Professional Drug Information > Rituximab

Rituximab (Systemic)

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Rituxan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Monoclonal antibody; antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


Accepted

Lymphomas, non-Hodgkin's (treatment)—Rituximab is indicated for treatment of relapsed or refractory low-grade or follicular CD20-positive, B-cell non-Hodgkin's lymphoma.^{01}Rituximab is also indicated for use in [first-line treatment, as a single agent, in combination with the CHOP regimen, or in combination with other agents active in this disease.]^{1{45}{46}{47}{48}{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}{65}{66}{67}{68}}
—Rituximab is also indicated in [relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma, as a single agent, in combination with the CHOP regimen, or in combination with other agents active in this disease.]^{1{69}{70}{71}{72}{73}{74}{75}{76}{77}{78}{79}{80}{81}{82}{83}{84}{85}{86}{87}{88}} It is also indicated for [first-line treatment of diffuse aggressive non-Hodgkin's lymphoma, in combination with the CHOP regimen or other agents active in this disease. Use as a single agent, for first-line treatment, is appropriate only in selected elderly patients with diffuse aggressive non-Hodgkin's lymphoma.]^{1{58}{59}{70}{71}{72}{77}{83}{85}{89}{90}{91}}

[Leukemia, chronic lymphocytic (treatment) ]¹—Rituximab is indicated for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).^{{03}{04}{05}{06}{07}{08}{09}{10}{11}{12}{13}{14}{15}{16}{17}{18}{19}{20}{21}{22}{23}{24}{25}{26}{27}}

[Waldenstrom's macroglobulinemia (treatment) ]¹—Rituximab is indicated for the treatment of relapsed/refractory waldenstrom's macroglobulinemia.^{{28}{30}{29}{31}{32}{33}{34}{35}{36}{37}{38}}

[Thrombocytopenic purpura, immune or idiopathic (treatment)]¹—Rituximab is indicated for the treatment of immune or idiopathic thrombocytopenic purpura.^{{39}{40}{41}{42}{43}{44}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic (genetically engineered) chimeric murine/human monoclonal antibody, an IgG1-kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences ^{01}. It is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis) ^{01}. The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium containing gentamicin (although gentamicin does not appear in the final product) ^{01}. Purification procedure includes affinity and ion exchange chromatography, as well as specific viral inactivation and removal procedures ^{01}.
Molecular weight—
    145 kilodaltons ^{01}


pH
    6.5 ^{01}.


Binding affinity
    For CD20 antigen: Approximately 8 nanomolar ^{01}.

Mechanism of action/Effect:

Rituximab, a murine/human monoclonal antibody, binds to the antigen CD20 (human B-lymphocyte–restricted differentiation antigen, Bp35). This antigen is a hydrophobic transmembrane protein, with a molecular weight of approximately 35,000 daltons, that is located on pre-B and mature B lymphocytes. It is also expressed on more than 90% of B-cell non-Hodgkin's lymphomas but not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates an early step or steps in the activation process for cell cycle initiation and differentiation and may also function as a calcium ion channel. It is not shed from the cell surface and does not internalize upon antibody binding. No free CD20 antigen is found in the circulation. ^{01}

The mechanism of antineoplastic action may involve mediation of B cell lysis (seen in vitro ) by means of binding of the Fab domain of rituximab to the CD20 antigen on B lymphocytes and by recruitment of immune effector functions by the Fc domain. Cell lysis may be the result of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In addition, the antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. ^{01}

Rituximab binds to lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. However, there appears to be little or no binding to non-lymphoid tissues. ^{01}

Half-life:


Intravenous infusion (for four doses):

After the first dose: Mean, 59.8 hours (range, 11.1 to 104.6 hours) ^{01}.

After the fourth dose: Mean, 174 hours (range, 26 to 442 hours) ^{01}.

Note: The wide range may be related to variable tumor burden among patients, as well as the changes that were seen in CD20-positive (normal and malignant) B-cell populations with repeated administration ^{01}.
No difference has been found in the rate of elimination of rituximab, as measured by serum half-life, in responders versus nonresponders ^{01}.
Rituximab has been found to be detectable in serum for 3 to 6 months after completion of treatment ^{01}.



Onset of action:

Depletion of circulating B cells (measured as CD19-positive cells)—Within the first three doses ^{01}.

Depletion of tissue-based B cells (measured in lymph node biopsies)—Fourteen days after a single dose ^{01}.

Note: Rituximab treatment results in depletion of both circulating and tissue-based B cells ^{01}.


Peak serum concentration:

Inversely correlated with baseline values for the number of circulating CD20-positive B cells and measures of disease burden ^{01}.

