The current status and future impact of targeted therapies in non-Hodgkin lymphoma

Abstract

A number of new, biologic targeted therapies have been developed for the treatment of lymphoid malignancies. These include anti-CD20 monoclonal antibodies designed with greater binding affinities and different mechanisms of action profiles compared with rituximab. Other extracellular antigens on B cells and T cells are also being targeted. Monoclonal antibodies have been conjugated to radioisotopes and cellular toxins. In addition, several exciting new small-molecule kinase inhibitors are in development that target intracellular pathways that contribute to the pathogenesis of these diseases. Drugs that affect the tumor microenvironment are also under investigation. The advantage of these targeted agents compared with standard chemotherapy is greater tumor specificity, a more favorable toxicity profile, and, when combined with scientific rationale, and in the appropriate setting, perhaps a better long-term outcome.

Keywords::

• antibody–drug conjugate
• bispecific T-cell-engager molecules
• Hodgkin lymphoma
• immunomodulatory agent
• monoclonal antibody
• non-Hodgkin lymphoma
• radioimmunotherapy
• small-molecule kinase inhibitor
• targeted therapy

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/experthematology; (4) view/print certificate.

Release date: 2 April 2013; Expiration date: 2 April 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe potential advantages of new, biologic targeted therapies for NHL compared with traditional chemotherapy and with rituximab, based on a review

• • Describe the role of newer monoclonal antibodies and antibody-drug conjugates in the treatment of patients with NHL, based on a review

• • Describe the role of radioimmunotherapy, immunomodulatory agents, and small-molecule kinase inhibitors in the treatment of patients with NHL, based on a review

Financial & competing interests disclosure

EDITOR

Eliza Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Eliza Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC.

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Chaitra Ujjani, MD

Lombardi Comprehensive Cancer Center, Georgetown University Washington, DC, USA

Disclosure: Chaitra Ujjani, MD, has received support from Boehringer Ingelheim, Ltd. and MedImmune.

Bruce D Cheson, MD

Lombardi Comprehensive Cancer Center, Georgetown University Washington, DC, USA

Disclosure: Bruce D Cheson, MD, has received support from Genentech, Gilead Sciences, Inc., Celegene, Pharmacyclics and Teva, Ltd.

The availability of safe and effective monoclonal antibodies has markedly altered treatment strategies for patients with lymphoma. The first to demonstrate clinical benefit was rituximab, a chimeric anti-CD20 monoclonal antibody that induces cell death through antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC) and induction of apoptosis. Not only does rituximab improve response rates in most histologies of B-cell non-Hodgkin lymphoma (NHL; B-NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and other indolent and aggressive histologies, but, unlike various combinations of multiagent chemotherapy, progression-free (PFS) and overall survival (OS) is prolonged. Following the success of rituximab, considerable efforts have been made in exploring similar and alternative targets of the malignant lymphocyte (Table 1). By exploiting specific pathways of the tumor cell, biologic therapeutic agents allow for not only greater tumor specificity, but less nonspecific toxicity and better utilization of tumor-specific mechanisms of action as well.

Monoclonal antibodies directed against CD20

Despite the success of rituximab in patients with B-cell malignancies, considerable room for improved outcome remains. FL, MCL and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) remain incurable, while up to 40% of those with DLBCL fail initial treatment and most of those die from their disease. At least ten antibodies have been developed to target CD20, with a variety of modifications designed to improve on the rituximab molecule.

Ofatumumab is a fully human antibody that binds to a different epitope on CD20 than rituximab, and induces only CDC and ADCC. It was approved by the US FDA for the treatment of fludarabine and alemtuzumab-refractory CLL based on a Phase II study by Wierda et al. that demonstrated an overall response rate (ORR) of 58% (0% complete response [CR]) and median OS of 13.7 months [1]. Although ofatumumab has a role in refractory CLL, it does not appear to be a replacement for rituximab. In an international study of 61 previously untreated CLL patients who received standard doses of fludarabine and cyclophosphamide (FC) with either 500 or 1000 mg of ofatumuamb, responses were lower than historical data with similar rituximab-based regimens; ORR of 77% (CR: 32%) and 73% (CR: 50% [2]). The most common grade 3–4 toxicity was myelosuppression, with 48% neutropenia.

The clinical utility of ofatumumab in NHL has yet to be demonstrated. In a Phase I/II study of relapsed and refractory FL by Hagenbeek et al., 40 patients treated with ofatumumab at four dose levels had ORRs of 20–63% with a median duration of response (DOR) of 29.9 months [3]. In a subsequent multicenter Phase II study in rituximab-refractory FL, ofatumumab achieved less promising results: ORR of 10% (1000 mg cohort) and 13% (500 mg cohort) with a median PFS of 5.6 months [4]. The ORR was 22% in patients who were refractory to rituximab monotherapy and 7% for those who were refractory to rituximab-chemotherapy regimens. Over half of the patients experienced a reaction with the first infusion, three of which were grade 3. Reactions were noted with each weekly infusion in up to 12% of the patients by the final infusion. When combined with chemotherapy in NHL, ofatumumab may have comparable efficacy to rituximab. Fowler et al. demonstrated an ORR of 98% (CR: 60%) with ofatumumab and bendamustine in previously untreated advanced-stage indolent B-cell NHL (B-NHL) [5]. When given at one of two doses with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in untreated advanced-stage FL, Czuczman et al. found an ORR of 90% with CR of 55 and 69% [6]. Based on laboratory assessment, there was a 90% incidence of grade 3–4 neutropenia, which is significantly higher than previously reported with CHOP plus rituximab (R-CHOP) in this setting. A direct comparison of rituximab and ofatumumab in the front-line setting would be necessary to establish which agent is superior. Thus far, it appears that ofatumumab is associated with more toxicity without greater efficacy.

