Novel Biologic Agents for Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia-Part 1: Monoclonal Antibodies

The incidence of non-Hodgkin lymphomas is on the rise worldwide. The aggressive non-Hodgkin lymphomas can potentially be cured with front-line therapy, but indolent ones, such as chronic lymphocytic leukemia/small lymphocytic lymphoma, cannot. Relapsed/refractory non-Hodgkin lymphomas have a poor overall outcome, typically with shorter responses after each relapse. Novel therapies are sought to improve outcomes in this patient population. This review discusses the promising new biologic therapies that have emerged over the last 5 years. Some have already achieved US Food and Drug Administration approval, while others are undergoing active investigation in order to ultimately gain approval. Here, in Part 1, we discuss monoclonal antibodies. In Part 2, we will discuss adoptive cellular immunotherapies, small-molecule inhibitors, and immunomodulatory agents.

Background

The incidence of non-Hodgkin lymphoma has been increasing over the last few decades.[1] It is the fifth most common cancer in the United States[2] and includes a wide spectrum of lymphoid malignancies, ranging from indolent diseases (such as chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, marginal-zone lymphoma, and cutaneous T-cell lymphoma) to aggressive diseases (such as diffuse large B-cell lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma). There have been numerous therapeutic advances in the treatment of non-Hodgkin lymphoma over the last few decades, including new chemotherapy regimens, monoclonal antibodies, radioimmunotherapy, and targeted therapy with small-molecule inhibitors of pathways of cell survival and growth. However, patients with relapsed/refractory disease still do poorly, and the search for novel treatment modalities that will yield improved and durable outcomes in such patients is ongoing.

Here-and later in Part 2-we review biologic agents, classified by their targets and mechanisms of action, that have received US Food and Drug Administration (FDA) approval for the treatment of non-Hodgkin lymphoma/chronic lymphocytic leukemia in the last 5 years, as well as promising agents that are more advanced in development. In Part 1, we have focused on monoclonal antibodies.

Anti-CD19 Antibody

Blinatumomab

The B-cell surface marker CD19 is expressed at most stages of B-cell development and is present in the majority of cases of B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. It is intricately involved in the functioning and survival of B cells due to its role in the B-cell receptor pathway, which comprises a number of molecules across the B-cell membrane (surface immunoglobulin [Ig], CD79a, CD79b, CD19), the extracellular engagement of which leads to activation of intracellular cytoplasmic signaling molecules such as Bruton tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and phosphoinositide 3-kinase (PI3K).[3] CD19 is therefore an attractive target in B-cell malignancies, especially since it is absent in hematopoietic stem cells, plasma cells, and other normal cells of the body, aside from B lymphocytes.

Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3.[4,5] It is a chimeric, single-chain monoclonal antibody that binds both CD3-positive cytotoxic T cells and CD19-positive B cells simultaneously in an attempt to harness the high cytotoxic potential of T cells in order to destroy B cells. Preclinically, it can induce robust T-cell proliferation and generation of proinflammatory cytokines in the presence of CD19-positive target cells.[5,6] In a phase I study of blinatumomab administered by continuous intravenous (IV) infusion over 4 to 8 weeks in 38 patients with relapsed/refractory B-cell non-Hodgkin lymphoma, a total of 11 major responses (4 complete responses [CRs], 7 partial responses [PRs]) were observed at doses of 0.015 mg/m²/d IV or higher.[7] Tumor regressions were seen in mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, and were durable. The median number of prior therapies in this study was 3, and 87% of patients had received rituximab in the past. Patients were hospitalized during the first 2 weeks of treatment. Subsequently, they were released from the hospital and continued treatment at home via a pump. Patients without evidence of disease progression after 4 weeks were offered the option of continuing treatment for an additional 4 weeks and/or 1 to 2 additional treatment cycles. The most common grade 3 or higher adverse events (AEs) were lymphopenia (68%), increase in C-reactive protein level (34%), leukopenia (24%), neutropenia (16%), and thrombocytopenia (16%). Central nervous system toxicities were also observed, although uncommonly; these included disorientation, confusion, speech disorders, tremor, and convulsions. The etiology of these is unclear, but they were all fully reversible with interruption of blinatumomab infusion. Prophylactic use of limited doses of dexamethasone can curtail some of these adverse effects by blunting the immediate cytokine release; the cytotoxicity of blinatumomab-activated T cells is not affected.[6]