Note: Trough serum concentrations also are inversely correlated with baseline values for the number of circulating CD20-positive B cells and measures of disease burden ^{01}.
Median steady-state serum concentrations have been found to be higher in responders than in nonresponders ^{01}.
Serum concentrations have been found to be higher in patients with International Working Formulation (IWF) subtypes B, C, and D as compared to those with subtype A ^{01}.


Duration of action:

Depletion of circulating B cells (measured as CD19-positive cells)—Up to 6 to 9 months after treatment ^{01}, with median B-cell levels returning to normal by 12 months following completion of treatment ^{01}.

Note: Sustained and statistically significant reductions in IgG and IgM serum concentrations occurred from the fifth through the eleventh month after administration, but only 14% of patients experienced reductions in IgG and/or IgM serum concentrations to values below the normal range ^{01}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to murine proteins may also be sensitive to rituximab ^{01}.

Carcinogenicity

Long-term studies in animals have not been done ^{01}.

Mutagenicity

Long-term studies in animals have not been done ^{01}.

Pregnancy/Reproduction
Fertility—
Studies in animals have not been done ^{01}.

Pregnancy—
Studies in humans have not been done ^{01}.

Studies in animals have not been done ^{01}.

Immunoglobulin G (IgG) is known to cross the placenta and therefore could cause fetal B cell depletion ^{01}.

It is recommended that women of childbearing potential use effective contraception during treatment and for up to 12 months following treatment with rituximab ^{01}. Risk-benefit should be considered before use of rituximab during pregnancy ^{01}.

FDA Pregnancy Category C ^{01}.

Breast-feeding

It is not known whether rituximab is distributed into human breast milk ^{01}. However, human IgG is distributed into human milk, although the potential for absorption and consequent immunosuppression in the infant is unknown ^{01}. It is recommended that women treated with rituximab not breast-feed until circulating drug levels are no longer detectable ^{01}.

Pediatrics

Safety and efficacy have not been established ^{01}.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Antihypertensive medications    (withholding of antihypertensive medications for 12 hours prior to rituximab administration should be considered because rituximab may cause hypotension ^{01})


Vaccines, killed virus or
Vaccines, live virus    (rituximab theoretically may inhibit the generation of an anamnestic or humoral response to any vaccine ^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
B-cell counts and
Immunoglobulin concentrations    (may be decreased; B cell depletion is associated with a decrease in serum immunoglobulin concentrations in a minority of patients; however, incidence of infection does not appear to be increased ^{01})


Blood pressure    (may be increased or decreased ^{01})


Calcium, serum    (decreases in concentrations have been reported infrequently ^{01})


Glucose, serum    (increases in concentrations [hyperglycemia] have been reported infrequently ^{01})


Hemoglobin concentrations and
Hematocrit    (may be decreased ^{01})


Lactate dehydrogenase (LDH), serum    (increases in values have been reported infrequently ^{01})


Neutrophil counts and
Platelet counts    (may be decreased ^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Sensitivity (type I) or previous anaphylactic reaction to rituximab^{01}
» Sensitivity (type I) or previous anaphylactic reaction to murine proteins^{01}
Risk-benefit should be considered when the following medical problems exist
Cardiac conditions (history of), including
Angina
Arrhythmias    (recurrences have been reported during rituximab therapy; monitoring throughout the infusion and immediately postinfusion is recommended ^{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood counts, complete and^{01}
Platelet counts    (recommended at periodic intervals during therapy, more frequently in patients who develop cytopenias ^{01})


Electrocardiogram (ECG)    (continuous monitoring recommended during administration of rituximab and during the immediate post-infusion period in patients with pre-existing cardiac conditions, including angina and arrhythmias; for patients who develop clinically significant arrhythmias during rituximab administration, continuous monitoring is recommended during subsequent administrations ^{01})






