I. Introduction: Overview and Epidemiology

Lymphomas are cancers of the immune system. While 10% of all lymphomas are classified as Hodgkin lymphoma (HL), the remaining 90% are classified as non-Hodgkin lymphoma (NHL). Treatment using targeted therapies has significantly improved outcomes for patients in recent years. This review focuses on the use of targeted agents in the post-transplant setting and changing paradigms in the frontline setting. Lymphoma detection, diagnosis, and staging will be examined, as well as risk stratification and current standard therapeutic options.

Hodgkin lymphoma is a relatively rare type of cancer. In the United States, HL will account for an estimated 9050 new cancer cases each year, or 0.5% of all new cancer cases, resulting in an estimated 1150 deaths in 2015.

The annual incidence of new cases is 2.7 per 100,000 people per year. Hodgkin lymphoma is most commonly diagnosed in people 20 to 34 years of age, with a median age of diagnosis of 38 years (

).2 Hodgkin lymphoma is classified as either classical HL, which accounts for 95% of HL cases,

or nodular lymphocyte-predominant, which accounts for the remaining 5% of cases. Classical HL is further subdivided into the four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted, and lymphocyte rich.

While the nodular lymphocyte-predominant type of HL is not associated with the Epstein-Barr virus, all classical HL subtypes have an intermediate to strong association with the virus.

At a histologic level, HL is characterized by the presence of mononuclear Hodgkin cells and multi- nucleated Reed-Sternberg cells that have a B-cell origin.

Hodgkin lymphoma can develop in any part of the lymphatic system, most commonly in the lymph nodes and less commonly in the spleen, thymus, tonsils, and bone marrow (

). Risk factors for HL include younger age, male gender, previous infection with the Epstein-Barr virus, and a positive diagnosis of HL in a first-degree relative.

Non-Hodgkin lymphoma is the seventh most common cancer in the United States, accounting for approximately 4% of all new cancer cases. In 2015, an estimated 71,850 new cases of NHL will be diagnosed, resulting in an estimated 19,790 deaths.

The annual incidence of new cases of NHL is 19.7 per 100,000 people per year. It is most commonly diagnosed in people 65 to 74 years of age, with a median age of diagnosis of 66 years (

). Like HL, NHL is more commonly diagnosed in men than in women.

Among the many subtypes of NHL, the prevalence varies significantly by geographic region.

As with HL, NHL can develop in almost any part of the lymphatic system but typically occurs in the lymph nodes. Among this heterogeneous group of cancers, 85% to 90% of subtypes derive from B lymphocytes and the remaining subtypes develop from T lymphocytes or from natural killer lymphocytes.

These subtypes also range from indolent lymphomas, such as follicular lymphoma, to more aggressive lymphomas, such as Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL).

lists the subtypes of NHL based on the World Health Organization (WHO) classification of tumors in hematopoietic and lymphoid neoplasms.

For both HL and NHL, patients usually present with painless lymphadenopathy, often in the cervical or supraclavicular regions. In more than 50% of cases of HL, a mediastinal mass is present that is either asymptomatic or presents as cough, dyspnea, or superior vena cava obstruction. For both diseases, the clinical presentation depends on the site involvement, pathophysiology of the lymphoma subtype, and presence or absence of B symptoms that include night sweats, loss of bodyweight greater than 10%, and fever.

Guidelines for the diagnosis and staging for HL and NHL have been developed by the National Comprehensive Cancer Network (NCCN) and are well accepted.

The standard for detection of HL is excisional biopsy followed by evaluation by immunohistochemistry (IHC).

For diagnosis of NHL, a core needle biopsy or fine needle aspiration is obtained. However, this sample is often not sufficient for an initial diagnosis because of the need for additional molecular testing that may be required to obtain a differential diagnosis. Such testing may include flow cytometry, polymerase chain reaction (PCR) analysis, fluorescence in situ hybridization (FISH), or IHC. Most NHL subtypes require immunophenotyping using an IHC panel or flow cytometry analysis to detect cell surface markers, such as CD5, CD10, CD19, CD20, and CD23, or other distinguishing markers, such as cyclin D1, B-cell lymphoma-2 (BCL-2), and Ki-67. Most NHL subtypes have a unique immunophenotype profile. Essential workup procedures for either disease may include assessment of B symptoms, a complete blood count, comprehensive metabolic panel, bone marrow biopsy, and various imaging methods.

Computed tomography (CT) and positron emission tomography (PET) are commonly used for disease staging and assessment. While imaging of the neck, chest, abdomen, and pelvis for staging has been traditionally performed using contrast-enhanced CT, the use of PET scanning with 18F-fluorodeoxyglucose (18F-FDG) has risen in recent years because of its increased accuracy, its ability to delineate margins for radiotherapy, and its ability to provide baseline, interim, and end-of-treatment assessments.

In HL, 18F-FDG PET is particularly sensitive for detecting focal bone-marrow infiltration and has the potential to reduce the frequency of invasive trephine biopsies needed for staging.