A recent multicenter, open-label phase II trial enrolled 189 patients with relapsed/refractory Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia.[8] Patients were treated with blinatumomab at 9 μg/d continuous IV infusion on days 1–7 and 28 μg/d thereafter over 4 weeks every 6 weeks for up to 5 cycles. A total of 81 patients (43%) achieved a CR or CR with partial hematologic recovery of peripheral blood counts, with 60 of 73 evaluable responders becoming negative for minimally residual disease (MRD). Thirty-two of these patients were able to then undergo allogeneic hematopoietic stem cell transplantation. Median relapse-free survival was 6.9 months for the MRD-negative patients, and median overall survival (OS) was 11.5 months. The most common grade 3 or higher AEs were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Three patients (2%) experienced grade 3 cytokine release syndrome, 20 (11%) had grade 3 neurotoxicity, and 4 (2%) had grade 4 neurotoxicity. There were three sepsis-related deaths.

Based on these data, in December 2014, the FDA granted accelerated approval for blinatumomab for the treatment of relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia. Further studies in B-cell non-Hodgkin lymphoma, especially in some very aggressive subtypes, are currently ongoing.

Anti-CD20 Antibodies

Obinutuzumab

Rituximab is a chimeric type 1 monoclonal antibody that targets and kills B cells primarily via complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) after binding to CD20, a marker present on the majority of B cells and B-cell non-Hodgkin lymphoma cells.[9] When added to chemotherapy, rituximab has added significant benefit for patients with chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.[10] Obinutuzumab is a novel, humanized, glycoengineered type 2 antibody that also targets CD20.[11] In preclinical studies, obinutuzumab showed better efficacy than rituximab, which was achieved via the induction of direct cell death and enhanced ADCC; obinutuzumab also exhibited less complement-dependent cytotoxicity.[12-16] Patients with chronic lymphocytic leukemia who have coexisting illnesses may not be eligible for combined IV chemoimmunotherapy because of its potential deleterious side effects. The combination of immunotherapy and oral chlorambucil may be better tolerated in such patients.

To determine whether obinutuzumab plus chlorambucil would yield results superior to those seen with rituximab plus chlorambucil in relapsed/refractory chronic lymphocytic leukemia patients with coexisting illnesses, an open-label, randomized, multicenter phase III trial was conducted.[17] Patients were randomly assigned to three groups in a 1:2:2 fashion: chlorambucil alone (Clb), obinutuzumab plus chlorambucil (G-Clb), and rituximab plus chlorambucil (R-Clb). After 118 patients enrolled in the Clb arm, that group was closed to accrual as stipulated by predefined criteria, and enrollment continued on a 1:1 basis in the remaining two arms. If patients in the Clb arm experienced disease progression during treatment or within 6 months of completing treatment, they were allowed to cross over to the G-Clb arm. All treatments were given in six 28-day cycles. The dose of chlorambucil was 0.5 mg/kg on days 1 and 15 of each cycle. Obinutuzumab was administered IV at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1, then on day 1 of cycles 2 through 6. The first dose of obinutuzumab could be split over 2 days (100 mg on day 1 and 900 mg on day 2) for better tolerability with respect to infusion-related reactions. Rituximab was given IV at a dose of 375 mg/m² on day 1 of cycle 1, and then at 500 mg/m² on day 1 of cycles 2 through 6. A total of 781 patients were enrolled and treated. There were 118 patients in the Clb arm, 238 in the G-Clb arm, and 233 in the R-Clb arm (intention-to-treat population). The median age was 73 years (range, 39–90 years). The median Cumulative Illness Rating Scale score, which indicated the severity of coexisting illnesses, was 8 in all three arms of the study, and median creatinine clearance was 62 mL/min. Treatment with G-Clb or R-Clb, as compared with Clb, significantly increased the overall response rate (ORR) (77.3% vs 31.4%, P < .001; and 65.7% vs 31.4%, P < .001; respectively) and prolonged progression-free survival (PFS) (median PFS, 26.7 months vs 11.1 months, P < .001; and 16.3 months vs 11.1 months, P < .001; respectively). In addition, treatment with G-Clb, as compared with R-Clb, prolonged PFS significantly (P < .001) and produced more CRs (20% vs 7%) and more molecular responses (bone marrow, 19.5% vs 2.6%, P < .001; and blood, 37.7% vs 3.3%, P < .001-in patients who had MRD analysis available). There were no CRs in the Clb arm. Infusion-related reactions were more common in the G-Clb arm (20% of patients experienced grade 3/4 events, all in the first cycle only) than in the R-Clb arm (in which 4% of patients experienced grade 3/4 events), but risk of infection was not increased (12% in the G-Clb arm vs 14% in the R-Clb arm).

