The era of -free treatment for follicular lymphoma

G. Salles ABSTRACT The improvement in the management of patients with follicular lymphoma achieved using anti- Hospices Civils de Lyon, Service CD20 , essentially , has set the path to develop alternative approaches sparing the d’Hématologie; Université Claude use of chemotherapy in this disease. These include the optimization of the use of rituximab itself or Bernard, Faculté de Médecine Lyon- its combination with other agents. The evaluation of antibodies directed against other B-cell Sud Charles Mérieux, Université de Lyon, France as “doublets” has still not provided outstanding results. Based on a rational understanding of immune mechanisms involved in rituximab activity, the combination of molecules that may potentiate its Correspondence: activity, including cytokines (such as ), immunomodulatory drugs (IMIDs®, such as lenalido - Gilles Salles mide) or antibodies targeting the immune checkpoints (e.g. the anti-PD1 ) have shown E-mail: [email protected] promising clinical results in early reports. Other drugs targeting kinases involved in the intracellular signaling pathways such as the PI3K-delta inhibitor idelalisib have also demonstrated a substantial Disclosure information: activity in patients with follicular lymphoma. How this growing armamentarium will modify and Received honoraria for participation expand the daily management of patients with follicular lymphoma remains a challenge given the cur - to advisory board meetings and/or rent results achieved with rituximab and chemotherapy combinations, especially in the first-line set - talks from Roche Genentech, ting. Hence, future studies should evaluate in a comparative design the efficacy, toxicities, and Janssen, Celgene, Gilead, cost/benefit ratios of new “chemo-free” regimens. Mundipharma, Chugai and Amgen. Learning goals At the conclusion of this activity participants should be able to: Hematology Education: - understand and enumerate the different developments of chemotherapy-free approaches in the education program for the patients with follicular lymphoma; annual congress of the European - summarize the results of clinical trials with rituximab single agent, and combinations of rituximab Hematology Association with other monoclonal antibodies or with immunomodulatory agents; 2014;8:151-158 - summarize current results achieved with kinase inhibitors in patients with follicular lymphoma; - discuss how the alternatives to chemotherapy will eventually enter into clinical practice for the daily management of patients with follicular lymphoma.

Introduction dition for which they are (or will be) approved. Their potential benefit in treating FL patients, however, still has to be determined. With the introduction of anti-CD20 antibod - Based on several hypotheses regarding the ies, the treatment of patients with follicular mode of action of anti-CD20 antibodies, and lymphoma (FL) has dramatically evolved over the immune-related mechanisms supporting the last 15 years. The efficacy of the first anti- their clinical activity, investigators have CD20 monoclonal , rituximab, was explored the combination of rituximab with rapidly tangible for physicians and patients, various immunomodulatory agents (interfer - even when used as single agent. The demon - on, -2, GM-CSF, etc.) and more stration that rituximab plus chemotherapy recently , achieving interesting combination was able to improve overall sur - clinical results. Combination of anti-CD20 vival in randomized trials further accelerated antibodies with other monoclonal antibodies the therapeutic success of this antibody. directed against distinct cell surface antigens, Several groups also investigated prolonged B-cell specific or not, was also examined. treatment (maintenance) with rituximab, either Alongside these therapeutic approaches after rituximab alone or after chemotherapy based on , new agents target - plus or minus rituximab. 1 Nowadays, virtually ing intra-cellular pathways (signal transduc - all patients with FL receive rituximab during tion, apoptosis) were recently developed and their disease course, and epidemiological sur - will likely expand the options for managing veys indicated a substantial prolongation of patients with FL without chemotherapy. This patients’ life expectancy. Other anti-CD20 educational review will summarize available antibodies have been developed, and two of data in the field. Because the mechanisms of them (namely ofatumomab and obinutuzum - action of antibodies coupled with cytotoxic ab) have demonstrated significant activity in agents (antibody drug conjugates) or with chronic lymphocytic leukemia, a disease con - radionuclides (radio-immunotherapy) still rep - Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 151 | 19 th Congress of the European Hematology Association

