eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Diffuse Mixed

Clifford H Pemberton, MD, Instructor in Medicine, Jefferson Medical College; Medical Director, Jefferson Hospice and Palliative Care Program; Consulting Staff, Department of Medicine, Division of Hematology/Oncology, Lankenau Hospital
Asher A Chanan-Khan, MD, Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo

Updated: Dec 18, 2008

Introduction

Background

In 1956, Rappaport initially described a subset of non-Hodgkin lymphoma (NHL) that was characterized by a mixed population of diffusely infiltrating malignant histiocytes and lymphocytes; he referred to them as mixed histiocytic-lymphocytic malignant lymphomas. These malignant histiocytes were later identified as lymphocytes; thus, the term malignant lymphoma, mixed small and large cell, was adopted. Histologically, these lymphomas contain an equal number of small and large cells (30-70%).

In the Working Formulation classification system proposed by a National Cancer Institute working group in 1982, these lymphomas were classified as an intermediate-grade non-Hodgkin lymphoma, representing 3-11% of all non-Hodgkin lymphomas.

With the development of immunophenotypic and molecular diagnostics, the Revised European-American Lymphoma (REAL) classification was subsequently proposed and then modified by the World Health Organization (WHO) in 2001. Diffuse mixed lymphoma is now classified as diffuse large B-cell lymphoma. Clinically, patients with this type of lymphoma usually present with advanced and, often, extranodal disease.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Pathophysiology

Diffuse large B-cell lymphomas (diffuse mixed lymphomas) are more or less composed of equal numbers of small and large cells. The small cells are usually slightly larger than normal lymphocytes, and they have a cleaved or indented nucleus and coarse chromatin. The large cells can be cleaved or noncleaved. The cytoplasm of these cells is pale, and the cells have an irregular, central, indented nucleus with inconspicuous nucleoli. A subset of the large cells has rounded nuclei with one or more nucleoli; these are the noncleaved large cells and are somewhat larger compared with the cleaved cells.

Similar to all other intermediate-grade lymphomas, the mixed small and large cell non-Hodgkin lymphomas most often manifest as primary nodal disease, although involvement of the spleen and other organs is common.

Frequency

International

Diffuse large B-cell lymphomas (diffuse mixed lymphomas) comprise approximately 30% of all non-Hodgkin lymphomas.

Mortality/Morbidity

Based on the International Prognostic Index (IPI), patients with diffuse large B-cell lymphomas (diffuse mixed lymphomas) can be grouped into the prognostic categories of low risk (category 0 or 1), low-intermediate risk (category 2), high-intermediate risk (category 3), and high risk (category 4 or 5).¹ The 5 factors rated in the IPI are age, lactate dehydrogenase (LDH) level, stage, performance status, and number of extranodal sites.²

For intermediate and aggressive lymphomas, the complete remission (CR) rate for low-risk patients is 87%, and the 5-year overall survival (OS) rate is 73%.
The CR rate for high-risk patients is 44%, and the 5-year OS rate is 26%

Sex

Diffuse large B-cell lymphoma (diffuse mixed lymphoma) affects females more often than males.

Age

Most patients with diffuse large B-cell lymphomas (diffuse mixed lymphomas) are diagnosed during the seventh or eighth decade of life, with a median age of 63 years.

Clinical

History

Patients with diffuse large B-cell lymphomas (diffuse mixed lymphomas) usually present with lymphadenopathy, most commonly affecting either the cervical or inguinal region. Other common complaints from the history findings may include the following:

B symptoms (eg, fever, night sweats, >10% weight loss)
Anorexia
Pedal edema (caused by pelvic lymphadenopathy)
Fatigue
Chest discomfort or shortness of breath (caused by mediastinal lymphadenopathy)

Physical

Common findings upon physical examination are as follows:

Lymphadenopathy (ie, cervical, axillary, inguinal)
Splenomegaly
Low-grade fever
Pedal edema, resulting from extensive pelvic lymphadenopathy

Causes

A number of risk factors have been associated with non-Hodgkin lymphomas in general. These include Epstein-Barr virus, HIV, pesticides, hair dyes, primary and transplant-related immunodeficiency, and rheumatoid arthritis and other autoimmune disorders. Occupational factors have a weak or an inconsistent risk.

