`
`SEVENTEENTH EDITION
`
`THE
`MERCK
`MANUAL
`
`OF
`
`DIAGNOSIS AND THERAPY
`
`Editors
`MARKH. BEERS, M.D., and ROBERT BERKOW,M.D.
`
`Senior Assistant Editors
`ROBERT M. BOGIN, M.D., and
`ANDREWJ. FLETCHER, M.B., B.Chir.
`
`Editorial Board
`
`Philip K. Bondy, M.D.
`Preston V.Dilts, Jr., M.D.
`Douglas A. Drossman, M.D.
`L. Jack Faling, M.D.
`EugeneP. Frenkel, M.D.
`Glen O. Gabbard, M.D.
`Robert A. Hoeckelman, M.D.
`Gerald L. Mandell, M.D.
`Fred Plum, M.D.
`G. Victor Rossi, Ph.D.
`Paul H. Tanser, M.D., F.R.C.P.(C)
`
`Published by Merck RESEARCH LABORATORIES
`Division of Merck & Co., INC.
`Whitehouse Station, N.].
`
`1999
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`CHAPTER 139 — LYMPHOMAS / 955
`
`stimulating factor, granulocyte-macrophage
`colony-stimulating factor) increase neutro-
`phil counts, and erythropoietin increases
`RBC production in 20 to 25% of cases, but
`
`survival advantage has not been shown.Re-
`sponse of MDS to AML chemotherapyis sim-
`ilar to that of AML, after age and karyotype
`are considered.
`
`139 / LYMPHOMAS
`
`A heterogeneous group of neoplasms arising in the reliculoen-
`dothelial and lymphatic systems.
`
`The major types are Hodgkin’sdisease and
`non-Hodgkin’s lymphoma. An uncommon
`type is mycosis fungoides.
`
`HODGKIN’S DISEASE
`Localized or disseminated malignant pro-
`liferation of tumor cells arisingfrom the
`lymphoreticular system, primarily in-
`volving lymph node tissue and the bone
`marrow.
`
`Incidence and Etiology
`In the USA, 6000 to 7000 new cases are
`diagnosed annually. The male:femaleratio is
`14:1, Hodgkin's diseaseis rare before age 10
`and has abimodal agedistribution that peaks
`at ages 15 to 34 and after age 60. However,
`the second peak maybe an artifact of inac-
`curate pathologic diagnosis, because most
`Cases diagnosed after age 60 are inter-
`Mediate-grade non-Hodgkin’s lymphomas
`(NHL—see below). Epidemiologic studies
`find no evidence of horizontal spread. The
`
`cause is unknown, but patients with [Hodg-
`kin’s disease appear Lo have a genetic sus-
`ceptibility (as demonstrated in twin studies)
`and environmental associations (eg, occu-
`pation, such as woodworkers; Epstein-Barr
`virus infection; HIV infection).
`
`Pathology
`Diagnosis depends on identification of
`Reed-Sternberg cells
`(large. binucleated
`cells) inlymph nodesorothersites. The back-
`ground cellular infiltrate is heterogeneous
`and consists of histiocytes,
`lymphocytes,
`monocytes, plasma cells, and eosinophils.
`Hodgkin's disease has four histopathologic
`subtypes (see TABLE 139-1).
`Reed-Sternberg cells are usually CD15*
`and CD30* on immunophenotyping. Lym-
`phocyte-predominant Hodgkin’s disease
`may be confused with T-cell-rich B-cell
`NHL; nodular sclerosis, mixed cellularity,
`and lymphocyte-depleted Hodgkin’s disease
`may be confused with Ki-1 anaplastic large
`cell NHL.
`
`TABLE 139-1.
`
`HISTOPATHOLOGIC SUBTYPES OF HODGKIN’S DISEASE
`
`__Type
`Lymphocyte-
`Predominant
`Nodular
`Sclerosis
`
`Incidence
`
`Progression
`
`3%
`
`Relatively slow or indolent
`
`67%
`
`25%
`
`Intermediate or moderately
`progressive; relatively slow
`or indolent (occasionally)
`Intermediate or moderately
`progressive; aggressive
`
`5%
`
`Aggressive
`
`Appearance
`Few Reed-Sternberg cells and
`
`many lymphocytes
`
`Densefibrous tissue*
`surroundsnodules of
`Hodgkin’s tissue
`
`A moderate number of Reed-
`Mixed
`
`Sternberg cells with a
`cellularity
`
`mixed backgroundinfiltrate
`Numerous Reed-Sternberg
`Lymphocyte-
`
`cells and extensive fibrosis
`depleted
`“Showscharacteristic birefringence with polarized light.