Subtypes of NHL have varied affinity for detection using 18F-FDG PET. For example, follicular, DLBCL, and mantle cell lymphoma (MCL) are consistently 18F-FDG PET avid, while small lymphocytic lymphoma (SLL), T-cell, and extranodal marginal-zone lymphomas demonstrate variability with 18F-FDG PET avidity. In NHL subtypes that are consistently avid, 18F-FDG PET scanning detects with 80% sensitivity and 90% specificity.

When used for diagnostic purposes, 18F-FDG PET can result in disease upstaging and has been shown to be superior to CT in sensitivity of detection.

Upstaging from early-stage to advanced-stage disease, which occurs in 10% to 15% of patients with HL, has the potential to modify clinical management of the disease.

Perhaps the greatest benefit of 18F-FDG PET is its use in the interim analysis after initial cycles of chemotherapy to determine which patients need escalation or de-escalation of treatment. In HL, assessment after two cycles of chemotherapy has shown to be a better predictor of outcomes than traditional risk stratification analysis.

18F-FDG PET uptake is quantified using the 5-point Deauville scale, which compares the lesion uptake value with that of the liver or mediastinum.

Staging of both HL and NHL is made using the Ann Arbor system and Cotswold modification (

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Clinical Articles

This feature covers the "I. Introduction: Overview and Epidemiology" and the "II. Detection, Diagnosis, and Staging" sections of the current Evolving Paradigms in Lymphoma issue.

Evolving Paradigms in Lymphoma: Overview, Epidemiology, Detection, Diagnosis, and Staging

Risk stratification varies somewhat by research group but generally divides the disease into early or advanced stages. The German Hodgkin Study Group (GHSG) and the European Organization for Research and Treatment of Cancer (EORTC) stratify early disease into favorable and unfavorable subtypes based on the presence or absence of risk factors. Unfavorable disease is usually defined by bulk and the presence of B symptoms. Conversely, the National Cancer Institute (NCI) and the National Cancer Research Institute (NCRI) do not subdivide early disease and classify patients with B symptoms and one or more risk factors as having advanced disease.

Clinical data suggest that the intensity of chemotherapy and radiation regimens can be reduced with early-stage disease, favoring identification of these patients as soon as possible.

In advanced-stage HL, the international prognostic score, or Hasenclever score, is used to predict prognosis. The score is based on clinical parameters that include male sex, age >45 years, hemoglobin concentration <105 g/L, serum albumin concentration <40 g/L, stage IV disease, lymphopenia (0.6 x 109 lymphocytes/L or <8% of total white cell count), and leukocytosis (&ge;15 x 109 white cells/L). Each risk factor reduces the 5-year overall survival (OS) by approximately 8%.

The Hasenclever score should be used in conjunction with 18F-FDG PET imaging

for both early-stage and advanced-stage disease to assess risk. Overall, the prognosis for patients with HL is very good; the OS for patients with early-stage disease is often 90%; and the OS for patients with advanced-stage disease is 75% to 90%.

The most widely used prognostic model for patients with NHL is the International Prognostic Index (IPI). Risk stratification (IPI score) is based on several clinical factors, including age >60 years, elevated lactate dehydrogenase concentration, Eastern Cooperative Oncology Group performance status &ge;2, Ann Arbor stage III or IV disease, and &ge;2 extranodal disease sites.

With one point assigned to each risk factor, patients are assigned to one of four risk groups: low risk, having zero or one clinical factor; low-intermediate risk, having two clinical features; high-intermediate risk, having three clinical features; and high risk, having four to five clinical features. Reported 5-year survivals of patients using this risk stratification are 73%, 51%, 43%, and 26%, respectively.

The heterogeneity of NHL has proven challenging in finding a prognostic model that is effective for all subtypes, especially for those that are slow-growing, such as follicular lymphoma. In 2004, the Follicular Lymphoma International Prognostic Index (FLIPI) was developed to account for the differences in disease progression. The FLIPI shares three prognostic variables with IPI: age, Ann Arbor stage, and elevated lactate dehydrogenase. The FLIPI differs from IPI in two variables, specifically hemoglobin concentration (<12 g/L) and the number of involved nodal sites (>4).

Using these prognostic criteria, patients are stratified into low risk, having zero to one clinical feature; intermediate risk, having two clinical features; and high risk, having three or more clinical features. The 10-year survival rates for patients in these prognostic groups are 71%, 51%, and 36%, respectively.

Though risk stratification using clinical factors is essential, gene expression profiling and other molecular techniques have emerged in recent years to further categorize NHL subgroups and provide prognostic value. One example of this advancement using genetic profiling has been in DLBCL. Profiling identified three additional subgroups: germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma. The germinal-center B-cell-like subgroup uniquely harbors 2 common molecular events, BCL-2 translocation and c-Rel amplification, and has the highest 5-year survival rate after chemotherapy among the subgroups.