Obinutuzumab, formerly known as GA-101, is a glycoengineered humanized type II antibody that employs ADCC and apoptosis. In contrast to type I antibodies such as rituximab, obinutuzumab does not utilize CDC but was designed to have superior ADCC and apoptosis. In relapsed and refractory indolent B-NHL, obinutuzumab produced an ORR of 43% (CR: 24%) with DOR ranging from 5 to 21 months [7]. Of the FL patients, 69% achieved a response (CR: 38%). The GAUSS study compared obinutuzumab to rituximab in relapsed and refractory indolent B-NHL. Obinutuzumab produced a higher ORR of 42 versus 24.1% by independent review, but similar response rates (43 vs 36%) by investigator assessment. More infusion reactions were experienced with obinutuzumab than with rituximab, with no difference in PFS [8]. In the GAUDI study of relapsed and refractory FL, obinutuzumab plus FC or CHOP produced an ORR of 93 (CR: 26%) and 96.4% (CR: 27%), respectively [9]. Grade 3–4 neutropenia rates were similar to those previously reported with these chemotherapy regimens, 50 and 39%, respectively. In the second phase of this study, obinutuzumab was combined with CHOP or bendamustine [10]. Responses were similar; 95% (CR: 35%) in the CHOP arm and 93% (CR: 39%) in the bendamustine arm. Genentech’s (CA, USA) registration trial for obinutuzumab, a randomized Phase III study of bendamustine versus bendamustine with obinutuzumab in rituximab-refractory indolent NHL, is currently recruiting patients. Trials comparing obinutuzumab with rituximab in combination with multiagent chemotherapy in DLBCL and indolent NHL as upfront regimens are also underway.

In order for another anti-CD20 antibody to replace rituximab, it must show superior efficacy to rituximab or have efficacy where rituximab fails. Yet, none of the newer CD20 antibodies have achieved this objective. Studies comparing obinutuzumab with rituximab in the front-line setting are ongoing, but ofatumumab is only being evaluated in patients who have previously received rituximab. Although some of these agents may eventually show superior benefit, their future is unclear given the development of rituximab biosimilars. Unless one of these new antibodies can provide a clinically significant benefit, their future remains uncertain in lymphoma treatment.

Monoclonal antibodies directed against alternative targets

Epratuzumab is a humanized monoclonal antibody against CD22, which is involved in B-cell receptor signaling. Single-agent epratuzumab was found to have a 43% ORR in recurrent FL [11] but only 15% in DLBCL [12]. When given in conjunction with rituximab in relapsed and refractory indolent NHL, the ORR were more impressive; 54% (CR/unconfirmed CR [CRu]: 24%) in FL and 57% (CR/CRu: 43%) in SLL [13]. In FL, the median DOR was 13.4 months in all treated patients, but 29.1 months in patients with a CR/CRu. The Cancer and Leukemia Group B (CALGB) achieved an ORR of 84% (CR: 33%) in previously untreated FL using the doublet for induction followed by every other month for four doses [14]. At a median follow-up time of 2.7 years in the 35 patients who have not progressed, the median PFS was 3.5 years, with an estimated probability of PFS of 0.60 at 3 years. At 3 years, the probability of survival was 0.91. In an attempt at improving the survival in DLBCL, Micallef et al. combined epratuzumab with R-CHOP. The ORR was 96% (CR/CRu: 74%) and 3-year OS was 80% [15]. Although these results appear favorable when compared with those previously reported with R-CHOP, there was significant toxicity including 85% incidence of grade 3 or higher neutropenia. Moreover, the patients were selected to be positive for CD22, making a determination of the role of the antibody difficult. A direct comparison with longer follow-up would be necessary to determine the superiority of either regimen. In addition, it should be noted that not all DLBCL express CD22 and these negative patients were excluded from this study. Thus, it is difficult to determine the impact of antigen expression on response to treatment.

The several members of the Fcγ receptor family vary in antibody binding affinity due to their different molecular structures. It has been established that polymorphisms of FcγRIIIa can impact the binding affinity of rituximab and, thus, its efficacy in different populations. Afucosylation allows for greater FcγRIII-specific infinity and better activity. MEDI-551 is an afucosylated antibody to CD19, a regulating protein of the B-cell receptor signaling pathway that is expressed on nearly all B-cell lymphomas. In a recent Phase I/II study of 63 patients with lymphoid malignancies and multiple myeloma, MEDI-551 produced CRs and partial responses (PRs) in both DLBCL and FL [16]. In order to evaluate the potential superiority of MEDI-551 in relapsed and refractory setting of DLBCL, Medimmune (MD, USA) is conducting a randomized Phase II study of ICE (ifosphophamide, carboplatin and etoposide) or DHAP (dexamethasone, cytarabine and cisplatin) in combination with either MEDI-551 or rituximab as a bridge to autologous stem cell transplantation (ASCT).

CT-011 is a humanized monoclonal antibody that was designed to target PD-1, an inhibitory protein involved in T-cell and natural killer (NK)-cell regulation. CT-011 functions primarily via apoptosis and is being studied in many cancers. In a recent Phase II study of relapsed follicular lymphoma, CT-011 produced an ORR of 66% (CR: 52%) with a median PFS of 21 months and minimal toxicity [17]. CT-011 is being studied in combination with rituximab in relapsed FL and as maintenance therapy after ASCT in DLBCL.

