eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Follicular

Cesar O Freytes, MD, FACP, Director of Bone Marrow Transplant Program, Professor, Department of Internal Medicine, Division of Hematology, University of Texas Health Science Center at San Antonio
Julianna A Burzynski, PharmD, BCOP, BCPS, Clinical Pharmacy Specialist in Hematology/Oncology, Mayo Clinic

Updated: Nov 3, 2009

Introduction

Background

Non-Hodgkin lymphoma is a heterogeneous group of malignancies of lymphocyte origin that usually arise or are present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow. Nevertheless, lymphomas can arise in any organ and usually are referred to as primary extranodal lymphomas. Microscopically, follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers. Despite the fact that most follicular lymphomas are advanced at the time of diagnosis, the median survival of patients with follicular lymphomas is approximately 8-10 years, and many patients may not require treatment for prolonged periods of time.¹ (See images below and Images 1-3.)

Follicular lymphoma, low-power view: Note the nodular pattern reminiscent of germinal centers. Photograph courtesy of Aamir Ehsan, MD.

Diffuse lymphoma: Note the absence of the nodular pattern observed in follicular lymphomas. Photograph courtesy of Aamir Ehsan, MD.

A patient with follicular lymphoma who was diagnosed 6 years earlier presents to his hematologist's office because of rapidly growing lymphadenopathy and a new onset of fever, severe night sweats, and weight loss. In the past, he had been treated with chlorambucil and prednisone when his submandibular lymph nodes became large enough to make him uncomfortable. This treatment had worked well, and he has not required any treatment recently. A biopsy of an involved lymph node is obtained (see image). The diagnosis is transformation to diffuse non-Hodgkin lymphoma.

Pathophysiology

Most lymphomas originate from lymph node tissue and frequently metastasize to other organs. Lymphomas can invade any organ, including the skin and central nervous system. Lymphomas cause detrimental effects by organ invasion and by obstruction of anatomical structures by a tumoral mass.^2,3 For example, ureteral obstruction by enlarged lymph nodes can lead to renal failure.

Frequency

United States

Non-Hodgkin lymphoma is the fifth most frequently diagnosed malignancy in the United States. Estimates indicate that more than 66,000 cases of non-Hodgkin lymphoma were diagnosed in 2008. Of those, 15-20% were follicular lymphomas.⁴

International

In general, age-adjusted incidence rates of non-Hodgkin lymphoma are higher in more developed countries. The age-adjusted incidence rates of non-Hodgkin lymphoma varied from 3.7-14 per 100,000 person years from 1983-1987 in different countries.

Mortality/Morbidity

• The overall survival rate at 5 years is 72-77%. Median survival is approximately 8-10 years.
• The Follicular Lymphoma International Prognostic Index (FLIPI) is predictive of survival in patients with follicular lymphomas. Five adverse prognostic factors have been shown to be correlated with reduced overall survival: age older than 60 years, Ann Arbor stage III or IV disease, hemoglobin less than 12 g/dL, presence of more than 4 nodal sites of disease, and serum lactate dehydrogenase above normal. Patients with 3 or more of the above risk factors have a 10-year overall survival rate of 36% compared with 71% for those with one or none of the above variables.

Race

Variations in racial incidence are found throughout the world. The incidence of follicular lymphomas is low in China and Japan. People of Jewish ancestry have a higher incidence of lymphoma. In the United States, the incidence is 2-3 times higher in Caucasians than in African Americans.

Sex

The male-to-female ratio is approximately 1:1.

Age

Median age at diagnosis is 60-65 years. The incidence of follicular lymphomas increases with age. Follicular lymphomas are extremely rare in children.

Clinical

History

• Painless, slowly progressive adenopathy is the most frequent clinical presentation.
• Some patients have waxing and waning adenopathy.
• Systemic symptoms, such as fever, night sweats, weight loss in excess of 10%, or asthenia, are infrequent at presentation but can be observed in later stages of the disease. Progression to an intermediate-grade or high-grade lymphoma should be considered when a patient develops systemic symptoms.
• Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can be observed in the later stages of the disease.

Physical

• All lymph node areas should be examined, including the retroauricular, submandibular, cervical, supraclavicular, axillary, epitrochlear, inguinal, and popliteal areas.
• Involved nodes typically are nontender, firm, and rubbery in consistency.
• Splenomegaly is present in approximately 50% of patients at presentation.
• The throat should be examined for involvement of the oropharyngeal lymphoid tissue (ie, Waldeyer ring).