resent classical, although targeted, delivery of respectively achieved with a shorter standard treatment (4 weekly infu - chemotherapy or radiation therapy, these approaches will sions), but no difference was found with this scheme in not be covered in this review. terms of time to next cytotoxic therapy or overall survival. The RESORT randomized study (organized by the US- based ECOG group) recruited patients with similar char - Rituximab single agent activity in patients with acteristics and after the administration of 4 weekly ritux - follicular lymphoma imab infusions compared in randomized design rituximab maintenance versus rituximab re-treatment. 14 Although the Although the use of rituximab single agent may appear time to initiation of cytotoxic therapy was slightly (but today less common than its use in combination with significantly) delayed in patients receiving rituximab chemotherapy, the therapeutic activity of this antibody maintenance, this trial indicated a lack of significant ben - when used as monotherapy is worth mentioning here, efit in terms of time to treatment failure for rituximab since rituximab represents the standard to which all other maintenance in this setting. Recently, 15 the study conduct - non-chemotherapeutic approaches (including their combi - ed by the Swiss SAKK group (with less stringent inclusion nation with rituximab) are compared. The first evaluation criteria) failed as per protocol to demonstrate a significant of rituximab as single agent in patients with FL, with 4 2 advantage of five years rituximab maintenance (every 2 weekly doses of 375 mg/m , was performed in relapsing months) over a short prolonged treatment (4 weekly infu - patients (previously untreated with anti-CD20 antibodies). sions followed by 4 infusions every 2 months). A subse - The overall response rate (ORR) was 48% (with only 6% quent unplanned analysis of a restricted patient set sug - of the patients achieving a complete response, CR) and 2 gested a longer PFS for those patients with long-term time to progression was 13 months. These results were treatment. Altogether, these results suggest that although a reproduced in several studies in relapsing rituximab naïve significant delay in time to progression can be achieved patients. In previously untreated patients, rituximab with a long or unlimited chemotherapy-free rituximab demonstrated a greater activity with 70-75% ORR and maintenance approach, the ultimate benefit (if any) in 30% CR, with a time to treatment failure of approximately 3-7 terms of time to the initiation of chemotherapy, safety and 20-24 months. cost, appears quite uncertain. Furthermore, no overall sur - Rituximab re-treatment was assessed only in relatively vival benefit with a prolonged treatment was observed in few studies in patients with FL, usually including patients any of those studies. who were responsive to previous rituximab administra - 8,9 10 Despite the fact that it has been used now for over 15 tions or in studies which were essentially retrospective. years, several questions regarding rituximab activity as Scarce data regarding the efficacy of rituximab as single single agent still remain unanswered. One of those is the agent in rituximab exposed patients can also be retrieved potential activity (or lack of activity?) of rituximab (used from prospective controlled studies. In one of them, eval - with its classical weekly schedule) in patients who were uating rituximab (8 infusions) versus rituximab plus borte - characterized as being “rituximab refractory” as defined zomib, the median time to progression in rituximab pre- 11 by patients with “no response or progression within 6 treated patients was 9.2 months. The centrally reviewed months of its last administration”. Although this definition response rate in another study comparing rituximab versus 12 is commonly used to register patients to be evaluated for was found to be 28%. It then appears that new anti-CD20 antibodies or new agents, little is known rituximab retains some activity in patients who had about the residual activity that rituximab might have in already received the antibody, but the parameters that may those patients, who may not all have developed a true influence the response rate and the duration of response “resistance” to the antibody. Another unresolved question have been poorly investigated in this particular setting. is the potential activity of higher doses or different admin - It was also rapidly shown that the prolongation of treat - istration schemes 9,16 of rituximab. Indeed, some investiga - ment duration with rituximab resulted in a higher exposure tors have addressed the dose-effect