Differential Diagnoses

Lymphoma, Mantle Cell
Lymphoma, Non-Hodgkin
Sarcoidosis
Tuberculosis

Workup

Laboratory Studies

Complete blood cell (CBC) count: Involvement of the bone marrow may result in anemia, thrombocytopenia, and/or leukopenia.
Serum electrolyte levels: Electrolyte abnormalities may occur from renal involvement with lymphoma. Abnormal renal function may require a chemotherapy dose adjustment.
LDH level: An elevated level of LDH corresponds with the tumor burden and the extent of disease. The LDH value is part of the IPI and a useful indicator of the response to treatment; it can be used as an early nonspecific indicator of disease relapse.¹
Uric acid level: An elevated level signifies a high tumor burden and an increased likelihood of tumor lysis syndrome with chemotherapy.
Flow cytometry: Expression of different immunophenotypes helps in determining a clonal cell population and in differentiating between B- or T-cell origins.
Cytogenetic or fluorescent in situ hybridization (FISH) studies may reveal common chromosomal translocations:
- t(3q27) (bcl-6) – Occurs in 35% of patients
- t(14;18)(q32;q21) (bcl-2) – Occurs in 15-20% of patients
- t(8;14)(q24;q32) – Occurs in fewer than 5% of patients
Hepatitis B testing for combination chemoimmunotherapy with rituximab (risk of activation
Gene expression profiling may be able to distinguish 2 separate subtypes of diffuse large B-cell lymphomas (diffuse mixed lymphomas) with different prognoses (normal germinal center B-cell pattern vs activated B-cell–like).
Results from gene rearrangement studies can be used to establish clonality.

Imaging Studies

Computed tomography (CT) scans (neck, chest, abdomen, pelvis)
- These studies are used to help identify the degree of lymphadenopathy, the presence or absence of extranodal disease, and/or the presence of visceral involvement. CT scans are also part of the complete staging workup for diffuse large B-cell lymphoma (diffuse mixed lymphoma).
- Baseline CT scan findings aid in disease follow-up care after chemotherapy to assess the degree of response to therapy, as well as aid in planning consolidating radiation therapy, if used.
Findings from gallium scans provide an estimate of the extent of disease and are sometimes used as a means of assessing sites of relapse.
Findings from positron emission tomography (PET) scanning for glucose uptake can indicate areas of increased metabolic activity and can be useful to help determine whether residual masses represent scars or persistent lymphoma, in addition to their frequent use in initial disease staging. PET scan findings are being investigated as prognostic indicators during treatment (after 2-4 cycles), but the clinical utility of this is still unclear.

Other Tests

Findings from multiple gated acquisition (MUGA) scans are used to evaluate the patient's ejection fraction before chemotherapy, because anthracyclines have a potential cardiotoxic effect.

Procedures

Perform bone marrow aspiration and biopsy as part of the staging process to help rule out involvement with lymphoma.
Lymph node biopsy is required to establish a definitive diagnosis of non-Hodgkin lymphoma. This should be an excisional biopsy rather than a needle biopsy, because nodal architecture is often difficult to assess when small amounts of tissue are used.

Staging

Diffuse large B-cell lymphomas (diffuse mixed lymphomas) are staged according to the commonly used Ann Arbor staging system.

Stage I – Involvement of a single lymph node region or lymphoid structure (ie, spleen, thymus, Waldeyer ring) or involvement of a single extralymphatic site (IE)
Stage II – Involvement of 2 or more lymph node regions on the same side of the diaphragm; localized contiguous involvement of only 1 extranodal site and 1 lymph node region on the same side of the diaphragm
Stage III – Involvement of lymph node regions on both sides of the diaphragm
Stage IV – Diffuse or disseminated involvement of 1 or more extranodal organs or tissues, with or without associated lymph node involvement.