Causes

• Acquired nonrandom chromosomal translocations
  • The most common in patients with follicular lymphomas is the t(14;18) translocation, which is found in more than 80% of cases. This chromosomal translocation brings the bcl2 protooncogene under the transcriptional influence of the immunoglobulin heavy-chain gene. This translocation leads to the overexpression of a functionally normal bcl-2 protein. Overexpression of the bcl-2 protein, a protein of the mitochondrial membrane, confers a survival advantage to the cancer cells by inhibiting programmed cell death, or apoptosis. Although the exact mechanism of action of bcl-2 is unclear, its interaction with other homologs is felt to determine the likelihood of a cell undergoing apoptosis.
  • The detection of the t(14;18) product by polymerase chain reaction is used frequently in the diagnosis and follow-up of patients with follicular lymphomas. Nevertheless, this translocation has been detected in healthy patients and in patients with other types of tumors.
• Viruses have been implicated as etiologic factors for lymphomas, including the Epstein-Barr virus, human T-cell lymphotropic virus type I, and the herpesvirus associated with Kaposi sarcoma (ie, human herpesvirus 8). Nevertheless, these viruses have been linked mostly to diffuse or high-grade lymphomas.
• Chemicals, such as pesticides and hair dyes, have been associated with lymphoma.
• Immunodeficiency states
  • Congenital immunodeficiencies have been associated with lymphoma.
  • Acquired immunodeficiencies may include infection with the human immunodeficiency virus. Most lymphomas associated with the human immunodeficiency virus are intermediate-grade or high-grade lymphomas.
  • Patients who have been on immunosuppressant drugs after organ transplantation may develop lymphoma. Most of the lymphomas observed after organ transplantation are diffuse or high-grade lymphomas.

Differential Diagnoses

Chronic Lymphocytic Leukemia
Lymphoma, Diffuse Large Cell
Lymphoma, Diffuse Mixed
Lymphoma, Lymphoblastic
Mucosa-Associated Lymphoid Tissue

Other Problems to Be Considered

Autoimmune disorders
Chronic infections

Workup

Laboratory Studies

• Complete blood count should be obtained, including examination of the peripheral blood smear.
• Frequently, abnormal lymphocytes can be identified in the blood smear.
• Blood chemistries, including LDH, uric acid, liver function tests, and creatinine, should be assessed.
• LDH is an indicator of tumor load.
  • Elevated LDH is a negative prognostic factor.
  • Hyperuricemia can be observed upon presentation or during therapy.
  • Allopurinol should be considered in patients with hyperuricemia and before treatment to prevent uric acid nephropathy.
  • Increased creatinine can be observed in patients with renal obstruction caused by lymphadenopathy.
  • Increased alkaline phosphatase and bilirubin can be observed in patients with biliary obstruction due to lymphadenopathy.

Imaging Studies

• Chest radiograph should be performed.
• CT scan of chest should be considered if the findings from the chest radiograph are abnormal or cause suspicion.
• CT scans of the abdomen and pelvis should be performed to determine if abdominal or pelvic adenopathy is present.
• CT scans allow visualization of the kidneys, ureters, and the hepatobiliary system. At times, these organs are affected by obstruction due to lymphadenopathy or by parenchymal involvement with lymphoma.
• Positron emission tomography (PET) scanning complements standard radiologic testing, but only a minority of patients will be diagnosed with a higher stage of disease.
• PET scanning can distinguish between viable tumor and fibrosis in patients with residual lymphadenopathy after therapy, but because the majority of patients with follicular lymphoma are not curable, this finding will not change management. This is in contrast to Hodgkin lymphoma and intermediate-grade lymphoma where a positive PET scan might prompt salvage chemotherapy or radiation.

Procedures

• Pathologic diagnosis from biopsy specimen
  • Biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy of an involved node.
  • A needle aspiration is not adequate for the initial diagnosis of lymphoma. If the disease is extranodal, a surgical biopsy sample should be obtained from the involved organ.
• Bilateral posterior iliac crest bone marrow aspiration and biopsies
  • Although a diagnosis of follicular lymphoma can be established based on histologic findings from lymph nodes and involvement of the bone marrow can be diagnosed using morphologic criteria, cytogenetic analysis of bone marrow cells should be performed because the t(14;18) translocation is found in the majority of patients with follicular lymphoma and can help establish the diagnosis.
  • Immunophenotyping of bone marrow using flow cytometry also should also be performed. It can detect an abnormal clone of B cells, which also can help establish the diagnosis.
  • Polymerase chain reaction for bcl-2 in bone marrow also can help establish the diagnosis because the majority of follicular lymphomas are positive for bcl-2.

Histologic Findings

Follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers. This follicular pattern of growth contrasts with diffuse lymphomas, which usually are intermediate or high-grade neoplasms.

