Diffuse Large Cell Lymphoma 

The non-Hodgkin lymphomas (NHLs) constitute a heterogeneous group of lymphoid system neoplasms with varying presentation, natural history, and response to therapy.

Under the International Working Formulation in the classification of intermediate-grade diffuse large cell lymphomas (DLCLs), approximately 79% of DLCLs were of B-cell origin, 16% of T-cell origin, and 5% were unclassifiable. Exceptional cases expressed both B-cell and T-cell markers.

Incorporation of the Revised European-American Lymphoma (REAL) classification system for lymphomas has been strongly encouraged. In addition to morphologic descriptions, this schema includes immunologic, cytogenetic, and molecular information in order to define distinct lymphoma entities. Currently, the diffuse large B-cell lymphomas are considered in the REAL classification as the classic diffuse large cell lymphoma (DLCL) of B-cell origin defined by the working formulation. Lymphomas of T-cell or NK-cell origin exhibit biologic and clinical features distinct from diffuse large B-cell lymphomas.

The diffuse large cell lymphoma (DLCL) of the REAL classification combines the large cell and the immunoblastic categories of the working formulation. These lymphomas are currently considered a single group, because they behave similarly and, therefore, have similar prognoses. Diffuse large cell lymphoma (DLCL) is the most common lymphoma, representing 31% of NHLs, and it is rapidly fatal if untreated.

Historical classification of NHLs

Since the late 20th century, considerable progress has been made in NHL classification.^[1] In 1982, the National Cancer Institute introduced the International Working Formulation, a translation system for other older classifications, including the Rappaport and the immunologically oriented Lukes-Collins and Kiel systems. The working formulation provided a conceptual framework that groups lymphomas as low grade (indolent), intermediate grade, or high grade with respect to their natural histories.

In 1994, the International Lymphoma Study Group proposed the REAL classification schema. It classifies NHLs as being derived from B or T/NK-cells, and it includes new disease entities that were not part of the working formulation.

See Staging.

Below are histologic and radiologic images, respectively, of diffuse large cell lymphoma (DLCL).

Go to Non-Hodgkin Lymphoma for complete information on this topic.

Non-Hodgkin lymphomas (NHLs) have been associated with the following conditions:

• Hereditary immunodeficiency disorders such as ataxia-telangiectasia syndrome, Bruton-type agammaglobulinemia, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, Duncan syndrome, and Chediak-Higashi syndrome
• Infections such as with human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), Helicobacter pylori, hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), and human herpes viruses (HHVs)^[2]
• Autoimmune disorders such as rheumatoid arthritis, Sjögren syndrome, and systemic lupu s erythematosus
• Use of drugs such as immunosuppressants and chemotherapeutic agents^[2]
• Exposure to environmental toxins such as herbicides, vinyl chloride, and organic solvents^{[2, 3]}

B-cell restricted markers (CD19, CD20, CD22) are expressed consistently in diffuse large cell lymphoma (DLCL). Activation antigens are variably expressed by B-cell DLCLs, with human leukocyte antigen (HLA)-DR being the most frequent and CD23 being expressed uncommonly (0-25%). The presence of CD10 or CD5 suggests that at least one third of diffuse large cell lymphomas (DLCLs) may have transformed from follicular lymphomas or a small lymphocytic lymphoma.

The majority of B-cell diffuse large cell lymphomas (DLCLs) demonstrate rearrangements of the immunoglobulin genes by DNA hybridization techniques, proving their B-cell lineage.

Mutations or allelic losses of the TP53 tumor suppressor gene or 17p13.1 are common in diffuse large cell lymphomas (DLCLs), particularly in the immunoblastic type. Changes of TP53 appear especially involved in the evolution of follicular lymphoma to diffuse large cell lymphoma (DLCL).^[4] A number of cytogenetic abnormalities have been reported in these neoplasms, including t(14;18), t(8;14), trisomy 12, and deletion of 6q.^[5]

A study by Pasqualucci et al describes somatic mutations in diffuse large cell lymphoma (DLCL). Their findings suggest that chromatin-modifying agents may be effective treatments.^[6]

Alizadeh et al conclude that the measurement of LMO2 and TNFRSF9 can be used to predict overall survival in patients with diffuse large cell lymphomas (DLCLs).^[7]

The incidence of non-Hodgkin lymphoma (NHL) has been increasing more rapidly than many other malignancies. Overall, the incidence has increased more than 73% between 1973 and 1991. The current US age-adjusted rate is 15.1 cases per 100,000 person-years for both sexes. The estimated rate for diffuse large cell lymphomas (DLCLs) is approximately 4.68 cases per 100,000 person-years.