Mogamulizumab is a fully humanized defuscolyated antibody against CCR4, which is expressed on malignant T cells and regulatory T cells. Via ADCC, mogamulizumab has demonstrated activity in adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma and peripheral T-cell lymphoma (PTCL). In a multicenter Phase II Japanese study of 28 patients with relapsed adult T-cell lymphoma, mogamulizumab produced an ORR of 50% (eight CRs), median PFS of 5.2 months and median OS of 13.7 months [18]. The most common toxicities were infusion-related reactions and skin rashes. In a multicenter Phase II study of mogamulizumab in primarily cutaneous T-cell lymphoma, responses were seen in 15 of the 38 patients, two of which were CR [19]. In relapsed PTCL, mogamulizumab produced an ORR of 34% among the 29 patients including ALK-negative anaplastic large cell, angioimmunoblastic and PTCL-not otherwise specified subtypes [20]. Mogamulizumab is now being studied further in PTCL. Given these promising results, mogamulizumab may be more effective in the front-line setting with chemotherapy.

Radioimmunotherapy

Perhaps one of the most effective, yet underutilized, agents in the treatment of NHL is radioimmunotherapy (RIT). RIT consists of an antibody bound to a radioisotope, providing the dual benefit of radiation and targeted immunotherapy. ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumomab have been approved for the treatment of relapsed and refractory FL and low-grade lymphomas [21,22]. Although not approved for a front-line indication, both have impressive ORRs of ≥95% (CR/CRu: 64–75%) in previously untreated primarily advanced-stage FL [23,24]. ⁹⁰Y-ibritumomab tiuxetan has been approved as a consolidative regimen based on the FIT study. In a large randomized Phase III trial in advanced-stage FL, Morschhauser et al. showed that those who received ⁹⁰Y-ibritumomab tiuxetan after achieving at least a PR with one of a variety of induction regimens (generally not including rituximab) experienced a significantly longer median PFS of 36.5 months, compared with 13.3 months in those who did not [25]. One important observation in that study was the number of patients with PR who were converted to CR with RIT, with an apparent improvement in outcome. However, in a similar setting, a Southwest Oncology Group (SWOG)-led intergroup trial demonstrated that the addition of ¹³¹I-tositumomab after CHOP produced no benefit compared with R-CHOP alone [26]. While RIT may not have a major role as a consolidative regimen in indolent lymphomas, it provides patients with an option for reinduction.

Unlike the low-grade lymphomas, MCL is typically unable to achieve durable responses with R-CHOP. The Eastern Cooperative Oncology Group recently evaluated the ability of ⁹⁰Y-ibritumomab tiuxetan consolidation to improve survival in patients who received R-CHOP induction (four cycles) [27]. The ORR after completion of all therapy was 82% with 55% CR/CRu. RIT improved the quality of response in 22 patients; 16 converted from a PR to CR/CRu while six converted from stable disease to a CR or PR. The median time to treatment failure was 34.2 months and the estimated 5-year OS was 73%. These survival data were better than those previously reported with R-CHOP in MCL, regardless of whether additional therapy with interferon or rituximab was administered. The most common grade 3–4 toxicities during RIT were neutropenia and thrombocytopenia, but there were no reports of infection, neutropenic fever or bleeding. It should be noted that there is a risk of secondary acute myeloid leukemia and myelodysplastic syndrome (MDS) with RIT. In relapsed and refractory NHL ⁹⁰Y-ibritumomab tiuxetan was associated with a 5% incidence of acute myeloid leukemia and MDS, with a median time to the development of 2 years [28]. These secondary malignancies have been reported in patients who received chemotherapy prior to RIT but not yet in patients who received only RIT as their initial treatment [29,30]. Regardless, caution must be taken with the use of these agents, particularly in indolent NHL. As with most cancer therapies, significant investigation is required to understand where RIT best fits into our treatment strategies. It appears that RIT may provide a more plausible option for patients who are unable to undergo more aggressive chemotherapy regimens or ASCT. Further evaluation in randomized fashion of different induction regimens followed by consolidation with RIT and ASCT would be worthwhile.

Antibody–drug conjugates

Perhaps one of the most fascinating modifications of the monoclonal antibody is the antibody–drug conjugate (ADC). These agents consist of a monoclonal antibody linked to an anticancer drug or toxin. Once the antibody binds the surface of the lymphocyte, the ADC is internalized into a lysosome, and the toxin is released into the cytoplasm leading to cellular death. Brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated to the antimicrotubulin agent monomethyl auristatin E, is the only ADC currently commercially available for the treatment of lymphoma. CD30, a TNF receptor thought to play a role in apoptosis, is highly expressed on the surface of classical Hodgkin and anaplastic large cell lymphoma cells, as well as 30% of other T-cell NHL (T-NHL) and 20–25% of DLBCL. Prior efforts exploiting the CD30 antigen with naked antibodies, despite modifications such as afucosylation, have been unsuccessful in these histologies [31]. The lack of significant activity prompted the development of immunoconjugates, such as brentuximab vedotin.

