Lymphoma

The incidence rates of non-Hodgkin lymphoma (NHL) in the United States have almost doubled between 1970 and 1990, representing one of the largest increases of any cancer. Although the overall incidence rates of NHL began to stabilize in the late 1990s, the temporal trends varied by histologic subtype. Some of this increase may be artifactual, resulting from improved diagnostic techniques and access to medical care, or directly related to the development of NHL in 25- to 54-year-old men with human immunodeficiency virus (HIV) infection. However, additional factors must be responsible for this unexpected increase in frequency of NHL that has been observed throughout the United States.

In 2009 approximately 8,510 new cases of Hodgkin lymphoma (HL) will be diagnosed in the United States. Over the past 4 decades, advances in radiation therapy and the advent of combination chemotherapy have tripled the cure rate of patients with HL. In 2009, more than 80% of all newly diagnosed patients can expect a normal, disease-free life span.

Induction therapy with higher daily doses of daunorubicin improved complete response and boosted overall survival in younger patients with acute myelogenous leukemia, according to results of the phase III ECOG E1900 trial.

No branch of oncology has been more attuned to the vision of new genetically engineered targeted therapies than the field of hematopoietic malignancies. Ujjani and Cheson have produced a masterful summary of one extremely important component of the targeted therapy revolution-the realm of monoclonal antibodies directed against malignant lymphoma surface antigens.[1] The review presents a wonderful update and a glimpse of future potentially curative macromolecular cocktails. It is an attractive vision.

he treatment of B-cell malignancies has been revolutionized by the availability of safe and effective monoclonal antibodies. The addition of rituximab to standard chemotherapy regimens prolongs the survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular non-Hodgkin lymphoma. Nevertheless, indolent and mantle cell lymphomas remain incurable, and 30% to 40% of patients with DLBCL still die from their disease. Much ongoing research has focused on optimizing monoclonal antibody use, integrating them into multiagent regimens, and developing newer antibodies. Attempts to improve on the efficacy of monoclonal antibody–based therapy have included altering the dosing schedule, optimizing patient selection, maintenance therapy, improving upon the rituximab molecule, radioimmunotherapy, as well as combinations with cytotoxic molecules and other novel agents. Preliminary data with a number of treatment regimens are promising in indolent and aggressive lymphomas. The eventual goal of targeted therapies is to individualize treatment to increase response and survival, while reducing treatment-related toxicity.

In this review, Ujjani and Cheson present a useful overview of the array of existing and developing roles for monoclonal antibodies in the management of B-cell non-Hodgkin lymphomas (NHLs). These roles may be characterized as single-agent antibody therapy, use in combination with chemotherapy and/or other antibodies, and use following an initial regimen (consolidation/maintenance). Rituximab (Rituxan), the first monoclonal antibody approved for B-cell NHL, clearly has had greatest application in each of these arenas, but it has now been joined by alemtuzumab (Campath) and ofatumumab (Arzerra) as approved single-agent therapies. Also highlighted are a number of other antibodies aimed at B-cell targets: veltuzumab, GA101, AME-133 (CD20), epratuzumab (CD22), lumiliximab (CD23), galiximab (CD80), dacetuzumab (CD40), mapatumumab, lexatumumab (TRAIL), and approaches to improve antibody therapy such as conjugation with radioisotopes or toxins.

Peripheral T-cell lymphomas (PTCLs) are uncommonly encountered malignancies in the United States, and hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and enteropathy-type T-cell lymphoma (ETTCL) are rare subtypes of PTCLs that often present with primarily extranodal disease. Despite the fact that these tumors have distinct clinical and pathologic features, they are often diagnosed after significant delay. The combination of delay in diagnosis with ineffective therapies has resulted in a poor prognosis in most cases. Techniques that identify T-cell receptor gene rearrangements and flow cytometry that can identify characteristic immunophenotypes have guided our understanding of the underlying cell of origin of these rare PTCLs. As knowledge regarding the biology of these lymphomas increases alongside the development of newer therapeutics with novel mechanisms, clinicians must accordingly improve their familiarity with the clinical settings in which these rare malignancies arise as well as the pathologic features that make them unique

In this issue of ONCOLOGY, Dr. Tobinai presents a thorough and thoughtful review of the current state of the art of HTLV-related adult T-cell leukemia/lymphoma (ATLL). As described, ATLL is most prevalent in Asia, where it has also been most studied, but is also seen in patients from other HTLV-endemic areas including the Caribbean, South America, and parts of Africa. ATLL is rare in North America and Europe, representing 1% to 2% of T-cell lymphomas compared to 25% in Asia.[1]

In this issue of ONCOLOGY, Tobinai reviews the management of human T-cell lymphotropic virus type 1 (HTLV-1)–associated adult T-cell leukemia/lymphoma (ATL). Although rare in the United States, an estimated 10 to 20 million people are infected with HTLV-1 worldwide and 2% to 5% will develop ATL.[1]

Adult T-cell leukemia/lymphoma (ATL) is defined as a histologically or cytologically proven peripheral T-cell malignancy associated with a retrovirus, human T-cell lymphotropic virus type I (HTLV-1).[1] Southwestern Japan is the district with the highest prevalence of HTLV-1 infection and the highest incidence of ATL in the world. A high prevalence of HTLV-1 infection is also found in the Caribbean islands, tropical Africa, South America, and northern Oceania.

The purpose of this review is to familiarize oncologists with the clinical and pathologic features of this relatively rare disease spectrum. This should enable appropriate clinical management and reassurance of patients concerned about their prognosis.