Anaplastic large-cell lymphoma (ALCL) has also been divided into prognostic subgroups based on genetic profiling and the presence or absence of anaplastic lymphoma kinase (ALK) chromosomal rearrangements. The WHO has accepted three distinct subgroups: primary cutaneous ALCL, systemic ALK-positive ALCL, and systemic ALK-negative ALCL. Clinical outcomes vary with the subgroup; primary cutaneous ALCL is associated with excellent outcomes, ALK-positive ALCL is associated with favorable outcomes, while ALK-negative ALCL outcomes vary.

Furthermore, PET scans are prognostic indicators of the response to initial therapy. In general, a negative PET scan after treatment signifies a better prognosis than a residual, positive PET scan.

The 5-point Deauville criteria are now the standard reporting method for treatment response.

Treatment regimens for lymphomas are well established and have been included in the guidelines developed by the NCCN. Lymphomas are treated with combinations of chemotherapy, radiation therapy, and, more recently, with targeted therapy using monoclonal antibodies, antibody-drug conjugates (ADCs), and small molecule inhibitors. The remainder of this review will focus on these therapeutic strategies, with an emphasis on targeted agents approved in recent years and those still in clinical development. As more novel, potentially effective agents are being rapidly identified, clinicians should focus on incorporating these new agents into standard-of-care treatment regimens.

Current standard regimens in Hodgkin lymphoma

Classic HL treatment strategies are largely based on disease stage and number of risk factors. The most commonly used combination chemotherapy regimens, and those recommended by the NCCN, are ABVD (Adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine), escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone).

Patients with early favorable HL are commonly treated with two cycles of ABVD followed by involved-site radiation therapy (ISRT), while patients with early unfavorable HL can be treated with four cycles of ABVD followed by a slightly higher involved site radiation therapy (ISRT).

Escalated BEACOPP, considered a more aggressive chemotherapy regimen and used in unfavorable bulky disease, has shown some superiority in clinical outcomes, though not in OS, compared with ABVD.

In recent years, therapeutic strategies have concentrated on reducing treatment-related toxicity while improving treatment efficacy for patients with early-stage disease. Clinical data have shown that decreasing the number of chemotherapy cycles and reducing radiation doses can be as effective as more aggressive regimens in patients with early-stage HL.

Recent studies have also evaluated radiation-free regimens with the hope of reducing treatment-related toxicity even more. PET scanning is crucial in the process of determining interim tumor response with this approach. In one study conducted by the NCRI, radiation-free treatment, using 3 cycles of ABVD and combined modality treatments, were found to have similar rates of progression-free survival (PFS) and OS at a 3-year follow-up. PFS was more than 90% for both treatment groups.

For patients with advanced-stage (stages III-IV) HL, treatment cycles with ABVD or escalated BEACOPP are commonly used worldwide, although NCNN guidelines also recommend Stanford V in select cases. Clinical studies and a systemic review of the literature indicate significantly greater OS with BEACOPP therapy than with ABVD for patients with advanced disease.

Despite these data, ABVD continues to remain an acceptable frontline therapy because of the higher rates of acute toxicity associated with escalated BEACOPP. Nonetheless, a cure rate of 75% to 80% in patients with advanced HL is expected, independent of the first-line therapy chosen.

Approximately 10% of patients with early-stage HL and 20% to 30% of patients with advanced-stage HL relapse after, or are refractory to, frontline initial treatment.

The clinical management of relapsed/refractory HL generally offers salvage chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplant (ASCT). More than half of all patients with HL who receive ASCT will relapse. Second-line therapy for relapsed/refractory disease may include a number of multiagent therapies but typically include platinum-based or gemcitabine-based salvage regimens, such as ICE (ifosfamide, carboplatin, etoposide), C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone), or GCD (gemcitabine, carboplatin, dexamethasone).

Brentuximab vedotin (discussed in more detail below) can also be used as a second-line therapy if two prior combination chemotherapy regimens or ASCT have failed. Currently, brentuximab is the only targeted agent approved for the treatment of relapsed HL after ASCT.

The prognosis for patients with relapsed/refractory disease depends on multiple factors, including stage at the time of relapse, time to relapse, and performance status. Patients who relapse within 3 months after initial treatment experience worse outcomes than patients with longer remission durations. Those who relapse within 1 year after ASCT only have a median survival time of 1.3 years after disease progression. As such, there remains a critical need to develop novel therapeutic agents that can improve outcomes for relapsed/refractory disease, as well as in the frontline setting.

Although most patients with HL are cured with standard chemotherapeutic regimens, many experience shortened life spans because of delayed treatment-related toxicity, including secondary malignancies and cardiovascular diseases.

While standard-of-care regimens have focused on reducing chemotherapy cycles and radiation dosage, more novel agents are needed to further decrease long-term toxicity in patients. The development and subsequent FDA approval of targeted agents, such as brentuximab vedotin, have significantly added therapeutic options for patients with relapsed/ refractory disease.