Treatment

Medical Care

The diagnosis of diffuse large B-cell lymphoma (diffuse mixed lymphoma) is usually confirmed after positive findings are obtained from a lymph node biopsy specimen. Pathology findings should be reviewed by an expert hematopathologist because lymphomas can be difficult to classify.
Most patients are treated in an outpatient setting.
Patients with a high tumor burden may need to be admitted to the hospital for prevention of tumor lysis syndrome to receive prophylaxis with allopurinol and alkaline hydration.
Combination chemoimmunotherapy is the standard of care for all stages of diffuse, mixed-cell non-Hodgkin lymphoma, with abbreviated chemotherapy and local irradiation as an option for early-stage disease.

Surgical Care

Because multiple chemotherapy cycles are usually administered, an implanted venous access device is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

Consultations

Consult a surgeon to obtain a lymph node or tissue biopsy sample and for subcutaneous venous access.
Consultation with a radiation oncologist may be sought in early-stage diffuse large B-cell lymphoma (diffuse mixed lymphoma) disease.

Diet

A regular diet is recommended; however, a neutropenic diet is suggested during periods of neutropenia.

Activity

No activity limitations are recommended; however, the lymphoma, its treatment, or both may result in substantial fatigue.

Medication

For early-stage diffuse large B-cell lymphoma (diffuse mixed lymphoma) disease (stage I or nonbulky stage II), combined-modality therapy, usually incorporating 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (CHOP/R) with involved-field radiation, has been used. The addition of rituximab, an anti-CD20 antibody, has proved very beneficial in lymphoma treatment. Studies have suggested that 4 cycles of CHOP may be at least as good as CHOP plus radiotherapy (RT) in patients older than 60 years. For advanced-stage disease (II bulky, III, and IV), systemic chemotherapy with the CHOP/R regimen is the standard of care. This combination has been shown to be superior to CHOP alone.^3,4,5

The CHOP/R regimen is administered intravenously (IV) every 21 days and consists of 750 mg/m² of cyclophosphamide (Cytoxan) on day 1, 50 mg/m² of doxorubicin (Adriamycin) on day 1, 2 mg of vincristine on day 1, 375 mg/m² of rituximab on day 1, and oral (PO) 100 mg of prednisone on days 1-5. This combination is moderately emetogenic and should be accompanied by aggressive antiemetics.

Dose-dense CHOP/R is a more intensive regimen given every 14 days instead of 21, with the addition of growth factors (colony-stimulating factor [G-CSF] or granulocyte monocyte colony stimulating factor [GM-CSF]). This regimen is being evaluated as compared to standard CHOP/R in an ongoing trial.

The following regimens have also been used for the treatment of intermediate-grade non-Hodgkin lymphoma and may be used as salvage therapy in cases of relapse.

The DHAP chemotherapy regimen
- Dexamethasone (40 mg PO/IV on days 1-4)
- Cisplatin (100 mg/m²/d via continuous infusion on day 1)
- Cytarabine (2000 mg/m² IV q12h for 2 doses on day 2)
The ESHAP chemotherapy regimen
- Etoposide (40 mg/m² IV on days 1-4)
- Methylprednisolone (500 mg IV on days 1-4)
- Cisplatin (25 mg/m² via continuous infusion on days 1-4)
- Cytarabine (2000 mg/m² IV on day 5)
- ICE (ifosfamide, carboplatin, etoposide)

Other regimens are now only considered for patients whose condition relapses and who are not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT).