Side/Adverse Effects

Note: Patients treated with rituximab were evaluated for the presence of human antimurine antibody (HAMA) and human antichimeric antibody (HACA); development of these titers is associated with allergic or hypersensitivity reactions in patients treated with murine or chimeric monoclonal antibodies. No HAMA was detected and HACA was detected in less than 1% of patients. ^{01}
Severe and life-threatening (grades 3 and 4) reactions have occurred in a total of 10% of patients ^{01}. These included (in some cases, only in one patient) abdominal pain, anemia, angioedema, arthralgia, arrhythmia, asthenia, asthma, bronchiolitis obliterans, bronchospasm, chills, coagulation disorder, dyspnea, headache, hypertension, hypotension, hypoxia, increased cough, leukopenia, nausea, neutropenia, pruritus, rhinitis, skin rash, thrombocytopenia, urticaria, and vomiting ^{01}.
In most cases, incidence of side/adverse effects is the same for one course or several courses of treatment. However, side/adverse effects seen more frequently in re-treated subjects have included anemia, anorexia, asthenia, dizziness, flushing, leukopenia, mental depression, night sweats, peripheral edema, pruritus, respiratory symptoms, tachycardia, throat irritation, and thrombocytopenia. ^{01}
The incidence of any side/adverse effect in patients with bulky disease versus those with lesions less than 10 centimeters in diameter was similar. However, incidence of specific side/adverse effects (dizziness, neutropenia, thrombocytopenia, myalgia, anemia, chest pain) was higher in patients with lesions greater than 10 centimeters in diameter. In addition, the incidence of any grade 3 or 4 event was higher (31% versus 13%) and the incidence of grade 3 or 4 neutropenia, anemia, hypotension, and dyspnea was higher in patients with bulky disease versus those with lesions less than 10 centimeters in diameter. ^{01}
Although rituximab depletes B cells in 70 to 80% of patients, with an associated decrease in serum immunoglobulins in a minority of patients, the incidence of infection does not appear to be increased. Most infections that occur are not serious. Serious (grade 3) bacterial events reported in clinical trials included sepsis due to listeria, staphylococcal bacteremia, and polymicrobial sepsis; in the posttreatment period (30 days to 11 months after the last dose), bacterial infections reported included sepsis, and significant viral infections reported included herpes simplex infections and herpes zoster. ^{01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Infusion-related reaction ^{01}
including angioedema ^{01} (feeling of swelling of tongue or throat), bronchospasm or dyspnea ^{01} (shortness of breath), fatigue ^{01} (unusual tiredness), fever and chills ^{01}
flushing of face ^{01}
headache ^{01}
hypotension ^{01} (dizziness), nausea ^{01}
pruritus ^{01} (itching), rhinitis ^{01} (runny nose), urticaria ^{01} (skin rash), and vomiting ^{01}

Note: Fever and chills occur in a majority of patients during the first rituximab infusion ^{01}. Infusion-related reactions usually occur within 30 minutes to 2 hours of the beginning of the first infusion and can be resolved by slowing or interrupting the infusion and administering supportive care (intravenous saline, diphenhydramine, and acetaminophen) ^{01}. The incidence of these reactions is decreased with subsequent infusions ^{01}.
Mild to moderate hypotension may require interruption of the infusion, with or without administration of intravenous saline (sodium chloride) ^{01}.
Severe infusion reactions have been reported and have been associated with fatal outcomes; especially female gender, pulmonary infiltrates, and chronic lymphocytic leukemia or mantle cell lyphoma. Interruption of treatment may be needed and supportive care measures should be started as deemed medically needed, and treatment may be resumed at a reduced rate when symptoms have completely resolved.^{02}
Isolated cases of a severe infusion-related reaction requiring administration of epinephrine have been reported with use of rituximab for indications other than the labeled indication ^{01}.
Approximately 25% of patients who experienced bronchospasm have required treatment with bronchodilators ^{01}.


Incidence less frequent
    
Anemia ^{01} ( unusual tiredness or weakness)—usually asymptomatic
    
conjunctivitis ^{01} ( red, itchy lining of eye)
    
hypertension ^{01} —asymptomatic
    
mucocutaneous reactions, severe
including paraneoplastic pemphigus ( blisters in the mouth; blisters on the trunk, scalp, or other areas ; itching), stevens-johnson syndrome ( blistering, peeling, loosening of skin ; chills; cough ; diarrhea ; itching ; joint or muscle pain; red irritated eyes; red skin lesions, often with a purple center; sore throat; sores, ulcers, or white spots in mouth or on lips ; unusual tiredness or weakness), lichenoid dermatitis
vesiculobullous dermatitis
and toxic epidermal necrolysis ( blistering, peeling, loosening of skin; chills ; cough ; diarrhea; itching ; joint or muscle pain ; red irritated eyes ; red skin lesions, often with a purple center; sore throat ; sores, ulcers, or white spots in mouth or on lips; unusual tiredness or weakness)^{02}
    
neutropenia ^{01} (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination )—usually asymptomatic
    
pain at site of injection ^{01}
    
peripheral edema ^{01} (swelling of feet or lower legs)
    
thrombocytopenia ^{01} ( unusual bleeding or bruising; black, tarry stools; blood in urine or stools ; pinpoint red spots on skin)
    
tumor lysis syndrome
resulting in acute renal failure (lower back or side pain; decreased frequency or amount of urine; bloody urine; increased thirst ; loss of appetite; nausea ; vomiting ; unusual tiredness or weakness ; swelling of face, fingers, lower legs; weight gain ; troubled breathing; increased blood pressure), hyperkalemia ( confusion; irregular heartbeat ; nervousness ; numbness or tingling in hands, feet, or lips ; shortness of breath; difficult breathing ; weakness or heaviness of legs), hypocalcemia
hyperuricemia (joint pain lower back or side pain swelling of feet or lower legs), and hyperphosphatemia ( muscle cramps; numbness, tingling, pain, or weakness in hands or feet; shortness of breath or troubled breathing)^{02}

