the last decade, especially following the discovery that antiCD20 antibody therapy can significantly change the outlook for patients with both aggressive and indolent lymphomas. Although investigators have previously attempted to prevent relapses by intensifying chemotherapy programs for patients with poor-risk disease, further improvements in treatment will require development of biologic agents that can be added to current programs and exploitation of currently available drugs that can prevent recurrence of these diseases with good tolerability. This review analyzes currently available plans that can be used to maintain responses or consolidate initial responses to therapy, programs that may prevent relapse and potentially cure more patients with lymphomas, with a review of current ongoing trials designed along these lines. Keywords Lymphoma . Rituximab . Maintenance . Radioimmunotherapy

improved results of treatment for patients with not only aggressive but also indolent non-Hodgkins lymphomas (NHLs), and the success of this drug spurred investigators to develop newer antibodies that might improve upon those results [1]. However, to date, none of these have been better than rituximab at improving progression-free survival (PFS) results, and investigators have turned to development of biologic agents other than monoclonal antibodies to improve responses with standard regimens, hoping for minimal added toxicity, especially protein inhibitors and immunomodulators [28]. Other investigators have turned to efforts at consolidation of initial response in order to prevent relapses, including high-dose therapy followed by stem cell rescue (SCT), although it remains unclear that such therapy improves overall survival (OS) results for any lymphoma when administered as part of initial therapy. Finally, others have developed therapies much more tolerable than SCT in an attempt to prolong PFS and OS results. In this report, we review results of consolidation and maintenance therapies, and describe newer agents in clinical trials that might improve results for patients with these diseases.

Introduction Therapy for patients with lymphomas has seen significant improvements in results over the last decade, especially since the discovery and easy clinical usage of monoclonal antibodies and other biologic therapies that have been developed within the last few years. Rituximab itself has
F. B. Hagemeister (*) Department of Lymphoma/Myeloma, M. D. Anderson Cancer Center, 1515 Holcombe, Unit 429, Houston, TX 77030, USA e-mail: fhagemei@mdanderson.org

Indolent NHL Rituximab as Maintenance Therapy This anti-CD20 chimeric antibody induced a 48% response rate in patients with relapsed indolent NHLs and was approved by the US Food and Drug Administration (FDA) in 1997 for treatment of these diseases [1]. Multiple investigators have subsequently studied this drug as initial therapy for indolent NHLs, and in combination with chemotherapy or following chemotherapy as initial therapy

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or for relapses of indolent NHLs [9, 10, 1117, 1823, 24, 25]. In four randomized phase 3 trials of initial therapy and in two randomized trials of therapy for relapsed disease, rituximab plus chemotherapy for patients with follicular lymphomas (FL) resulted in better PFS and OS rates than did chemotherapy alone [9, 10, 1115]. In a recent meta-analysis of these studies, Schultz et al. [16] found that combined immunochemotherapy with rituximab appeared to improve survival in treatment of patients with these diseases. Because of these trials, investigators agree that rituximab should now be included as part of initial therapy for all patients with indolent lymphomas. However, the use of this drug as maintenance or consolidation has been controversial. Ghielmini and colleagues [17, 18] first studied maintenance therapy with rituximab following induction with rituximab versus observation alone; in this trial, at longterm follow-up of these patients, those who received prolonged rituximab therapy enjoyed an event-free survival (EFS) rate that was almost double that reported for those who were on the observation arm. Remarkably, 25% of those with previously untreated disease who received maintenance rituximab were still free of progression at 8 years of follow-up [18]. Since this first report, multiple investigators have found that retreatment with maintenance rituximab is an effective way to prolong the duration of remission achieved with induction therapy, although, until recently, the results have only been reported from trials testing rituximab maintenance versus observation in therapy of patients who had received rituximab or chemotherapy alone as induction therapy [19]. In a phase 3 trial conducted in a group of 331 treatment-nave patients with indolent NHLs, 282 of whom had FL, those who received maintenance rituximab following induction with CVP chemotherapy (cyclophosphamide, vincristine, prednisone) had a median PFS rate of 52 months from the start of rituximab therapy compared to only 16 months for those who were randomized to observation alone (P <0.001) [19]. Three-year OS rates were 91% and 86%, respectively (P =0.08). In three other randomized studies of therapy for patients with relapsed disease, investigators also found that maintenance rituximab improved results. In the trial reported by Hainsworth and colleagues [20], patients who received maintenance rituximab following rituximab induction had median PFS results of 31.3 months compared to only 7.4 months for those who did not receive rituximab maintenance. Forstpointner and colleagues [13] found that patients with relapsed FL or mantle cell lymphomas who received maintenance rituximab or were observed without further therapy following induction with R-FCM (rituximab, fludarabine, chlorambucil, mitoxantrone) had 3-year OS rates of 77% and 57%, respectively. Finally, in a study that treated patients with relapsed and chemotherapy-