relationship of ritux - to the drug in vivo . One randomized study showed that imab in animal models 17 and shown a correlation between after 4 weekly rituximab infusions, 4 additional doses, dose and tumor response. Given also the influence of each delivered every two months, was able to improve the tumor burden on the pharmacokinetic profile of rituximab, response rate (at one year: 60% vs. 44%) and the event- those data suggest that it may be relevant to examine if free survival (median 23 months vs. 11 months) in 2 5 higher doses (i.e. higher than the approved 375 mg/m relapsed or untreated FL. Based on these results and oth - dose) may be useful in patients with a high tumor burden ers, several clinical trials have demonstrated an improved and / or different pharmacodynamic profiles. 18 progression-free survival and sometimes overall survival when rituximab maintenance was delivered after chemotherapy or immunochemotherapy. 1 The evaluation The development of new anti-CD20 antibodies of single agent rituximab induction followed by rituximab maintenance was tested in 3 recent prospective studies in Several other anti-CD20 antibodies, recognizing differ - previously untreated patients with FL. The mature results ent epitopes on the CD20 molecule and/or being engi - of the UK-based study, 13 restricted to patients with a low neered to increase the complement dependent cytotoxicity tumor burden, and assessing 4 weekly infusions of ritux - (CDC) or antibody dependent cellular cytotoxicity imab followed by two years of rituximab maintenance (1 (ADCC) potency, have been investigated in clinical tri - infusion every 2 months), showed an ORR of 88%, with als. 19 The most advanced in their clinical development are 59% CR or unconfirmed CR (CRu), and a 3-year progres - ofatumomab, 20 veltuzumab, 21 and obinotuzumab. 22 sion-free survival (PFS) of 82%. These results also com - Although in vitro experiments and some phase I/II early pared favorably in terms of ORR and PFS to those results suggested that these antibodies may have an activ -

| 152 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 ity superior to that observed with rituximab, or be active in resulting in a specific ‘vaccinal’ effect. 31,32 Based on these rituximab refractory patients, 23 few conclusive or compar - assumptions, and on other in vitro experiments, various ative data are yet available regarding patients with FL. A immunomodulating agents were combined with ritux - specific study investigated the activity of ofatumomab in imab. During the last ten years, alpha-interferon, 33-35 inter - rituximab refractory patients and showed an overall leukin-2, 36,37 interleukin-12 38 and GM-CSF 39 were com - response rate of 11%, with 22% of response in patients bined with rituximab in phase II clinical trials. Some of 24 previously refractory to rituximab monotherapy. those data suggested prolonged response duration (with Veltuzumab has not been compared head to head to ritux - interferon) or a higher CR rate (with GM-CSF). Immune imab as single agent, and its activity in rituximab refracto - monitoring of these patients also revealed some interesting ry patients remains unknown. Finally, obinotuzumab has patterns of immune cell stimulation. In these studies, the been compared to rituximab in a randomized phase II side-effects associated with these combinations were pre - study including 175 patients (149 with FL); preliminary dominantly those observed with these cytokines, including results indicated significantly superior response rates fever, fatigue, and other common side-effects reported (43% vs. 28% as assessed by central review) but no differ - 12 with interferon or GM-CSF administration. Following ence in PFS. Based on these current findings, it seems these preliminary results, the Nordic Lymphoma Study premature to predict that one of these antibodies will be group conducted one large randomized study evaluating better than rituximab in chemotherapy-free approaches. the combination of rituximab and alpha-interferon. However, combination studies of lenalidomide with these Although a higher CR/CRu rate was observed in the inter - new anti-CD20 antibodies have been initiated ( clinicaltri - feron-rituximab combined arm (41% CR/CRu vs. 22% als.gov identifier : 01582776 and 01060384) and one may CR/CRu with rituximab alone), this did not translate into hope that the clinical activity of antibody optimized for a significant improvement in time to treatment failure. 