Note: Tumor lysis syndrome was reported within 12–24 hours after the first infusion; risks appear to be greater in patients with high numbers of circulating malignant cells or high tumor burden. ^{02}


Note: During the treatment period, and for up to 30 days following the last dose, severe anemia, neutropenia, or thrombocytopenia has been reported in 1%, 1.9%, and 1.3% of patients, respectively ^{01}.


Incidence rare
    
Angina ^{01} ( chest pain)
    
cardiac arrhythmias, including ventricular tachycardia, supraventricular tachycardia, trigeminy, and irregular pulse ^{01} (irregular heartbeat)

Note: Bradycardia also has been reported ^{01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
—1 to 5%    
Abdominal or stomach pain ^{01}
    
agitation or anxiety ^{01}
    
arthralgia ^{01} (joint pain)
    
asthenia or hypotonia ^{01} (feeling of weakness)
    
back pain ^{01}
    
change in taste ^{01}
    
diarrhea ^{01}
    
dyspepsia ^{01} (heartburn)
    
hypesthesia or paresthesia ^{01} (numbness or tingling of hands or feet)
    
increased cough ^{01}
    
insomnia ^{01} (trouble in sleeping )
    
lacrimation disorder ^{01} (dry eyes)
    
loss of appetite ^{01}
    
malaise ^{01} (general feeling of discomfort or illness)
    
myalgia ^{01} (muscle pain)
    
nervousness ^{01}
    
sore throat ^{01}
    
swelling of stomach ^{01}



Those indicating the need for medical attention if they occur after medication is discontinued
    
Anemia ^{01} ( unusual tiredness or weakness)—usually asymptomatic
    
neutropenia ^{01} ( fever or chills; cough or hoarseness ; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia ^{01} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

Note: During the treatment period, and for up to 30 days following the last dose, severe anemia, neutropenia, or thrombocytopenia has been reported in 1%, 1.9%, and 1.3% of patients, respectively ^{01}.





Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Type I sensitivity or previous anaphylactic reaction to rituximab or to murine proteins

Pregnancy—Use of contraception recommended in women of child-bearing potential; risk-benefit should be considered during pregnancy





Breast-feeding—Not recommended as long as rituximab is detectable in the blood because of the risk of absorption and consequent immunosuppression in the infant

Proper use of this medication

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially infusion-related reaction (angioedema, bronchospasm or dyspnea, fatigue, fever and chills, flushing of face, headache, hypotension, nausea, pruritus, rhinitis, urticaria, vomiting), conjunctivitis, pain at site of injection, peripheral edema, thrombocytopenia, angina, and cardiac arrhythmias

Asymptomatic side effects, including anemia, hypertension, and neutropenia.


General Dosing Information
Rituximab is recommended for administration by intravenous infusion only ^{01}. Rapid intravenous (push or bolus) administration is not recommended ^{01}.

It is recommended that medications for hypersensitivity reactions (e.g., epinephrine, antihistamines, corticosteroids) be available for each administration of rituximab ^{01}.

Premedication with acetaminophen and diphenhydramine may attenuate the hypersensitivity reaction and should be considered before each dose of rituximab ^{01}.

If a severe infusion-related reaction occurs, it is recommended that the infusion be discontinued. The infusion may be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Treatment of symptoms with diphenhydramine and acetaminophen is recommended, along with bronchodilators or intravenous sodium chloride if indicated. In most cases, the occurrence of non–life-threatening reactions has not prevented completion of the full course of therapy. ^{01}

If a serious or life-threatening cardiac arrhythmia occurs, it is recommended that the infusion be discontinued. Cardiac monitoring during and following subsequent infusions is recommended in patients who develop clinically significant arrhythmias. ^{01}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

RITUXIMAB CONCENTRATE FOR INJECTION

Usual adult dose
Lymphomas, non-Hodgkin's (treatment)
Intravenous infusion, 375 mg per square meter of body surface area once a week for four doses (on days 1, 8, 15, and 22) ^{01}.

