REVIEW Targeted therapies in B-cell non-Hodgkin lymphomas The incidence of non-Hodgkin lymphomas has risen in recent years. Although several chemotherapy regimens are efficacious in non-Hodgkin lymphoma, the addition of targeted therapies has become an indispensable part of their treatment. Monoclonal antibodies directed against lymphocytes in different stages of maturation have changed the treatment paradigm for lymphoma. Since these antibodies bind with high affinity to cell surface antigens, they target malignant cells and spare normal tissue, thereby causing less nonspecific toxicity. Rituximab, a monoclonal antibody directed against CD20, was the first antibody to be US FDA-approved for the treatment of lymphoma. Several clinical trials are ongoing that will help to establish the role of targeted agents in the treatment of non-Hodgkin lymphoma. This review provides a summary of targeted agents already approved or in clinical trials for the treatment of non-Hodgkin lymphoma. KEYWORDS: mAbs monoclonal antibodies non-Hodgkin lymphoma Sapna Khubchandani & radioimmunoconjugates rituximab targeted therapies Myron S Czuczman† †Author for correspondence: Roswell Park Cancer Institute, Non-Hodgkin lymphomas (NHLs) are increas- include: DLBCL and its variants, Burkitt lym- Elm and Carlton Streets, ing in incidence and will be diagnosed in more phoma, PTCL, immunodeficiency-associated Buffalo, NY 14263, USA than 55,000 individuals this year alone [1,2]. The lymphoproliferative disorder, precursor B lym- Tel.: +1 716 845 3221 13 most frequent clinical classes recognized in phoblastic leukemia/lymphoma, and precursor Fax: +1 716 845 3894 the lymphoma classification include diffuse T lymphoblastic leukemia/lymphoma [5]. myron.czuczman@ large B-cell lymphoma (DLBCL), follicular roswellpark.org lymphoma (FL), small lymphocytic lymphoma Diffuse large B-cell lymphoma (SLL) mantle cell lymphoma (MCL), periph- Anti-CD20 antibody: rituximab eral T-cell lymphoma (PTCL), marginal B-cell Diffuse large B-cell lymphoma is the most fre- lymphoma of mucosa associated lymphoid tis- quently diagnosed NHL [3]. Cyclophosphamide, sue (MALT), primary mediastinal large B-cell adriamycin, vincristine and prednisone admin- lymphoma, anaplastic large T/null cell lym- istered every 21 days (CHOP-21) used to be the phoma, lymphoblastic lymphoma, Burkitt-like ‘gold standard’ of upfront therapy for DLBCL lymphoma, marginal zone B-cell lymphoma of and resulted in an overall survival of 30–40% the nodal type, lymphoplasmacytic lymphoma at 5 years [6,7]. The addition of rituximab, a and Burkitt lymphoma [3]. therapeutic antibody directed against a pan The ultimate goal of any tumor therapy B-cell antigen CD20, altered the treatment involves the destruction of tumor cells by target- paradigm for DLBCL. Rituximab is a chi- ing tumor-specific surface or intracellular prop- meric anti-CD20 human IgG1 monoclonal erties and thereby sparing normal tissue [4]. In antibody US FDA-approved for treatment of NHL, monoclonal antibodies binding to anti- DLBCL. Phase II studies of rituximab with gens specific to lymphocytes in different stages CHOP (R-CHOP) demonstrated safety in of maturation have recently changed the treat- patients with DLBCL [8,9]. This led to sev- ment paradigms for this disease. Some of the eral prospective, randomized Phase III stud- antigens being targeted include CD20, CD22, ies. In a landmark study of R-CHOP versus CD19, CD37 and CD80 on B-cell surface; and CHOP in previously untreated elderly patients CD52, CD4, CD3 and CD8 on T cells [4]. with DLBCL, the French study group Groupe d’Etude des Lymphomes de l’Adulte (GELA) Antibody-targeted therapy in demonstrated a 7-year progression-free sur- aggressive lymphomas vival of 52% for R-CHOP-21 versus 29% for Aggressive lymphomas are potentially cur- CHOP-21 (p < 0.001), and an overall survival of able with chemotherapy. These lymphomas 53% for R-CHOP-21 versus 36% for CHOP-21 10.2217/THY.09.19 © 2009 Future Medicine Ltd Therapy (2009) 6(3), 371–380 ISSN 1475-0708 371 REVIEW Khubchandani & Czuczman Targeted therapies in B-cell non-Hodgkin lymphomas REVIEW (p = 0.004). Benefit was observed in patients carmustine–cytarabine, etoposide, melphalan with low risk, as well as high-risk, International (BEAM) high-dose therapy and autologous Prognostic Index [10]. stem cell transplant [18]. The Intergroup/Eastern Cooperative Oncology Group trial (ECOG 4494) [11,12] Anti-CD20-based also demonstrated that the addition of rituxi- radioimmunoconjugates mab to CHOP-21 or CHOP-14 significantly One approach to improve the cytotoxic poten- improves the outcome of elderly patients with tial of monoclonal antibodies is to attach them aggressive B-cell lymphomas. In the analysis of to radionuclides to form a radioimmunoconju- this study, R-CHOP significantly decreased the gate. Experience with radioimmunotherapy in risk of treatment failure compared with CHOP NHL is largely limited to the relapsed, refractory alone (hazard ratio: 0.64; 95% CI: 0.47–0.85; settings. Currently, two drugs are registered in p = 0.003) with an estimated failure-free sur- the USA: 90Y-ibritumomab tiuxetan (Zevalin®, vival of 52% for R-CHOP and 39% for CHOP. Genentech [CA, USA] and BiogenIDEC The second random assignment in responders to [MA, USA]) and 131I-tositumomab (Bexxar®; maintenance rituximab failed to demonstrate a GlaxoSmithKline [Middlesex, UK]). benefit after R-CHOP at the initial report and Ibritumomab, a murine anti-CD20 antibody, at follow up in 5.5 years. is labeled to Yttrium-90 to form 90Y-ibritumomab A Canadian population study confirmed the tiuxetan. Unlabeled rituximab is infused prior to overall survival advantage of R-CHOP versus the radiolabeled product to improve biodistribu- CHOP [13]. This was a retrospective study of tion. A nonrandomized multicenter Phase II study patients in the pre-rituximab era treated with was conducted to study the safety and efficacy of a CHOP-like chemotherapy versus the post- single dose of this drug in patients with relapsed/ rituximab era where patients were treated with refractory DLBCL who were not candidates for rituximab 24–72 h after each CHOP infusion. stem cell transplant. The ORR to 90Y-ibritumomab The recently published RICOVER-60 study tiuxetan was 19% in patients who were previously by the German High Grade Lymphoma Study treated with rituximab [19]. The ORR was 52% in Group (DSHNHL) treated elderly patients with patients who failed induction therapy and 53% aggressive lymphomas with 6–8 cycles of CHOP- in patients who relapsed after complete remis- 14 or R-CHOP-14 (time interval between courses sion (CR). The median progression-free survival/ of 14 days) [14]. The best results were seen with overall survival was 5.9 months/21.4 months R-CHOP-14, with event-free survival and overall in those for whom induction therapy failed, survival of 67 and 78%, respectively. 3.5 months/22.4 months in patients who relapsed The Mabthera International Trial (MINT) after CR and 1.6 months/4.6 months in patients study was an international trial in young newly who were treated with chemotherapy and rituxi- diagnosed good-risk patients with DLBCL [15]. mab, respectively. Two patients died of cerebral This study demonstrated that the addition of hemorrhage associated with grade 4 thrombocy- rituximab to six courses of CHOP or CHOP- topenia; 43% patients experienced grade 3 or 4 like chemotherapy improved 3-year event-free hematological toxicities. survival to 79% (95% CI: 75–83) versus 59%, In a Phase I/II trial of 90 Y-ibritumomab (95% CI: 54–64) and increased 3-year sur- tiuxetan the ORR was 43% in patients with vival to 93% (95% CI: 90–95) versus 84% intermediate-grade histology [20]. In long-term (95% CI: 80–88). follow-up, 58% of patients with DLBCL had a response, with a median duration of response of Rituximab in salvage therapy 49.8 months [21]. In a Phase II trial of R-CHOP The standard of care for DLBCL with primary followed by Y-ibritumomab tiuxetan in high-risk refractory or recurrent disease typically involves patients (International Prognostic Index 2 and salvage therapy followed by high-dose therapy 3) the intent to treat overall survival was 63% with stem cell transplantation. In Phase II trials, and event-free survival was 59%. All patients the addition of rituximab to salvage chemother- who received ibritumomab tiuxetan remained apy regimens may improve the overall response relapse-free at a median of 21 months [22]. rate (ORR) with ifosfamide, carboplatin and Tositumomab is a murine monoclonal anti- etoposide (ICE) and dexamethasone, high- body that binds to CD20 and is radiolabeled dose cytarabine and cisplatin (DHAP) [16,17]. to Iodine-131. This has been evaluated in five Currently, a randomized Phase III study is studies in patients who are not candidates for comparing R-DHAP with R-ICE followed by stem cell transplantation and have undergone 372 Therapy (2009) 6(3) future science group REVIEW Khubchandani & Czuczman Targeted therapies in B-cell non-Hodgkin lymphomas REVIEW a median of four prior therapies [23]. A CR rate A US-based Phase II study of lenalidomide of 25% and an ORR of 39% has been observed monotherapy in relapsed or refractory aggres- at a median follow up of 19.4 months. The sive NHL demonstrated an ORR of 34% for median duration of response was 20 months and all patients and 24% for DLBCL patients, with median time to progression was 4.2 months in a median time-to-progression of approximately all patients. 7 months in responders [39]. A larger interna- A Phase I/II trial of tositumomab, in place of tional trial in the same relapsed aggressive B-cell total-body irradiation, in combination with high- lymphoma population has reached accrual and dose etoposide and cyclophosphamide followed preliminary results appear to validate the earlier, by autologous stem cell transplant demonstrated smaller Phase II study [40]. Lenalidomide was promising therapeutic outcomes [24].