ICE – Ifosfamide, carboplatin, etoposide
ProMACE-MOPP – Prednisone, methotrexate, leucovorin calcium, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone
MACOP-B – Methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone, leucovorin calcium, trimethoprim/sulfamethoxazole DS, ketoconazole
ProMACE-CytaBOM – Prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin calcium, concomitant trimethoprim/sulfamethoxazole DS

Patients whose condition relapses and who have chemoresponsive disease, as evaluated after salvage therapy, should be considered for HDC followed by stem cell rescue. The Parma trial unequivocally established the superiority of HDC and ASCT over conventional salvage treatments.⁶ In this trial, patients younger than 60 years with non-Hodgkin lymphoma ranging from intermediate grade to high grade who were in their first or second relapse were given 2 doses of the DHAP chemotherapy regimen.⁶

Those patients with responsive disease were then randomly selected to receive either 4 courses of conventional chemotherapy or HDC plus ASCT. At 8-year follow-up, the reported OS rate was 47% in the HDC arm versus 27% (P = .042) in the DHAP arm, and the event-free survival rate was 36% in the HDC arm compared with 11% (P = .002) in the DHAP arm. How these results can be applied in the current era, in which the initial treatment almost always incorporates rituximab, is unclear.

The Groupe d' Etudes des Lymphomes de l' Adults studied the role of HDC and ASCT in early or late intensification. The OS rate in the late intensification arm was 44% versus 22% in the early intensification group, thus suggesting that HDC plus ASCT should not be considered in patients with untested relapse.

Current recommendations are to consider HDC and ASCT for patients in their first relapse, after chemoresponsiveness is established with a second-line salvage therapy. The role of HDC plus ASCT in first CR for patients whose disease has a slow initial response to first-line chemotherapy, those with poor initial prognostic factors, or as upfront therapy has not been clearly defined and remains controversial.

A German trial explored the safety and feasibility of dose-escalated CHOP-etoposide with 3 ASCTs as aggressive up-front therapy in young patients with high LDH levels.⁷ The investigators found the therapy safe and feasible, but its role is unclear. Rituximab was not used, and whether these intensive regimens are better than less intense chemotherapy plus rituximab is currently under investigation.

Antisense therapy (Bcl-2 antisense therapy) has entered clinical trials with promising results; however, its role outside a clinical trial is not yet established.

The addition of bortezomib, a protease inhibitor approved for treatment of myeloma, to CHOP/R is also being investigated in phase I and II trials.⁸

Multicenter trials of radioimmunotherapy with ibritumomab tiuxetan (Yttrium-90 [⁹⁰ Y] Zevalin) and iodine-131 [¹³¹ I] tositumomab (Bexxar), CD20-targeting radiolabeled antibodies approved for use in follicular lymphomas, are also ongoing.

Antineoplastic Agents

Chemotherapy remains the mainstay of treatment in patients with diffuse large B-cell lymphoma (diffuse mixed lymphoma). Many different regimens are used, but, to date, no single regimen has been shown to be superior to the standard CHOP/R regimen.

Cyclophosphamide (Cytoxan, Neosar)

Prototypical alkylator that is cell-cycle independent. Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of active metabolites may involve the cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Dosing

Adult

CHOP: 750 mg/m² IV on day 1

M-BACOD: 600 mg/m² IV on day 1

Pediatric

CHOP: Administer as in adults.

Interactions

Allopurinol may increase the risk of bleeding or infection and may enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and the antimicrobial effects of quinolones; chloramphenicol may increase the half-life while decreasing metabolite concentrations; may increase the effect of anticoagulants; coadministration with high doses of phenobarbital may increase the rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Myelosuppression, nausea, vomiting, hemorrhagic cystitis, impaired hepatic function, impaired renal function, SIADH, pulmonary fibrosis, carcinogenesis, mutagenesis, and impaired fertility may occur; regularly examine the patient's hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine the patient's urine for RBCs, which may precede hemorrhagic cystitis

Doxorubicin (Adriamycin)

Anthracycline antibiotic that can intercalate with DNA, affecting many functions of DNA, including synthesis. Forms DNA-cleavable complexes by interaction with topoisomerase II, which is responsible for cytocidal activity. Administered via IV and is distributed widely into tissues, including the heart, kidneys, lungs, liver, and spleen. Does not cross the blood-brain barrier and is excreted primarily in bile.