Brentuximab vedotin is an ADC that is composed of the monoclonal anti-CD30 antibody linked to monomethyl auristatin E (MMAE). The CD30 antigen, a transmembrane glycoprotein, became an attractive target for therapeutic agents because of its restricted expression in lymphomas, especially in HL and ALCL.

The cytotoxic agent MMAE is a tubulin modifier that blocks cell division. Binding of brentuximab vedotin to CD30 on the cell surface, internalization through a receptor-mediated mechanism, and subsequent release of MMAE in the cytosol are highly effective and induce growth arrest and apoptosis selectively in lymphoma cells.

The initial phase I, dose-escalation study of brentuximab vedotin showed tumor regression in 86% of patients with relapsed/refractory HL and ALCL.

The pivotal phase II study, which led to FDA approval of brentuximab vedotin in 2011, was completed in patients with relapsed/ refractory HL who had received ASCT. The overall response rate (ORR), the primary endpoint of the study, was 75%, with 34% of patients demonstrating complete remission. Tumor regression was observed in 94% of patients. The median time to treatment response was rapid, just 5.7 weeks, with complete remission achieved in 12 weeks. The median PFS was nearly 6 months for all patients and the median duration of response was more than 20 months for patients with complete response. The median OS was 40.5 months. The safety profile of brentuximab vedotin was acceptable and the most common treatment-related adverse events (AEs) were peripheral sensory neuropathy, nausea, fatigue, diarrhea, and neutropenia.

The AETHERA trial was a randomized, placebo-controlled, phase III study comparing brentuximab vedotin plus best supportive care (BSC) with placebo plus BSC in patients with HL at high risk of relapse or progression following ASCT. The initial findings of the study were recently published; compared with placebo, brentuximab vedotin improved PFS by 43% and extended PFS by nearly 19 months.

The most common AEs in the brentuximab group were peripheral sensory neuropathy and neutropenia. Based on the results of the AETHERA study, the FDA granted priority review for brentuximab vedotin and in August 2015, granted its approval as a consolidation therapy following ASCT in patients with HL.

Nivolumab is a fully humanized antiprogrammed cell death 1 (PD-1) antibody that functions as a checkpoint inhibitor. The PD-1 pathway normally acts as a regulator of T-cell activation. When one of the PD-1 ligands, PD-L1 or PD-L2, binds to the PD-1 receptor found on the surface of T cells, the receptor is inactivated. Cancer cells evade an immune response by expressing PD-1 ligands that bind the PD-1 receptor on immune effector cells. Nivolumab binds to PD-L1, preventing binding to the PD-1 receptor, and thus allows T cells to remain active and target the tumor.

In 2014, the FDA granted nivolumab Breakthrough Therapy Designation for the treatment of patients with HL after failure of ASCT or brentuximab vedotin. The designation was largely based on the results of the ongoing phase Ib trial, CheckMate-039. Most patients (87%) treated with nivolumab achieved an objective response and the remaining patients (13%) had stable disease; PFS was 86% after 24 weeks. The safety profile of nivolumab was acceptable, with rash and thrombocytopenia the most common AEs. Grade 3 AEs were noted in 22% of patients.

Current standard regimens in non-Hodgkin lymphoma

The heterogeneity of NHL subtypes creates complexity in the standard of care. The various subtypes of NHL range from indolent to very aggressive in physiologic behavior and clinical outcome. Thus, the standard treatment regimens described herein will focus on the most prevalent subtypes and those that have received updates with targeted agents in recent years. The most up-to-date standards of care are outlined in the NCCN guidelines.

DLBCL accounts for approximately one-third of all NHL cases and is the most commonly diagnosed histologic subtype. The choice of therapy for DLBCL depends on disease stage and IPI score. Clinical presentation of localized disease is fairly uncommon, but combination chemoimmunotherapy plus involved-field radiation is recommended. The standard therapeutic approach for advanced-stage DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. The addition of rituximab, an anti-CD20 monoclonal antibody, to standard CHOP therapy significantly improved both event-free survival and OS in younger and older patients.

Intensification strategies, such as more frequent R-CHOP treatment cycles and ASCT as a first-line treatment, have not shown significant clinical benefit.

Thus, R-CHOP remains the gold standard for advanced disease and is being investigated with additional novel agents, such as lenalidomide and ibrutinib, in clinical trials.

Progressive disease after R-CHOP therapy should be tested repeatedly by biopsy to confirm disease recurrence. Most patients should receive combination salvage chemotherapy and subsequent ASCT with successful treatment response. Commonly used salvage chemotherapy regimens, such as rituximab plus ICE and rituximab plus dexamethasone, cisplatin, and cytarabine (DHAP), contain cisplatin and/or gemcitabine agents and produce similar ORRs, event-free survival, and OS.