40 increased ADCC might be further enhanced with lenalido - Interestingly, engineering antibodies obtained by cou - mide (see below) or other agents. pling cytokine such as interferon-alpha 41,42 to anti-CD20 antibodies (immunocytokines) have been shown in vitro to Combining anti-CD20 with monoclonal antibodies have a remarkable activity against B-cell tumors in pre- against other B-cell targets clinical models, and these approaches may eventually reach clinical development in the future, hoping for a bet - Several studies were launched to evaluate new mono - ter tolerability and an increased efficacy of these mole - clonal antibodies recognizing different B-cell antigens as cules. therapy of FL. 25 While the threshold level of activity of rit - uximab was never achieved with these ‘naked’ antibodies Combining rituximab with oral immunomodulatory in phase I/II studies, some interesting results were agents such as IMIDs® obtained from studies designed as combinations (“dou - blets”) of rituximab with these new antibodies. For Recently, lenalidomide appeared as another potentially instance, the anti-CD80 antibody galiximab demonstrated 26 active drug to be combined with rituximab. As a single limited activity as single agent and was then investigated 27 agent, responses to lenalidomide were quite modest and with rituximab, either in relapsing or in untreated FL 43 28 observed in approximately 25% of patients with FL. But patients. In this last study, 61 patients received this com - several in vitro data indicate that lenalidomide may poten - bination and the observed ORR was 72%, with 48 tiate rituximab-induced tumor cell kill by enhancing CR/CRu and a median PFS of 2.9 years. However, these immune synapse formations and NK cell activity, result - results were not considered to be significantly superior to 44 ing in increased ADCC. This rationale prompted several those observed with rituximab single agent, and the devel - investigators to conduct combination studies in FL opment program of this drug was later discontinued. patients, with variable schemes and doses of lenalidomide Another antibody, , directed against the B- cell CD22 , was also evaluated with a similar and rituximab, combined or not with steroids. design in patients with FL 29 and responses were found to In relapsed or refractory disease, small series of patients be comparable to those achieved with a combination of rit - were reported with response rates ranging from 49% to 86% (25% in a study including only grade 3 FL) and uximab plus chemotherapy (ORR 88%, 42% CR) with an 45-48 estimated median PFS of 3.5 years. Although these results CR/CRu rates from 13% to 50%. The North-American appear quite promising, the role of this monoclonal anti - CALGB group reported a prospective randomized study evaluating lenalidomide versus rituximab plus lenalido - body in FL management remains uncertain and its devel - 49 opment has been shifted to the autoimmune disease field. mide in 99 patients with relapsed FL. The response rates were higher in the combination arm (ORR 75%, 32% CR/CRu) compared to lenalidomide alone (ORR 49%, Potentiating rituximab efficacy with immunomodu - 13% CR/CRu) and a significant improved event-free sur - lating cytokines vival (median of 2 years with the combination vs . 1.2 year with lenalidomide alone; P=0.0063). The precise mode of action of rituximab accounting for In the front-line setting, the MD Anderson Cancer its therapeutic activity in vivo remains imperfectly under - Center investigators reported a series of 110 patients, 46 of 50 stood. It may involve complement dependent cytotoxicity, them with FL. The treatment scheme included lenalido - direct effects of the antibody on tumor cells, or, more like - mide 20 mg/ day for 21 days out of 28 days, and one infu - ly, ADCC. 30 Another hypothesis is the possibility that after sion of rituximab every month, all for six months, with a tumor cell lysis by rituximab or immune cells, a specific few patients completing the treatment with another six T-cell based anti-tumor response might be elicited, hence months of this combination. The observed ORR was 98%

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with 87% of CR/CRu. Interestingly, responses in patients planned to be initiated. with FL were observed regardless of the FLIPI score 51 or The PD1-PDL1 pathway has also been shown to be crit - the GELF tumor bulk criteria. 52 A metabolic complete ical in T-cell mediated anti-tumor response. 58 The co- response was achieved in 42 of 45 patients assessed using inhibitory receptor program cell death protein PD1 on PET-CT, and all evaluable patients demonstrated a clear - tumor infiltrating impairs the functions of these T ance of PCR-detectable IGH-BCL2 translocation. In this cells when engaged by PD-L1 and PD-L2 ligands present - study, grade 3 neutropenia was observed in 40% of the ed by tumor cells. Based on this rationale, several anti- patients, and thrombocytopenia in 4%. Other common PD1 and anti-PD-L1 antibodies have been developed and non-hematologic toxicities included rash (approx. half of evaluated in various cancers. Recently, the activity of the the patients, but only a minority, i.e. 7%, with grade 3) and anti-PD1 pidilizumab antibody in combination with ritux - muscle pain (grade 3, approx. 