eMedicine Specialties > Hematology > Stem Cells and Disorders
Lymphoma, Diffuse Mixed: Treatment & Medication
Updated: Dec 18, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
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.
Adult
CHOP: 750 mg/m2 IV on day 1
M-BACOD: 600 mg/m2 IV on day 1
Pediatric
CHOP: Administer as in adults.
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
Documented hypersensitivity; severely depressed bone marrow function
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.
Adult
CHOP: 50 mg/m2 IV on day 1
M-BACOD: 45 mg/m2 IV on day 1
Pediatric
CHOP: 40 mg/m2 IV
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
Documented hypersensitivity; severe CHF; cardiomyopathy; preexisting myelosuppression; complete cumulative doses of daunorubicin, doxorubicin, and idarubicin
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.
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
Acute pulmonary reaction may occur when taken concurrently with mitomycin-C.
Documented hypersensitivity
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.
Adult
CHOP: 100 mg/d PO days 1-5
Pediatric
CHOP: 40 mg/m2/d PO for 28 d
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.
Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction, GI disease; viral infection, connective tissue infections, fungal or tubercular skin infections
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.
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
Effects decrease with the coadministration of barbiturates, phenytoin, and rifampin; decreases the effect of salicylates and vaccines used for immunization
Documented hypersensitivity; active bacterial or fungal infection
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.
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
Increases the toxicity of bleomycin and ethacrynic acid
Documented hypersensitivity; preexisting renal insufficiency, myelosuppression, hearing impairment
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.
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
Decreases the effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity.
Documented hypersensitivity
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.
Adult
ESHAP: 60 mg/m2 IV on days 1-4
Pediatric
ESHAP: Not established
May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Documented hypersensitivity; IT administration may cause death
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.
Adult
ESHAP: 500 mg IV on days 1-4
Pediatric
ESHAP: Not established
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.
Documented hypersensitivity; viral, fungal, or tubercular skin infections
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.
Adult
M-BACOD: 3000 mg/m2 IV on day 15
Pediatric
M-BACOD: Not established
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
Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiency syndromes, preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
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.
Adult
M-BACOD: 4 mg/m2 IV on day 1
Pediatric
M-BACOD: Not established
May decrease the plasma levels of digoxin and phenytoin; cisplatin may increase the toxicity
Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
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.
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.
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
Documented hypersensitivity
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.
Adult
2-4 mg/kg IV q2h prn
0.5-2 mg/kg PO q3-4h
Pediatric
Not established
Effects antagonized by anticholinergic drugs and narcotics; additive sedative effects with narcotics, hypnotics, and tranquilizers; caution use with MAOIs
Documented hypersensitivity; pheochromocytoma; gastrointestinal obstruction, hemorrhage, or perforation; known seizure disorder
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.
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
Concomitant administration of propranolol and phenothiazine results in the increased plasma level of both drugs.
Documented hypersensitivity; do not use in CNS depressant state or in patients who are comatose; children <2 y
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.
Adult
150-300 U/kg SC twice/wk or 40,000 U/wk SC
Pediatric
Not established
None reported
Documented hypersensitivity; uncontrolled hypertension (relative)
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.
More on Lymphoma, Diffuse Mixed |
| Overview: Lymphoma, Diffuse Mixed |
| Differential Diagnoses & Workup: Lymphoma, Diffuse Mixed |
 Treatment & Medication: Lymphoma, Diffuse Mixed |
| Follow-up: Lymphoma, Diffuse Mixed |
| Multimedia: Lymphoma, Diffuse Mixed |
| References |
| Further Reading |
| « Previous Page | Next Page » |
References
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Further Reading
Related eMedicine Topics
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].
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