In general, the age-adjusted incidence of diffuse large cell lymphomas (DLCLs) is higher in developed countries. For men, it varies from 3.7 to 14 cases per 100,000 persons per year from 1983 to 1987. Over the past 2 decades, rates for both men and women have increased by 50% or more in 20 different countries. The rates by subtype, such as Burkitt lymphoma (Epstein-Barr virus [EBV]–associated) and human T-cell leukemia virus (HTLV) type 1–related lymphoma/leukemia, also vary widely in different geographic areas and are much more frequent in endemic areas.

White individuals have higher rates than people of African or Asian descent^[8] ; the Surveillance, Epidemiology, and End Results registry demonstrates rates in white men that are 49% higher than in black men, 54% higher than in Japanese American men, and 27% higher than in Chinese American men.^[9] These differences also apply to women, although there is a slight male disease preponderance, with a male-to-female disease incidence ratio of 1.3:1.

Although diffuse large cell lymphomas (DLCLs) can occur at any age, in general, they occur in middle-aged and older adults.

The clinical manifestations of diffuse large cell lymphomas (DLCLs) are diverse and depend on the site of disease involvement. These tumors have a rapid growth rate and present as masses, causing symptoms when they infiltrate tissues or obstruct organs. Pain in an enlarged lymph node or organ may be noted if the lymphomatous mass enlarges rapidly.

As with other types of non-Hodgkin lymphoma (NHL), diffuse large cell lymphomas (DLCLs) can present with B symptoms, including fever, drenching night sweats, and weight loss. Generalized pruritus may also be present.

On physical examination, keep in mind that, most frequently, diffuse large cell lymphomas (DLCLs) appear in lymphoreticuloendothelial tissues, which include the lymph nodes, spleen, liver, and bone marrow. However, any extranodal site may be primarily or secondarily involved, including the central nervous system (CNS), lungs, gastrointestinal tract, genitourinary tract, and the bones.

Involvement of sanctuary sites, including the CNS and testicles, is more frequently associated with Burkitt and non-Burkitt lymphoma, human immunodeficiency virus (HIV)–associated lymphoma, human T-cell leukemia virus (HTLV) type 1–associated lymphoma, primary CNS lymphoma, and primary testicular diffuse large cell lymphoma (DLCL).

Involvement of the cerebrospinal fluid (CSF) with diffuse large cell lymphoma (DLCL) is observed more frequently with advanced-stage disease and bone marrow involvement.

The Ann Arbor staging system, originally designed for Hodgkin disease, is traditionally used to assess the extent of disease involvement by non-Hodgkin lymphoma (NHL), as follows:

• Stage I is disease involvement of a single lymph node region or of a single extranodal organ or site (I E).
• Stage II is involvement of 2 or more lymph node regions on the same side of the diaphragm or localized involvement of an extranodal site or organ (II E) and involvement of 1 or more lymph node region on the same side of the diaphragm.
• Stage III is involvement of lymph node regions on both sides of the diaphragm, which may be accompanied by localized involvement of an extranodal organ or site (III E), the spleen (III S), or both (III SE).
• Stage IV is diffuse or disseminated involvement of 1 or more distant extranodal organ, with or without associated lymph node involvement.

The presence of systemic symptoms, including fever higher than 38°C, night sweats, and/or weight loss of more than 10% of body weight in the 6 months preceding diagnosis, are denoted by the suffix B. Staging of asymptomatic patients is denoted by the suffix A.