In November 2013, based on the data from the G-Clb and Clb arms of this trial, the FDA approved obinutuzumab in combination with chlorambucil for patients with previously untreated chronic lymphocytic leukemia.

Ofatumumab

Ofatumumab was the first humanized, second-generation anti-CD20 monoclonal antibody to demonstrate preclinical activity superior to that of rituximab in chronic lymphocytic leukemia cells; its effects are achieved primarily via more potent complement-dependent cytotoxicity, even in cells with low expression of CD20 and in those resistant to rituximab.[18-20] Ofatumumab has also shown higher, durable ORRs in patients with refractory chronic lymphocytic leukemia[21,22] and was granted accelerated FDA approval in October 2009 for the treatment of chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

Because elderly patients and those with comorbidities are unable to tolerate combination IV chemoimmunotherapy easily, a randomized, phase III multicenter trial evaluating ofatumumab in combination with oral chlorambucil (O-Clb) vs chlorambucil alone (Clb) was initiated in previously untreated chronic lymphocytic leukemia patients who were not eligible for fludarabine-based therapy.[23] Randomization was done in a 1:1 fashion, and a total of 447 patients (226 in the O-Clb arm and 221 in the Clb arm) were enrolled. Median age was 69 years (range, 35–92 years). Eighty-two percent of patients had two or more comorbidities and/or were 65 years of age or older. Chlorambucil was given orally at 10 mg/m² on days 1–7 of each 28-day cycle. Ofatumumab was administered IV at 300 mg on day 1 of cycle 1 and at 1,000 mg on day 8 of cycle 1, then at 1,000 mg on day 1 of each subsequent cycle for a minimum of 3 and a maximum of 12 cycles. PFS was significantly prolonged in the O-Clb arm compared with the Clb arm (22.4 months vs 13.1 months, P < .001). Also, the ORR was higher in the O-Clb arm (82% vs 69%, P = .001), with a superior CR rate (12% vs 1%). Thirty-seven percent of the patients in the O-Clb arm who achieved a CR were MRD-negative. Median OS was not reached at a median follow-up of 29 months. Grade 3 or higher AEs were observed in 50% of patients in the O-Clb arm and in 43% of those in the Clb arm; the most common AE was neutropenia (26% vs 14%, respectively). Infusion reactions were noted in 10% of patients in the O-Clb arm, and infections were equally distributed between the two arms (15% vs 14%).

Based on these data, in April 2014, the FDA approved ofatumumab in combination with chlorambucil for the treatment of previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate.

Anti-CD22 Antibodies

Inotuzumab ozogamicin

The antibody-drug conjugate (ADC) inotuzumab ozogamicin (INO) is a humanized anti-CD22 IgG4 monoclonal antibody conjugated to the potent antitumor agent calicheamicin. Most B-cell non-Hodgkin lymphomas express CD22, making this an attractive target, although a naked anti-CD22 monoclonal antibody does not have any significant antitumor activity. As an ADC, INO binds to CD22, is rapidly internalized, and delivers the calicheamicin payload intracellularly, which then leads to double-stranded DNA breaks and subsequent apoptosis.[24] In a phase I trial of 79 patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the ORR was 68% for the patients with follicular lymphoma and 15% for those with diffuse large B-cell lymphoma who were treated.[25] Median PFS was about 10.4 months for follicular lymphoma and 1.8 months for diffuse large B-cell lymphoma. The most common AEs were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). One patient developed veno-occlusive disease (VOD) of the liver after treatment. This patient had undergone prior autologous stem cell transplantation, had received external beam radiation to the liver, and had a history of a VOD-like syndrome as well.

A phase I/II trial combined INO with rituximab in 118 patients with B-cell non-Hodgkin lymphoma.[26] The most common grade 3 or higher AEs were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and elevated aspartate aminotransferase level (36%). The ORRs were 87%, 74%, and 20%, respectively, in patients with relapsed follicular lymphoma (n = 39), relapsed diffuse large B-cell lymphoma (n = 42), and refractory aggressive non-Hodgkin lymphoma (n = 30). The 2-year PFS was 68% (median not reached) for follicular lymphoma and 42% (median, 17.1 months) for diffuse large B-cell lymphoma.