`
`
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`956 /
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`SECTION 11 —- HEMATOLOGY AND ONCOLOGY
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`Symptomsand Signs
`Symptoms and signs primarily relate to
`the site, amount, and extent of nodal mass
`involvement. Mostpatients present with cer-
`vical and mediastinal adenopathy and with-
`out systemic complaints. Other manifesta-
`tions develop as the disease spreads through
`the reticuloendothelial system, generally
`among contiguoussites. The rate of progres-
`sion varies accordingto histopathologic sub-
`type (see TABLE 139-1). Intense pruritus may
`occurearly; fever, night sweats, and weight
`loss are frequent wheninternal nodes (bulky
`mediastinal or
`retroperitoneal), viscera
`(liver), or bone marrowis involved. Pel-Eb-
`stein fever (a few days of high fever regularly
`alternating with a few days to several weeks
`of normal or subnormal temperature) occa-
`sionally occurs. Although the mechanism is
`unclear, immediate pain may occur in dis-
`eased areas after drinking alcoholic bever-
`ages, providing an early clue to diagnosis.
`Boneinvolvement is often asymptomatic
`but may produce pain with vertebral osteo-
`blastic lesions
`(“ivory” vertebrae) and,
`rarely, osteolytic lesions and compression
`fracture. Pancytopenia
`is
`occasionally
`caused by bone marrow invasion, usually by
`the lymphocyte-depleted type. Epidural in-
`vasion that compresses the spinal cord may
`result in paraplegia. Horner’s syndrome and
`laryngeal paralysis may result when en-
`larged lymph nodes compressthe cervical
`sympathetic and recurrentlaryngeal nerves,
`respectively. Neuralgic pain follows nerve
`root compression. Intracranial, gastric, and
`cutaneouslesions occur rarely and, if pres-
`ent, suggest HIV-associated Hodgkin’s dis-
`ease,
`Intrahepatic or extrahepatic bile duct ob-
`struction by tumor masses produces jaun-
`dice. Leg edema may follow lymphatic
`obstruction in the pelvis or groin. Tracheo-
`bronchial compression can cause severe
`dyspnea and wheezing. Infiltration of lung
`parenchyma may simulate lobar consolida-
`tion or bronchopneumonia and mayresult in
`cavitation or lung abscess.
`Most patients have a slowly progressive
`defect in delayed or cell-mediated immunity
`(T-cell function) that contributes in ad-
`vanced disease to commonbacterial and un-
`usual fungal, viral, and protozoal infections
`(see in Ch. 151). Humoral immunity (anti-
`body production) or B-cell function also is
`depressed in advanced disease. Cachexia is
`
`common, and patients frequently die of sep.
`sis.
`
`Laboratory Findings
` polymorphonuclear
`Slight-to-moderate
`leukocytosis may be present. Lymphocyto-
`penia may occur early and become pro-
`nounced with advanced disease. Eosino-.
`philia is present in about 20% ofpatients, and
`thrombocytosis may be observed. Anemia,
`often microcytic, usually develops with ad-
`vanced disease. In advanced anemia, defec.
`tive iron reutilization is characterized by low
`serum iron, low iron-binding capacity, and
`increased bone marrow iron. Hypersplenism
`may appear, but mainly in patients with
`marked splenomegaly. Elevated serum al-
`kaline phosphatase levels usually indicate
`bone marrow orliver involvement or both,
`Increases in leukocyte alkaline phosphatase,
`serum haptoglobin, ESR, serum copper, and
`other acute-phase reactants usually reflect
`active disease.
`
`Diagnosis
`The symptom complex of lymph nodeen-
`largement(especially cervical) and medias-
`tinal adenopathy, with or without fever,
`night sweats, and weightloss, suggests lym-
`phoma; however, Hodgkin’s disease can be
`definitively diagnosed by lymph node biopsy
`that reveals Reed-Sternberg cells in a char-
`acteristic histologic setting. Hodgkin's dis-
`ease is very rare in the absence of lymphad-
`enopathy. Biopsy specimens then can be
`obtained from bone marrow,liver, or other
`parenchymal tissue. Monoclonal antibodies
`to certain antigens on Reed-Sternberg cells
`(eg, Leu-M1 [CD15] and CD30 [Ber-H2]) are
`importantin casesthat can be confused with
`NHL.
