ISSUES IN HEMATOLOGY AND ONCOLOGY
| LYMPHOMAS —Edward J. Benz, Jr, MD, Richard and Susan Smith Professor of Medicine, Professor of Pediatrics and
Pathology, Harvard Medical School, and President and Chief Executive Officer, Dana-Farber Cancer Institute, Boston, MA
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| Lymphoid malignancies: Hodgkin’s lymphoma—relatively small number of patients; highly treatable or highly lethal,
depending on type and patient’s age and sex; non-Hodgkin’s lymphoma—increasing in incidence, partly because
of aging population; consists of indolent disease (slow growing with prolonged survival; no effective treatments) and aggressive
disease (rapid growth with short survival; sometimes curable with traditional chemotherapy); occurs in men and
women with equal frequency; disease seen in younger patients; patients may have puzzling symptoms
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| Etiology of lymphoid malignancies
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 | Infectious causes: may increase incidence of lymphomas; Hodgkin’s disease and Burkitt’s lymphoma linked to Epstein-
Barr virus (EBV); AIDS-related lymphomas aggressive and associated with HIV infection; some lymphomas appear in
patients with AIDS because of secondary infections (lymphogenic effect); also occur in transplant patients
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| Genetic factors: age and exposure to substances that cause DNA damage increase incidence of lymphoma (immune cells
susceptible to cancer-causing agents that cause DNA damage); mutations occur frequently in immune cells under normal
conditions; progenitors of B lymphocytes and T lymphocytes undergo series of gene rearrangements through reactions
to antigenic stimuli, customizing surface with T cell receptors or secreting immunoglobulin in response to antigen
(eg, infection, foreign substance, vaccine); abnormal chromosomal rearrangements or translocations in chromosomes
involved in cell growth (transcription factors that turn on DNA synthesis and stimulate cell growth or antiapoptosis cell
proteins that prevent cell death) can lead to perpetual or inappropriate expression of genes that stimulate cell growth or
block apoptosis, resulting in lymphoma; likelihood of abnormal breakage and reunion events increase with time
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| Classification: classification of lymphomas by genetic factors or infectious origin evolving; classification scheme factors
in affected part of lymph node, whether small- or large-cell, whether T cells or B cells involved, and whether lymphoma
related to particular stage of development (eg, multiple myeloma associated with plasma cells; chronic
lymphocytic leukemia usually related to mature resting memory B cells), molecular markers, and stage of lymphoid maturation;
these factors determine approach to management
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| Staging and prognosis: more advanced stages of disease associated with worsening prognoses; stage I—lymphoma
localized to single node or closely clustered group of nodes in single chain; surgically excise nodes and observe patient;
stages II and III—intermediate grade; malignant nodes on one side of diaphragm in stage II and on both sides of diaphragm
in stage III; aggressive combined chemoradiation effective treatment for stage II and III disease; used to treat
stage III disease with extended field radiotherapy (associated with esophagitis, secondary breast cancer, and cardiac toxicity);
stage IV—disease involves dissemination into other viscera and extended sites in body; treat with intensive chemotherapy
and focused radiotherapy to treat acute complications (eg, spinal compression)
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| Other prognostic factors: include patient-related factors (age and comorbidities), disease-related factors (stage, biologic
features [markers, eg, β2 -microglobulin]), and treatment-related factors (eg, rapid response to treatment, remission,
relapse rate); good prognosis associated with rapid response to treatment that brings long-term remission (>6 mo to 1 yr)
without detectable disease by traditional histopathologic criteria; poorer prognosis and shorter survival associated with
short time to relapse, even if second remission occurs; many patients with lymphoma survive 5 to 15 yr after diagnosis
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| Treatment of indolent lymphomas: watchful waiting necessary in some patients; some lymphomas progress over
period of years and some never progress; some patients experience recurrences over period of years while disease
slowly progresses; indolent lymphomas largely incurable, and no definitive therapies exist; new agents can increase
period of disease-free survival
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| Single alkylating agents: response seen in some patients; leukemogenic and toxic; used as last resort
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| Radiotherapy: largely used for treatment of local complications; extended field radiotherapy used in carefully selected
patients