Several pathologic classification systems have been used since the late 1960s, including the Rappaport, Lukes-Collins, Kiel, Working Formulation, Revised European-American Classification of Lymphoid Neoplasms (REAL), and World Health Organization (WHO). Early classification systems relied solely on the architecture and cytologic appearance of lymph nodes. As more sophisticated tests became available, immunophenotypic, cytogenetic, and molecular criteria were incorporated in the diagnosis of lymphomas. REAL was based on the premise that a classification should attempt to define disease entities using all available information, including morphology characteristics and immunophenotypic, genetic, and clinical features.

More recently, the WHO classification of lymphoid neoplasms adopted the REAL classification and proposed several changes. The WHO classification changed the nomenclature from follicle center cell lymphoma to follicular lymphoma. The WHO classification calls for grading of the follicular lymphoma from grades 1-3 based on the number of centroblasts per high-power field (hpf) and recognizes the importance of reporting on the presence of diffuse areas. In addition, the WHO classification recognizes 2 variants of follicular lymphomas: cutaneous follicle center cell lymphoma and diffuse follicle center lymphoma. Follicular lymphoma according to the WHO classification is staged as grade 1 (0-5 centroblasts per hpf), grade 2 (6-15 centroblasts per hpf), and grade 3 (>15 centroblasts). Variants include cutaneous follicle center cell lymphoma and diffuse follicle center cell lymphoma.

Importantly, progression to diffuse large-cell lymphoma occurs in 10-50% of patients depending on the duration of disease presence. Transformation to diffuse large-cell lymphoma frequently is associated with rapid progression of the disease, including increasing adenopathy, development of systemic symptoms, and infiltration of extranodal sites. Progression to large-cell lymphoma is a poor prognostic factor, and most patients who experience transformation succumb to the disease.

Staging

Most patients with follicular lymphoma present at an advanced stage. Most patients have bone marrow involvement at diagnosis.

• Stage I - One involved lymph node or lymph node area
• Stage II - Two or more involved lymph nodes or lymph node areas on the same side of diaphragm
• Stage III - Involved lymph node or lymph node areas on both sides of diaphragm
• Stage IV - Disseminated disease such as bone marrow, liver, or central nervous system involvement

Treatment

Medical Care

• The rare patient who presents with localized disease should be treated with radiation therapy with curative intent; approximately half of these patients will be cured with radiation alone. Unfortunately, fewer than 10% of patients with follicular lymphoma present with localized disease.
• The treatment for advanced stage disease is considered palliative, because most follicular lymphomas are disseminated and incurable at the time of diagnosis. Many experts recommend observation until the patient develops systemic symptoms, such as fever, weight loss, or bulky lymphadenopathy, because early therapy has not been shown to impact overall survival. Patients in whom treatment is deferred should be followed closely for complications such as ureteral or biliary obstruction. No universally accepted first-line treatment strategy exists for stage III/IV follicular lymphoma.
• Single-agent chemotherapy is an option for patients with symptomatic disease.⁵ Single agents tend to have lower response rates and provide a shorter duration of disease control than do combination chemotherapy regimens. Nonetheless they are appropriate for selected patients, because they may be simpler to administer, induce less toxicity, and palliate symptoms.
  • Chlorambucil is an oral alkylating agent that is often reserved for elderly patients with a poor performance status or those who wish to defer intravenous therapy. Few patients will have a complete response and there is no impact on overall survival.
  • Single-agent fludarabine must be administered intravenously and causes a significant degree of myelosuppression and immunosuppression. There is also some concern that therapy with fludarabine may impair the ability to collect hematopoietic stem cells for an autologous stem cell transplant. Fludarabine is associated with higher response rates than single-agent chlorambucil is, but with no impact on overall survival.
  • Rituximab (Rituxan), a monoclonal antibody targeting the CD20 antigen expressed on the cell surface of most lymphoma cells, has demonstrated efficacy as a single agent and as part of combination chemotherapy regimens. It is generally well tolerated but is significantly more expensive than most other therapies; there has been no definitive improvement found in overall survival when the drug is administered as a single agent. Clinical trials using rituximab as maintenance therapy suggested that this strategy prolonged progression-free survival in patients who had an objective response or stable disease following rituximab monotherapy.^6,7
• Combining multi-agent chemotherapy and rituximab is the most common first line treatment strategy in the United States. Several studies have compared combination chemotherapy with and without rituximab; the rituximab containing regimens generally produce a higher response rate and a more durable response. A meta-analysis confirmed an improvement in overall survival in patients with follicular lymphoma, associated with the addition of rituximab to combination chemotherapy regimens.
• Combination chemotherapy regimens vary; they include the following:
  • Rituximab, cyclophosphamide, vincristine, prednisone (R-CVP)
  • Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)
  • Fludarabine, cyclophosphamide, rituximab (FCR)
  • Rituximab, fludarabine, cyclophosphamide, mitoxantrone (R-FCM)
  • Fludarabine, rituximab (FR)
• Hematopoietic stem cell transplantation has a role in the treatment of follicular lymphoma, especially in younger patients with relapsed or recurrent disease. Allogeneic hematopoietic stem cell transplantation can induce long-term remissions in patients with follicular lymphoma, but transplant-related mortality is high. Autologous hematopoietic stem cell transplantation has a low transplant-associated mortality and prolongs progression-free survival; in one randomized, controlled trial, improvement in overall patient survival was observed. However, most patients eventually relapse after undergoing this therapy, and there is an increased rate of secondary malignancies. Hematopoietic stem cell transplantation is generally reserved for patients with relapsed or refractory disease.
• Follicular lymphoma is inherently radiosensitive, so the development of targeted radioimmunotherapy⁹ to the CD20 marker expressed on B cells has been a significant advance. It enables the delivery of cytocidal doses of radiation to all sites of disseminated disease. Currently, 2 agents are available for this type of treatment: iodine-131 – labeled tositumomab (Bexxar) and yttrium-90 – labeled ibritumomab tiuxetan (Zevalin).⁸ Both agents have produced high response rates in patients with relapsed or refractory and treatment-naive follicular lymphoma.
• Iodine-131 – labeled tositumomab and yttrium-90 – labeled ibritumomab tiuxetan have demonstrated improvements in progression-free survival but not in overall patient survival. Ongoing clinical trials are utilizing these agents in consolidation therapy following an initial chemotherapy regimen or as part of a hematopoietic stem cell transplantation regimen, in an attempt to achieve a complete response in a higher proportion of patients.
• The use of radioimmunoconjugates is limited in United States by the need for highly trained staff and specialized equipment, the expense of therapy, the risk for secondary malignancies, and the relatively short duration of follow-up.