`Hodgkin’s disease may be difficult to dif-
`ferentiate from lymphadenopathy caused by
`infectious mononucleosis,
`toxoplasmosis,
`cytomegalovirus, NHL, or leukemia.
`.The
`clinical picture can also be simulated by lung
`carcinoma,sarcoidosis, TB, and various dis-
`eases in which splenomegaly is the predom-
`inant feature (see Ch. 141).
`
`Staging
`Radiotherapy, chemotherapy, or a combi-
`nation of both is potentially curative, but the
`extent or stage of disease mustfirst be delin-
`eated. The Ann Arbor staging system is com
`monly used (see TABLE 139-2). The Cots-
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`CHAPTER 139 —- LYMPHOMAS / 957
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`TABLE 139-2. ANN ARBORSTAGING OF
`HODGKIN’S DISEASE AND NON-
`
`HODGKIN’S LYMPHOMA
`Stage*
`Criteria
`
`wold modification of the Ann Arbor stage
`uses X to designate a bulky disease site (>
`1/3 of the chest diameter or > 10 cm in di-
`ameter).
`Noninvasive procedures for staging in-
`clude CT of the thorax, abdomen,and pelvis
`and gallium scanning. Bone scanning and
`MRI are usually not required. Bipedal lymph-
`angiography may be indicated in patients
`with normal abdominal and pelvic CT scans.
`Clinical studies attempting to detect disease
`below the diaphragm maybefalsely positive
`or negative in 25 to 33% of patients. Laparot-
`omy(including splenectomy), biopsy of mes-
`enteric and retroperitoneal
`lymph nodes
`(especially those enlarged on CT or lymph-
`angiography), and core biopsy of the bone
`marrow andliver should be considered when
`therapeutic decisionswill be significantly af-
`fected. However, staging laparotomy indi-
`cations have been narrowedsignificantly in
`recent years. Only patients whoseclinical
`stage is ILA or less and in whom mantle ra-
`diation is planned may be considered.If the
`patient is to receive chemotherapy, staging
`laparotomyis not needed.
`Treatment
`
`Chemotherapy or radiotherapy regimens
`cure most patients. Nodal disease can be
`eradicated in > 95% of cases with 4 to 4.5
`wk of 4000 to 4400 cGy within the treated
`field.
`In addition,
`irradiation of adjacent
`regions (extendedfield) to 3600 cGyis stan-
`dard because the disease spreads by lym-
`Phatic contiguity. Patients with subclassifi-
`cation E may also respondto radiotherapy,
`although combined chemotherapy andradio-
`therapy is often recommended. Treatmentis
`based mainly on pathologically staged pa-
`tients, although selected patients may be
`Considered for primary radiotherapy with-
`ut pathologic staging.
`Stage I and IIA disease can be treated
`With radiotherapyalone to an extendedfield
`at includes all lymph node-bearing areas
`. Dove the diaphragm and, in most cases, the
`Periaortic lymph nodesto the aortic bifur-
`eon and spleen or splenic pedicle. Such
`i fatment cures about 80% of patients. Cure
`efers to being disease-free at 5 years post-
`€rapy, after which relapse is very rare. In
`Patients with bulky mediastinal disease, ra-
`motetapy alone has a high relapserate; che-
`Otherapy followed by radiotherapy results
`4 prolonged relapse-free survival in about
`
`1
`
`2
`
`I
`I
`
`I
`
`In one lymph nodeonly
`In two or more lymph nodes on the
`sameside of the diaphragm
`In the lymph nodes,spleen, or both
`and on bothsides of the
`diaphragm
`Abovethe renal vessels (eg, spleen;
`splenic, hilar, celiac, and portal
`nodes)
`In the lower abdomen(periaortic,
`pelvic, or inguinal nodes)
`Extranodal involvement (eg, bone
`Iv
`
`marrow, lung,liver)
`*Subclassification E indicates extranodal involve-
`ment adjacent to an involved lymph node(eg, disease
`of mediastinal nodes and hilar adenopathy with ad-
`jacent lung infiltration is classified as stage IIE).
`Stages can be further classified by A to indicate the
`absence or B to indicate the presence of constitu-
`tional symptoms (weightloss, fever, or night sweats).