In relapsed and refractory anaplastic large cell lymphoma, Pro et al. demonstrated an ORR of 86% (CR: 57%) and estimated median PFS of 13.3 months with brentuximab [32]. The majority of these 58 patients were ALK-negative and had primary refractory disease, while a quarter had failed prior ASCT. Younes et al. evaluated the same regimen in 102 patients with Hodgkin lymphoma who had relapsed or had refractory disease after ASCT or had failed two regimens but were not considered suitable candidates for ASCT [33]. Brentuximab produced an ORR of 75% (CR: 34%) and median DOR of 20.5 months in those who achieved a CR. Common toxicities included grade 1–2 neuropathy, fatigue and nausea. Grade 3 neuropathy, due to the antimicrotubulin portion of the molecule, occurred in 12–17% of the patients and was largely reversible with dose reduction and delay. Based on these studies, brentuximab was approved for relapsed or refractory anaplastic large cell lymphoma and Hodgkin lymphoma. Brentuximab has undergone Phase I investigation in previously untreated advanced-stage Hodgkin lymphoma in combination with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) and adriamycin, vinblastine and dacarbazine (AVD) [34]. Of the 25 patients in the ABVD cohort, all 15 patients who had completed six cycles of ABVD achieved a CR. Forty percent of the patients experienced pulmonary toxicity (grade 3–4: 11%) in the ABVD cohort compared to none with AVD. Future treatment strategies are aimed at replacing bleomycin with brentuximab, particularly given bleomycin’s questionable clinical utility. The pivotal trial of ABVD versus brentuximab, adriamycin, vinblastine and dacarbazine has been initiated. Brentuximab is also being studied as consolidation and as salvage prior to transplantation in Hodgkin lymphoma, as well as in combination with other cytotoxic therapies in T-cell and NK-cell NHL. In a Phase I front-line study of brentuximab in combination with standard CHOP or cyclophosphamide, doxorubicin and prenisone (CHP) for CD30⁺ T-cell and NK-cell lymphomas, the ORR was an impressive 100% (CR 88%) among the 26 patients [35]. Brentuximab vedotin has also shown response in relapsed and refractory CD30⁺ DLBCL and gray-zone lymphoma [36].

Inotuzumab ozogamicin (CMC-544) is a CD22 antibody linked to calicheamicin, a cytotoxin. In a Phase I study of relapsed and refractory CD22⁺ B-NHL, Advani et al. found an ORR of 39% with inotuzumab [37]. Responses varied with specific subtype: 68% with a median PFS of 10.4 months in FL and 15% with a median PFS of 49 days in DLBCL. The most common toxicity was thrombocytopenia, which was reversible and uncomplicated. Twenty two percent of the patients had to discontinue therapy because of persistent thrombocytopenia, which questions the clinical utility of this drug in patients who are often cytopenic. In relapsed and refractory indolent B-NHL, inotuzumab produced an ORR of 53% (CR: 19%) in patients who had received at least two prior anti-CD20-based therapies [38]. Inotuzumab is now being studied in combination with a variety of agents such as temsirolimus, rituximab and cytotoxic chemotherapy with promising results [39,40].

Other ADCs include SAR3419, a humanized CD19 antibody attached to DM4, another tubulin inhibitor. In a small study of SAR319 in 25 patients with relapsed or refractory NHL, 68% of the patients experienced some level of tumor reduction including two PRs and three CRs [41]. Less common ADC targets include CD70, a protein expressed on solid tumors, multiple myeloma and NHL, as well as CD79b and CD22, which exist on the surface of B cells. SGN-75 is an ADC against CD70 and is currently being studied in CD70⁺ NHL. DCDS4501A and DCDT2980S are ADCs conjugated to monomethyl auristatin E that target CD79b and CD22, respectively, and have shown antitumor activity in relapsed and refractory B-cell NHL [42,43]. Both agents will be administered with rituximab in an upcoming randomized Phase II study in DLBCL and FL.

Bispecific T-cell-engager molecules

Bispecific T-cell-engager molecules, also known as BiTEs^® (Amgen, CA, USA), are single-chain dual-specific antibodies that target both CD3 on the surface of T-cells and a specific antigen on the surface of the malignant cell in order to induce cellular lysis. Blinatumomab (MEDI-538) is a BiTE with specificity to CD19. Each cycle of treatment consists of a 4–8 week continuous intravenous infusion. In a trial of blinatumomab in multiply relapsed and refractory DLBCL, of the nine evaluable patients, five had a response (four CR/CRu) [44]. Three of the responses were in patients with prior ASCT. The median duration of response was 6 months; the longest duration of response at the time of abstract publication was over a year. In relapsed FL and MCL, blinatumomab produced responses in 14 of the 18 patients, with a median duration of response of 26 months [45]. In addition, blinatumomab has demonstrated excellent response rates in relapsed precursor B-cell acute lymphoblastic leukemia with complete remissions or complete remissions with partial hematological recovery experienced in 72% of the patients in a Phase II study by Topp et al. [46]. The median OS for this group of responders was 14 months, and 13 of them proceeded to transplant. Six of the 18 patients in the study developed seizures or encephalopathy, which was reversible with discontinuation of the drug. With reinitiation of treatment at a lower dose, two patients developed recurrent symptoms. Blinatumomab is now primarily being studied in precursor B-cell acute lymphoblastic leukemia.