Surgical Care

The role of the surgeon is to obtain an excisional biopsy adequate to establish the diagnosis. The surgeon should be instructed about the proper handling of the specimen and the special tests required because the biopsy might require special handling. The surgeon should probably discuss these issues with the pathologist prior to performing the biopsy.

Consultations

Radiation oncologist: Radiation therapy with curative intent should be used in patients with stage I disease, although this represents a minority of cases of follicular lymphoma. Radiation therapy also can be used to treat localized or bulky lymphadenopathy that is causing obstruction or when a more urgent response is desired to relieve obstruction. Radiation therapy usually is tolerated well and, in many instances, can spare the patient the need for additional chemotherapy. The radiation oncologist is also involved in the care of patients receiving radioimmunotherapy.

Medication

All of the medications listed below should only be ordered by physicians who have training and/or experience in antineoplastic agents.

Antineoplastic Agent, Alkylating Agent

These agents inhibit cell growth and proliferation.

Chlorambucil (Leukeran)

A bifunctional alkylating agent of the nitrogen mustard type that has been found to be active against selected human neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2chlorethyl)amino]benzene butanoic acid.
Entire daily dose may be given at one time. These dosages are for initiation of therapy or for short courses of treatment. The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as an abrupt fall in the white blood cell count occurs.

Dosing

Adult

0.4 mg/kg PO once q2wk, titrate as needed; or daily dosing as 0.1-0.2 mg/kg PO daily for 3-6 weeks as needed; usual dose for average patient is 4-10 mg/d

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; previous resistance to medication; pregnancy

Precautions

Pregnancy

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

Precautions

Because of carcinogenic properties, should not be given to patients with conditions other than malignant lymphomas or chronic lymphatic leukemia; convulsions, infertility, leukemia, and secondary malignancies observed when employed in therapy of malignant and nonmalignant diseases
Most common adverse effect is bone marrow suppression; although bone marrow suppression frequently occurs, usually reversible if chlorambucil withdrawn early enough; irreversible bone marrow failure reported; should not be given at full dosages until 4 wk after a full course of radiation therapy or chemotherapy because of vulnerability of bone marrow to damage under these conditions; if pretherapy leukocyte or platelet counts are depressed from bone marrow disease process prior to institution of therapy, treatment should be instituted at reduced dosage
GI disturbances (eg, nausea and vomiting, diarrhea, and oral ulceration) occur infrequently
Tremors, muscular twitching, confusion, agitation, ataxia, flaccid paresis, and hallucinations reported as rare adverse effects that resolve upon discontinuation of the drug
Rare, focal, and/or generalized seizures reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens and in acute overdose
Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) reported
Other reported adverse reactions include pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies
Cross-hypersensitivity (skin rash) may occur between chlorambucil and other alkylating agents

Cyclophosphamide (Cytoxan)

Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA is considered cytotoxic.
In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T-cell functions.

