Non-Hodgkin Lymphoma, Adult
The term lymphoma describes a heterogenous group of malignancies with different biology and prognosis. In general lymphomas are divided into 2 large groups of neoplasms, namely non-Hodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is the sixth decade of life, with some exceptions. (Burkitt lymphoma and lymphoblastic lymphoma occur in younger patients.) NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.
Currently, several NHL classification schemas exist, reflecting the growing understanding of the complex diversity of the NHL subtypes. The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade). In the 1990s, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. The World Health Organization (WHO) classification further elaborates upon the REAL approach. This classification divides NHL into those of B-cell origin and those of T-cell and NK-cell origin.
For clinical oncologists, the most practical way of sorting the currently recognized types of NHL is according to their predicted clinical behavior; each classification schema contributes to a greater understanding of the disease, which dictates prognosis and treatment.
NHLs are tumors originating from lymphoid tissues, mainly of lymph nodes. Various neoplastic tumor cell lines correspond to each of the cellular components of antigen-stimulated lymphoid follicles. NHL represents a progressive clonal expansion of B cells or T cells and/or natural killer (NK) cells arising from the accumulation of genetic lesions that affect proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. These oncogenes can be activated by chromosomal translocations (ie, the genetic hallmark of lymphoid malignancies), or tumor suppressor loci can be inactivated by chromosomal deletion or mutation. In addition, the genome of certain lymphoma subtypes can be altered with the introduction of exogenous genes by various oncogenic viruses. Several cytogenetic lesions are associated with specific NHLs, reflecting the presence of specific markers of diagnostic significance in subclassifying various NHL subtypes.
Most NHLs are of B-cell origin (almost 85%); only 15% are derived from T/NK cells, and the small remainder stem from macrophages. These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histologic pattern of growth. For many of the B-cell NHL subtypes, the pattern of growth and cell size may be important determinants of tumor aggressiveness. Tumors that grow in a nodular pattern, which vaguely recapitulate normal B-cell lymphoid follicular structures, are generally less aggressive than lymphomas that proliferate in a diffuse pattern. Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness. However, some subtypes of high-grade lymphomas are characterized by small cell morphology.
Treatment Medical Care
The treatment of non-Hodgkin lymphomas (NHLs) varies greatly depending on tumor stage, phenotype (B-, T- or NK/null-cell), histology (ie, whether low-, intermediate-, or high-grade), symptoms, performance status, patient's age, and comorbidities.
Follicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal).
Indolent stage I and contiguous stage II NHL
Standard management consists of radiotherapy alone. Forty percent of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe.1 No randomized study has shown combined chemotherapy and radiation to be better than radiation alone. Radiation therapy (2500-4000 cGy) produces a 10-year failure-free survival (FFS) rate of 50-60%, with an overall survival (OS) rate of 60-80%. Offering adjuvant chemotherapy to selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in asymptomatic patients has not been shown to improve survival.
Indolent noncontiguous stage II, III, and IV NHL
The treatment of indolent B-cell lymphomas continues to evolve as newer therapies are becoming available with potent antitumor activity and limited toxicity. Monoclonal antibodies are changing the treatment paradigm of patients with B-cell lymphomas. However, controversies persist regarding the best treatment strategy and also the best time to initiate treatment.
The disease course of indolent lymphomas is characterized by a continuous decrease in the quality and the duration of response with each subsequent treatment or treatments. This effect is primarily due to the acquisition of chemotherapy resistance. Advanced indolent lymphomas have been accepted to be not curable with currently available therapies. However, sustained complete remissions can be achieved with various treatment modalities. Recently the use of rituximab, a monoclonal antibody targeting CD20 antigen present in benign and malignant B-cells, in combination with systemic chemotherapy has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas when compared to chemotherapy. Prospective studies and 2 metaanalyses suggest that the rituximab-chemotherapy, also known as chemo-immunotherapy, may be changing the natural progression of indolent lymphomas.
Asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. Early intervention in asymptomatic patients does not appear to prolong survival. The median time to progression is 4-6 years, and OS is 6-10 years.
The treatment of symptomatic patients with indolent lymphomas should be focussed on achieving the best possible quality of response without producing excessive toxicity. Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. However, only a few achieve remission; most achieve palliation.
Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin-vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and fludarabine alone or in combination (cyclophosphamide, mitoxantrone). Combination agents are useful in bulky and rapidly progressive disease and have increased response rates as compared to single agents, but there is no improvement in overall survival.
Recently, longer duration of remission, with more patients achieving a complete response and/or complete molecular response, has become possible with newer biological agents like rituximab. Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy.2 When used in combination with chemotherapy, rituximab has shown higher response rates, longer time to progression and longer survival than chemotherapy. Randomized trials have shown better responses when rituximab was combined with chemotherapy regimens (CHOP, CVP). Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of high tumor burden.