6%). A few patients had to imab has been reported in relapsed patients with FL 59 interrupt the trial due to adverse events, and a few patients (assessed as sensitive to previous rituximab treatment). also developed repeated infusion-related reactions after Responses were observed in 19 of 32 patients (66%) with rituximab infusions. CR in 14 of them, suggesting a higher clinical activity as Altogether, these promising results prompted the launch compared to that expected with rituximab single agent. of 2 randomized studies in previously untreated patients This combination was well tolerated, but 5 patients pre - with FL. The Swiss and Nordic lymphoma groups sented grade 2 pulmonary infections. Other anti-PD1 anti - designed a study ( clinicaltrials.gov identifier : 01307605) bodies, such as or MK-3475, are currently comparing single agent rituximab (4 weekly infusions being evaluated in phase II studies in FL then 4 infusions administered every other month) with the (clinicaltrials.gov identifier : 02038946) or other PD-L1 same regimen combined with a continuous dose of 15 mg positive lymphoma ( clinicaltrials.gov identifier : of lenalidomide. The study objective was to accrue 152 01953692). patients in order to compare the response rate achieved at week 23, and accrual has recently been completed. Proteasome inhibitors Another large collaborative intergroup international study clinicaltrials.gov identifier ( : 01650701) has been organ - Proteasome inhibitors represent a class of agents distinct ized by the LYSA group and US-based investigators with from chemotherapy, which have been shown to have activ - the objective of comparing the rituximab-lenalidomide ity in several hematologic malignancies, including lym - combination to rituximab-chemotherapy. In the control phoma, 60 although the positioning of bortezomib, the first arm, patients are treated according to the PRIMA study 61 53 to be developed, in FL management remains unclear. A protocol, with different possible choices of chemothera - large randomized phase III study evaluating bortezomib in py (bendamustine, CHOP or CVP) followed by two years combination with rituximab against rituximab alone has of rituximab maintenance. In the experimental arm, been performed in patients with relapsed FL. 11 Despite sig - patients receive 4 weekly infusions of rituximab followed nificantly higher response rates observed in the combina - by one infusion every month together with lenalidomide tion arm (ORR 63% vs. 49% and CR/CRu 25% vs. 18%), 20 mg for 21 days out of 28. During the maintenance peri - the benefit in terms of PFS was found to be very modest od, rituximab is administered every two months for two (median PFS 12.8 months in the combination vs. 11 years and lenalidomide for one year at reduced dose (10 months in the rituximab arm; P=0.039) given the con - mg). The primary objective is a composite end point con - straints and toxicities associated with the use of borte - sisting in either PFS or CR rate at 120 weeks. A total of zomib. 1000 patients are expected to be randomized and accrual is planned to be completed at the end of 2014. The development of kinase inhibitors in follicular lymphoma Other immunomodulatory approaches using mono - clonal antibodies An exciting development in recent years has been the demonstration of the therapeutic activity of kinase Another approach currently undergoing pre-clinical inhibitors in B-cell lymphoid malignancies. Several agents development is to target with monoclonal antibodies mol - are currently being actively investigated, with promising ecules that may enhance the activity of anti-CD20 anti - results in certain lymphoma subtypes. bodies. For instance, it was shown in vitro that the CD47 The first available agents were mTOR (the mamalian antigen expressed on lymphoma cells neutralizes the target of rapamycin) inhibitors. In patients with relapsed phagocytosis induced in the presence of rituximab, while FL, used as a single agent (intravenously) co-administration in animal models of anti-CD47 antibody exhibited overall and complete response rates of 54% and with rituximab was able to increase the lymphoma cure 26%, respectively, and patients experienced a median PFS 54 rate. The CD137 co-stimulatory molecule modulates of 12.7 months. 