refractory FL, van Oers and colleagues [14] reported that patients who received rituximab maintenance following CHOP chemotherapy induction, with or without rituximab, had significantly better median PFS results (51.5 months) than did those who underwent observation alone (14.9 months). None of these randomized phase 3 trials addressed the benefit of rituximab following rituximab plus chemotherapy induction for patients with previously untreated FL, but because of these findings, many clinicians began to administer this drug as maintenance following RCHOP, R-CVP, and R plus fludarabine-containing combinations. In these reported trials, investigators reported varying administration methods for this drug as maintenance therapy, including once every 2 months, once every 3 months, or once weekly doses for 4 weeks every 6 months, for 1 to 2 years after completion of initial induction therapy [13, 14, 17, 1820]. Finally, in a phase 2 trial of single-agent induction followed by maintenance rituximab, Gordon et al. [21, 22] scheduled rituximab administration based on serum levels, treating patients whenever these dropped below 25 g/mL. Therefore, a number of questions regarding dosing and scheduling remain. The drug is still undergoing robust clinical investigation as maintenance therapy. The ongoing randomized RESORT trial for patients with FL and low tumor burden is evaluating single-agent rituximab as initial therapy followed by a randomization to maintenance single-dose rituximab every 3 months versus observation and retreatment with rituximab upon relapse. Recently, Salles and colleagues [23] reported results of a clinical trial that treated patients with rituximab plus chemotherapy, followed by randomization to maintenance rituximab or observation. In this study, known as the PRIMA trial, maintenance rituximab was administered every 8 weeks for 2 years to those assigned to that arm, and the majority of the 1018 randomized patients had previously received R-CHOP or R-CVP therapy as induction. With a median follow-up of 25 months from randomization, 2-year PFS results for those assigned to rituximab or observation were 82% and 66%, respectively (P < 0.0001). Grades 3 to 4 neutropenia occurred in 4% and grades 2 or greater infections in 37% of those receiving rituximab compared to<1% and 22% of those being observed. However, fewer deaths occurred in the group receiving rituximab. These authors have yet to report details regarding prognostic factors in this trial and any differences in results observed for those receiving RCHOP compared to those for patients receiving R-CVP induction. Regardless, this study has established that maintenance rituximab can prevent relapses in responders to induction chemotherapy plus rituximab for previously untreated patients with FL, and may have established a new standard of care for these patients [24]. Ongoing studies