Bone marrow transplant may have a role in patients with relapsed high-risk disease. Allogenic transplant has lower relapse rates but an increase in transplant-related mortality as compared to autologous transplant. The precise role of transplantation in indolent lymphomas is still being investigated.
Diffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas (high-grade lymphomas). Mantle-cell lymphomas also behave aggressively.
Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHL
Based on 2 large randomized trials (ie, Southwest Oncology Group [SWOG], Eastern Cooperative Oncology Group [ECOG]), the preferred treatment option for patients with intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field radiation therapy. According to SWOG data, patients who are treated with chemotherapy and involved-field radiation therapy have significantly better progression-free survival rates (ie, 77% versus 66%) and 5-year OS rates (ie, 82% versus 72%) compared to patients surviving 8 cycles of chemotherapy (ie, CHOP) alone. Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP.
Aggressive noncontiguous stage II, III, and IV NHL
Approximately 40-50% are cured with standard therapy, approximately 35-40% will respond but ultimately progress or relapse and the remainder will be primarily refractory. Scoring systems such the IPI score have been developed and validated to estimate the response rate or survival rate of a given patient with aggressive lymphomas (see Prognosis).
For many years, the treatment of aggressive lymphomas consisted of chemotherapy regimens using multiple drugs. Initial clinical studies were focused on investigating the use of more toxic regimens (higher doses or more drugs). A prospective randomized trial of 4 regimens (ie,  CHOP versus  prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide [ProMACE]–cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone [CytaBOM] versus  methotrexate, bleomycin, Adriamycin, cyclophosphamide, Oncovin, and dexamethasone [m-BACOD] versus  methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin [MACOP-B]) for patients with diffuse large cell lymphoma showed no difference in response rate (RR), OS, or time to treatment failure (TTF) at 3 years. The other 3 regimens were more toxic than CHOP therapy. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in some subtypes of NHL such as primary mediastinal large B-cell NHL.
After more than 2 decades of scientific investigations, the treatment of aggressive lymphomas switched by the clinical development of rituximab. Currently, 6-8 cycles of CHOP chemotherapy in combination with rituximab is the standard of care in patients with advanced disease.
The GELA (Groupe d'Etude des Lymphomas de a'Adulte) study was the first phase III trial to investigate the efficacy of combining rituximab with standard doses of CHOP chemotherapy for elderly (those older than 60 y) patients with diffuse large B-cell lymphoma. In this landmark study, patients were randomized to receive either CHOP plus rituximab or CHOP alone. At 5-year follow-up, rituximab and CHOP improved OS from 46% to 58% compared with CHOP alone. The results of this study were further validated by other international randomized studies favoring the use of rituximab and chemotherapy in elderly patients with aggressive B-cell lymphomas.
Similar results were observed in younger patients, where the combination of rituximab and CHOP chemotherapy resulted in an improved survival. A large international study, the MabThera International Trial (MINT) addressed the role of rituximab-chemotherapy in young patients with aggressive B-cell lymphomas. The study, which has been presented only in an abstract form, was a phase III trial in which 823 diffuse large B-cell, CD20+, non-Hodgkin lymphoma (DLBCL) patients (ages 18-60 y) were randomized to receive either rituximab plus a standard anthracycline-containing chemotherapy regimen (standard chemotherapy) or standard chemotherapy alone as induction therapy. The rituximab plus standard chemotherapy regimens increased 2-year overall survival (OS) from 86% to 95% compared with standard chemotherapy alone and resulted in significant improvement in time to treatment failure and projected overall survival.
Ongoing research is being focused on identifying patients at risk for treatment failure and developing tailored treatment for patients with aggressive lymphoma based on clinical scores (IPI score) or gene profiles.
Patients at high risk of relapse (IPI intermediate or poor risk groups) might have an improved 5-year event-free survival/overall survival from autologous and allogeneic bone marrow or peripheral stem cell transplantation following chemotherapy.
CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial.
PET scanning is more sensitive than CT scan or gallium scan for staging and response assessment. Early PET negativity with 2-4 cycles correlates with durable remission and vice versa. After remission is achieved, patients are monitored with CT scans every 6 months for the first 2-3 years, as most recurrences occur in the first 3 years.
Treatment of acute lymphoblastic lymphoma, a very aggressive form of NHL, is usually patterned after acute lymphoblastic leukemia (ALL) therapy. Other subtypes of high-grade lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, including the addition of high-dose methotrexate or other chemotherapy drugs and higher doses of cyclophosphamide.