62 + NK-cell and CD8 T-cell activity and anti-CD137 agonist The bruton tyrosine kinase inhibitors (BTKi) are oral antibodies display anti-tumor activity and were shown to agents rapidly emerging in lymphoma therapy. The early increase rituximab-induced ADCC when tested in vitro or and preliminary results of the first BTKi, ibrutinib, have 55,56 in murine models. Recently, similar findings were also been reported in 16 patients with relapsed FL. 63 The ORR reported with the use of anti-KIR antibodies. 57 Some of was 55% (with 3 CRs and 3 PRs, respectively). The these antibodies have already been tested as single agent response appeared to be durable (12 months) and the in cancer or lymphoma patients and clinical trials combin - median PFS was 13 months. Based on these early find - ing them with anti-CD20 antibodies (or other agents) are ings, several studies are currently ongoing. One of those

| 154 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 will evaluate the activity of ibrutinib as single agent in How to position chemo-free approaches for patients who are assessed to be refractory or early relaps - patients with follicular lymphoma? ing after rituximab and alkylating agent combinations (clinicaltrials.gov identifier : 01779791). Other studies Nowadays, in patients with FL, classical recommended will assess combinations of ibrutinib with rituximab ( clin - therapeutic strategies in first-line usually consist in radia - icaltrials.gov identifier : 01980654) or with lenalidomide tion or combined modality therapy for patients with local - and rituximab ( clinicaltrials.gov identifier : 01829568). ized disease, watchful waiting for those with a low tumor Ibrutinib toxicities are usually mild and may include burden, and rituximab-chemotherapy combinations for fatigue, diarrhea, rashes, and, more rarely, some fall in those with a high tumor burden. 67-69 Although not hematologic parameters or hemorrhage. approved by health authorities in this setting in Europe, The PI3 kinase enzymes are important in coupling rituximab single agent is also used sometimes as a first- extra-cellular signals to internal survival and proliferation line treatment for those patients who are uncomfortable pathways in many tissues and several isoforms have been with watchful waiting or who show a moderate and slow described. Multiple compounds inhibiting the PI3K are progression after an initial period of observation. Some being developed, but the activity of inhibitors of the delta studies are currently evaluating chemo-free regimens (rit - isoform, whose expression appears to be restricted to the uximab-lenalidomide) for patients with higher tumor bur - hematopoietic lineage, have been further investigated in den, but given the demonstrated survival benefit of patients with FL. After initial promising results in phase I immunochemotherapy combination in these patients, such studies, 64 the oral PI3K delta specific inhibitor idelalisib regimens are not recommended outside clinical trials. has been recently investigated in 125 patients with indo - Indeed, the promising results of rituximab maintenance in first-line patients responding to immunochemotherapy lent lymphoma who were refractory to both rituximab and 65 (59% of them are free of lymphoma recurrence after a fol - alkylating agents. In 78 FL patients, the response rate 70 low up of 6 years ) represent quite a challenge for chemo- was found to be 54%, with a median time to response of free regimens, which may turn out to also carry some tox - 1.9 months, and response duration (in the whole cohort) of icities and constraints for which they will then not be con - 12.5 months. Significant toxicities included essentially sidered to be ‘toxicity-free’. diarrhea (13% grade ≥3), pneumonia (7% grade ≥3), and When the disease recurs or progresses after first-line neutropenia, but some patients presented also with a sharp therapy, many options are still available. In spite of the elevation of transaminases, usually reversible with treat - fact that intensive therapy provides interesting results, 71 ment interruption. Several studies are currently being con - the majority of patients are not eligible for this approach ducted, including one randomized study comparing ritux - and some continue to relapse after autologous transplant. imab single agent versus rituximab plus idelalisib in With the prolonged survival expectancy of patients with relapsed FL ( clinicaltrials.gov identifier : 01732913). FL, it is then attractive to offer non-chemotherapeutic Another PI3K inhibitor active both on the delta and options, as long as they are not too toxic. Currently, only gamma isoforms is also currently being investigated in rituximab is approved in this setting in Europe, but kinase clinical trials. 66 inhibitors and other agents might soon be available.

Table 1. Options for chemotherapy-free approaches currently evaluated in patients with follicular lymphoma.