Dosing

Adult

CHOP regimen: 750 mg/m² IV on day 1, repeat q3wk
CVP regimen: 750 mg/m² IV on day 1, repeat q3wk
R-FCM regimen: 200 mg/m² IV on days 1-3, repeat q3wk
FCR regimen: 300 mg/m² IV on days 1-3, repeat q3wk
Oral regimens: 50-100 mg/m²/d PO continuously or 400-1000 mg/m² PO in divided doses for 4-5 d or 400-1800 mg/m² (30-50 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; concurrent etanercept may increase risk of developing noncutaneous solid malignancies; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase 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

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause sterility; nausea and vomiting are common with intravenous dosing regimen; anorexia, diarrhea, mucositis, and stomatitis are also seen; potentially fatal acute hemorrhagic cystitis may occur; facial flushing, headache, and rash may also occur

Antineoplastic, Antimetabolite

Interfere with metabolic pathways necessary for the survival of target cells.

Fludarabine (Fludara)

Contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing drug if neurotoxicity occurs. Optimal duration of treatment not clearly established. Recommended that 3 additional cycles of fludarabine be administered following achievement of maximal response, and then drug should be discontinued.

Dosing

Adult

25 mg/m² IV over approximately 30 min once daily for 5 d; repeat q28d
FR regimen: 25 mg/m² IV once daily for 5 d; repeat q28d
FCR regimen: 25 mg/m² IV once dailyfor 3 d; repeat q28d
R-FCM regimen: 25 mg/m² IV once daily for 3 d; repeat q28d

Pediatric

Not established

Interactions

Combination with other purine analogs (eg, pentostatin) because incidence of pulmonary toxicity is unacceptably high when used together

Contraindications

Documented hypersensitivity; breastfeeding; bone marrow suppression

Precautions

Pregnancy

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

Precautions

Perform frequent peripheral blood counts to detect development of anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust dose for renal impairment, severe bone marrow suppression, severe neurological effects, or life-threatening and fatal autoimmune hemolytic anemia

Antineoplastic Agent, Anthracycline

These agents inhibit DNA synthesis.

Doxorubicin (Adriamycin)

Cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var caesius. Blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. Binds to nucleic acids presumably by specific intercalation of anthracycline nucleus with DNA double helix. Also a powerful iron chelator. Iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Can also cause DNA strand breakage through effects on topoisomerase II. Maximum toxicity occurs during the S phase of the cell cycle.
Has multiphasic disappearance curve, with half-lives ranging up to 30 h. Does not cross blood-brain barrier but is taken up rapidly by the heart, lungs, liver, kidney, and spleen.
This drug is both mutagenic and carcinogenic. Dosage related to body surface area.

Dosing

Adult

CHOP regimen: 50 mg/m² IV once on day 1, repeat q3wk

Pediatric

Not established

Interactions

May decrease phenytoin, carbamazepine, and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity of doxorubicin; cyclophosphamide increases cardiac toxicity of doxorubicin; trastuzumab increases the incidence and severity of cardiac dysfunction; sorafenib may increase the plasma levels of doxorubicin

Contraindications

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression

Precautions

Pregnancy

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

Precautions

Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function

Mitoxantrone (Novantrone)

Incorporated into combination chemotherapy regimens for follicular lymphoma. Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Dosing

Adult

R- FCM regimen: mitoxantrone 8mg/m²/d IV once on day 1; repeat q28 days

Pediatric

Interactions

None reported

Contraindications

Documented hypersensitivity; baseline LVEF <50% in patients with multiple sclerosis

Precautions

Pregnancy

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

Precautions

Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly seen after cumulative dose of 120-160 mg/m², patients with MS should not receive a cumulative dose >140 mg/m²); CHF may occur either during treatment, or months to years after treatment termination; perform baseline and follow-up cardiac function tests (2D-echo and ejection fraction measurements); when treating MS, LVEF should be reevaluated by echocardiogram or MUGA prior to each dose; secondary acute myelogenous leukemia has been reported after treating cancer or MS

Antineoplastic Agent, Vinca Alkaloid

These agents inhibit cell growth and proliferation at the mitotic phase of the cell cycle.