`B symptoms generally occur with stages III and IV
`(20 to 30% of patients).
`
`75% of patients. For selected patients with
`stage IA disease and nodular sclerosis or
`lymphocyte-predominant histology, mantle
`field radiotherapy alone maysuffice.
`For stage IIIA1 disease, total nodal ir-
`radiation (mantle and inverted Y) results in
`an overall survival of 85 to 90%, with disease-
`free survival of 65 to 75% at 5 years. In se-
`lected cases (eg, minimal splenic disease
`only), lesser radiotherapy (omission of the
`pelvic field) has been equally effective. How-
`ever, for the majority of patients presenting
`with clinical stages IIB and IIIA1, chemo-
`therapy and radiotherapy are indicated. For
`stage IIIA2 disease, combination chemo-
`therapyis generally used with or withoutra-
`diotherapy of bulky nodal sites. Cure rates
`of 75 to 80% have been achieved.
`Becauseradiotherapy alone does not cure
`stage IIIB disease, combination chemo-
`therapy alone or in conjunction with radio-
`therapy is required. Survival ranges from 70
`to 80%.
`For stage IVA and B disease, combina-
`tion
`chemotherapy, particularly MOPP
`(mechlorethamine, vincristine, procarba-
`zine, prednisone) or ABVD (doxorubicin,
`
`Mt
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`i
`
`bleomycin, vinblastine, dacarbazine), has
`produced a complete remission in 70 to 80%
`of patients, with > 50% remaining disease-
`free at 10 to 15 yr. ABVD has becomethe
`standard regimen for most cases based on
`theresults of recent randomizedstudies. Al-
`ternating MOPP and ABVD orhybrid com-
`binations have not proven superior to ABVD
`in prospective studies. Other effective drugs
`include nitrosoureas, ifosfamide, cisplatin or
`carboplatin, and etoposide. Patients whofail
`to achieve complete remission or who re-
`lapse within 6 to 12 mo have a poor progno-
`sis. Autologous transplantation using bone
`marrow orperipheral cell products has been
`carried out in selected patients; conven-
`tional salvage regimensare generally not cu-
`rative. Autologoustransplantation can cure
`up to 50% ofpatients who are physiologically
`eligible for intensification therapy and re-
`sponsive to salvage induction chemother-
`apy. Allogeneic transplantation has not been
`shown to be superior and is not recom-
`mended. Autologous transplantation is also
`being studied in selected high-risk patients
`at initial diagnosis.
`
`NON-HODGKIN’S
`LYMPHOMAS
`Malignant monoclonalproliferation oyflym-
`phoid cells in sites ofthe immune system,
`including lymph nodes, bone marrow,
`spleen, liver, and GI tract.
`Pathologic classification ofnon-Hodgkin's
`lymphomas (NHLs) continues to evolve,
`reflecting newinsights into the cells of origin
`and the biologic bases of these heteroge-
`neous diseases. The course of NHL varies
`from indolentand initially well tolerated to
`rapidly fatal. A leukemia-like picture may
`develop in up to 50% of children and about
`20% of adults with sometypes of NHL.
`incidence and Etiology
`NHL occurs more often than Hodgkin's
`disease. In the USA, about 50,000 new cases
`are diagnosed annuallyin all age groups, the
`incidence increasing with age. Its cause is
`unknown,although, as with the leukemias,
`substantial experimental evidence suggests
`a viral cause for some lymphomas. For ex-
`ample,the retrovirus human T-cell leukemia-
`lymphomavirus (HTLV-Dhas beenisolated
`and appears to be endemic in southern Ja-
`
`
`
`pan, the Caribbean, South America, anq the
`southeastern USA. The acute illness of adult
`|
`T-cell leukemia-lymphomais characteriza
`by a fulminating clinical course with ski
`infiltrates, lymphadenopathy, hepatospleng,
`megaly, and leukemia. The leukemic cq
`are malignantT cells, many with convolute
`nuclei. Hypercalcemia often develops, re.
`lated to humoralfactors rather than to diregy
`boneinvasion.
`The incidence of NHL, particularly immy.
`noblastic and small noncleaved (Burkitt's
`lymphoma)cell types, is increased in HIy
`patients. Primary CNS involvement and dis.
`seminated disease have been reported. In
`about 30% of cases, the lymphomas are pre.