Dosing

Adult

CHOP: 50 mg/m² IV on day 1

M-BACOD: 45 mg/m² IV on day 1

Pediatric

CHOP: 40 mg/m² IV

Interactions

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease the plasma levels; cyclosporine may induce coma or seizures; mercaptopurine, verapamil, streptozocin, paclitaxel, and progesterone increase toxicity; cyclophosphamide increases cardiac toxicity

Contraindications

Documented hypersensitivity; severe CHF; cardiomyopathy; preexisting myelosuppression; complete cumulative doses of daunorubicin, doxorubicin, and idarubicin

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May produce severe local toxicity in irradiated tissues, even when the 2 therapies are not administered concomitantly; caution in patients who have received radiotherapy; cardiomyopathy is a well-known adverse effect; monitor for drug-induced cardiomyopathy; the mortality rate is >50% once cardiomyopathy has developed; extravasation may result in severe local tissue necrosis; reduce the dose in patients with impaired hepatic function

Vincristine (Oncovin)

Mechanism of action is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production.

Dosing

Adult

CHOP: 1.4 mg/m² (not to exceed 2 mg) IV push on day 1

M-BACOD: 1 mg/m² IV on day 1

Pediatric

CHOP: 1.5 mg/m² (not to exceed 2 mg) IV qwk for 6 doses

Interactions

Acute pulmonary reaction may occur when taken concurrently with mitomycin-C.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients diagnosed with severe cardiopulmonary or hepatic impairment and patients with preexisting neuromuscular disease

Prednisone (Deltasone, Orasone, Sterapred)

Glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. Also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability. Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites excreted via kidneys. Most adverse effects are dose- or duration-dependent.

Dosing

Adult

CHOP: 100 mg/d PO days 1-5

Pediatric

CHOP: 40 mg/m²/d PO for 28 d

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with the coadministration of diuretics.

Contraindications

Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction, GI disease; viral infection, connective tissue infections, fungal or tubercular skin infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use.

Dexamethasone (Decadron)

Immunosuppressant that may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity.

Dosing

Adult

DHAP: 40 mg PO/IV on days 1-4

M-BACOD: 6 mg/m² PO on days 1-5

Pediatric

DHAP: Not established

M-BACOD: Not established

Interactions

Effects decrease with the coadministration of barbiturates, phenytoin, and rifampin; decreases the effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases the risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.

Dosing

Adult

DHAP: 100 mg/m²/d continuous infusion on day 1

ESHAP: 25 mg/m² d continuous infusion on days 1-4

Pediatric

DHAP: Not established

ESHAP: Not established

Interactions

Increases the toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity; preexisting renal insufficiency, myelosuppression, hearing impairment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Administer adequate hydration before and 24 h after dosing to reduce the risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur.

Cytarabine (Cytosar-U)

Converted intracellularly to active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. Inhibition halts viral replication.

Dosing

Adult

DHAP: 2000 mg/m² IV q12h for 2 doses on day 2

ESHAP: 2000 mg/m² IV on day 5

Pediatric

DHAP: Not established

Interactions

Decreases the effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

If there is a significant increase in bone marrow suppression, reduce the number of treatment days; patients with hepatic or renal insufficiencies are at higher risk for CNS toxicity after administration of a high dose (reduce the dose).

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of cell cycle.

Dosing

Adult

ESHAP: 60 mg/m² IV on days 1-4

Pediatric

ESHAP: Not established

Interactions

May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; IT administration may cause death

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur.

Methylprednisolone (Solu-Medrol)

Immunosuppressant that may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

ESHAP: 500 mg IV on days 1-4

Pediatric

ESHAP: Not established

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking the medication concurrently with diuretics.

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications.

Methotrexate (Folex PFS, Rheumatrex)

Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells; may suppress the immune system.