Agents or pathways Rationale or hypotheses tested Candidates under development Current status and/or limitations Anti-CD20 antibodies Further optimizing dose and scheme Rituximab itself Studies to be designed on pre-clinical rationale of rituximab administration Engineering more potent anti-CD20 antibodies Ofatumumab, veltuzumab, obinotuzumab, Clinical superiority as single agent yet to be ocaratuzumab, unblituximab, etc. demonstrated in randomized studies Naked antibodies against Should provide an anti-tumor effect if the target anti-CD80 (galiximab), anti-CD22 (epratuzumab), Limited efficacy as single agents and mostly other B-cell antigens is well chosen anti-CD37, etc. investigated as doublets with anti-CD20 Cytokines Intrinsic activity and/or increased effector cell alpha-interferon, GM-CSF, interleukin-2 No major clinical benefit and toxicities activity in the presence of anti-CD20 antibodies or -12, etc. associated with cytokines Immumodulatory agents Intrinsic activity and/or increasing effector cell IMIDs® (lenalidomide) Encouraging preliminary results, risk /benefit ratio activity in the presence of anti-CD20 antibodies to be determined by current randomized trials Modulating effector cell activity anti-PD1 (pidiluzumab), anti-PDL1, Early development, some encouraging preliminary data anti-CD47, anti-CD137 Targeted therapies Inhibition of the proteasome machinery to target Proteasome inhibitors: bortezomib, carfilzomib, etc. Toxicity and low efficacy the NF-kB pathway Inhibition of critical pathways activated in PI3K inhibitors (idelalisib, IPI-145, etc.) Phase II results encouraging B-cell malignancies BTK inhibitors (ibrutinib, etc.) Preliminary signals of activity Counteracting anti-apoptotic molecules anti-bcl2 (ABT-199) Early stage of development Epigenetic modifiers Demethylating agents, inhibitors of HDAC, EZH2 Early stage of development inhibitorsE GM-CSF: granulocyte-macrophage colony stimulating factor; PI3K: phosphoinositide-3-kinase; BTK: bruton tyrosine kinase; HDAC: histone deacetylases.

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The current results with new agents should also be inter - ticenter phase II study. Cancer Sci. 2011;102(9):1698-705. 10. Johnston A, Bouafia-Sauvy F, Broussais-Guillaumot F, preted with caution, given the small numbers of patients Michallet AS, Traulle C, Salles G, et al. Retreatment with rit - included in some series, the lack of further details regard - uximab in 178 patients with relapsed and refractory B-cell ing clinical or pathological characteristics (such as, for lymphomas: a single institution case control study. Leuk Lymphoma. 2011;51(3):399-405. example, histological grade) in others, and the molecular 11. Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, heterogeneity and intra-tumor diversity of FL. Offner F, et al. Bortezomib plus rituximab versus rituximab The current understanding of lymphoma biology and alone in patients with relapsed, rituximab-naive or rituximab- tumor immunology clearly allows foreseeing the time sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12(8):773-84. when specific and targeted treatments, currently investi - 12. Sehn LH, Goy A, Offner FC, Martinelli G, Friedberg J, gated (Table 1), may replace chemotherapy containing Lasserre SF, et al. Randomized Phase II Trial Comparing regimens. Beside the paths described above, other targeted GA101 (Obinutuzumab) with Rituximab in Patients with 72 Relapsed CD20 Indolent B-Cell Non-Hodgkin Lymphoma: agents such as inhibitors of the BCL2 protein or Preliminary Analysis of the GAUSS Study. ASH Annual inhibitors of epigenetic machinery (such as the histone Meeting Abstracts. 2011;118(21):269-. methyltransferase EZH2, mutated in 27% of patients with 13. Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al. Rituximab versus a watch-and-wait approach FL) will also be investigated in patients with FL. in patients with advanced-stage, asymptomatic, non-bulky fol - Obviously, many combinations of new agents will be licular lymphoma: an open-label randomised phase 3 trial. assessed in clinical studies for their efficacy. But one Lancet Oncol. 2014;15(4):424-35. 14. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, should keep in mind the toxicities potentially associated Krauss JC, et al. Results of Eastern Cooperative Oncology with some of these regimens, the quality of life for patients Group Protocol E4402 (RESORT): A Randomized Phase III on long-term therapy (even when they are oral agents), Study Comparing Two Different Rituximab Dosing Strategies and the current lack of long-term follow up of these for Low Tumor Burden Follicular Lymphoma. ASH Annual Meeting Abstracts. 2011;118(21):LBA-6-. approaches. 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