Note: An initial intravenous infusion rate of 50 mg per hour (mg/hr) is recommended ^{01}. If hypersensitivity or other infusion-related events do not occur, the infusion rate may be increased in 50 mg/hr increments every thirty minutes up to a maximum rate of 400 mg/hr ^{01}. For subsequent infusions, an initial rate of 100 mg/hr may be used, increased in 100 mg/hr increments at thirty-minute intervals up to a maximum rate of 400 mg/hr ^{01}.


Note: In the [first-line treatment of low-grade non-Hodgkin's lymphoma]^1{68}, [first-line treatment of diffuse aggressive non-Hodgkin's lymphoma]^1{91}, and treatment of [relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma]^1{88}, several doses and regimens using rituximab are showing activity. Therefore, no individual dose/regimen is listed here. Consult the medical literature and/or experts in the field of oncology for information on dosage.^{68}{88}{91}


[Leukemia, chronic lymphocytic ]¹or
[Waldenstrom's macroglobulinemia ]¹
Because several doses and regimens using rituximab are working well, no individual dose/regimen is listed here. Consult the medical literature and/or experts in the field of oncology for information on dosage.^{27}{38}

[Thrombocytopenic purpura, immune or idiopathic (treatment)]¹
Intravenous infusion, 375 mg per square meter of body surface area once a week for four weeks. ^{{39}{40}{41}{42}{43}{44}}.


Usual pediatric dose
Safety and efficacy have not been established ^{01}.

Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Rituxan (sodium chloride ) (sodium citrate dihydrate) ( polysorbate 80)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) ^{01}. Protect from direct sunlight ^{01}.

Preparation of dosage form:
Rituximab concentrate for injection is prepared for administration by intravenous infusion by withdrawing the necessary amount of drug and diluting it, in an infusion bag, to a final concentration of 1 to 4 mg per mL (mg/mL) with 0.9% sodium chloride injection or 5% dextrose injection ^{01}. The bag is then gently inverted to mix the solution ^{01}.

Stability:
Contains no preservative; any unused portion of a vial should be discarded ^{01}. Rituximab solutions prepared for intravenous infusion are stable for 24 hours at 2 to 8 °C (36 to 46 °F) and for an additional 12 hours at room temperature. Incompatibilities between rituximab and polyvinyl chloride or polyethylene infusion bags have not been observed ^{01}.

Developed: 03/23/1998
Revised: 12/09/2002

References

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4. Seipelt G, Bohme A, Koschmieder S, et al. Effective treatment with rituximab in a patient with refractory prolymphocytoid transformed B-chronic lymphocytic leukemia and Evans syndrome. Ann Hematol 2001; 80(3): 170-3.
   

5. O'Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19(8): 2165-70.
   

6. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice-weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19(8): 2153-64.
   

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11. Weiss MA. Novel treatment strategies in chronic lymphocytic leukemia. Curr Oncol Rep 2001; 3(3): 217-22.
    

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14. Rai KR, Gupta NK, Janson D, et al. Rituximab, cyclophosphamide and decadron combination is highly effective in auto-immune hemolytic anemia associated with chronic lymphocytic leukemia. Blood 2000; 96(11): 754a [Abst 3264].
    

15. Lanum SA, Lynch JW, Johnson ML, et al. Rituximab use at Shands-University of Florida. Proc Am Soc Clin Oncol 2000; 19: 37a [Abst 139].
    

16. Ladetto M, Bergui L, Ricca I, et al. Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukemia patients. Med Oncol 2000; 17(3): 203-10.
    

17. Herold M, Schulze A, Hartwig K, et al. Successful treatment and re-treatment of resistant B-cell chronic lymphocytic leukemia with the monoclonal anti-CD 20 antibody rituximab. Ann Hematol 2000; 79(6): 332-5.
    

18. Keating M, O'Brien S. High-dose rituximab therapy in chronic lymphocytic leukemia. Semin Oncol 2000; 27(6 Suppl 12): 86-90.
    

19. Keating MJ, O'Brien S, Lerner S, et al. Combination chemo-antibody therapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) achieves a high CR rate in previously untreated chronic lymphocytic leukemia (CLL). Blood 2000; 96(11): 514a [Abst 2214].
    

20. Itala M, Geisler CH, Kimby E, et al. Efficacy and tolerability of rituximab in chronic lymphocytic leukemia: results from a Nordic multicenter pilot study. Blood 2000; 96(11): 288b [Abst 4988].
    