`ceded by generalized lymphadenopathy,
`suggesting that polyclonal stimulation of B
`cells precedes lymphomagenesis. C-mye
`gene rearrangements are characteristic of
`some AIDS-associated lymphomas. Re.
`sponse to chemotherapyis possible, but tox.
`icity is commonand opportunistic infections
`continue to occur,resulting in short survival,
`Pathology
`The Working Formulation classifies
`NHLinto prognostic categories having ther-
`apeutic implications as follows (NOTE: The
`prognostic designations are based on sur-
`vival data ofpatients treated before 1980 and
`may not accurately reflect outcomesin pa-
`tients undergoing modern therapy, as dis-
`cussed under Treatment, below):
`° Low-grade lymphomas (38%): diffuse,
`small
`lymphocytic;
`follicular,
`small
`cleaved cell; follicular mixed, small and
`large cell.
`Intermediate-grade lymphomas (40%):
`follicular large cell; diffuse, small cleaved
`cell; diffuse mixed, small and large cell;
`diffuse large cell.
`Immu-
`High-grade lymphomas (20%):
`noblastic lymphoma; lymphoblastic lym-
`phoma; small noncleaved cell lymphoma
`(Burkitt's and non-Burkitt’s type).
`Miscellaneous lymphomas (2%): com-
`posite lymphomas, mycosis fungoides,
`true histiocytic, other, and unclassifiable
`types.
`A new pathologic classification, the REAL
`(Revised European-American Lymphoma)
`Classification, has recently been introduced
`and is gradually being adopted. This classi-
`fication is valuable for identifying entities
`
`
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`CHAPTER 139 — LYMPHOMAS / 959
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`y ::
`
`:| ' \=
`
`ae
`
`not recognized in the Working Formulation
`and has special strengths by incorporating
`immunophenotype, genotype, and cytoge-
`netics into the diagnostic categories. Among
`the most important new lymphomas are mu-
`cosa-associated lymphoid tumors (MALT—
`see Ch. 23); mantle cell lymphoma, a poor
`prognosis disease previously categorized as
`diffuse small cleaved cell lymphoma; and
`anaplastic large cell lymphoma (Ki-1 lym-
`phoma).
`Immunophenotyping, using fixed or fresh
`tumortissue, reveals that 80 to 85% of NHLs
`arise from B cells, 15% from T cells, and <
`5% from true histiocytes (monocyte-macro-
`phages) or undefined null cells. Further-
`more, immunologic studies have shown that
`lymphomas arise from different stages of
`normal lymphoid activation and differentia-
`tion. However, except in certain T-cell lym-
`phomas, immunologic classification has not
`yet played a majorrole in treatmentstrategy.
`
`Symptomsand Signs
`Although variousclinical manifestations
`exist, many patients present with asymp-
`tomatic peripheral
`lymphadenopathy. En-
`larged lymph nodesare rubbery and discrete
`and later become matted. Local disease is
`apparent in some patients, but most have
`multiple areas of involvement. Waldeyer’s
`ring (especially the tonsils) is an occasional
`site of disease. Mediastinal and retroperito-
`neal lymphadenopathy may cause pressure
`symptoms on various organs. Extranodal
`sites may dominate the clinical picture (eg,
`gastric involvement can simulate GI carci-
`noma;intestinal lymphoma may cause a mal-
`absorption syndrome). The skin and bones
`areinitially involved in 15% of patients with
`diffuse large cell lymphomaand in 7% with
`diffuse, small lymphocytic lymphoma, About
`33% of patients with extensive abdominal or
`thoracic disease develop chylous ascites or
`pleural effusion (see Ch. 80), respectively,
`owing to lymphatic obstruction. Weightloss,
`fever, night sweats, and asthenia indicate
`disseminated disease.
`Two problems are commonin NHL, but
`rare in Hodgkin’s disease: (1) Congestion
`and edemaof the face and neck can result
`from pressure on the superior vena cava (su-
`perior vena cava or superior mediastinal syn-
`drome), and (2) ureteral compression from
`pelvic lymph nodes mayinterfere with uri-
`nary flow and cause secondary renal failure.