Additional maintenance therapy after ASCT has not shown significant clinical benefit over no additional therapy.53 Disease progression after ASCT is associated with a very poor prognosis. Relapsed/refractory disease can be treated with allogeneic stem-cell transplantation (allo-SCT) but is not highly recommended for patients with DLBCL because of the likelihood of failure and high nonrelapse mortality rate, especially in patients older than 45 years of age.

Follicular lymphoma accounts for about 20% of all lymphomas and is the second most commonly diagnosed lymphoma in the United States. Patients rarely present with stage I or stage II disease. For those who do present with early-stage disease, radiation therapy is recommended and is associated with very good outcomes.

Most patients present with advanced-stage disease, with 70% experiencing bone marrow involvement. Though rare, transformation of follicular lymphoma to a more aggressive lymphoma occurs at a rate of approximately 2% per year.

Clinical management of advanced disease should be assessed based on symptoms and disease bulk. Patients who are asymptomatic and have low tumor bulk might not require therapy until other symptoms appear, such as compromised end-organ function, pancytopenia, or constitutional symptoms, and could be managed through watchful waiting.

The OS of patients with follicular lymphoma has improved significantly with the incorporation of rituximab into treatment strategies. Compared with watchful waiting, rituximab monotherapy has significantly improved PFS and quality of life.

Generally, patients with low tumor burden and moderate symptoms are initially treated with rituximab followed by a continued rituximab maintenance strategy.

Rituximab plus chemotherapy is a common approach for patients with greater tumor burden. Both bendamustine plus rituximab and R-CHOP or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) have produced ORRs greater than 90%.

Chemoimmunotherapy-responsive patients will typically receive ongoing rituximab maintenance therapy, which has been shown to improve the complete response rate and PFS compared with observation alone.

Similar results in complete response rate and PFS have been reported with consolidation radioimmunotherapy.

Many therapeutic options are available for patients with relapsed/refractory follicular lymphoma, including alternative rituximab-containing chemotherapies, radioimmunotherapy, or treatment with novel agents still in clinical trials. ASCT may also be considered for relapsed patients and has been shown to improve PFS and OS in patients compared with chemotherapy.

Although allo-SCT has shown clinical efficacy in patients with relapsed/refractory disease, a retrospective analysis has demonstrated a significantly greater 3-year OS with autologous SCT than with allo-SCT.64 Recently, idelalisib was approved for use in patients with relapsed/ refractory disease.

Mantle cell lymphoma accounts for 5% to 7% of all lymphomas and has a significant male predominance. As with DLBCL and follicular lymphoma, most patients with MCL present with advanced disease, often with bone marrow, peripheral blood, and gastrointestinal involvement.

While a small subset of patients have indolent disease that can initially be addressed with watchful waiting, most will require treatment at the time of diagnosis.

Chemoimmunotherapy has been the cornerstone of MCL treatment. Although R-CHOP was the standard of care for many years, recent randomized studies have demonstrated that bendamustine plus rituximab therapy produced improved PFS with less toxicity than R-CHOP as a first-line therapy.

Younger patients may benefit from a more aggressive initial treatment approach, such as with cytarabine plus ASCT or with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine (R-Hyper-CVAD).

Alternatively, rotating R-CHOP and R-DHAP treatments followed by ASCT during first remission may be implemented.

Most patients with MCL will progress despite the use of ASCT.

The targeted agents bortezomib and ibrutinib have been approved for use in MCL in the frontline and relapsed settings respectively, and ongoing trials are evaluating other therapeutic agents.

ALCL accounts for 3% to 8% of all lymphomas and 10% to 20% of all childhood lymphomas. While systemic ALK-positive ALCL occurs more frequently in children and young adults and is associated with a better prognosis, ALK-negative disease commonly presents in older adults and is associated with worse outcomes.

Similar to many other types of NHL, patients with ALCL typically present with advanced-stage disease. For the small subset of patients with early-stage disease, a short-course CHOP regimen plus radiotherapy is recommended for both ALK subtypes. A therapy approach similar to that of early-stage DLBCL is acceptable.

This feature covers the "III. Risk Stratification and Prognosis" and the "IV. Current Treatment Strategies" sections of the current Evolving Paradigms in Lymphoma issue.

Evolving Paradigms in Lymphoma: Risk Stratification, Prognosis, and Current Treatment Strategies

Several agents are in clinical trials for the treatment of HL and NHL. A greater understanding of the molecular mechanisms driving these diseases has prompted the development of novel, highly active agents. Clinical research efforts aim to improve cure rates while reducing treatment-related toxicity. Some of the most promising agents, which are being studied in the frontline and in relapsed/refractory settings, include monoclonal antibodies, antibody-drug conjugates, and small molecule inhibitors.

provides an overview of clinical trials using targeted agents that are now recruiting participants.