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include varying dosing schedules of rituximab following single-agent rituximab or rituximab and bendamustine; however, because the drug is well tolerated, it is likely that many schedules of therapy will work, and the decision to use one over the other may be one of convenience. Radioimmunotherapy These drugs, 131I tositumomab (Tos) and 90Y ibritumomab (Ibr), have demonstrated effectiveness in treatment of patients with relapsed indolent NHLs [25, 26]. Following approval of these drugs in the United States, investigators have found that they can be effective in therapy of patients with rituximab-refractory disease, can induce long-term remissions, appear more effective if used earlier in the treatment plan rather than later, can be combined with SCT therapy, and are associated with low rates of longterm complications [2736]. However, these drugs have also been used in phase 2 trials as consolidation therapy for patients induced into first remission by chemotherapy or chemoimmunotherapy [3745]. The Southwest Oncology Group recently completed a study that treated patients with newly diagnosed FL on a randomized trial of CHOPR, using the original design formulated by Czuczman, versus CHOP followed by Tos, based on a phase 2 study of CHOP followed by Tos, conducted by Press and colleagues [45]. In that phase 2 trial, 96% had stage III to IV disease, and bulky tumor greater than 10 cm was noted in 23%. The CR rate after six cycles of CHOP was 44%, but after Tos, it increased to 74%; at 5 years, the PFS and OS rates for all patients were 67% and 87%, respectively. The FLIPI score appeared to play some role in the outcomes; patients who had high FLIPI scores had 52% PFS and 79% OS rates at 5 years. Reports from the randomized trial will be particularly important because no rituximab was administered to those patients on the latter arm of this study. More importantly, Morschhauser and colleagues [46] have reported results of the FIT trial, a study in which patients who entered first remission with chemotherapy or rituximab plus chemotherapy were enrolled and received randomized therapy with Ibr or underwent observation. In this trial, there was a significant improvement in the failure-free survival rate for those who received radioimmunotherapy (RIT) consolidation; however, this difference was seen mainly in those who had received induction therapy with only chemotherapy. Using an intent-to-treat analysis, no significant differences were observed between the consolidation and observation arms for those patients who had received rituximab as part of induction therapy, due to low enrollment numbers. Nonetheless, RIT may play an important role in consolidation of responses in FL, and further studies are warranted.

Vaccines Three trials have been recently completed using different anti-Id vaccines as prevention of relapse of FLs. Levy and colleagues [47] treated 287 patients with newly diagnosed FL with CVP chemotherapy for 21 weeks, followed by vaccine therapy versus observation. Median PFS results were 19.1 months for the vaccine group versus 23.3 months for the controls; further studies with this drug were abandoned. In a second trial with a different vaccine, Freedman and colleagues [48] reported no differences in time to progression (TTP) results for patients with initially diagnosed FL who received the vaccine versus placebo following induction therapy with rituximab alone. TTP results were 11.9 months versus 17.2 months, respectively; for those with relapsed FL, results following the vaccine were actually inferior; no future trials with this agent are planned. More recently, Shuster and colleagues [49] presented their results of a phase 3 randomized trial, in which PACE (cyclophosphamide, doxorubicin, etoposide, prednisone) chemotherapy was used to induce CR, and then within the next 12 months the patients received either vaccine therapy or placebo. Of the 234 patients enrolled on trial, only 66% maintained CR for at least 6 months, and were able to undergo randomization. Median disease-free survival (DFS) results for those receiving vaccine and control were 44.2% and 30.6%, respectively (P =0.045), although OS results were similar for the two arms. Unfortunately, no patient in this trial had received rituximab; therefore, these findings may not play an important role in therapy administered in clinical practice today, in which patients with FL almost universally receive rituximab as part of induction therapy, and a significant number receive maintenance therapy. There is an ongoing trial of a plant-based vaccine in patients with relapsed FL, although induction for these patients does not include rituximab [50]. Further studies are needed to confirm the value of this therapeutic approach in patients receiving rituximab with untreated and relapsed disease.

Aggressive NHL Certain problems hamper development of agents that might prolong PFS for aggressive lymphomas, represented by the most common of these, diffuse large B-cell lymphoma (DLBCL). First, with R-CHOP therapy, approximately 50% of patients who develop disease progression will do so during or shortly after therapy, signifying resistance to both chemotherapy and rituximab. By definition, these patients have diseases considered refractory to initial standard chemotherapy, often have poor responses to therapy for relapse, and may not be the best candidates for consolida-