Benign Inoculation Lymphoreticulosis should be considered in the differential diagnosis of diffuse large cell lymphomas (DLCLs), as well as the following conditions:

• Lymphoma, Diffuse Mixed
• Lymphoma, Follicular
• Lymphoma, Lymphoblastic
• Lymphoma, Malignant Anaplastic (Ki 1+)
• Lymphoma, Mantle Cell
• Lymphoma, Mediastinal
• Lymphoma, Non-Hodgkin
• Lymphomatoid Granulomatosis

After histology and immunology confirm the diagnosis of diffuse large cell lymphoma (DLCL), a pretreatment staging evaluation should be performed. At minimum, patients should have routine blood counts and blood chemistries, particularly a lactate dehydrogenase (LDH) level, which is a prognostic parameter.

Note that tumor lysis syndrome manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium; this can lead to a sudden death from electrolyte abnormalities.

Carefully examine the peripheral blood smear for any abnormal lymphoid cells.

Radiologic staging studies include chest radiography and computed tomography (CT) scanning of the chest, abdomen, and pelvis. Bone scans, gallium scans, positron emission tomography (PET) scans, and plain films, may be helpful in selected patients.

Gastrointestinal imaging

Upper and lower gastrointestinal series, in conjunction with appropriate endoscopic studies, are indicated in patients with gastrointestinal symptoms, but these studies need not be performed routinely in asymptomatic patients.

CNS imaging

Patients with central nervous system (CNS) symptoms require brain evaluation by CT scan with contrast (see the image below) or magnetic resonance imaging (MRI) with gadolinium. Based on the findings of these studies, examination of the cerebrospinal fluid (CSF) for malignant cells may be indicated.

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Bone imaging

Patients with unexplained bone pain or elevated alkaline phosphatase levels should be evaluated with a bone scan. Obtain plain radiographs of any abnormal area on the bone scan to check for lymphomatous involvement of the skeleton.

Imaging for disease staging and activity

Gallium-67 (⁶⁷ Ga) scans are valuable in the staging of diffuse large cell lymphomas (DLCLs). Gallium uptake correlates with disease activity and is useful as an indicator of response and prognosis. Uptake of⁶⁷ Ga occurs in approximately 50% of indolent lymphomas and in most aggressive and highly aggressive types.

Positron emission tomography (PET) scans increasingly are being used to stage disease by using fructose diphosphate glucose (FDG) as a measure of disease metabolic activity.^[10] PET scanning may be more sensitive than gallium scans for more indolent lymphoproliferative diseases, but definitive data comparing gallium to PET scanning in lymphomas are not available.

An excisional lymph node biopsy should be performed for the diagnosis of diffuse large cell lymphoma (DLCL) (see image below), and bilateral iliac crest bone marrow biopsies should be performed as a part of the staging.

Because bone marrow involvement increases the likelihood of lymphomatous involvement of the meninges, in patients with advanced stage disease, a lumbar puncture for cytologic and chemical analysis of the cerebrospinal fluid (CSF) may be necessary.

Therapy for aggressive non-Hodgkin lymphoma (NHL) has evolved significantly in the last 30 years. Chemotherapy is usually given on an outpatient basis, patients should be admitted to the hospital if a treatment complication arises. Transfer to an appropriate facility may be necessary for further diagnostic evaluation and medical or surgical interventions.

In general, the role of surgery in diffuse large cell lymphomas (DLCLs) is limited. Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy. However, surgery can be helpful in obtaining tissue for diagnosis or, rarely, to palliate a complication. A study by Kim et al determined that although the quality of life (QOL) of patients with intestinal diffuse large B-cell lymphoma who underwent surgery and chemotherapy was lower than chemotherapy alone, its difference was acceptable.^[11] Thus, surgical resection followed by chemotherapy may be an effective treatment strategy for these patients.

The cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP) regimen was among the first combinations to produce complete response (CR) rates and long-term survivors.

New treatments to increase complete responses have shown improvement in survival. For patients with advanced diffuse large cell lymphoma (DLCL), another standard therapy exists: the addition of a monoclonal antibody against CD20 (rituximab) to CHOP. In addition, high-dose chemotherapy in the setting of stem cell/bone marrow transplantation has become a useful treatment modality in the management of this disease.