Researchers are exploring ways to manipulate rituximab (Rituxan) when added to the current standard therapy for diffuse large B-cell lymphoma, specifically shortening the number of treatment days. Preliminary results of a phase III trial showed that rituximab plus CHOP over a 14-day cycle achieved similar response rates and comparable toxicity compared to CHOP on a 21-day cycle in newly diagnosed patients.

Lymphoblastic lymphoma (LBL) is a rare disease, comprising about 2% of all non-Hodgkin lymphomas (NHLs) in adults.[1] It is a highly aggressive subtype of lymphoma, most commonly of precursor T-cell origin, occurring most frequently in adolescents and young adults, with male predominance and frequent mediastinal, bone marrow, and central nervous system (CNS) involvement.

Lymphoblastic lymphoma (LBL) is a rare disease, most commonly of T-cell origin, that shares biologic features with acute lymphoblastic leukemia (ALL). Indeed, LBL and ALL are considered a single entity (lymphoblastic leukemia/lymphoma, T and B types) in the World Health Organization (WHO) classification of precursor lymphoid neoplasms.

After almost a decade of research and two trials of a follicular lymphoma vaccine with negative results, a study of a personalized idiotype vaccine has achieved positive results. BiovaxID prolonged median disease-free survival by more than a year in a subset of patients who maintained complete remission after one year of chemotherapy and then received the vaccine.

A large, population-based study of the association between venous thromboembolism and mortality in hematologic malignancies found an increased risk of death in patients with acute lymphoblastic leukemia, but not in those with acute myelogenous leukemia. The authors had no explanation for the differential association between the two types of acute leukemia.

In their Areas of Confusion article, “Management of Relapsed Mantle Cell Lymphoma: Still a Treatment Challenge,” Ruan et al attempt to make the case that the relative merits of different upfront approaches for mantle cell lymphoma (MCL) are difficult to appreciate due to the differences in eligible patient populations and limited randomized data.

Dr. Ruan and colleagues provide an excellent summary of available treatment options, as well as new drugs on the horizon, for the management of relapsed mantle cell lymphoma (MCL). As the authors emphasize, treatment of relapsed MCL is strongly influenced by the patient’s first-line therapy and needs to be individualized based on both patient and disease characteristics.

Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma that occurs most commonly in older patients with advanced-stage disease.

On August 22, 2008, the US Food and Drug Administration (FDA) granted marketing approval (licensure) to romiplostim (Nplate, Amgen Inc) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

An 8-year randomized, controlled phase III clinical study has shown that a patient-specific therapeutic vaccine, BiovaxID, significantly prolongs disease-free survival in follicular non-Hodgkin’s lymphoma. The study, featured in ASCO’s plenary session, found that patients who received the vaccine experienced a median disease-free survival of approximately 44 months compared to approximately 30 months for those who received a control vaccine-an increase of 47% (abstract P2).

The addition of rituximab (Rituxan) to systemic chemotherapy has improved the response rates, progression-free survival, and overall survival of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) compared to chemotherapy alone. In the front-line setting, the use of rituximab is changing the biology and clinical behavior in DLBCL patients who fail to respond or relapse following chemoimmunotherapy.

Chemoimmunotherapy has been the most significant step in recent years to improving overall survival (OS) and progression-free survival (PFS) rates in patients with diffuse large B-cell lymphoma ­(DLBCL).[1] Despite this major therapeutic advance, a significant proportion of patients will relapse or remain refractory to initial chemoimmunotherapy. The pivotal PARMA trial confirmed the place of high-dose chemotherapy and autologous stem cell transplant (ASCT) as the optimum salvage treatment.

Drs. Hernandez-Ilizaliturri and Czuczman should be complimented on their comprehensive review of management options for patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL).

According to published statistics, in 2008 approximately 66,120 new cases of non-Hodgkin lymphoma (NHL) were diagnosed and 19,160 lymphoma patients died from their disease despite currently available treatment.[1] Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell NHL, has an aggressive clinical course and, as demonstrated by gene-profiling studies, can be further divided into subgroups with distinct biologic characteristics and prognoses.[2]

Sargramostim (Leukine) paired with a patient-specific immunotherapy mitumprotimut-T (Specifid), failed to reduce time to remission in patients with CD20+ follicular lymphoma following therapy with rituximab (Rituxan), according to the highly anticipated results of a phase III clinical trial.

Cephalon, Inc, announced that the US Food and Drug Administration (FDA) has approved injectable bendamustine hydrochloride (Treanda) for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab (Rituxan) or a rituximab-containing regimen. The data supporting the FDA approval show that bendamustine is effective, has a tolerable side effect profile in patients with indolent NHL, and that treatment results in a high durable response rate. In March of this year, bendamustine received approval for the treatment of patients with chronic lymphocytic leukemia, the most common form of leukemia in the United States.

Results of the first clinical study examining the use of fostamatinib disodium, an investigational treatment that targets a protein called SYK (spleen tyrosine kinase), showed that the new agent represents a safe and novel therapeutic approach that should be further developed for the treatment of B-cell non-Hodgkin lymphoma.

The results of an international randomized trial found that the use of dexamethasone in the induction phase of combination chemotherapy led to a one-third reduction in the risk of relapse as compared with the standard corticosteroid, prednisone, translating into a significant benefit in terms of event-free survival in children with acute lymphoblastic leukemia.

Burkitt lymphoma (BL) is a unique B-cell lymphoma characterized by a high proliferation rate and cytogenetic changes related to c-myc proto-oncogene overexpression. Burkitt lymphoma is a highly aggressive B-cell lymphoma that is most frequently seen in children and young adults in endemic areas.