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tion or maintenance strategies. Second, older patients have worse outcomes with standard R-CHOP therapy than do younger patients, and would be the ideal candidates for consolidation or maintenance therapies because of higher rates of relapse. However, many of these may be ineligible for investigational trials due to comorbid illnesses, or may have social issues that prohibit their enrollment in studies. Finally, randomized trials are necessary to demonstrate the benefit of maintenance therapies, and patients may be reluctant to enroll in such trials that would include a placebo arm. Nonetheless, there are three drugs currently being tested as maintenance therapy in the treatment of DLBCL: enzastaurin, lenalidomide, and everolimus. Enzastaurin This drug is an oral, serine threonine kinase inhibitor that targets the PKCBeta and PI3/AKT signaling pathways, suppressing tumor cell proliferation, inducing cell death, and causing tumor-induced angiogenesis. PKCBeta was identified by gene-expression profiling and other preclinical studies as a rational target in DLBCL, and the drug has been granted orphan drug status by the FDA for treatment of DLBCL. In one clinical trial of 55 patients with relapsed disease, three entered CR, and the drug was well tolerated [51]. The PRELUDE trial (Preventing Relapse in Lymphoma Using Daily Enzastaurin) is a randomized, placebo-controlled study in older patients at high risk of relapse following CR induction with initial therapy; the primary end point of the study is DFS, and the trial is enrolling at more than 100 sites worldwide [52]. Lenalidomide This analogue of thalidomide is active in therapy of lymphoproliferative malignancies. The drug is classified as an immunomodulatory agent, and has significant effects on the normal cells in the tumor microenvironment, besides having some effects on tumor cells themselves [53, 54]. Some of these effects include inhibition of binding of tumor cells to the tumor bed, inhibition of release and activity of cytokines associated with tumor cell proliferation, suppression of tumor-induced angiogenesis, and activation of natural killer cells and macrophages, although its major mechanisms of action in patients with lymphoproliferative diseases are still uncertain. It is currently approved in the United States for treatment of patients with relapsed myeloma in combination with dexamethasone and in therapy of myelodysplastic syndrome with 5q deletion with or without other cytogenetic abnormalities. However, investigators have discovered that this drug also demonstrates significant activity in therapy of relapsed indolent and aggressive NHLs, and may even play an important role in initial therapy of these diseases [5460].

In a recent update of the current knowledge regarding this agent in management of aggressive NHLs, Witzig and colleagues [57] reported results of therapy for 217 patients with aggressive NHLs, 108 of whom had DLBCL. Other histologies included mantle cell lymphoma, transformed lymphoma, and FL, grade 3. The median number of prior therapies for these patients was three, 44% were considered to have disease refractory to their last therapy, and 34% had previously undergone SCT. Overall, 13% of the patients in this analysis demonstrated CR, and the OR and median PFS rates for those with DLBCL were 28% and 2.3 months, respectively, with a median duration of response of 4.5 months. The drug was only modestly myelosuppressive, with grades 2 to 3 neutropenia and thrombocytopenia in 41% and 18%, respectively. Because of this activity, investigators have begun to combine lenalidomide with R-CHOP in therapy of previously untreated large-cell lymphomas [60]. More recently, investigators have also suggested that germinal center B-cell lymphomas may not respond as well to therapy with this agent as do non-germinal B-cell lymphomas, a provocative finding that is the subject of a large international trial to more precisely define the true benefit of this drug in treatment of aggressive lymphomas [61]. For this reason, investigators in the Group Etudes de Lymphome de lAdulte are conducting a trial testing the value of this agent as a maintenance agent in treatment of patients with high-risk aggressive lymphomas. Everolimus The mammalian target of rapamycin (mTOR) is a key tyrosine kinase in the PI3K/Akt pathway, regulating growth factor signaling and intracellular nutrients, and activation of this kinase promotes cell growth, cell growth and proliferation, angiogenesis, and cellular metabolism [6264]. Inhibition of mTOR slows G1-S transition, and inhibits proliferation of lymphoma cell lines [65, 66]. Therefore, investigators have developed inhibitors to this important target, temsirolimus and everolimus, and have studied these drugs in a variety of tumor types. In 2007, temsirolimus was approved by the FDA in the United States for initial therapy of advanced renal cell carcinoma, and in 2009, everolimus was approved to treat patients with relapsed renal cell carcinoma following failure of sorafenib or sunitinib [67, 68]. These drugs are also known to have activity in therapy of relapsed NHLs, and in vitro studies suggest synergism with standard agents known to be active in lymphoma therapy [6971]. Witzig and colleagues [71] presented results of everolimus therapy for 143 patients with a wide variety of relapsed or refractory lymphomas, 47 of whom had DLBCL. The median number of prior therapies was four (range 115). Grades 3 to 4 hematologic toxicities included anemia (16%), neutropenia (17%), and thrombocytopenia (35%). Nonhematologic tox-