In a study of 435 patients with diffuse large cell lymphoma (DLCL), Villa et al found that the risk of central nervous system (CNS) relapse was significantly reduced with the addition of rituximab to the CHOP regimen compared with that of patients treated with CHOP alone.^[12] This reduction even more evident in patients who achieved a complete response.

A study by Phan et al found that overall survival and progression-free survival was significantly improved among patients who received consolidation radiation therapy after undergoing rituximab plus CHOP (R-CHOP) therapy.^[13]

At relapse, cell of origin appears to have a better response to rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) than to rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in patients with germinal center B (GCB)-like diffuse large B-cell lymphoma.^[14] This needs confirmation in a prospective study.

A study of 215 patients treated with R-CHOP revealed improved event-free survival (EFS) in patients treated with epratuzumab plus R-CHOP (ER-CHOP). ER-CHOP is well tolerated, and these results suggest combination therapy is promising.^[15]

Récher et al compared the addition of rituximab to a regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with R-CHOP and found significant improvement in survival among patients with diffuse large B-cell lymphoma with low-intermediate risk aged 18-59 years on the R-ACVBP regimen.^[16]

Consultations

A surgical oncologist may be consulted if an open biopsy is needed for the diagnosis or to treat a complication such as perforated viscus.

A radiation oncologist may be consulted if the primary therapy involves a combination of chemotherapy and radiotherapy. In addition, an initial large lymphoma mass or a large residual mass following completion of chemotherapy may be considered for involved field radiotherapy (IFRT).

Diet and activity

No specific diet is recommended for patients with diffuse large cell lymphoma (DLCL) except a salt restriction when steroids are administered as part of the chemotherapy regimen.

Patients undergoing cytotoxic chemotherapy may develop severe neutropenia, as defined by an absolute neutrophil count of less than 500/µL. These patients should be advised to maintain a low microbial diet for the expected duration of neutropenia.

No specific limitation of activity is necessary unless the patient is thrombocytopenic, in which case activity restriction may be necessary to avoid traumatic bleeding or bruising.

Current data suggest that either 6 cycles of a regimen of cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP) or 3-4 cycles of CHOP followed by involved-field radiation therapy (IFRT) is reasonable treatment of early-stage, nonbulky, diffuse large cell lymphoma (DLCL) (stage IA and IIA, nonbulky). The best approach to early-stage disease remains to be defined.

In patients treated with IFRT alone, relapses occur in nodal sites within and outside the irradiated field. In addition, relapses in the bone marrow and other parenchymal organs suggest the presence of microscopic disease in these organs at the time of diagnosis. As a result, radiation therapy as the sole treatment of early-stage disease has been abandoned. Treatment with either chemotherapy alone or a combination of chemotherapy and IFRT is considered the standard of care.

When the CHOP regimen was established as effective therapy for advanced-stage disease, some pursued the use of this regimen for early-stage disease. Connors and associates conducted a prospective study employing 3 cycles of CHOP followed by IFRT in 78 patients, in which approximately 99% of these patients achieved a complete response, and 86% remained free of disease with a median follow-up of 30 months.^[17] The actuarial survival rate for the entire group was 84%. Tordini and colleagues reported similar results in a large series of patients.

The Southwest Oncology Group (SWOG) conducted a randomized trial in patients with localized intermediate-grade or high-grade non-Hodgkin lymphoma (NHL) and determined that 3 cycles of CHOP followed by IFRT was more effective and less toxic than 8 cycles of CHOP for early-stage diffuse large cell lymphoma (DLCL).^[18] The investigators compared the 2 curative approaches with respect to differences in survival, time to treatment failure, and toxicity. The 5-year estimated overall survival rates were 74% for CHOP (8 cycles) and 82% for CHOP (3 cycles) plus radiation.^[18] Progression-free survival also was significantly different in the 2 groups (67% for CHOP and 76% for the combination).