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| Combination chemotherapy: limited benefit; usually used in patients with progressive disease after other treatment options
exhausted; temporary response seen in some patients
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| Newer treatments: biologic agents—eg, monoclonal antibodies (mAb) and purine analogues (highly immunosuppressive
chemotherapeutic agents); bone marrow transplantation—in selected patients (eg, younger patients, patients with
markers indicating poor prognosis); most studies focus on allogeneic transplants; 5-yr survival 50% in patients with
stage II to IV disease; associated with acute and chronic transplant-related toxicity (ie, graft vs host disease); mini-
transplantation—for patients with poor prognosis with advanced-stage disease; involves lower-dose chemotherapy
(does not wipe out patient’s bone marrow); less toxic and more immunosuppressive than bone marrow eradication
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| Treatment of aggressive lymphomas: patients die rapidly if untreated, but treatment results in ≈50% survival; same
outcome associated with all 4 chemotherapy regimens; cyclophosphamide, doxorubicin, vincristine, and prednisone
(CHOP) used most frequently and side effects managed effectively; recommend aggressive multiagent chemotherapy by
lymphoma specialist
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| Rational chemotherapy agents
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| Indolent lymphoma: mAb—newer agents target markers identified on cell surface, eg, rituximab (Rituxan), alemtuzumab
(Campath); antibodies bind to lymphoma cells and attacked by immune system or trigger apoptotic pathways in
cancer cells; studies show additive effect on disease-free survival and survival in some forms of B cell lymphoma; antiangiogenesis
agents—eg, bevacizumab (Avastin); play ancillary role in treatment of unusual forms of lymphoma;
“smart bombs”—mAb tagged with radioactive isotope; bind to surface of cell, internalized, and kill cell; purine nucleoside
analogues—somewhat cytotoxic; act on immune cells to cause cell death; work on adenosine deaminase or
enzymes in same biochemical pathway that play critical role in development of immunocytes; include pentostatin, fludarabine,
and cladribine
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| Aggressive treatment: genomic technology—look at gene expression in human genome on microprocessor chip; referred
to as chip array, oligonucleotide array, or microarray analysis; using computer, can compare expression of genes
in patients who respond to standard chemotherapy to expression of all genes in lymphoma cells in patients who do not
respond to chemotherapy; can break down patients according to gene expression patterns and predict which patients
likely to survive
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| NEWER MODALITIES IN MANAGING NON-HODGKIN’S LYMPHOMA —David Weisdorf, MD, Professor of Medicine,
University of Minnesota Medical School, Minneapolis
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| Indolent lymphoma: treatment options—watchful waiting, radiotherapy, chemotherapy, stem cell transplantation,
mAb therapy with rituximab or radiolabeled anti-CD20 antibodies (yttrium compound ibritumomab [Zevalin] or iodinated
compound tositumomab [Bexxar])
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| Antibody therapy: antibody recognizes specific surface antigen, either immunoglobulin or CD20 expressed on surface
of >95% of B-lineage lymphomas, binds to specific cell surface marker, triggering cell death; some therapeutic antibodies,
including rituximab, can induce complement activation, causing lysis of cell by complement; can use rituximab as
supplement to chemotherapy in patients with lymphoma or alone in patients with CD20-positive lymphoma (rituximab
binds to CD20 surface marker); rituximab—produces major response in 50% of patients; patients with follicular lymphomas
have better response rate than patients with small lymphocytic lymphoma; associated with duration of response
of 11 mo in 50% of patients, without myelosuppression, without substantive risk for serious infection, and without side
effects of chemotherapy; can augment frequency and duration of response when used with most chemotherapy regimens
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| Radiolabeled antibody therapy: radioactive molecule added to mAb to enhance potential of targeted therapy; antibody
binds to tumor cell, irradiates cell, causing death to tumor cell and cells in proximity to it; choice of radionuclide determines
size of kill zone; can use yttrium compound that binds to CD20 or iodinated compound with different antibody
that also binds to CD20; ibritumomab (Zevalin)—refers to CD20 antibody and tiuxetan links mAb to radioactive heavy
metal; randomized trial compared radiolabeled CD20 antibody to rituximab alone; overall response rate 80% vs 56%;
34% of patients had partial response (20% with rituximab alone); patients treated with radioantibody therapy exhibit delayed
and prolonged myelosuppression; anti-CD45 antibody—CD45 present on all hematopoietic-derived cells; explored