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399 treatment program. J Clin Oncol 1998, 16:28252833. This article describes the pivotal experience with rituximab, the first antibody approved by the FDA for therapy of cancer. Hagenbeek A, Gadeberg O, Johnson P, et al.: First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008, 111:54865495. Morschhauser F, Leonard JP, Fayad L, et al.: Humanized antiCD20 antibody, veltuzumab, in refractory/recurrent nonHodgkin's lymphoma: Phase I/II results. J Clin Oncol 2009, 27:33463353. Morschhauser F, Marlton P, Vitolo U, et al.: Interim results of a phase I/II study of ocrelizumab, a new humanized anti-CD20 antibody in patients with relapsed/refractory follicular nonHodgkins lymphoma. Blood (ASH Annual Meeting Abstracts) 2007, 110:abstract 645. Salles G, Morschhauser F, Cartron P, et al.: A phase I/II study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant disease. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 234. Leonard P, Schuster S, Emmanouilides C, et al.: Durable complete responses from therapy with combined epratuzumab and rituximab. Cancer 2008, 113:27142723. Friedberg J, Younes A, Fisher D, et al.: Durable responses in patients treated with galiximab (anti-CD80) in combination with rituximab for relapsed or refractory follicular lymphoma: longterm follow-up of a phase II clinical trial. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 1004. Bargou R, Kufer P, Goebeler M, et al.: Sustained response duration seen after treatment with single agent blinatumomab (MT103/MEDI-538) in the ongoing phase I study MT103-104 in patients with relapsed NHL. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 267. Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005, 106:37253732. Marcus R, Imrie K, Belch A, et al.: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005, 105:14171423. This was the first study that demonstrated in a randomized fashion that rituximab plus chemotherapy provided better PFS and OS results than did chemotherapy alone. Herold M, Haas A, Srock S, et al.: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007, 25:1986 1992. Salles G, Mounier N, de Guibert S, et al.: Rituximab combined with chemotherapy and interferon for follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008, 112:48244831. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German LowGrade Lymphoma Study Group. Blood 2004, 104:30643071. van Oers M, Glabbeke MV, Baila L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkins lymphoma: long-term outcome of the EORTC 20981 phase III

icities included hypercholesterolemia, hyperglycemia, and hypertriglyceridemia. The OR and CR rates for all patients were 43% and 3.5%, respectively; corresponding results for those with DLBCL were 30% and 2%. For all patients, the median TTP was 4.3 months, and the duration of remission for 48 responders was 6.8 months. The drug is currently in trials in combinations with panobinostat and bortezomib for relapsed lymphoma; however, a trial is also underway to explore the value of this drug as maintenance in patients with large-cell lymphoma [72].