Blinatumomab is a bispecific anti-CD19/CD3 antibody that is ap- proved for the treatment of relapsed/refractor acute lymphoblas- tic leukemia. It belongs to a class of molecules known as BiTE, or bispecific T-cell engager. These molecules recruit and activate endogenous T cells to target CD19-postive B cells and therefore act as a bridge between a cancer cell and a T cell. Bispecific antibod- ies, such as blinatumomab, are clinically advantageous for their low effector-to-target ratio and high tissue penetration.

Recent clinical trials have focused on the efficacy of blinatumomab in B- cell NHL and B-cell acute lymphoblastic leukemia.

In an initial phase I trial in patients with NHL, 10% achieved com- plete response and 18% achieved a partial response with blinatu- momab therapy over 4 to 8 weeks with tumor cell clearance from the liver and bone marrow. Patients demonstrated high rates of grade 3 or higher AEs, including lymphopenia, elevated C-reactive protein levels, leukopenia, neutropenia, and thrombocytopenia. In a more recent phase I study, investigators found that circulating B cells were completely depleted using a modest concentration of blinatumomab.

A phase II multicenter trial of patients with re- lapsed/refractory DLBCL is ongoing. Investigators will assess ORR (complete or partial) during the first treatment cycle using the Che- son criteria from data obtained using CT and PET scans.

Rituximab is an anti-CD20 antibody that is approved for use with standard chemotherapy regimens as a frontline therapy in patients with follicular lymphoma, CLL/SLL, and DLBCL. Ongoing studies with rituximab are focused on its use in the frontline setting in com- bination with other multiagent chemotherapies or immunomodula- tory agents. Initial phase II clinical trials in patients with HL were promising and demonstrated event-free survival and OS rates of 83% and 96%, respectively, when combined with ABVD.

Another phase II trial completed at the MD Anderson Cancer Center has in- vestigated rituximab in combination with lenalidomide in patients with follicular lymphoma, marginal zone lymphoma, and SLL. An ORR of 90% with a complete response of 63% was observed. Among the follicular, marginal zone, and SLL NHL subtypes, complete re- sponse rates of 87%, 67%, and 23% were achieved, respectively. Le- nalidomide plus rituximab was well tolerated, with neutropenia as the most common grade 3 or 4 AE.

To date, researchers at the German Hodgkin Study Group completed the only phase III trial of rituximab in combination with escalated BEACOPP in patients with HL; the addition of rituximab did not improve OS or PFS after 3 years, and more than 90% of patients experienced grade 4 toxic- ity.

Investigators at the Sidney Kimmel Comprehensive Cancer Center are recruiting participants in a pilot study of rituximab and brentuximab vedotin in patients with chemosensitive relapsed HL. One-year failure-free survival is the primary outcome of the study.

Ofatumumab is another humanized anti-CD20 antibody that is approved for the treatment of relapsed/refractory CLL/SLL.

In preclinical models of MCL, ofatumumab demonstrated superior- ity to rituximab, even in a rituximab-resistant setting.

Clini- cal trial data of ofatumumab for treatment of MCL are limited.

Therefore, two phase II trials are being conducted to determine the effect of ofatumumab in MCL. The first study, conducted at the Memorial Sloan Kettering Cancer Center, will evaluate the effect of ofatumumab alone or in combination with the alkylating agent bendamustine in MCL. The primary outcomes are single-agent and multiagent efficacy, and secondary outcomes include OS, PFS, remission duration, and response duration.

Roswell Park Can- cer Institute is conducting the second phase II trial, which will evaluate the effectiveness of ofatumumab in combination with hy- perfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (O-HyperCVAD) and alternating with ofatumumab in combination with cytarabine and methotrexate. Investigators will determine the percentage of patients who achieve a complete response as the main outcome.

In the large phase III ORCHARRD study of patients with DLBCL or refractory follicular lymphoma, ofatumumab plus dexamethasone, cytarabine, and cisplatin failed to demonstrate clinical superiority in PFS when compared with rituximab plus dexamethasone, cytarabine, and cisplatin.

Epratuzumab is a humanized IgG1 antibody that targets the B- cell antigen CD22, which regulates cellular adhesion and B-cell activation. CD22 is an attractive drug target because most B-cell NHLs express it at high levels. The clinical utility of epratuzumab has been evaluated in combination with standard chemotherapy regimens and other monoclonal antibodies. In one phase II study, investigators compared the efficacy of epratuzumab plus R-CHOP (ER-CHOP) with standard R-CHOP therapy in patients with DLB- CL. Those who received ER-CHOP showed improved PFS compared with R-CHOP alone.

A phase II trial that evaluated the combi- nation of epratuzumab with rituximab immunotherapies demon- strated complete and partial responses above 40%, with 60% of patients remaining in remission at the 3-year follow-up, levels that are comparable to chemotherapy-containing regimens.

An ongo- ing phase II study will evaluate the efficacy of radiolabeled epratu- zumab in combination with veltuzumab, an anti-CD20 antibody, in patients with aggressive, refractory NHLs, including DLBCL, MCL, and follicular lymphoma. Safety and dose-limiting toxicity are the primary outcomes of the study.