in University of Minnesota Medical School study in patients with active advanced acute leukemia, advanced
myelodysplastic syndrome, advanced chronic myelogenous leukemia (CML), and patients with advanced non-Hodgkin’s
lymphoma
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| Transplant therapy: can use bone marrow, peripheral blood, or umbilical cord blood; hematopoietic cell transplants
intended to kill cancer cells, reduce toxicity and myelosuppression, and restore immunocompetence; recovery of immune
function necessary to prevent posttransplant infection and tumor recurrence; patients must deal with toxicity from
chemoradiation; requires successful engraftment if patient has partially matched donor; potential for graft vs host disease;
need to avoid recurrence of cancer; use of high-dose chemotherapy in conventional transplantation associated with mucositis,
pulmonary injury, and venoocclusive disease of liver; reduced-intensity hematopoietic stem cell or bone marrow
transplantation—involves sufficiently immunosuppressive lower-intensity conditioning to allow engraftment of
donor cells; limits posttransplant immunosuppression; can boost graft by giving additional cells from donor; real clinical
question posed over last several years whether safer reduced-intensity transplantation can be used in patients of advanced
age or in very sick patients; has acceptable relapse rate; can include patients who had previous transplants or have acquired
second cancer and patients with compromised organ function; associated with decreased morbidity and mortality;
allogeneic transplantation—only 30% of patients have matched sibling donors; close HLA typing important; most patients
who are ethnic minorities do not have HLA-matched donors available; umbilical cord blood potential source of alternative
stem cells; collect cord blood from placenta after baby delivered; small number of hematopoietic cells in
placenta have superior proliferative capacity and capable of grafting an appropriately treated recipient; cells have naïve
immune system and associated with less risk for graft vs host disease, even with partial HLA matching; can extend donor
pool and provide suitably matched HLA donors for patients in variety of ethnic minority groups who cannot be served by
current available donor pool
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| HEMOCHROMATOSIS —Ronald Rubin, MD, Professor of Medicine, Temple University School of Medicine, Philadelphia,
PA
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| Genetic background: most common hereditary disease in persons of Northern European descent; caused by single base
change in HFE gene on chromosome 6; traced back to single Celtic/Viking ancestor ≈2000 yr ago; physiologic and phenotypic
effects have variable penetrance
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| Etiology: long asymptomatic period between increased gastrointestinal iron (Fe) absorption and Fe overload; excess Fe
leads to increased transferrin saturation, increased storage as ferritin, and finally Fe spills into tissues; symptoms usually
occur in midlife; usually requires 20 yr for ferritin to reach 1000 mµ/L
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| Organ involvement: liver—ranges from elevated transaminases to frank cirrhosis; keep suspicion high in patient with
idiopathic cirrhosis, ascites, spider angioma, no history of alcohol abuse, and clean hepatology and serology;
endocrine—pancreas; look for “bronze diabetes” and hypogonadism; rheumatologic—arthritis and joint dysfunction,
especially in hands, wrists, and fingers; cardiac—Fe infiltrates myocardium, resulting in infiltrative cardiomyopathy,
congestive heart failure, and arrhythmia; cardiac Fe overload most frequent terminal event
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| Diagnostic principles: keep suspicion high for hemochromatosis if patient presents with liver and endocrine dysfunction
simultaneously; in patients suspected of hemochromatosis, measure Fe and Fe-binding capacity; consider diagnosis
in patients with unexplained fatigue, arthralgia, elevated liver enzymes, or if liver edge can be felt; screen patient for serum
ferritin and check Fe-binding capacity; look for transferrin saturation >45% (other hematologic illness and active
hepatitis C); perform genetic testing to look for HFE mutations C282Y and H63D; make diagnosis if patient homozygotic,
and consider screening relatives; follow if patient heterozygotic with normal serum ferritin; diagnosis made if serum
ferritin persistently elevated after excluding liver disease (perform liver biopsy for hepatic Fe index)
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| Treatment: perform phlebotomy to remove excess Fe; start phlebotomy schedule in any patient with clinical findings or
in asymptomatic patient with serum ferritin >1000 µg/L; goals to decrease transferrin saturation to <50% and decrease
ferritin to <100 µg/L
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Educational Objectives
| The goal of this program is to educate the listener about non-Hodgkin’s lymphoma and hemochromatosis. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Discuss the etiology of lymphoid malignancies.