Vincristine (Oncovin, Vincasar)

Binds to microtubular protein of the mitotic spindle, inhibiting key steps in the cell cycle

Dosing

Adult

CHOP regimen: 1.4 mg/m² IV once q3wk maximum single dose not to exceed 2 mg

Pediatric

Not established

Interactions

Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP450 3A4 inhibitors (eg, itraconazole, posaconazole, voriconazole, quinupristin/dalfopristin, ritonavir, aprepitant), sargramostim, filgrastim, or nifedipine may increase toxicity associated with vincristine; CYP450 3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects of vincristine; coadministration with warfarin may result in elevated supratherapeutic anticoagulation. Concomitant administration with digoxin may result in subtherapeutic digoxin levels.

Contraindications

Documented hypersensitivity; intrathecal administration

Precautions

Pregnancy

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

Precautions

Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or pre-existing neuromuscular dysfunction; Constipation, paralytic ileus, and urinary tract disturbances may occur

Corticosteroids

Have anti-inflammatory effects in disorders of many organ systems. Corticosteroids also are lympholytic and modify the body's immune responses to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity. Induction of cell death in immature lymphocytes.

Dosing

Adult

60-100 mg PO qd for 5 d; repeat q21d

Pediatric

Not established

Interactions

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

Contraindications

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

Precautions

Pregnancy

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

Precautions

Abrupt discontinuation of glucocorticoids 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
Prolonged use of corticosteroids may produce posterior subcapsular cataracts and glaucoma with possible damage to optic nerves and may enhance establishment of secondary ocular infections due to fungi or viruses
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium; effects are less likely to occur with synthetic derivatives, except when used in large doses; dietary salt restriction and potassium supplementation may be necessary
All corticosteroids increase calcium excretion
Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids; killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids, but response may be diminished
Use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate antituberculous regimen; if corticosteroids are indicated in latent tuberculosis or tuberculin reactivity, close observation necessary because reactivation of the disease may occur
During prolonged corticosteroid therapy, patients should receive Pneumocystis prophylaxis; if exposed to chicken pox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated; if exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated; if chicken pox develops, treatment with antiviral agents may be considered

Monoclonal antibodies

Bind to target cells and recruit immune-effector functions to mediate target-cell lysis.¹⁰

Rituximab (Rituxan)

A chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Rituximab binds to the cell surface and activates complement-dependent cytotoxicity and binds to human Fc receptors, mediating cell death through antibody-dependent cellular toxicity.

Can be used as first-line or salvage therapy, as monotherapy, or in addition to combination chemotherapy regimens.

Dosing

Adult

375 mg/m² given as IV infusion qwk for 4 doses (days 1, 8, 15, and 22)
375 mg/m² given as IV infusion qwk for 4 doses (days 1, 8, 15, and 22); repeat every 6 months for up to 16 doses for maintenance therapy
In combination with chemotherapy 375 mg/m² IV infusion on day 1; repeat q21 - 28 days.

Pediatric

Not established

Interactions

Prior exposure to monoclonal antibodies may increase the risk for allergic reactions to rituximab

Contraindications

Documented hypersensitivity to murine proteins or any component of formulation

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

An infusion-related symptom complex consisting of fever and chills/rigors may occur; other frequent infusion-related symptoms include nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites; reactions generally occur within 30 min to 2 h of beginning of first infusion and resolve with slowing or interruption of infusion and with supportive care (IV isotonic sodium chloride solution, diphenhydramine, and acetaminophen)
Mild-to-moderate hypotension that requires interruption of infusion with or without administration of IV isotonic sodium chloride solution may occur
Adverse effects include angioedema, bronchospasm, asthenia, throat irritation, flushing, tachycardia, anorexia, leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory symptoms, night sweats, and pruritus
Severe thrombocytopenia, arrhythmias, neutropenia, anemia, aplastic anemia (pure red cell aplasia), chills, leukopenia, hypotension, bronchospasm, urticaria, headache, abdominal pain, asthenia, hypertension, nausea, vomiting, coagulation disorder, angioedema, arthralgia, pain, rhinitis, increased cough, dyspnea, bronchiolitis obliterans, hypoxia, asthma, pruritus, and rash may occur
Hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and death may occur.

Tositumomab and Iodine 131 (Bexxar)

Murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, found on surface of normal and malignant B lymphocytes. Radiolabeled tositumomab (ie, iodine I131 tositumomab) is administered following nonradiotherapeutic version to direct treatment precisely to the malignancy. Possible mechanisms of action include apoptosis, complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and ionizing radiation. Indicated for CD20 positive non-Hodgkin lymphoma that has relapsed following chemotherapy and is refractory to rituximab.