Immunomodulatory agents

Lenalidomide is an immunomodulatory agent with multiple proposed mechanisms of action including targeting NF-κB, inhibition of angiogenesis and manipulation of the tumor microenvironment. Approved in multiple myeloma and del 5q MDS, lenalidomide is now being studied in lymphoid malignancies. In relapsed and refractory indolent NHL, lenalidomide produced an ORR of 23% (CR: 7%) and median DOR was estimated to be longer than 16.5 months [47]. The CALGB/Alliance studied lenalidomide with or without rituximab in a Phase II study of recurrent FL. The ORR and median event-free survival were higher with the combination, 75% (CR: 32%) and 2 years versus 49% (CR: 13%) and 1.2 years, respectively [48]. Higher responses were seen in the front-line setting. Fowler et al. demonstrated an ORR of 90% (CR: 64%) in indolent B-NHL with an estimated 2-year PFS of 83% [49]. Eighty seven percent of the FL patients achieved a CR, the majority of which were high risk according to the Follicular Lymphoma International Prognostic Index (FLIPI). The most common grade 3–4 toxicity was neutropenia, but only three patients developed a grade 3–4 infection.

In relapsed and refractory MCL, Habermann et al. demonstrated an ORR of 53% (20% CR) with a median DOR of 13.7 months with lenalidomide in a small study of 15 patients [50]. The median DOR had not been reached in the three patients who achieved a response. Responses were reported in patients with prior bortezomib therapy and ASCT. The most common grade 3–4 toxicities were neutropenia and thrombocytopenia, but only three grade 3 infections were reported. Given these promising results and activity of bortezomib in MCL, the CALGB evaluated the two agents in a Phase II study of 48 patients [51]. The results were less than expected: ORR: 40% (CR of 15%) and 1-year PFS of 41%. The majority of patients underwent dose reduction of at least one drug due to adverse events, and 39% had dose reductions of both drugs. This combination no longer appears to be promising in MCL. Wang et al. combined lenalidomide with rituximab in 58 patients with relapsed and refractory MCL [52]. The ORR was 57% (CR: 36%) with median DOR of 18.9 months. In relapsed and refractory aggressive B-NHL, Witzig et al. demonstrated an ORR of 35% (CR: 13%) with a median DOR of 10.6 months. For DLBCL, the ORR was 28% and median DOR was 4.6 months. Ivanov et al. demonstrated that lenalidomide and rituximab was effective in refractory DLBCL patients who had received at least three prior therapies, producing three CRs and two PRs among the eight evaluable patients [53]. One patient proceeded to ASCT and remained in complete remission. When lenalidomide was combined with R-CHOP in previously untreated DLBCL and grade III FL, the ORR was 100% (CR: 77% [54]). Of the 24 patients in this Phase I study, 20 had DLBCL. However, gene expression profiling information was not provided. A trial of R-CHOP with or without lenalidomide is upcoming. Single-agent lenalidomide has produced ORR of 30% in relapsed and refractory T-cell and Hodgkin lymphomas [55,56]. Lenalidomide continues to be studied in B-NHL, T-NHL and Hodgkin lymphoma.

Small-molecule kinase inhibitors

Whereas monoclonal antibodies target lymphocyte surface receptors, a number of small molecules have been designed to interfere with specific intracellular pathways downstream of the B-cell receptor (Table 2). These signaling pathways impact B-cell proliferation, survival, differentiation and migration, thus, the B-cell receptor plays a critical role in the initiation and maintenance of B-cell malignancies. The first of these small-molecule kinase inhibitors was fostamatinib disodium, an inhibitor of Syk which contributes to the initiation and amplification of B-cell receptor signaling. In a Phase I/II study by Friedberg et al., ORRs were encouraging: 55% SLL/CLL, 22% DLBCL, 10% FL and 11% MCL, but the median PFS was only 4.2 months [57]. Given the relatively short duration of response, fostamatinib is no longer being explored in lymphoid malignancies. Several other downstream targets such as Bruton’s tyrosine kinase (BTK), PI3K and mTOR, all of which contribute to lymphoma cell proliferation, migration and survival, are now being explored. Some of the agents directed against these pathways have already proven their success in different malignancies, while others are relatively newer and are still being evaluated.

Ibrutinib is an inhibitor of BTK, a mediator of B-cell antigen receptor signaling, which is necessary for the initiation and maintenance of B-cell malignancies. In a Phase I study of relapsed and refractory B-cell malignancies, ibrutinib produced an ORR of 54% (CR: 14%) and median PFS of 13.6 months [58]. Responses were seen in all histologies including FL, CLL, DLBCL, MCL and marginal-zone lymphoma. In relapsed and refractory FL, ibrutinib produced an ORR of 55% with a median PFS of 13.4 months [59]. In MCL, ibrutinib demonstrated a better ORR of 66% (CR: 19%) in 115 patients with relapsed and refractory disease [60]. Responses were independent of prior bortezomib therapy. In the activated B-cell-like subtype of relapsed and refractory DLBCL, the ORR was 40%, whereas no significant activity was noted in the germinal center B-cell-subtype [61]. Ibrutinib has also shown remarkable activity in CLL, with ORRs of 71% in elderly treatment-naive patients, 67% in relapsed and refractory patients and 50% in high-risk patients as defined by del 17p or relapse within 2 years of chemoimmnunotherapy [62]. When combined with ofatumumab in relapsed and refractory CLL, the ORR was 100% (zero CR) among the 24 patients [63]. The most common grade 3–4 toxicities were anemia and pneumonia in 11%. There were no unexpected toxicities when ibrutinib was combined with bendamustine and rituximab in the same setting. O’Brien et al. demonstrated an ORR of 90% (CR: 10%) in 30 patients with 47% grade 3–4 neutropenia and 10% grade 3–4 thrombocytopenia [64]. Ongoing and upcoming studies are evaluating ibrutinib in the front-line setting. A Phase I study of ibrutinib in combination with CHOP for front-line B-NHL has recently opened, and the CALGB/Alliance will be opening a trial of ibrutinib, rituximab and lenalidomide for previously untreated FL shortly [Ujjani C, Pers. Comm.]. AVL-292 is another BTK inhibitor that does not appear to have much activity in CLL or B-NHL [65].