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Conclusions
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Therapy for patients with NHLs has become more successful over the last 10 years, mainly because of the development of the monoclonal antibody, rituximab. A few studies have suggested that results could be further improved by the use of consolidation therapy, consisting of high-dose therapy followed by SCT, but this mode of treatment has not gained popularity among clinicians and patients alike because of expense and tolerability issues. However, a number of promising trials have suggested that more tolerable treatments might also improve results, and one of these, the addition of maintenance rituximab following induction immunochemotherapy, has recently been reported for patients with previously untreated FL. Other trials have been reported with vaccine therapies and RIT, and have met with mixed opinions, mainly because most of these trials have not been conducted with patients receiving immunochemotherapy, which has become a standard for many patients with NHLs. For aggressive NHLs, a variety of protein inhibitors are being studied as maintenance therapy for patients who have been induced into remission with immunochemotherapy.
Acknowledgment The author wishes to recognize the expert technical assistance of Thao Phan in the preparation of this manuscript. Disclosure No potential conflict of interest relevant to this article was reported.

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References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance
1. McLaughlin P, Grillo-Lopez AJ, Link BK, et al.: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose 13.

14.

400 randomized intergroup study. J Clin Oncol (ASCO Annual Meeting Abstracts) 2008, 26:abstract 836. van Oers M: Rituximab maintenance therapy: a step forward in follicular lymphoma. Haematologica 2007, 92:826832. Schulz H, Skoetz N, Bohlius J, et al.: Does combined immunochemotherapy with the monoclonal antibody rituximab improve overall survival in the treatment of patients with indolent non-Hodgkins lymphoma? Preliminary results of a comprehensive meta-analysis. Blood (ASH Annual Meeting Abstracts) 2005, 106:abstract 351. Ghielmini M, Schmitz S, Cogliatti S, et al.: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004, 103:44164423. This study provided information suggesting that rituximab maintenance was effective in prolonging remission following single-agent rituximab as induction. Ghielmini M, Hsu Schmitz S, Martinelli G, et al.: Long-term follow-up of patients with follicular lymphoma (FL) receiving single-agent rituximab at two different schedules in study SAKK 35/98. J Clin Oncol (ASCO Annual Meeting Abstracts) 2009, 27: abstract 8512. Hochster H, Weller E, Gascoyne R, et al.: Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 study. J Clin Oncol 2009, 27:16071614. Hainsworth J, Litchy S, Shaffer D, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkins lymphomaa randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2005, 23:10881095. Berinstein N, Grillo-Lopez AJ, White CA, et al.: Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkins lymphoma. Ann Oncol 1998, 9:9951001. Gordan L, Grow W, Pusateri A, et al.: Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol 2005, 23:10961102. Salles G, Seymour J, Feugier P, et al.: Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010, 23:abstract 8044. These authors performed the first randomized study of rituximab maintenance following initial therapy for FL using rituximab and chemotherapy, and changed patterns of care. Hagemeister F: Rituximab for the treatment of non-Hodgkins lymphoma and chronic lymphocytic leukaemia. Drugs 2010, 70:26612672. Witzig T, Gordon L, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkins lymphoma. J Clin Oncol 2002, 20:24532463. Kaminski MS, Zelenetz AD, Press OW, et al.: Pivotal study of iodine I-131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkins lymphomas. J Clin Oncol 2001, 19:39183928. Wiseman G, Witzig T: Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-cell non-Hodgkins lymphoma. Cancer Biother Radiopharmaceuticals 2005, 20:185188. Witzig T, Flinn I, Gordon L, et al.: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkins lymphoma. J Clin Oncol 2002, 20:3262 3269. Carella A, Nati S, Orcioni F, et al.: 90Y Ibritumomab tiuxetan as initial treatment for follicular lymphoma (ZEUS Protocol). An