Dosing

Adult

Dosimetric step: Tositumomab 450 mg IV infused over 1 h, followed by iodine I-131 tositumomab (5 mCi I-131 and 35 mg tositumomab) IV infused over 20 min
Therapeutic step (7-14 d following dosimetric step): Tositumomab 450 mg IV infused over 1 h, followed by iodine I131 (precise dose is dependent on current platelet count)

Pediatric

Not established

Interactions

No formal drug interaction studies have been performed. Due to the frequent occurrence of severe and prolonged thrombocytopenia, the potential benefits of medications that interfere with platelet function and/or anticoagulation should be weighed against the potential increased risk of bleeding and hemorrhage. Coadministration with other drugs causing bone marrow suppression may cause additive effects

Contraindications

Documented hypersensitivity to tositumomab or murine antibodies

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause severe or life-threatening cytopenias (ie, 71% experience grade 3 or 4); may cause hypersensitivity, including anaphylaxis; may cause secondary malignancies or hypothyroidism; infusion-related symptoms (eg, fever, rigors, chills, sweating) may occur; 1 d prior to administration, administer protectant SSKI; administer acetaminophen and diphenhydramine on administration day
Myelodysplastic syndrome (MDS) and/or acute leukemia were reported in 10% of patients enrolled in clinical studies and 3% of patients included in expanded access programs

Ibritumomab tiuxetan (Zevalin)

A murine monoclonal antibody that targets the CD20 antigen, which is chelated to the radioisotopes indium-111 or yttrium-90. Used in conjunction with rituximab to treat B-cell non-Hodgkin lymphoma (NHL) or rituximab-refractory follicular NHL. The regimen consists of 2 low doses of rituximab, an imaging dose, 2-3 whole body scans, and a therapeutic dose, which are all delivered on an outpatient basis over 8 d.

Dosing

Adult

Day 1: Rituximab (250 mg/m²) IV. Followed by ibritumomab 1.6 mg (5 mCi indium¹¹¹) within 4 hours, IV push over 10 min; followed by a whole body scan at 2-24 h
Day 2-6: Biodistribution is assessed. The first image is 2 to 24 hours after In-111 ibritumomab tiuxetan and the second image is 48 to 72 hours after In-111 ibritumomab tiuxetan. A third image, 90 to 120 hours after In-111 ibritumomab tiuxetan, is optional
Day 7-9: Rituximab (250 mg/m²) IV infused over 4-5 h; followed by ibritumomab 0.4 mCi/kg of yttrium⁹⁰ IV push over 10 min; not to exceed 32 mCi
Note that the dose of rituximab is lower when used with ibritumomab than when rituximab is used as single agent

Pediatric

Not established

Interactions

Coadministration with antiplatelet or anticoagulant drugs may increase risk of cytopenias and bleeding

Contraindications

Documented hypersensitivity; prior sensitization to murine proteins; greater than or equal to 25% lymphoma bone marrow involvement; prior myeloablative therapies; platelet count <100,000 cells/mm³; neutrophil count <1500 cells/mm³;
hypocellular bone marrow (<15% cellularity of marked reduction in bone marrow precursors); history of failed stem cell collection; breastfeeding

Precautions

Pregnancy

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

Precautions

Therapeutic regimen, which includes rituximab administration may cause severe, and potentially fatal, infusion reactions (typically occur during first rituximab infusion with time to onset of 30-120 min) and may require interruption of drug administration (signs and symptoms of severe infusion reactions may include hypotension, angioedema, hypoxia, or bronchospasm); treatment may cause severe and prolonged thrombocytopenia and neutropenia; do not administer to those with altered biodistribution (according to body scan results); use only as single course of treatment; follow radionucleotide precautions; decrease Y-90 ibritumomab to 0.3 mCi/kg with mild thrombocytopenia (ie, 100,000-149,000 platelets/mm³); severe mucocutaneous reactions, some with fatal outcomes, have been reported with the therapeutic regimen
Myelodysplastic syndrome and/or acute myelogenous leukemia were reported in 2.6% of patients included in clinical studies and expanded access programs.

Follow-up

Further Inpatient Care

• Most patients with follicular lymphoma do not require hospitalization during the early stages of the disease.
• Patients with bulky disease at the time of treatment should be followed closely for tumor lysis syndrome. Allopurinol should be considered in these patients. Institute close follow-up of renal function and electrolyte balance.