The PI3Ks are frequently activated in cancer and contribute to tumor cell proliferation, migration and survival. The delta and gamma isoforms of these kinases are primarily expressed in the hematopoietic cell lines. Idelalisib, previously known as GS-1101 and CAL-101, is an inhibitor of the delta isoform of PI3K p110 (PI3K-δ). Inhibition of this particular isoform allows for the targeting of lymphocytes and preservation of non-neoplastic cells. In a Phase I study of 55 patients with relapsed and refractory NHL, Kahl et al. demonstrated an ORR of 62% in indolent NHL, 62% in MCL and 0% in DLBCL [66]. DORs were longer in indolent NHL (>16 months) compared with a maximum of 8 months in MCL. When idelalisib was administered with rituximab and/or bendamustine in previously treated indolent B-cell malignancies, the ORR among all regimens was greater than 75%, with 13–30% CRs [67]. The same group of investigators evaluated these regimens in relapsed and refractory CLL, and found ORRs of 78–87% [68]. Preclinical studies suggest that idelalisib may also have utility in Hodgkin lymphoma as well [69]. Ongoing studies include a Phase III study of rituximab with or without idelalisib in relapsed CLL patients who are unfit for cytotoxic therapy, and idelalisib in combination with ofatumumab in previously treated CLL. Upcoming studies in NHL include idelalisib with lenalidomide and rituximab in recurrent FL and lenalidomide in MCL. Additionally, IPI-145, which targets both the gamma and delta isoforms of PI3K, and GDC-0980, which inhibits PI3K and mTOR, are both in Phase I investigation.

The mTOR pathway is upregulated in solid tumors and NHL, inhibiting apoptosis and promoting cancer cell survival. Temsirolimus and everolimus, inhibitors of mTOR, are approved in renal cell carcinoma. Everolimus also has indications in breast cancer and pancreatic neuroendocrine tumors. In relapsed and refractory nonmantle cell NHL, Smith et al. demonstrated an ORR of 54% (CR: 25%) and median PFS of 12.7 months with temsirolimus in 39 FL patients [70]. Results were inferior in the 32 patients with DLBCL or transformed FLs: ORR of 28.1% (CR: 12.5%) and median PFS 2.6 months. In relapsed MCL, Ansell et al. found an ORR of 41% (CR: 3.7%) with a median time to progression of 6 months among 29 patients who received temsirolimus [71]. When compared with investigator’s choice in a Phase III study of 162 patients, Hess et al. found temsirolimus was superior (ORR: 22%; median OS: 12.8 months) [72], but not as good as previously reported. Although patients were similar in terms of age and stage, the authors felt that their requirement for prior alkylator, anthracycline and CD20 antibody may have explained the discrepancy in results. The majority of patients in Ansell et al.’s study, however, had fulfilled these criteria. As the patient characteristics were otherwise fairly similar, the difference in results may been related to sample size alone. Temsirolimus was approved for relapsed and refractory MCL by the European Medicines Agency based on this study, but not the FDA. Everolimus has similar activity to temsirolimus in relapsed DLBCL with responses of 35% [73]. In relapsed Hodgkin lymphoma, everolimus produced an ORR of 42% with a median PFS of 9 months [74]. In MCL, however, minimal activity was seen with everolimus in the PILLAR-1 study of bortezomib-refractory patients: ORR of 9% (zero CR) [75]. mTOR inhibitors may have better activity in combination with other anticancer therapies. Temsirolimus and rituximab produced an ORR of 59% (CR: 19%) in 69 patients with relapsed and refractory MCL [76], while temsirolimus, bendamustine and rituximab produced an ORR of 100% in six patients with relapsed MCL and FL [77]. When everolimus was combined with CHOP in a Phase I study of advanced-stage aggressive T-cell lymphomas, responses were seen in an impressive 14 of 15 patients with seven CRs [78]. The most common toxicity was myelosuppression, which was manageable. Temsirolimus and everolimus are being combined with a number of chemotherapeutic agents in B-NHL and T-NHL.

Alisertib is an inhibitor of Aurora A kinase, a mitotic regulating protein that is overexpressed in a number of malignancies. In Phase II study of alisertib in multiple relapsed and highly refractory aggressive B-cell and T-cell lymphomas, Friedberg et al. found an ORR of 32% among the 48 patients: 20% in DLBCL, 23% in MCL and 57% in T-cell lymphoma [79]. The most common toxicities were neutropenia (63%) and thrombocytopenia (31%). Alisertib is currently being investigated as a single agent in a multicenter Phase II SWOG study and a Phase III randomized trial of relapsed and refractory T-cell lymphoma, in which patients receive alisertib or investigator’s choice of romidepsin, gemcitabine or pralatrexate [80]. Alisertib is also being studied in combination with rituximab, with or without vincristine, in relapsed and refractory DBLCL or transformed FL [81].