Dosing

Adult

M-BACOD: 3000 mg/m² IV on day 15

Pediatric

M-BACOD: Not established

Interactions

Oral aminoglycosides may decrease the absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives, contained in some vitamins, may decrease response; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase the plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides (including trimethoprim-sulfamethoxazole [TMP-SMZ]) may increase effects and toxicity; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiency syndromes, preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor CBC count monthly and liver and renal function every 1-2 mo during therapy (monitor more frequently during the initial dosing, dose adjustments, or when the risk of elevated levels exists [eg, dehydration]); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in the blood cell count occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measure in the management of several neoplasms.

Dosing

Adult

M-BACOD: 4 mg/m² IV on day 1

Pediatric

M-BACOD: Not established

Interactions

May decrease the plasma levels of digoxin and phenytoin; cisplatin may increase the toxicity

Contraindications

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment

Antiemetic Agents

Antiemetic agents are used as supportive medication for the prevention of chemotherapy-induced nausea and vomiting.

Palonosetron (Aloxi) is a selective 5-HT3 receptor antagonist with a long half-life (40 h). The adult dose is 0.25 mg IV once (30 min before chemotherapy). Administer IV over 30 seconds, and do not repeat the dose within 7 days. May cause headache, constipation, diarrhea, or dizziness.

Granisetron (Kytril)

Antinauseant and antiemetic available as an injection for IV use and as a pill. A selective 5-hydroxytriptamine 3 (5-HT3) receptor antagonist with minimal to no affinity to other serotonin receptors.

Dosing

Adult

10 mcg/kg IV administered within 30 min of emetogenic chemotherapeutic agents

Pediatric

<2 y: Not established

2-16 y: 10 mcg/kg IV

>16 y: Administer as in adults.

Interactions

No definitive drug-to-drug interactions noted in humans; because it is metabolized by hepatic cytochrome P-450 enzyme, inducers or inhibitors of this enzyme may alter pharmacokinetics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Whether it is excreted in human milk is not known; therefore, advise caution when breastfeeding

Metoclopramide (Reglan)

Stimulates GI motility without an increase in gastric, biliary, or pancreatic secretions. Antiemetic effects most likely result from antagonism of peripheral and central dopamine receptors.

Dosing

Adult

2-4 mg/kg IV q2h prn

0.5-2 mg/kg PO q3-4h

Pediatric

Not established

Interactions

Effects antagonized by anticholinergic drugs and narcotics; additive sedative effects with narcotics, hypnotics, and tranquilizers; caution use with MAOIs

Contraindications

Documented hypersensitivity; pheochromocytoma; gastrointestinal obstruction, hemorrhage, or perforation; known seizure disorder

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hypertension; renal failure; may impair mental or physical ability to operate heavy machinery or drive

Prochlorperazine (Compazine)

Usually preferred in the initial treatment of delayed-onset nausea and vomiting from emetogenic chemotherapeutic agents.

Dosing

Adult

10 mg PO q4-6h

10-40 mg IV q3-4h

10 mg IM q3-4h

25 mg PR q3-4h

Pediatric

Not recommended in children <2 y or <20 lb

20-29 lb: 2.5 mg PO/PR qd/bid; not to exceed 7.5 mg

30-39 lb: 2.5 mg PO/PR bid/tid; not to exceed 10 mg

40-85 lb: 2.5 mg PO/PR tid or 5 mg bid; not to exceed 15 mg

IM dosage: Calculate each dose on the basis of 0.06 mg/lb, given as a deep IM injection

Interactions

Concomitant administration of propranolol and phenothiazine results in the increased plasma level of both drugs.

Contraindications

Documented hypersensitivity; do not use in CNS depressant state or in patients who are comatose; children <2 y

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Careful use in elderly patients; extrapyramidal symptoms may develop; hypotension

Growth Factors

Growth factors stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell hematopoiesis. Recombinant human erythropoietin (epoetin alfa) stimulates erythropoiesis in anemic conditions. Colony-stimulating factors act on hematopoietic cells to stimulate hematopoietic progenitor cells proliferation and differentiation. Interleukins stimulate stem cell proliferation.