Further Outpatient Care

• Patients should be monitored periodically to facilitate avoidance or early treatment of complications of the disease.
• Patients should be asked about the development of systemic symptoms such as fever, weight loss, and asthenia. These symptoms may herald progression of the disease or transformation to more aggressive intermediate-grade lymphoma.
• The physical examination should include a complete examination of the lymph nodes and reticuloendothelial system. Particular attention should be given to the abdominal examination, looking for the presence of splenomegaly or hepatosplenomegaly.
• Laboratory evaluation should include complete blood counts and serum chemistries. The serum chemistries should include liver function tests to be able to detect complications such as biliary obstruction and BUN and creatinine to detect ureteral obstruction and metabolic abnormalities such as hyperuricemia and hypercalcemia.

Complications

• Complications due to increased adenopathy causing obstruction, such as biliary obstruction, ureteral obstruction, and bronchial obstruction, should be considered during the follow-up monitoring of patients with follicular lymphomas.

Prognosis

• The overall survival rate of patients with follicular lymphoma is 72-77% at 5 years.
• Median survival is approximately 8-10 years.
• Patients who have 4 or more of the following adverse prognostic factors have a 10-year survival rate of approximately 36%:
  • Age 60 years or older
  • Ann Arbor Stage III or IV
  • LDH above the upper limit of normal at diagnosis
  • Hemoglobin less than 12 g/dL
  • Presence of more than 4 extranodal sites of disease

Patient Education

• Patients should be educated regarding the signs and symptoms of progression of the disease, including new systemic symptoms, new lymphadenopathy, or rapidly enlarging lymphadenopathy.
• Similar to patients with chronic lymphocytic leukemia, patients with follicular lymphoma also are more prone to infections and should be instructed to contact their physician early if they develop signs or symptoms of infection.

Miscellaneous

Medicolegal Pitfalls

• The most common pitfall is to confuse follicular lymphomas with other types of lymphomas. The diagnosis of lymphomas is complex, and tissue biopsies should be reviewed by pathologists with experience in interpreting lymph node biopsies and other diagnostic material.
• Supporting tests, such as immunophenotyping and cytogenetics, should be performed, especially if some doubt exists regarding the diagnosis.

Multimedia

Media file 1: Follicular lymphoma, low-power view: Note the nodular pattern reminiscent of germinal centers. Photograph courtesy of Aamir Ehsan, MD.

Media file 2: Diffuse lymphoma: Note the absence of the nodular pattern observed in follicular lymphomas. Photograph courtesy of Aamir Ehsan, MD.

Media file 3: A patient with follicular lymphoma who was diagnosed 6 years earlier presents to his hematologist's office because of rapidly growing lymphadenopathy and a new onset of fever, severe night sweats, and weight loss. In the past, he had been treated with chlorambucil and prednisone when his submandibular lymph nodes became large enough to make him uncomfortable. This treatment had worked well, and he has not required any treatment recently. A biopsy of an involved lymph node is obtained (see image). The diagnosis is transformation to diffuse non-Hodgkin lymphoma.

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Keywords

follicular lymphoma, non-Hodgkin's lymphoma, nodular lymphomas, low-grade lymphomas, indolent lymphomas, non-Hodgkin lymphoma, lymphoid tissue, lymph nodes, spleen, bone marrow, primary extranodal lymphoma

Contributor Information and Disclosures

Author

Cesar O Freytes, MD, FACP, Director of Bone Marrow Transplant Program, Professor, Department of Internal Medicine, Division of Hematology, University of Texas Health Science Center at San Antonio
Cesar O Freytes, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Association for the Advancement of Science, American Association of Blood Banks, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, International Society for Experimental Hematology, and New York Academy of Sciences
Disclosure: Genzyme Grant/research funds Review panel membership; Otsuka Consulting fee Review panel membership

Coauthor(s)

Julianna A Burzynski, PharmD, BCOP, BCPS, Clinical Pharmacy Specialist in Hematology/Oncology, Mayo Clinic
Julianna A Burzynski, PharmD, BCOP, BCPS is a member of the following medical societies: American College of Clinical Pharmacy
Disclosure: Nothing to disclose.

Medical Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
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.

Related eMedicine topics
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Clinical guidelines
Rituximab for the treatment of follicular lymphoma.
National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]. 2006 Sep. 20 pages. NGC:005739

Ibritumomab tiuxetan in lymphoma: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2006 Jul 17. 42 pages. NGC:005224


Clinical trials
Idiotypic Vaccination for Follicular Lymphoma Patients

Consolidation Treatment With Y90-Ibritumomab Tiuxetan After R-CHOP Induction in High Risk Patients According to Follicular Lymphoma International Prognostic Index (FLIPI) With Follicular Lymphoma

Bendamustine, Mitoxantrone, and Rituximab (BMR) for Patients With Untreated High Risk Follicular Lymphoma

Radiotherapy Versus Radiotherapy Plus Chemotherapy in Early Stage Follicular Lymphoma

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