The Bcl-2 protein family is a group of apoptotic proteins overexpressed in B-cell lymphoid malignancies. ABT-263 is an oral small molecule that inhibits the antiapoptotic members of the Bcl-2 family: Bcl-X_L, Bcl-2 and Bcl-w, inducing caspase-dependent apoptosis [82]. Early-phase studies have shown efficacy with ABT‑263 in lymphoid malignancies [83]. Thrombocytopenia was the most notable toxicity due to the significant inhibition of Bcl-X_L. Due to toxicity, the drug is no longer being investigated. ABT-199 is a newer Bcl-2-specific inhibitor that has 500-fold less activity against Bcl-X_L. In a Phase I study of multiply relapsed and refractory CLL and NHL, ABT-199 produced an ORR of 43% with antitumor activity in various B-cell histologies [84,85]. Among the high-risk CLL patients, PRs were noted in five out of seven patients with del 17p and nine out of the ten patients who were refractory to fludarabine [86]. The most common toxicities were gastrointestinal and only 10% of the patients experienced grade 3–4 neutropenia in this highly pretreated cohort. Dose-limiting thrombocytopenia was not experienced. Given the more favorable toxicity profile, ABT-199 is being investigated further for CLL and NHL.

The histone deacetyalases (HDAC) are a group of enzymes that impact DNA expression by regulating the conformation of histones. Inhibition of these enzymes induces differentiation, apoptosis and cell cycle arrest and prevents migration of tumor cells. The HDAC inhibitors vorinostat and romidepsin have been approved for previously treated cutaneous T-cell lymphoma [87–89]. Piekarz et al. evaluated romidepsin in relapsed and refractory PTCL, and found an ORR of 38% (CR: 18%) and median DOR of 8.9 months among the 45 patients [90]. Responses were seen despite prior transplantation. Coiffier et al. demonstrated an ORR of 25% (CR/CRu: 15%) in a larger but similar population of patients [91]. The median DOR was 17 months, with the longest response ongoing at 34+ months. Common grade 3/4 toxicities included thrombocytopenia (24%), neutropenia (20%) and infections (19%). Romidepsin is now being studied further in T-NHL and CLL, while vorinostat is being combined with other drugs such as bortezomib, alisertib and hypomethylating agents in NHL. Panobinostat is a newer HDAC inhibitor that has also shown promise in cutaneous T-cell lymphoma [92] as well as Hodgkin lymphoma. In a Phase II study of 129 patients with relapsed or refractory Hodgkin lymphoma after transplantation, Sureda et al. demonstrated an ORR of 27% with 5 CRs [93]. Responses were seen in 66% of the patients with primary refractory disease. The most common grade 3–4 toxicities were thrombocytopenia, anemia and neutropenia. The thrombocytopenia was reversible and manageable with dose delay and reduction. When combined with everolimus in relapsed and refractory Hodgkin lymphoma, Younes et al. reported an ORR of 50% with the common toxicities being thrombocytopenia (48%), neutropenia (48%) and anemia (20%) [94]. Ongoing studies are looking at combinations with everolimus in all lymphomas [94], lenalidomide in Hodgkin lymphoma [95] and bortezomib in MCL.

Expert commentary

An increasing number of novel therapies are becoming available for clinical trials with the potential not only to improve patient outcome, but to replace chemotherapy as the cornerstone of lymphoma treatment. Rather than using nonspecific cytotoxic treatments, these novel agents induce cellular death through different mechanisms of action. In addition, these agents potentially provide greater tumor specificity and less nonspecific toxicity. Efforts are now focused on how best to combine these agents with each other and integrate these combinations into our current treatment strategies. Similar to rituximab, these targeted therapies are initially being studied in the relapsed and refractory setting. Further investigation will provide insight as to whether these drugs are more effective in combination with standard induction regimens or other targeted agents, replacements for consolidation or maintenance therapies or options solely for patients with recurrent or refractory disease. For the past decade, the CALGB/Alliance has evaluated a number of dual-targeted therapy regimens. They were the first to conceptualize the idea of rituximab and lenalidomide in indolent NHL, and they have completed a front-line FL trial of rituximab and lenalidomide that is undergoing analysis. Other interesting combinations being evaluated include DCDT2980S and rituximab in FL, and vorinostat and alisertib in T-NHL. Correlative studies are being performed in conjunction with these trials to better understand the affected intracellular pathways, which are clearly complex. For example, does inhibition of one pathway induce upregulation of another pro-oncogenic pathway? Is dual pathway inhibition necessary to achieve a cure as opposed to just an interim suppression of disease, and if so, how do we determine which pathways should be targeted together? Are there phosphoproteins or other markers indicative of each pathway’s activity and how do they correlate with response to the corresponding targeted therapy? Answering these and related questions will help us create a personalized regimen for each of our patients.