A phase III trial of INO-rituximab compared with bendamustine-rituximab or gemcitabine-rituximab in relapsed/refractory aggressive non-Hodgkin lymphoma was recently discontinued after a scheduled interim analysis concluded that the primary objective of improving OS would not be met.[27] Overall, though, no new or unexpected safety issues were identified. INO continues to be evaluated in adult and pediatric acute lymphoblastic leukemia.

Epratuzumab

Epratuzumab is a humanized anti-CD22 monoclonal antibody that functions primarily through ADCC. In a phase II study of 63 patients with relapsed/refractory non-Hodgkin lymphoma, epratuzumab in combination with rituximab yielded an ORR of 47% (22% CRs); the best responses were seen in patients with follicular lymphoma or diffuse large B-cell lymphoma.[28] Another phase II study in 48 patients with relapsed/refractory indolent non-Hodgkin lymphoma (41 with follicular lymphoma, 7 with small lymphocytic lymphoma) demonstrated an ORR of 54% (with 10 CRs) in follicular lymphoma and 57% in small lymphocytic lymphoma (with 3 CRs).[29] Responses were durable. In the frontline setting, treatment of 107 diffuse large B-cell lymphoma patients with epratuzumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy produced an ORR of 96% (74% CRs) as assessed by CT imaging and 88% as assessed by positron emission tomography (PET) imaging in 81 eligible patients.[30] In the intention-to-treat population, the median event-free survival and OS at 3 years were 70% and 80%, respectively.

Phase III trials are being conducted, and epratuzumab is also being studied in B-cell acute lymphoblastic leukemia.

Anti-CD30 Antibody

Brentuximab vedotin

Systemic anaplastic large-cell lymphoma is an uncommon but aggressive type of T-cell non-Hodgkin lymphoma. Those patients whose tumors express anaplastic lymphoma kinase (ALK) have better outcomes in general than patients with ALK-negative disease. Relapse rates can be as high as 65% after conventional front-line therapy, and recurrent disease is generally resistant to further standard chemotherapy-although autologous stem cell transplantation may yield a 30% to 40% rate of long-term remission in patients with chemosensitive disease.[31] Expression of CD30 in anaplastic large-cell lymphoma tumors is high; however, early-phase studies with first-generation anti-CD30 monoclonal antibodies showed only modest antitumor activity (ORR, 17% with SGN-30[32]). Development of the ADC brentuximab vedotin has helped improve the efficacy of CD30 targeting immensely. This agent comprises an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent monomethy lauristatin E (MMAE).[33] Binding of the ADC to CD30 on the cell surface internalizes the entire ADC-CD30 complex. In the lysosome, the linker is cleaved by proteolytic activity, thereby releasing the MMAE, which then disrupts the microtubule network by binding to it.

This leads to cell cycle arrest and apoptosis. Preclinical as well as early-phase clinical trial activity was better than that of the naked monoclonal antibody. The ORR was 38% in the CD30-positive lymphoma phase I study, and there were 11 CRs, including 2 patients with anaplastic large-cell lymphoma.[34] The major AE was peripheral neuropathy; rates of this AE were lower with every-3-weeks dosing than with weekly dosing of brentuximab vedotin, although clinical activity was similar.

A pivotal, open-label, multicenter phase II trial was subsequently conducted for patients with recurrent anaplastic large-cell lymphoma.[31] Brentuximab vedotin was given to 58 patients at 1.8 mg/kg IV every 3 weeks for up to 16 cycles. The median age of the patients was 52 years (range, 14–76 years), and the median number of prior therapies was 2 (range, 1–6). Twenty-six percent of patients had undergone prior autologous hematopoietic stem cell transplantation. The median number of cycles of therapy received was 7 (range, 1–16). An objective response was achieved by 50 patients (86%), and this included CRs in 33 patients (57%) and PRs in 17 (29%). In the ALK-negative patients (n = 42), ORR was 88%, with 52% CRs; in the ALK-positive patients (n = 16), ORR was 81%, with 69% CRs. Overall, the median duration of response was 12.6 months, while for patients with a CR, it was 13.2 months. The estimated median PFS was 13.3 months overall, and in the patients with a CR, it was 14.6 months. Median OS was not reached, and the estimated 1-year survival rate was 70%. There was no difference in median PFS and duration of response by ALK expression. The most common grade 3 or higher AEs were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). There were no study-related deaths. Peripheral neuropathy of any grade occurred in 53% of patients, but there were no grade 4 events. Resolution or improvement of peripheral neuropathy symptoms occurred in 81% of affected patients at a median of 9.9 weeks after brentuximab vedotin was stopped or the dosage was decreased.