21. Garcia-Manero G, O'Brien S, Cortes J, et al. Combination fludarabine, cyclophosphamide and rituximab for previously treated patients with chronic lymphocytic leukemia (CLL). Blood 2000; 96(11): 757a [Abst 3275].
    

22. Nguyen DT, Amess JA, Doughty H, et al. IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol 1999; 62(2): 76-82.
    

23. Byrd JC, Waselenko JK, Maneatis TJ, et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17(3): 791-5.
    

24. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999; 62(4): 247-50.
    

25. Lim LC, Koh LP, Tan P. Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia. J Clin Oncol 1999; 17(6): 1962-3.
    

26. Winkler U, Jensen M, Manzke O, et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999; 94(7): 2217-24.
    

27. Reviewers' consensus on ballot for the use of rituximab in the treatment of chronic lymphocytic leukemia (CLL), 9/20/01.
    

28. Dimopoulos MA, Kiamouris C, Karkantaris C, et al. Prospective evaluation of rituximab for the treatment of waldenstrom's macroglobulinemia. Blood 2000; 96(11): 169a [Abst 727].
    

29. Foran JM, Rohatiner AZ, Cunningham D, et al. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000; 18(2): 317-24.
    

30. Treon SP, Agus DB, Link B, et al. Rituximab is an active agent in waldenstrom's macroglobulinemia (WM). Proc Am Soc Clin Oncol 2000; 19: 6a [Abst 13].
    

31. Weide R, Heymanns J, Koppler H. The polyneuropathy associated with Waldenstrom's macroglobulinemia can be treated effectively with chemotherapy and the anti-CD20 monoclonal antibody rituximab. Br J Haematol 2000; 109(4): 838-41.
    

32. Gertz MA, Fonseca R, Rajkumar SV. Waldenstrom's macroglobulinemia. Oncologist 2000; 5(1): 63-7.
    

33. Byrd JC, White CA, Link B, et al. Rituximab therapy in Waldenstrom's macroglobulinemia: preliminary evidence of clinical activity. Ann Oncol 1999; 10(12): 1525-7.
    

34. Weide R, Heymanns J, Koppler H. Induction of complete hematological remission after monotherapy with anti-CD20 monoclonal antibody (RITUXIMAB) in a patient with alkylating agent resistant Waldenstrom's macroglobulinemia. Leuk Lymphoma 1999; 36(1-2): 203-6.
    

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36. Weber DM, Gavino M, Huh Y, et al. Phenotypic and clinical evidence supports rituximab for Waldenstrom's macroglobulinemia. Blood 1999; 94(10 Suppl 1): 125a [Abst 551].
    

37. Treon SP, Shima Y, Preffer FI, et al. Treatment of plasma cell dyscrasias by antibody-mediated immunotherapy. Semin Oncol 1999; 26(5 Suppl 14): 97-106.
    

38. Reviewers' consensus on ballot for the use of rituximab in the treatment of waldenstrom's macroglobulinemia, 11/14/01.
    

39. Reviewers' consensus on ballot of 7/2002.
    

40. Saleh MN, Moore M, Feinberg B, et al. A pilot study of anti-CD20 MoAB rituximab in patients with refractory immune thrombocytopenic purpura (ITP). Blood 2001a;96:521a.
    

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42. Cooper N, Bussel J. Rituximab treatment in patients with immune thrombocytopenic purpura (ITP). Blood 2001a;98:521–522a.
    

43. Giangounidis AN, Anhuf J, Schneider P, et al. Treatment of relapsed idiopathic thrombocytopenic purpura with the anti-CD20 antibody rituximab. Blood 2001;98:523a.
    

44. Perotta A, Sunneberg TA, Scott J, et al. Rituximab in the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Blood 1999;94(10):14.
    

45. Rambaldi A, Lazzari M, Manzoni C, et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood 2002 Feb 1; 99(3): 856-62.
    

46. Czuczman MS, Fallon A, Mohr A, et al. Rituximab in combination with CHOP or fludarabine in low-grade lymphoma. Semin Oncol 2002 Feb; 29(1 Suppl 2): 36-40.
    

47. Solal-Celigny P. Rituximab as first-line monotherapy in low-grade follicular lymphoma with a low tumor burden. Anti-Cancer Drugs 2001; 12 (Suppl 2): S11-4.
    

48. Hainsworth JD, Burris III HA, Morrissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade NHL. Blood 2000 May 15; 95(10): 3052-6.
    

49. McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 2000 Dec; 27(6 Suppl 12): 37-41.
    

50. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999 Jan; 17 (1): 268-76.
    

51. Hainsworth JD, Burris III HA, Yardley DA, et al. Rituximab plus short duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma (NHL): a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol 2002; 21: [Abst 1070].
    