Five-year view

Correlative studies including predictive biomarkers and markers of pathway activation and inhibition are critical to provide insight as to who will most likely respond to these novel therapeutic agents and combinations. For example, a recent study of lenalidomide in activated B-cell-like DLBCL demonstrated that the overexpression of IRF-4 and absence of cereblon are both associated with tumor resistance [96]. This type of information will help design more effective regimens that target multiple aspects of the disease: surface receptors, intracellular pathways and the tumor microenvironment. Our goal in indolent lymphomas is to replace conventional chemotherapy with more tolerable, tumor-specific biologic therapy. Fowler’s data of rituximab and lenalidomide in previously untreated FL are comparable, if not better, to previous reports of rituximab and traditional chemoimmunotherapy [49] . The RELEVANCE trial comparing rituximab/lenalidomide to rituximab–chemotherapy (CHOP, CVP, or bendamustine) will potentially redefine the standard of care. Based on the preliminary success of their evaluation of rituximab and lenalidomide in FL, the CALGB/Alliance lymphoma committee is now evaluating this regimen in combination with ibrutinib and GS-1101 in two upcoming trials. By using three different agents, we will be able to inhibit multiple pathways simultaneously to induce cancer cell death. Ideally, we would like to compare the each of three regimens, placing patients into the most likely beneficial arm based on their individual tumor characteristics. In the aggressive lymphomas, we hope to improve survival outcomes by increasing the number of CRs and duration of response as well as focusing on the traditionally poorer prognostic subtypes. Early-phase evaluation of lenalidomide and R-CHOP in DLBCL demonstrated superior efficacy, but the upcoming study of R-CHOP with or without lenalidomide will clarify whether lenalidomide truly provides an additional benefit. However, achieving our goals in lymphoma is not without its difficulties. The unfortunate fact is that not only is there an overall lack of funds for clinical trials and correlative studies, many new drugs are unavailable for investigator-initiated trials. This is true for single-agent studies as well as combination regimens including drugs belonging to competitor pharmaceutical companies. These agents are also incredibly expensive once available commercially. They must be used judiciously, accounting for both cost and benefit. Therefore, we must make greater efforts to work together to support and promote clinical research in order to identify the most appropriate regimens for each patient. Only then will we be able to achieve our ultimate goal: a sustainable cure for our patients.

Table 1.  Antibody-based therapies.

Antibody-based therapy	Target
Monoclonal antibody
Ofatumumab	CD20
Obinutuzumab	CD20
Medi-551	CD19
Epratuzumab	CD22
CT-011	PD-1
Mogamulizumab	CCR4
Radioimmunotherapy
^90Y-ibritumomab tiuxetan	CD20
^131I-tositumomab	CD20
Antibody–drug conjugate
Brentuximab vedotin	CD30
Inotuzumab ozogamicin	CD22
SAR3419	CD19
SGN-75	CD70
DCDS4501A	CD79b
DCDT2980S	CD22
Bispecific T-cell-engager molecules
Blinatumomab	CD19

Table 2.  Small-molecule kinase inhibitors.

Small-molecule kinase inhibitors	Target
Fostamatinib	Syk
Ibrutinib	BTK
Idelalisib	PI3K-δ
Temsirolimus, everolimus	mTOR
Alisertib	Aurora A kinase
ABT-199	Bcl-2 family
Vorinostat, romidepsin, panobinostsat	Histone deacetylases

Key issues

• • The current focus in the treatment of lymphoma is biologic targeted therapies.

• • Newer monoclonal antibodies targeting CD20 have shown activity in rituximab-refractory patients, but have not yet shown superiority to rituximab.

• • Several monoclonal antibodies have been developed to target different antigens on B and T cells such as CD19, CD22 and CCR4.

• • Antibody–drug conjugates attack the cancer cell extracellularly and intracellularly to induce cell death. Brentuximab vedotin is the first to be US FDA approved in lymphoma.

• • Radioimmunotherapy provides the dual benefit of targeted therapy and radiation. Although approved in low-grade lymphomas, it may have a new role in mantle cell lymphomas.

• • Lenalidomide, an immunomodulatory agent, has shown activity in both indolent and aggressive non-Hodgkin lymphoma.

• • Small-molecule kinase inhibitors target the various intracellular pathways downstream to the B-cell receptor in malignant B cells.

• • Current research efforts are looking at combinations of these targeted agents for dual pathway inhibition in hopes to increase the quality and durability of response.

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The current status and future impact of targeted therapies in non-Hodgkin lymphoma

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are considering starting therapy with new, biologic targeted agents for your patient, a 28-year-old woman with non-Hodgkin lymphoma (NHL). Based on the review by Drs. Ujjani and Cheson, which of the following statements about potential advantages and disadvantages of these therapies is most likely correct?

• □ A New anti-CD20 monoclonal antibodies have the same mechanisms of action as rituximab and lower binding affinities

• □ B Compared with rituximab, new anti-CD20 monoclonal antibodies have been proven to be more effective

• □ C Compared with standard chemotherapy, some new targeted agents have greater tumor specificity and a more favorable toxicity profile

• □ D Direct comparisons have shown that ofatumumab is likely to replace rituximab in frontline treatment of NHL

2. Based on the review by Drs. Ujjani and Cheson, which of the following statements about the role of newer monoclonal antibodies and antibody–drug conjugates in the treatment of patients with NHL is most likely correct?

• □ A Mogamulizumab targets only B cells

• □ B Some of the newer monoclonal antibodies target CD19, CD22, or CCR4

• □ C Antibody-drug conjugates attack the cancer cell only extracellularly

• □ D The US Food and Drug Administration (FDA) has not approved brentuximab vedotin in lymphoma

3. Based on the review by Drs. Ujjani and Cheson, which of the following statements about the role of radioimmunotherapy, immunomodulatory agents, and small-molecule kinase inhibitors in the treatment of patients with NHL would most likely be correct?

• □ A The FDA has approved ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumomab to treat relapsed and refractory follicular and low-grade lymphomas

• □ B The immunomodulatory agent lenalidomide has a single proposed mechanism of action

• □ C Small-molecule kinase inhibitors target malignant T-cells

• □ D Responses with ibrutinib have been seen only in patients with chronic lymphocytic leukemia (CLL)