Based on these data, in 2011, brentuximab vedotin became the first FDA-approved agent for patients with anaplastic large-cell lymphoma in whom at least one prior line of multi-agent chemotherapy has failed.

Anti-IL6 Antibody

Siltuximab

Castleman disease is a rare lymphoproliferative disorder in which overproduction of interleukin 6 (IL-6) results in systemic symptoms. Targeting IL-6 signaling with tocilizumab, a humanized IL-6 receptor antibody, improved or resolved systemic symptoms, laboratory abnormalities, and lymphadenopathy in patients with plasma cell multicentric Castleman disease in a phase II study.[35,36] Siltuximab is a chimeric monoclonal antibody with high binding affinity for human IL-6.[37] In a recent dose-finding phase I study of non-Hodgkin lymphoma, multiple myeloma, and symptomatic multicentric Castleman disease patients, siltuximab was infused in 67 patients weekly, every 2 weeks, or every 3 weeks. Patients received a median of 16 doses over a median of 8.5 months (maximum, 60.5 months).[37] There were no dose-limiting or cumulative toxicities, and no antibodies against siltuximab were identified. The most common AEs possibly related to the study agent were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). There were no treatment-related deaths. C-reactive protein suppression was greatest with the 12-mg/kg every-3-weeks dosing. Thirty-two of the 37 multicentric Castleman disease patients (86%) improved clinically; 12 of the 36 evaluable multicentric Castleman disease patients had radiologic responses (1 CR, 11 PRs). Two of 14 evaluable non-Hodgkin lymphoma patients (14%) had PRs, and 2 of 13 multiple myeloma patients (15%) had CRs.

A subsequent randomized, double-blind, placebo-controlled phase II trial of siltuximab in patients with symptomatic multicentric Castleman disease who were negative for HIV and human herpesvirus-8 (HHV8) enrolled 79 patients in a 2:1 randomization pattern (53 in the siltuximab arm and 26 in the placebo arm).[38] All patients also received best supportive care. Siltuximab was dosed at 11 mg/kg IV every 3 weeks, and treatment was continued until treatment failure. Crossover to unblinded siltuximab was allowed at the time of treatment failure for patients in the placebo group; 13 patients (50%) took advantage of this. Median duration of treatment was 375 days (range, 1–1,031 days) for the siltuximab arm and 152 days (range, 23–666 days) for the placebo arm. Median duration of follow-up for this intention-to-treat population was 422 days (range, 55–1,051 days). Durable tumor and symptomatic responses were seen in 18 of the treated patients (34%, with 1 CR and 17 PRs) but in none of the patients in the placebo group (P = .0012). Median response duration was 383 days (range, 232–676 days). Rates of AEs and serious AEs were similar in both groups. The most common grade 3 or higher AEs were fatigue, night sweats, and anemia. Three of the 53 siltuximab-treated patients (6%) had serious AEs related to study treatment: lower respiratory tract infection, anaphylaxis, and sepsis. Overall, siltuximab plus best supportive care was found to be superior and well tolerated compared with best supportive care alone in these patients.

Based on these results, the FDA approved siltuximab in April 2014 for patients with multicentric Castleman disease who are HIV-negative and HHV8-negative.

Conclusions

Relapsed/refractory non-Hodgkin lymphoma patients as well as high-risk chronic lymphocytic leukemia patients generally do poorly. There are numerous promising novel agents being studied in clinical trials, as single agents and in combinations, in order to improve outcomes. Monoclonal antibodies and ADCs are in the forefront of this research, because of encouraging responses and general tolerability. Some of the agents reviewed here have already received FDA approval, while others are still being actively investigated. Rational combinations of monoclonal antibodies and ADCs with either chemotherapy or novel agents may ultimately lead to achievement of the goal of prolonged remissions in these patients, via targeted, personalized therapeutic plans.

Financial Disclosure:Dr. Siddiqi is a speaker for Janssen, Pharmacyclics, and Seattle Genetics. Dr. Rosen has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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