`
`Anemiais initially present in about 33% of
`patients and eventually develops in most. It
`may be caused by bleeding from GIinvolve-
`ment or low platelet levels, hemolysis from
`hypersplenism or Coombs’-positive hemo-
`lytic anemia, bone marrowinfiltration from
`lymphoma, or marrow suppression from
`chemotherapy or radiotherapy. A leukemic
`phase developsin 20 to 40% of lymphocytic
`lymphomas andrarely in intermediate-grade
`lymphomas.High-grade lymphomas mayfre-
`quently be leukemic. Hypogammaglobulin-
`emia caused by a progressive decrease in
`immunoglobulin production occurs in 15%
`of patients and may predispose to serious
`bacterial infection.
`Ki-1 anaplastic large cell lymphoma, a
`subset of intermediate-grade (diffuse large
`cell)
`lymphoma affecting children and
`adults, was recently codified by the Ki-l
`(CD30) antigen on the malignant cells. CD30
`is also seen on Reed-Sternberg cells,
`whereas CD15 is limited to Hodgkin’s dis-
`ease. The lymphomais heterogeneous; im-
`munophenotyping showsthat 75% of cases
`are of T-cell origin, 15% are of B-cell origin,
`and 10% are unclassified. Patients have rap-
`idly progressive skin lesions, adenopathy,
`and visceral lesions. It may be mistaken for
`Hodgkin’s disease or metastatic undifferen-
`tiated carcinoma.
`In children, NHL may beof the small non-
`cleaved cell (Burkitt’s lymphoma), diffuse
`large cell, or lymphoblastic type. Childhood
`lymphomas present special problems(eg, GI
`or meningeal involvement) and are managed
`differently than adult lymphomas. The lym-
`phoblastic type represents a variation of
`acute lymphoblastic leukemia (T-cell type)
`because both have a predilection for mar-
`row, peripheral blood, skin, and CNS in-
`volvement; patients often present with me
`diastinal adenopathy andsuperior vena cava
`syndrome. Follicular lymphomas rarely oc-
`curin children.
`
`Diagnosis
`NHL must be differentiated from Hodg-
`kin’s disease, acute and chronic leukemia,
`metastatic carcinoma, infectious mononu
`cleosis, TB (especially primary TB with hilar
`adenopathy), and other causes of lymphad.
`enopathy,
`including
`pseudolymphoma
`caused by phenytoin. Diagnosis can be made
`only by histologic study of excised tissue.
`Destruction of normal lymph node architec
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`ture and invasion ofthe capsule and adjacent
`fat by characteristic neoplastic cells are the
`usual histologiccriteria. Immunophenotyp-
`ing studies to determinethe cell of origin will
`identify specific subtypes and help define
`prognosis and mayaid in managementdeci-
`sions(see below). Demonstration ofthe leu-
`kocyte common antigen CD45 by immuno-
`peroxidase rules out metastatic carcinoma,
`whichis often in the differential diagnosis of
`“undifferentiated” malignancies. The test for
`leukocyte commonantigen can be done on
`fixed tissues. Most surface marker studies
`can also be doneonfixed tissue with immu-
`noperoxidase methods. Gene rearrange-
`ment (to documentB-cell or T-cell clonality)
`and cytogenetics require fresh tissue.
`Staging
`Localized NHL doesoccur,but the disease
`is disseminated in about 90% of follicular
`lymphomas and 70% of diffuse lymphomas
`whenfirst recognized. Clinical staging pro-
`cedures similar to those for Hodgkin's dis-
`ease (see above)are indicated, except that
`laparotomy and splenectomyare rarely re-
`quired. CT of the abdomen and pelvis may
`reveal para-aortic as well as mesenteric dis-
`ease sites. The final staging of NHL (see
`TABLE 139-2) is similar to that of Hodgkin's
`disease; however,it is more often based on
`clinical than pathologic findings.
`Initially, constitutional symptoms tend to
`be less common in NHLthan in Hodgkin’s
`disease and do not usually alter prognosis.
`
`Organinfiltration is more widespread, and
`the bone marrow andperipheral blood May
`be involved. Bone marrow biopsy to deter.
`mine marrow involvement should be done in
`all patients when it will change the manage.
`ment recommendation(eg, selecting Yradia.
`tion alone for
`localized low-grade lym.
`phoma, considering intrathecal therapy for
`intermediate-grade lymphoma, determinin
`the International Prognostic Index {IPI]).
`Prognosis and Treatment
`The histopathology, stage of disease, ang
`(in somereports) results of surface marker
`studies significantly influence the prognosis
`and responseto treatment. Patients with T:
`cell lymphomas generally have a worse prog-
`nosis than those with B-cell types, although
`results of recent intensive treatment pro-
`grams may lessen this difference. Otherfac-
`tors that adversely affect prognosis are poor
`performancestatus, age > 60 yr, elevated
`LDHlevel, bulky tumor masses (diameter >
`10 cm), and more than two extranodal sites
`of disease.