The CHOP regimen given for 6-8 cycles remains the standard treatment of diffuse large cell lymphoma (DLCLs). More complicated regimens generally fail to improve overall survival. Miller et al found that the combination regimen was also superior to the CHOP-alone regimen in treating localized intermediate- and high-grade non-Hodgkin's lymphoma.^[19]

See Prognostic factors of early stage DLCL (stage IA and IIA, nonbulky) under Prognosis and Prognostic Factors.

The cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP) regimen reportedly produces a complete response (CR) rate of 45-62% in aggressive lymphomas. With up to 14 years of follow-up, CHOP was found to be curative to 32% of patients with advanced diffuse large cell lymphoma (DLCL) (stages II bulky, III, and IV).

New and more complex regimens, such as M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, leucovorin), PROMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, leucovorin), and PROMACE-CYTABOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin), were developed in the 1970s and 1980s and are referred to as second-generation and third-generation regimens. Initial reports of single-institution pilot studies with third-generation regimens suggest 68-86% complete response rates and 58-69% survival rates. The survival rates decreased with longer follow-ups.

Conclusions about the efficacy of the new regimens awaited results of prospective randomized trials. The Southwest Oncology Group (SWOG) conducted a randomized trial comparing standard CHOP to M-BACOD, PROMACE-CYTABOM, or MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone) and found no difference in response rate, time to treatment failure, or overall survival among the groups after 6 years.^[20] However, the cost and toxicity of the new regimens were higher.^[20] Thus, CHOP remains the best available standard of care for most subtypes of diffuse large cell lymphoma (DLCL). However, the newer-generation regimens have demonstrated benefit in selected subgroups of patients with diffuse large cell lymphoma (DLCL).^[21]

Because CHOP cures less then 50% of patients with diffuse large cell lymphoma (DLCL), new treatments are needed. Investigations to improve treatment outcome include the following 3 goals:

• Identification of new active therapies: Rituximab (Rituxan), a chimeric antibody that targets CD20⁺ B cells, produces a 48% response rate in patients with low-grade lymphomas.^[22] It also has activity in diffuse large cell lymphoma (DLCL). A phase II pilot study of rituximab in combination with CHOP in patients with previously untreated DLCL or high-grade non-Hodgkin lymphoma (NHL) reported an overall response rate of 97% (32/33), with a 61% complete remission rate, a 36% partial remission rate, and a 3% progressive disease rate.^[23] Severe adverse events were similar to those observed with CHOP alone. These results are encouraging, and randomized studies currently are under way to determine if the addition of rituximab to standard chemotherapy should be considered the standard of care.
• Intensification of current drugs with colony-stimulating factor support: The SWOG is undertaking a randomized phase II study of dose-intensified CHOP with growth factor support.
• Risk stratification: The use of prognostic factors can help identify patients with a high risk of relapse who will benefit from more aggressive therapy, such as high-dose chemotherapy with bone marrow or peripheral stem cell transplantation.^[24]

The CHOP regimen given for 6-8 cycles remains the standard treatment of diffuse large cell lymphoma (DLCLs). More complicated regimens generally fail to improve overall survival. Miller et al found that the combination regimen was superior to the CHOP-alone regimen in treating localized intermediate- and high-grade non-Hodgkin lymphoma.^[19]

Because of inconsistent prognostic impact, stratification based on immunostaining algorithms should be cautiously used in guiding therapy.^[25]

A study by Musolino et al assessed the safety and activity of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab (DA-POCH-R) in elderly patients with poor-prognostic, untreated diffuse large B-cell non-Hodgkin lymphoma.^[26] The study determined that for patients aged 70 years or older, this combination was both safe and active and represents a reasonable alternative for elderly patients who were not considered to tolerate standard CHOP treatment.

A study by Peyrade et al found that rituximab combined with low-dose CHOP (R-miniCHOP) is a good compromise between efficacy and safety in patients aged 80 years or older and should be the new standard of treatment in this subgroup.^[27]

See Prognostic factors advanced-stage DLCL (stages II bulky, III, and IV) under Prognosis and Prognostic Factors.