Curr Oncol Rep (2010) 12:395401 Italian Cooperative Study Group. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 3061. Kaminski M, Tuck M, Estes J, et al.: 131 I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005, 352:441449. Fisher R, Kaminski M, Wahl R, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed nonHodgkins lymphomas. J Clin Oncol 2005, 23:75657573. Horning SJ, Younes A, Jain V, et al.: Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 2005, 23:712719. Czuczman M, Witzig T, Gaston B, et al.: Zevalin radioimmunotherapy is not associated with an increased incidence of secondary myelodyplastic syndrome (MDS) or acute myelogenous leukemia (AML). Blood (ASH Annual Meeting Abstracts) 2002, 100: abstract 1386. Ansell S, Ristow K, Habermann T, et al.: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkins lymphomas. J Clin Oncol 2002, 20:38853890. Dosik A, Coleman M, Kostakoglu L, et al.: Subsequent therapy can be administered after tositumomab and iodine I-131 tositumomab for non-Hodgkin lymphoma. Cancer 2006, 106:616622. Gopal A, Gooley T, Maloney D, et al.: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular nonHodgkin lymphoma: A multivariable cohort analysis. Blood 2003, 102:23512357. Shipley D, Greco F, Spigel D, et al.: Rituximab with short duration chemotherapy followed by 90Y ibritumomab tiuxetan as first-line treatment for patients with follicular lymphoma: update of a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol (ASCO Annual Meeting Abstracts) 2005, 23:abstract 6577. Jankowitz R, Foon K, Luong T, et al.: Phase II study of short course CHOP-Rituximab followed by 90-Y ibritumomab tiuxetan as first-line treatment for follicular lymphoma: an update and extension of preliminary findings on predictors of relapse. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 2001. Leonard J, Coleman M, Kostakoglu L, et al.: Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005, 23:56965704. Link B, Kaminski M, Coleman M, Leonard J: Phase II study of CVP followed by tositumomab and iodine I-131 tositumomab (Bexxar therapeutic regimen) in patients with untreated follicular non-Hodgkins lymphoma (NHL). J Clin Oncol (ASCO Annual Meeting Abstracts) 2004, 22:abstract 6520. McLaughlin P, Neelapu S, Fanale M, et al.: R-FND followed by radioimmunotherapy for high-risk follicular lymphoma. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 3056. Gregory S, Kassar M, Fung H, et al.: A prospective study evaluating the safety and efficacy of combination therapy with fludarabine plus mitoxantrone followed by yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) and maintenance rituximab as front line therapy for patients with intermediate or high risk follicular non-Hodgkins lymphoma. Blood (ASH Annual Meeting Abstracts) 2007, 110: abstract 1360. Miller T, Unger J, Spier C, et al.: Effect of adding ibritumomab tiuxetan (Zevalin) radioimmunotherapy consolidation to three cycles of CHOP plus involved-field radiotherapy for limitedstage aggressive diffuse B-cell lymphoma (SWOG 0313). Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 3598. Hamlin P, Moskowitz C, Wegner B, et al.: Early safety and efficacy analysis of a phase II study of sequential R-CHOP and

15. 16.

30.

31.

17.

32.

33.

18.

34.

19.

35.

36.

20.

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22.

38.

23.

39.

24.

40.

25.

41.

26.

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27.

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29.

44.

Curr Oncol Rep (2010) 12:395401 yttrium-90 ibritumomab tiuxetan (Zevalin) for elderly high risk patients with untreated DLBCL. Blood (ASH Annual Meeting Abstracts) 2005, 106:abstract 926. Press O, Unger J, Braziel R, et al.: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkins lymphoma: fiveyear follow-up of Southwest Oncology Group Protocol S9991. J Clin Oncol 2006, 24:41434149. This is the precursor study to the randomized SWOG trial testing rituximab plus CHOP versus radioimmunotherapy as consolidation following CHOP. Morschhauser F, Radford J, Van Hoof A, et al.: Phase III trial of consolidation therapy with Yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008, 26:51565164. Levy R, Robertson M, Ganjoo K, et al.: Results of a phase III trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkins lymphoma (fNHL). Clin Cancer Res (AACR Annual Meeting Abstracts) 2008, 99:abstract LB-204. Freedman A, Neelapu S, Nichols C, et al.: A placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T (Id-KLH) and GM-CSF following rituximab in patients with CD20+ follicular lymphoma. Blood 2008, 112: asbtract 236. Shuster M, Neelapu S, Gause B, et al.: Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: phase III clinical trial results. J Clin Oncol 2009, 27:abstract 2. These investigators demonstrated that vaccine therapy may prolong remissions in patients following induction with intensive chemotherapy. Inoges S, Rodriguez-Cavillo M, Zabalegui N, et al.: Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst 2006, 98:12921301. Robertson M, Kahl B, Vose J, et al.: Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2007, 13:17411746. Eli Lilly and Company Clinical Trial Registry. www.lillytrials. com. Accessed August 2010. Chng W, Lau L, Yusof N, Mow B: Targeted therapy in multiple myeloma. CA Control 2005, 12:91104. Drach J, Seidl S, Kaufmann H: Treatment of mantle cell lymphoma: targeting the microenvironment. Expert Rev Cancer 2005, 5:477485. Wiernik P, Lossos I, Tuscano J, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkins lymphoma. J Clin Oncol 2008, 26:49524957. Czuczman M, Vose J, Zinzani P, et al.: Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory diffuse large-B-cell lymphoma: results from an international study (NHL-003). J Clin Oncol (ASCO Annual Meeting Abstracts) 2009, 27:abstract 19504.