52. Drapkin R, Dibella N, Khan M, et al. Phase II multicenter trial of pentostatin (P) and rituximab (R) in patients (pts) with previously treated and untreated low grade B-cell non-Hodgkin's lymphoma (NHL). Proc Am Soc Clin Oncol 2002; 21: [Abst 1134].
    

53. Hainsworth JD, Burris III HA, Morrissey LH, et al. Rituximab as first-line and maintenance therapy for patients (pts) with indolent NHL. Proc Am Soc Clin Oncol 2001; 20: 294a [Abst 1175].
    

54. Maloney DG, Press OW, Braziel RM, et al. A phase II trial of CHOP followed by rituximab chimeric monoclonal anti-CD20 antibody for treatment of newly diagnosed follicular NHL: SWOG 9800. Blood 2001; 98: 843a [Abst 3502].
    

55. Gregory SA, Venugopal P, Adlet SS, et al. Safety and efficacy of fludarabine and mitoxantrone with rituximab in untreated low-grade NHL. Blood 2001; 98: 605a [Abst 2534].
    

56. Savage DG, Cohen NS, Hesdorffer CS, et al. Combined fludarabine and rituximab for low-grade lymphoma and chronic lymphocytic leukemia. Blood 2001; 98: 248b.
    

57. Vitolo U, Boccomini C, Astolfi M, et al. Chemoimmunotherapy with fludarabine + mitoxantrone + dexamethasone (FND) and rituximab in indolent NHL: a pilot study to evaluate feasibility, safety, clinical and molecular response. Blood 2001; 98: 251-2b [Abst 4737].
    

58. Kirschbaum MH, Nadav L, Goor O, et al. Day 1 rituximab followed by day 3 CHOP treatment protocol for bulky high- and low-grade lymphomas. Blood 2001; 98: 243b.
    

59. Rubio-Borja ME, Tripp FJ, Baez E, et al. Outcome and experience of the Mexican Hematology Study Group (MHSG) for NHL patients treated with rituximab. Blood 2001; 98: 248b.
    

60. Cabanillas F, McLaughlin P, Hagemeister F, et al. Molecular responses with FND + Rituxan chemoimmunotherapy for stage IV indolent follicular NHL. Blood 2000; 96(11): [Abst 1429].
    

61. Birhiray R, Rudolf D, Trynoski S, et al. CHOP, Rituximab, and Intron A® as initial therapy for follicular lymphomas. Blood 2000; 96(11): [Abst 4744].
    

62. Gutheil J, Finucane D, Rodriguez R, et al. Phase II study of rituximab (Rituxan) in patients with previously untreated low-grade or follicular NHL. Proc Am Soc Clin Oncol 2000; 19: 22a [Abst 79].
    

63. Hainsworth JD, Burris III HA, Morrissey LH, et al. Rituximab as Initial Therapy for Patients with Low-Grade Non-Hodgkin's Lymphoma (NHL). Proc Am Soc Clin Oncol 2000; 19: 46a [Abst 178D].
    

64. Hess GR, Flohr T, Hiddemann W, et al. First-line treatment of indolent CD20+ NHL with a combination of CHOP + Rituximab followed by consolidation with high-dose chemotherapy (HDT) and PBSC-transplantation. Blood 2000; 96(11): 370b [Abst 5352].
    

65. Jäger G, Brezinschek R, Neumeister P, et al. Consolidation with rituximab (MAB-THERA™) after CHOP-induction as first-line treatment of follicular lymphoma. A phase II study. Blood 2000; 96(11): [Abst 4766].
    

66. Kimby E, Geisler C, Hagberg H, et al. Rituximab (Mabthera®) as single agent and in combination with interferon-a-2a as treatment of untreated and first relapse follicular or other low-grade lymphomas. A randomized phase II study M39035. Blood 2000; 96: 577a [Abst 2479].
    

67. Emmanouilides C, Teletar M, Rosen P, et al. Excellent tolerance of Rituxan when given after mitoxantrone-cyclophosphamide: an effective and safe combination for indolent NHL. Blood 1999; 94(10 Suppl 1): [Abst 402].
    

68. Reviewers' consensus on the use of rituximab for the first-line treatment of low-grade non-Hodgkin's lymphoma (NHL) ballot, 12/2/02.
    

69. Flohr T, Hess G, Kolbe K, et al. Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL. Bone Marrow Transplant 2002 May; 29(9): 769-75.
    

70. Wilson WH, Gutierrez M, O'Connor P, et al. The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. Semin Oncol 2002 Feb; 29(1 Suppl 2): 41-7.
    