Up to 10% of patients with diffuse large cell lymphoma (DLCL) do not respond to induction chemotherapy (stable or progressive disease). These patients have a poor outcome.

Therapies that produce responses in 10% or fewer of these cases include the following:

• Salvage chemotherapy with DHAP (dexamethasone, high-dose cytarabine, and cisplatin)^[28]
• Salvage chemotherapy with ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)^[29]
• Salvage chemotherapy with MIME (mesna, ifosfamide, methotrexate, and etoposide)^[30]
• High-dose therapy with autologous bone marrow/stem cell support^[31]

Patients who achieve only a partial response with standard conventional therapy but are considered to have chemosensitive disease should be evaluated for high-dose therapy and autologous stem cell support. These patients may have better outcomes than those with primary refractory disease.

Of patients with diffuse large cell lymphoma (DLCL) who achieve an initial complete response (CR), 20-50% experience disease relapse. Numerous second-line salvage regimens have been used to induce a second remission. In general, 20-35% of patients who relapse achieve a second complete response using a combination chemotherapy regimen, including DHAP (dexamethasone, high-dose cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), MIME (mesna, ifosfamide, methotrexate, and etoposide), or IMVP-16 (ifosfamide, methotrexate, etoposide).^[32] However, the duration of the second complete response is frequently shorter than 1 year, and patients treated with salvage chemotherapy at conventional doses are considered incurable unless treated with high-dose therapy and autologous transplantation.

Based on a multicenter randomized trial that evaluated patients with chemosensitive, relapsed aggressive lymphomas, bone marrow transplantation for patients who experience relapse and have chemosensitive diffuse large cell lymphoma (DLCL) is considered the standard of care.^[33] The patients were treated with 2 cycles of DHAP and then randomized to receive an additional 4 cycles of DHAP or high-dose chemotherapy followed by autologous bone marrow transplantation. The patients in the transplant arm had a superior event-free survival rate (46% vs 12% at 5 y) and overall survival rate (53% vs 32% at 5 y) compared to those patients receiving conventional salvage therapy.^[33] Most series demonstrate that approximately 10-15% of patients with chemotherapy-resistant relapse also may benefit from this strategy.

A phase 2 study by Witzig et al found that the oral farnesyltransferase inhibitor tipifarnib has activity in refractory or relapsed lymphoma, particularly in heavily pretreated T-cell and Hodgkin lymphoma groups, with little activity in non-Hodgkin lymphoma. Further studies are warranted.^[34]

Tumor lysis syndrome (TLS) is a potential complication following treatment of diffuse large cell lymphoma (DLCL). This condition manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium, and it can lead to a sudden death from electrolyte abnormalities. Aggressive intravenous hydration, alkalinization of the urine, and the administration of allopurinol usually prevents tumor lysis syndrome. Occasionally, patients with significant tumor volume and rapidly growing disease can avoid tumor lysis syndrome by receiving dose-modified or attenuated chemotherapy as the first treatment, followed by conventional chemotherapy in subsequent treatment cycles.

Uric acid nephropathy, with or without tumor lysis syndrome, usually can be prevented by administering allopurinol or alkalinizing the urine.

Neutropenic fevers and sepsis are the most common potentially serious complications of chemotherapy. If not recognized and treated aggressively, these infections can cause rapid deterioration of the patient's condition, which could lead to death. The use of cytokines (granulocyte colony-stimulating factors [GCSFs] or granulocyte-macrophage colony-stimulating factors [GM-CSFs]) has been helpful in preventing infections by shortening, and in some cases preventing, the neutropenic period. The use of prophylactic antibiotics (especially with the fluoroquinolones [eg, ciprofloxacin, levofloxacin]) has been shown to be effective in preventing neutropenic infections.

Keep in mind that failure to completely stage the patient, to initiate treatment as soon as possible, to prevent uric acid nephropathy and tumor lysis syndrome, and to recognize and treat neutropenic sepsis may lead to medicolegal pitfalls.

Monitor patients very carefully while they are receiving chemotherapy, which is administered every 3 weeks. Order complete blood cell (CBC) counts and chemistries frequently for outpatient monitoring. Immediately see patients if they develop any chemotherapy-related adverse effects.