Clinical trials are investigating brentuximab vedotin in a frontline setting. Two trials, ECHELON-1 and ECHELON-2, are investigating brentuximab vedotin in combination with standard chemothera- peutic combination therapies. The ECHELON-1 trial is an open- label, multicenter, phase III study comparing brentuximab vedotin plus AVD with ABVC in patients with advanced HL. Modified PFS is the main outcome of the study.

The ECHELON-2 trial is a dou- ble-blind, multicenter, randomized phase III study comparing the safety and efficacy of brentuximab vedotin plus CHP (cyclophos- phamide, hydroxydaunomycin/doxorubicin, and prednisone) with standard-of-care CHOP in patients with CD30-positive mature T- cell lymphomas, including ALCL; PFS is the main outcome of the study.

Other phase II studies have investigated the efficacy of bren- tuximab vedotin as first-line salvage therapy prior to ASCT in patients with relapsed/refractory HL. Standard salvage therapies such as ICE or GCD are effective but have significant toxicities. In two independent studies, investigators determined whether brentuximab vedotin, used as salvage therapy, would negate the need for additional ICE therapy prior to ASCT. Interim analysis was performed by PET scan. The results indicated that 27% to 52% of patients were PET-negative after brentuximab vedotin treatment and proceeded directly to ASCT, eliminating ICE che- motherapy.

Another phase II trial assessed brentuximab vedotin in combination with bendamustine in patients with re- lapsed/refractory HL. The complete remission and ORR (both complete and partial) rates were 82% and 94%, respectively. The safety profile was manageable.

Ongoing phase III studies are exploring brentuximab versus physician&rsquo;s choice of treatment (methotrexate or bexarotene) in patients with CD30-positive cutaneous T-cell lymphoma156 and brentuximab plus combina- tion chemotherapy versus combination chemotherapy alone in patients with HL who are 2 to 18 years of age.

Inotuzumab ozogamicin is a humanized anti-CD22 IgG4 mono- clonal ADC covalently linked to the antitumor agent calicheami- cin. Inotuzumab ozogamicin works through an internalization mechanism whereby it binds to CD22 on the cell surface, is rapid- ly internalized, and delivers the antitumor drug internally, result- ing in double-stranded DNA breaks and apoptosis.

Completed phase I and phase II trials have shown moderate response rates with inotuzumab ozogamicin alone and with rituximab in patients with follicular lymphoma and DLBCL.

The Oncology Institute of Southern Switzerland is conducting an open-label phase I trial to study the effects of inotuzumab ozogamicin in combination with the mammalian target of rapamycin (mTOR) inhibitor, temsiroli- mus, in patients with CD22-positive B-cell NHLs. The primary out- come of the study is determining the safety profile, including AEs and the maximum tolerated dose.

University College, London, is conducting a randomized phase II trial comparing inotuzumab ozogamicin plus rituximab and CVP with gemcitabine plus ritux- imab and CVP as first-line treatments in patients with DLBCL who are not suitable for anthracycline-containing chemotherapy. The primary outcome of the study is PFS.122 Other ADCs in clinical phase I or II trials in patients with NHL include polatuzumab ve- dotin, pinatuzumab vedotin, SAR3419, and SGN-CD19A.

Nivolumab has not been approved for patients with HL; however, on- going phase II trials are under way. In the CheckMate-205 study, in- vestigators will determine the best ORR of either partial remission or complete remission and the duration of response with nivolumab in patients with HL.

Two additional phase II studies, CheckMate-139 and CheckMate-140, which are recruiting patients, will evaluate nivolumab in patients with NHL. CheckMate-139 will evaluate the effectiveness of nivolumab in patients with relapsed or refractory DLBCL after failure of ASCT or failure of at least two previous che- motherapy regimens, and CheckMate-140 will evaluate the effective- ness of nivolumab in patients with relapsed or refractory follicular lymphoma.

The ORR is the primary outcome for both studies.

Pembrolizumab is another antiPD-1 monoclonal antibody. It is approved in the US for the treatment of metastatic melanoma. A phase Ib trial, KEYNOTE-013, is recruiting participants to de- termine the safety, tolerability, and efficacy of pembrolizumab in patients with several different types of hematologic malignancies, including those with HL, mediastinal large B-cell lymphoma, PD- L1&ndash;positive NHL, follicular lymphoma, and DLBCL. The main out- comes include the number of participants that experience AEs, the number of participants that discontinue treatment because of AEs, ORR, and complete remission rate.

The Dana-Farber Cancer In- stitute is conducting a phase II trial to study the clinical efficacy of pembrolizumab in patients with relapsed/refractory HL or DLBCL when provided after ASCT. Investigators will determine the PFS 18 months after ASCT as the primary outcome.