401 57. Witzig TE, Wiernik PH, Moore, T, et al.: Efficacy of oral lenalidomide monotherapy in relapsed or refractory indolent non-Hodgkins lymphoma: final results of NHL-001. J Clin Oncol (ASCO Annual Meeting Abstracts) 2009, 27:abstract 15. 58. DeRook I, Odonnell R, Noble B, et al.: R2: Preliminary results of a phase II study of lenalidomide and rituximab in relapsed/ refractory indolent non-Hodgkins lymphoma (NHL). Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 3060. 59. Fowler N, McLaughlin P, Kwak L, et al.: Lenalidomide and rituximab for untreated indolent non-Hodgkins lymphoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2009, 27:abstract 8548. 60. Nowakowski G, LaPlant B, Habermann T, et al.: A phase I/II trial of lenalidomide and RCHOP (R2CHOP) in patients with newly diagnosed diffuse large B-cell (DLBCL) and follicular grade 3 Lymphoma. Blood (ASH Annual Meeting Abstracts) 2009, 114: abstract 1669. 61. Hernandez-Ilizaturri F, Deeb G, Zinzani P, et al.: Response of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with nongerminal center B-cell phenotype to lenalidomide (L) alone or in combination with rituximab (R). J Clin Oncol 2010, 28:abstract 8038. 62. Huang S, Bjornsti M, Houghton P: Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2003, 2:222232. 63. Fingar D, Blenis J: Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004, 23:31513171. 64. Lam L, Davis E, Peirce J, et al.: Small molecule inhibitors of IkB kinase are selectively toxic for subgroups of diffuse large cell lymphoma defined by gene expression profiling. Clin Cancer Res 2005, 11:2840. 65. Wanner K, Hipp S, Oelsner M, et al.: Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitizes DLBCL cells to rituximab. Br J Haematol 2006, 134:475484. 66. Haritunians T, Mori A, OKelly J, et al.: Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2007, 21:333339. 67. Hudes G, Carducci M, Tomczak, et al.: Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. N Engl J Med 2007, 356:22712281. 68. Motzer R, Escudier B, Oudard S, et al.: Phase III trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010, In press. 69. Witzig T: Current approaches for mantle cell lymphoma. J Clin Oncol 2005, 23:5347. 70. Ansell S, Inwards D, Rowland K, et al.: Low-dose single-agent temsirolimus for relapsed mantle cell lymphoma. A phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008, 113:508514. 71. Witzig T, Habermann T, Reeder C, et al.: A phase II trial of the oral mTOR inhibitor everolimus in relapsed non-Hodgkins lymphoma (NHL) and Hodgkins disease. Hematologica (EHA Annual Meeting Abstracts) 2009, 94:abstract 426. 72. ClinicalTrials.gov. www.clinicaltrials.gov. Accessed August 2010.

45.

46.

47.

48.

49.

50.

51.

52. 53. 54.

55.

56.