Antiemetics are always prescribed before and after the administration of chemotherapy. Administer intravenous fluids and/or supportive care with analgesics and growth factors, as necessary. Patients often are started on allopurinol with the induction of chemotherapy to avoid acute renal failure from tumor lysis syndrome (TLS) and uric acid nephropathy.

Mortality rates for diffuse large cell lymphoma (DLCL) have increased significantly in each race/sex group. The rates of change are highest in areas where human immunodeficiency virus (HIV) infection is epidemic and in patients with posttransplant lymphoproliferative diseases.

Data suggest that 5-year survival rates are higher for white persons compared to those of people of African descent, which may or may not reflect socioeconomic factors. Women also have a better survival outcome, as do patients younger than 65 years.^[35]

International non-Hodgkin lymphoma prognostic factors

The prognosis of patients with diffuse large cell lymphoma (DLCL) can be assessed by applying the 5 lymphoma prognostic factors as described by the International Prognostic Index (IPI), as follows^[36] :

• Age
• Tumor stage
• Number of extranodal sites involved
• Performance status
• Lactate dehydrogenase (LDH) value

Patients with low risk (ie, 0 or 1 adverse factors) have a 5-year survival rate of 73%, whereas in the high-risk group (ie, people with 4-5 adverse factors), the 5-year survival rate drops to 26%.

Prognostic factors of early stage DLCL (stage IA and IIA, nonbulky)

A number of studies have analyzed factors predicting better or worse survival rates of subjects with limited-stage disease treated with combined modality programs. In the Southwestern Oncology Group (SWOG) study described in Treatment of Early Stage DLCL, a subgroup analysis showed that the 5-year survival rate was better in patients who had a favorable IPI score.^[18] Similar results were found in a study of 308 patients with limited disease treated with 3 cycles of a doxorubicin-containing regimen followed by radiotherapy.

In an Eastern Cooperative Oncology Group (ECOG) study that compared 8 courses of a regimen of cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP) with or without radiation in patients with previously untreated bulky or extranodal stage I or II diffuse large cell lymphoma (DLCL), 10-year survival was similar in the 2 treatment arms (64% vs 60%).^[37] Patients with 3 or more disease sites or a poor performance status were more likely to have treatment failure with the CHOP regimen, with or without radiotherapy.

All these studies suggest that combined modality therapy is a successful approach for patients with limited stage I disease and a stage-modified IPI score of zero. This approach appears to be less successful in patients with bulky stage I or II disease, 3 or more involved disease sites, and/or a stage-modified IPI score of 1 or more.

Prognostic factors advanced-stage DLCL (stages II bulky, III, and IV)

The International Non-Hodgkin Lymphoma (NHL) Prognostic Factors Project developed a predictive model of outcome for aggressive NHL.^[36] The specific 5 pretreatment characteristics that were independently statistically significant for higher-risk disease were the following:

• Age older than 60 years
• Tumor stage III or IV (advanced)
• More than 1 extranodal site involved by disease
• Patient performance status of 2 or more
• LDH elevation above the reference range

Based on these 5 characteristics, patients were stratified into 4 categories, as follows:

• Low-risk patients had 0 or 1 adverse factors.
• Low-risk to intermediate-risk patients had 2 factors.
• High-risk to intermediate-risk patients had 3 factors.
• High-risk patients had 4 or 5 factors.

When patient outcomes were analyzed by risk stratification, they had different outcomes with regard to complete response (CR), disease-free survival, and overall survival. For example, patients with a low risk had a complete response rate of 87% and a 5-year survival rate of 73%, as compared to a complete response rate of 44% and a 5-year survival rate of 26% in the high-risk group.

Subsequent studies have confirmed the reproducibility of the IPI for predicting clinical outcome for patients with diffuse large cell lymphoma (DLCL). Currently, poor-risk patients (despite achieving complete response) may be considered for aggressive therapy with high-dose chemotherapy and peripheral stem cell/bone marrow transplantation in first remission.