Erythropoietin/Epoetin alfa recombinant (Epogen/Procrit)

Glycoprotein that stimulates red blood cell production. Has the same biologic effects as endogenous erythropoietin.

Dosing

Adult

150-300 U/kg SC twice/wk or 40,000 U/wk SC

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled hypertension (relative)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients with preexisting cardiac conditions should be monitored closely; hypertension should be treated aggressively; increased incidence of seizures have been noted in patients on erythropoietin; decrease the dose in patients whose hematocrit increase exceeds 4 points in any 2-wk period; patients whose condition does not respond should be evaluated for iron deficiency before the discontinuation of therapy.

Follow-up

Further Inpatient Care

Hospitalization may be necessary for patients with the following diffuse large B-cell lymphomas (diffuse mixed lymphomas) disease- or therapy-associated complications:
- Neutropenic fever: Patients are usually expected to be neutropenic approximately 10-14 days after a dose of chemotherapy, and individuals are most susceptible to infections at this point. If febrile, they should be admitted to the hospital and treated with intravenous antibiotics.
- Anemia and thrombocytopenia: Transfusions (red blood cells or platelets) should be administered as clinically indicated for anemia and thrombocytopenia.

Further Outpatient Care

Growth factor support: Patients with a previous episode of febrile neutropenia should be treated with growth factor (ie, GM-CSF, G-CSF) during subsequent cycles.
Anemia: Patients with persistently low hemoglobin values due to disease or chemotherapy may require red blood cell transfusions or erythropoietin or darbepoetin alfa (Aranesp) injections.

Inpatient & Outpatient Medications

Antiemetics are administered as required for control of nausea and vomiting.
- The 5-hydroxytriptamine 3 (5-HT3) antagonists such as granisetron (1 mg PO q12h) or ondansetron (8 mg PO q8h) for severe chemotherapy-induced nausea and vomiting
- Lorazepam (1 mg PO/SL q4-6h)
- Metoclopramide (0.5-2 mg/kg PO q3-4h)
- Prochlorperazine (10 mg PO q4-6h)
For patients with anemia, consider erythropoietin or epoetin alfa (Procrit) at 40,000-60,000 U subcutaneously [SC] once per week, or darbepoetin alfa 300 mcg SC weekly.

Transfer

Patients whose conditions relapse after multiple regimens or who have poor performance status are thus not candidates for further chemotherapy and should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:
- Pain management service
- Nursing home
- Terminal care facility (hospice)
- Home care with specialized nursing support for pain management
- Rehabilitative centers

Deterrence/Prevention

Patients who administer growth factors to themselves should be carefully advised on sterile techniques.
Fevers during periods of neutropenia should be immediately brought to the attention of the treating physician.

Complications

Chemotherapy-associated complications
- Cardiomyopathy (related to anthracycline)
- Infections (during neutropenia, postchemotherapy)
- Gonadal dysfunction (sterility related to chemotherapy)
- Secondary leukemias (exposure to alkylating agents)
- Alopecia
- Neuropathy
- Related to bone marrow transplantation

Prognosis

The 5-year relapse-free survival rate for low-risk patients is 70%, and the 5-year OS rate is 73%. For the high-risk group, the 5-year relapse-free survival rate is 40% and the 5-year OS rate is 26%.
The IPI uses 5 pretreatment characteristics to identify the various risk groups, which are as follows:
- Age ( <60 y vs >60 y)
- Number of extranodal sites of involvement ( <1 vs >1)
- Tumor stage I or II (localized) versus III or IV (advanced)
- Patient performance status (0 or 1 vs >2)
- Serum LDH level (normal vs abnormal)
Based on the 5 IPI characteristics, patients are classified into 4 categories:
- High risk: Four or 5 adverse factors
- High-intermediate risk: Three adverse factors
- Low-intermediate risk: Two adverse factors
- Low risk: No or 1 adverse factor