Everolimus is an mTOR inhibitor that is approved for the treat- ment of breast, pancreatic, and kidney cancers and for the treat- ment of subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Everolimus functions by binding to mTOR and preventing downstream activation of the PI3K/Akt signaling pathway, resulting in decreased tumor cell growth, an- giogenesis, and transcription.

Several clinical trials are inves- tigating everolimus in combination with other therapeutic agents in both HL and NHL. Most trials are in phase I or phase II. The first phase II trial is investigating everolimus and panobinostat, an HDAC inhibitor, in patients with relapsed/refractory DLBCL. The primary outcomes are ORR and the response rate predicted by molecular signatures developed from preclinical models.

The second phase Ib/II trial is investigating everolimus and AEB071, a protein kinase C inhibitor, in DLBCL with either the CD79 mutant or the ABC subtype. The primary outcomes are determining the dose-limiting toxicities and maximum tolerated dose.

The third phase II study, being conducted by investiga- tors at the Sidney Kimmel Comprehensive Cancer Center, will examine the combination of everolimus with rituximab as main- tenance therapy after high-dose chemotherapy in patients with B-cell lymphomas and HL. The primary outcomes are safety and tolerability.

Temsirolimus is an mTOR inhibitor that is approved for use in kidney cancer. Treatment with temsirolimus was shown to signifi- cantly improve PFS and objective response rate relative to the in- vestigator&rsquo;s choice of therapy in a phase III trial of patients with relapsed/refractory MCL.

Therefore, in a phase IV trial, investi- gators are comparing the safety and efficacy of two different doses of temsirolimus; PFS is the primary outcome of the study.

An ongoing phase III clinical trial is recruiting patients to in- vestigate the safety and efficacy of idelalisib in combination of rituximab in patients with indolent NHL who were previously treated. The primary outcome is PFS and secondary outcomes include ORR, complete response rate, OS, and lymph node re- sponse rate.

Duvelisib is an inhibitor of the delta and gamma isoforms of PI3K and, like idelalisib, has an affinity for hematologic cancer cells. Early clinical trials investigating duvelisib in patients with relapsed/refractory indolent NHL and T-cell lymphoma have shown ORRs above 50% and acceptable safety profiles, although transaminitis is a common AE.

In one phase III trial, investi- gators are comparing the efficacy of duvelisib monotherapy with ofatumumab monotherapy in patients with relapsed/refractory CLL/SLL; PFS is the primary outcome.

Another phase III trial is assessing the safety and efficacy of duvelisib in combination with rituximab versus rituximab monotherapy in patients with follicular lymphoma who are not suitable for chemotherapy. The primary outcome is PFS.

ABT-199 is a second-generation inhibitor of BCL-2, an important regulator of apoptosis. BCL-2 is an antiapoptotic protein that is overexpressed in several cancers. ABT-199 mimics the BH3 pro- tein, a ligand of BCL-2 that activates apoptosis, and thus restores death-promoting processes in tumor cells. In an ongoing phase I dose-escalation trial of patients with various types of relapsed/ refractory NHL, the ORR was near 50% and the most notable re- sponses were in patients with MCL and Waldenstr&ouml;m macroglobu- linemia. Responses were observed across a wide range of doses.

Clinical trials are evaluating the safety and efficacy of ABT-199 in combination with other therapeutic agents. An open-label, phase III, randomized study will evaluate the efficacy of ABT-199 plus rituximab and bendamustine plus rituximab in patients with relapsed/refractory CLL/SLL. The primary outcome is PFS.

A second multicenter, randomized, phase III trial will compare the safety and efficacy of ABT-199 plus obinutuzumab (an anti-CD20 antibody) with ABT-199 plus obinutuzumab and chlorambucil in patients with CLL/SLL. PFS is the primary outcome of the study.

The treatment of HL and NHL is rapidly evolving. Continual under- standing of the genetic and molecular profiles of lymphomas will promote better risk stratification and, simultaneously, enhance the development of novel, targeted agents. Several new agents have been approved in recent years and ongoing clinical trials have demonstrated promising results in both the frontline setting and in relapsed/refractory disease. The integration of these new agents into standard-of-care practices is key to improving the prognosis, clinical outcomes, and quality of life for patients.

This feature covers the "V. Emerging Therapies in Clinical Trials" and the "Conclusions" sections of the current Evolving Paradigms in Lymphoma issue.

Evolving Paradigms in Lymphoma: Emerging Therapies in Clinical Trials and Conclusions

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van Kampen RJW, Canals C, Schouten HC, et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin&rsquo;s lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry.

This feature covers the "References" section of the current Evolving Paradigms in Lymphoma issue.

Lymphoma

Evolving Paradigms in Lymphoma: Overview, Epidemiology, Detection, Diagnosis, and Staging

Evolving Paradigms in Lymphoma: Risk Stratification, Prognosis, and Current Treatment Strategies

Evolving Paradigms in Lymphoma: Emerging Therapies in Clinical Trials and Conclusions

Evolving Paradigms in Lymphoma: References