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| 2. Identify prognostic factors in non-Hodgkin’s lymphoma.
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| 3. Evaluate monoclonal antibody therapy and radioimmunotherapy in the treatment of indolent non-Hodgkin’s lymphoma.
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| 4. Describe reduced-intensity hematopoietic stem cell or bone marrow transplantation.
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| 5. Identify the diagnostic principles for hemochromatosis
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Discussed on This Program
Alemtuzumab [Campath]
Bevacizumab [Avastin]
Cladribine (2-chlorodeoxyadenosine; CdA) [Leustatin]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar]
Doxorubicin [Adriamycin PFS, Adriamycin RDF]
Fludarabine phosphate [Fludara]
Ibritumomab tiuxetan (yttrium-90 britumomab tiuxetan) [Zevalin]
Pentostatin (2'-deoxycoformycin; DCF) [Nipent]
Prednisone (several trade names)
Rituximab [Rituxan]
Tositumomab and 131 I-tositumomab [Bexxar]
Vincristine sulfate (VCR; LCR) [Oncovin, Vincasar PFS]
Suggested Reading
Ansell SM et al: Non-Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc. 80:1087, 2005; Armitage JO:
Staging non-Hodgkin lymphoma. CA Cancer J Clin. 55:368, 2005; Brandhagen DJ et al: Recognition and management
of hereditary hemochromatosis. Am Fam Physician. 65:853, 2002; Chan WC et al: Molecular diagnostics on lymphoid
malignancies. Arch Pathol Lab Med. 128:1379, 2004; Cheson BD: Radioimmunotherapy of non-Hodgkin
lymphomas. Blood. 101:391, 2003; Evans LS et al: Non-Hodgkin lymphoma. Lancet. 2003 362:139, 2003; McCune
SL et al: Monoclonal antibody therapy in the treatment of non-Hodgkin lymphoma. JAMA. 286:1149, 2001; Pietrangelo
A: Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 350:2383, 2004; Schmitt B et
al: Screening primary care patients for hereditary hemochromatosis with transferring saturation and serum ferritin level:
systematic review for the American College of Physicians. Ann Intern Med. 143:522, 2005; Staudt LM: Molecular diagnosis
of the hematologic cancers. N Engl J Med. 348:1777, 2003; Yen AW et al: Revisiting hereditary hemochromatosis:
current concepts and progress. Am J Med. 119:391, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, Dr. Benz receives
a salary from the Dana-Farber Cancer Institute and an honorarium from the New England Journal of Medicine.
Drs. Benz and Rubin were recorded March 26-31, 2006, at the 30th annual Family Practice Review, sponsored by Temple
University School of Medicine, Philadelphia, PA. Dr. Weisdorf was recorded May 23-27, 2005, at the Family Medicine
Review Update 2005, sponsored by the University of Minnesota Medical School, Minneapolis. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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