Patient Education

Patients with diffuse large B-cell lymphomas (diffuse mixed lymphomas) should be educated about the following:
- Febrile neutropenia
- Postchemotherapy thrombocytopenia and the tendency to bleed with minimal trauma
- Chemotherapy-associated alopecia
- Avoidance of pregnancy in reproductive-aged women
- Chemotherapy-induced nausea and vomiting
- Chemotherapy-associated menstrual dysregulation (females) and the possibility of sexual dysfunction
- Fatigue
- Sperm banking and risk of sterility for males

Miscellaneous

Medicolegal Pitfalls

Failure to inform patients with diffuse large B-cell lymphomas (diffuse mixed lymphomas) about the long-term sequelae of chemotherapeutic agents, which include the following:
- Infertility
- Secondary leukemias
- Myelodysplastic syndrome
- Possible anaphylactic reactions
- Serious and potentially fatal infections
Failure to clearly explain transfusions (both red blood cells and platelets) and associated complications
Failure to inform patients who require HDC and ASCT that long-term complications of higher doses of chemoradiotherapy and mortality rates as high as 3-5% from the conditioning regimen are possible
Cardiomyopathy

Special Concerns

The pathology findings in patients with possible diffuse, mixed cell non-Hodgkin lymphoma should be reviewed by an experienced hematopathologist.
Patients with induction-failure non-Hodgkin lymphoma (ie, those with chemosensitive disease who do not achieve CR with primary therapy) or recurrent non-Hodgkin lymphoma should be carefully selected for bone marrow transplantation. Only patients with chemosensitive disease should be considered for HDC and ASCT.

Multimedia

Media file 1: Diffuse large B-cell lymphoma (diffuse mixed lymphoma). Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost with a diffuse pattern of involvement.

Media file 2: Patient with diffuse mixed cell non-Hodgkin lymphoma with extranodal involvement. Picture shows an enlarged spleen and liver as a result of lymphomatous involvement.

Media file 3: Patient with diffuse mixed cell non-Hodgkin lymphoma with extranodal involvement (same patient as in Image 2). The patient has an enlarged spleen and liver as a result of lymphomatous involvement. Picture shows extensive retroperitoneal lymphadenopathy.

Media file 4: Gallium scans performed as part of a staging workup for a patient with diffuse mixed cell non-Hodgkin lymphoma, showing extensive hepatosplenic and multiple sites of nodal involvement with gallium-avid tumor.

References

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Keywords

diffuse mixed lymphoma, diffuse mixed-cell lymphoma, diffuse mixed small and large cell lymphoma, diffuse undifferentiated lymphoma, intermediate grade lymphoma, diffuse small and large cell lymphoma, malignant lymphoma, diffuse mixed type, intermediate-grade lymphoma, mixed histiocytic-lymphocytic malignant lymphoma, mixed small and large cell lymphoma, diffuse mixed lymphomas, cancer, malignant histiocytes, malignant lymphocytes, lymphatic sarcoma, mixed lymphocytic-histiocytic

Contributor Information and Disclosures

Author

Clifford H Pemberton, MD, Instructor in Medicine, Jefferson Medical College; Medical Director, Jefferson Hospice and Palliative Care Program; Consulting Staff, Department of Medicine, Division of Hematology/Oncology, Lankenau Hospital
Clifford H Pemberton, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians, American Medical Association, American Society of Hematology, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Asher A Chanan-Khan, MD, Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo
Asher A Chanan-Khan, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Michael Paul Kosty, MD, Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic
Michael Paul Kosty, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Further Reading

Related eMedicine Topics

Cutaneous CD30+ (Ki-1) Anaplastic Large-Cell Lymphoma
Lymphoma, Diffuse Large Cell
Malignant Lymphoma

Suggested Reading

Griffin TC, Weitzman S, Weinstein H, et al, and the Children's Oncology Group. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2009 Feb;52(2):177-81. [Medline].