71. Coiffier B. Rituximab in combination with CHOP improves survival in elderly patients with aggressive NHL. Semin Oncol 2002 Apr; 29(2 Suppl 6): 18-22.
    

72. Ladetto M, Zallio F, Vallet S, et al. Concurrent administration of high-dose chemotherapy and rituximab is a feasible and effective chemo/immunotherapy for patients with high-risk NHL. Leukemia 2001; 15: 1941-9.
    

73. Egerer G, Sauerland K, Ho AD. Remarkable response to rituximab in a 72-year-old patient with refractory non-Hodgkin's lymphoma and marrow aplasia. Leuk Lymphoma 2001 Jul; 42(3): 551-3.
    

74. Tsai DE, Moore HCF, Hardy CL, et al. Rituximab (anti-CD20 monoclonal antibody) therapy for progressive intermediate-grade non-Hodgkin's lymphoma after high-dose therapy and autologous peripheral stem cell transplantation. Bone Marrow Transplant 1999 Sep; 24(5): 521-6.
    

75. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade NHL and CLL. Am J Hem 1999; 62: 247-50.
    

76. Tobinai K, Kobayashi Y, Narabayashi M, et al Feasibility and pharmacokinetics study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. Ann Oncol 1998; 9: 527-34.
    

77. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 96 (6 Suppl 15) 1927-32.
    

78. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 1997 Oct; 15(10): 3266-74.
    

79. Igarashi T, Itoh K, Kobayashi Y, et al. Phase II and pharmacokinetic study of rituximab with eight weekly infusions in relapsed aggressive B-cell non-Hodgkin's lymphoma (B-NHL). Proc Am Soc Clin Oncol 2002; 21: [Abst 1142].
    

80. Leonard JP, Coleman M, Matthews JC, et al. Epratuzumab (anti-CD22) and rituximab (anti-CD20) combination immunotherapy for non-Hodgkin's lymphoma: preliminary response data. Proc Am Soc Clin Oncol 2002; 21: [Abst 1060].
    

81. Jost LM, Jermann M, Stahel RA, et al. Rituximab-EPOCH - an effective salvage regime for relapsed, refractory, or transformed B-cell lymphoma. Results of a phase II study. Proc Am Soc Clin Oncol 2001: 20: 290a [Abst 1157].
    

82. Lanum SA, Lynch JW, Johnson ML, et al. Rituximab use at Shands-University of Florida. Proc Am Soc Clin Oncol 2000; 19: 37a [Abst 139].
    

83. Gutierrez ME, Grossbard ML, Little RF, et al. Dose-adjusted EPOCH chemotherapy (CT) and rituximab (EPOCH-R): an effective regimen in poor prognosis aggressive B-cell non-Hodgkin's lymphoma (NHL). Proc Am Soc Clin Oncol 2000; 19: 26a [Abst 95].
    

84. Pan D, Moskowitz CH, Zelenetz AD, et al. Clinical outcomes of patients treated with rituximab for relapsed or refractory aggressive NHL in the post-transplant setting. Blood 2000; 96: 405a [Abst 1746].
    

85. Winkler U, Shultz HR, Klein TO, et al. Treatment of patients with mantle-cell and aggressive B-cell non-Hodgkin's lymphoma using the monoclonal anti-CD20 antibody rituximab (Rituxan™): evaluation of safety and response. Blood 1999; 94 (Suppl 1): 270b [Abst 4419].
    

86. Aung A, Krishnan J, Lessin L, et al. A pilot study of combined therapy with rituximab and EPOCH in refractory or relapsed diffuse large B-cell nonHodgkin's lymphoma (NHL). Blood 1999; 94(10 Suppl 1): 257b [Abst 4358].
    

87. Jensen M, Schulz H, Winkler T, et al. Treatment of low and high-grade B-cell lymphoma with the monoclonal anti-CD20 antibody rituximab: monocenter experience in 71 patients. Ann Oncol 1999 Jun; 10(Suppl 3): 178 [Abst 658].
    

88. Reviewers' consensus on the use of rituximab for the treatment of relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma (NHL) ballot, 12/2/02.
    

89. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 2001 Jan 15;19(2):389-97.
    

90. Wilson WH, Frankel SR, Drbohlav N, et al. Phase II study of dose-adjusted EPOCH-Rituximab in untreated high-risk large B-cell lymphomas. Proc Am Soc Clin Oncol 2001; 20: 290a [Abst 1158].
    

91. Reviewers' consensus on the use of rituximab for the first-line treatment of diffuse aggressive non-Hodgkin's lymphoma (NHL) ballot, 12/2/02.
    

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