`Recently, a prognostic index for diffuse
`mixed,diffuse large cell, and immunoblastic
`lymphomas has been reported. The IPI con-
`siders five categories: age, performance
`status, LDH level, number of extranodal
`sites, and stage. Prognostic groups oflow,
`low intermediate, high intermediate, and
`high risk maybe defined (see TABLE 139-3).
`The IPI is also being studiedin low-grade and
`high-grade lymphomas.
`
`TABLE 139-3. OUTCOME ACCORDING TO RISK GROUP AS DEFINED
`BY THE INTERNATIONAL PROGNOSTIC INDEX
`2-Yr
`5-Yr
`Relapse-
`_Relapse-
`Free
`Free
`Survival
`Survival
`(%)
`(%)
`79
`70
`66
`50
`
`2-Yr
`Survival
`(%)
`84
`66
`
`5-Yr
`Survival
`(%)
`73
`51
`
`Risk
`Group
`
`Low
`Low-
`Intermediate
`
`Risk
`Factors
`(a)
`Oorl
`2
`
`Complete
`Patients* Response
`(%)
`(%)
`35
`87
`27
`67
`
`High-
`Intermediate
`
`3
`
`22
`
`55
`
`59
`
`49
`
`54
`
`43
`
`44
`16
`4or5
`High
`
`
`
`40 3458 26
`*Patients total 2031, including 1385in the training sample and 646in the validation sample.
`Adapted from The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: “A predictive model
`for aggressive non-Hodgkin's lymphoma.” N Engl J Med 329(14);987-994, 1997.
`
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`Treatmentoflocalized disease (stages
`I and IJ): In low-grade lymphomas,pa-
`tients rarely present with localized disease,
`but when they do,regional radiotherapy may
`offer long-term control. However, relapses
`may occur > 10 yr after radiotherapy.
`About 1/2 of patients with intermediate-
`grade lymphomas present with localized
`disease. These patients must receive com-
`bination chemotherapy and regional irradi-
`ation, which is usually curative.
`Patients with high-grade lymphomas,
`lymphoblastic lymphomas, or small non-
`cleaved cell
`lymphomas
`(Burkitt’s lym-
`phoma), even if apparently localized, must
`receive intensive combination chemother-
`apy with meningeal prophylaxis. Treatment
`may require maintenance chemotherapy
`(dymphoblastic), but cure is expected.
`Treatment
`of
`advanced
`disease
`(stages III and IV): Treatment varies con-
`siderably in patients with low-grade or in-
`dolent lymphomas. A watch-and-wait ap-
`proach, treatment with a single alkylating
`drug, or two-drug and three-drug regimens
`may be used. Interferon and other biologic
`response modifiers may be of benefitin some
`cases, Recent reports of radiolabeled-anti-
`body therapy also appear promising. Al-
`though survival may be prolonged in terms
`of years, late relapse occurs, resulting in an
`unfavorable long-term prognosis.
`In patients with intermediate-grade
`lymphomas, the drug combination CHOP
`(cyclophosphamide, doxorubicin, vincris-
`tine, prednisone) is standard. Complete re-
`gression of disease in 50 to 70% of patients
`is expected, depending on the IPI category.
`About 70% of complete responders are
`cured, and relapses after 2 yr off treatment
`are rare.
`using
`regimens
`New chemotherapy
`growth factor support are understudy. Pre-
`liminary data suggest that these high-dose
`regimens may be superior to CHOP.An in-
`tensive alternating regimen for small non-
`cleaved cell (Burkitt’s) lymphoma, CODOX-
`M/IVAC (cyclophosphamide, vincristine,
`doxorubicin, methotrexate, ifosfamide, eto-
`Poside, cytarabine), has been reportedto re-
`Sult in a cure rate of > 90% for children and
`adults.
`Patients with T-cell lymphoblastic lym-
`Phoma are managed in a similar fashion to
`those with acute childhoodT-cell leukemia,
`le, with intensive chemotherapy regimens,
`
`‘
`
`CHAPTER 139 — LYMPHOMAS / 961
`
`including prophylactic treatment of the CNS.
`Results are encouraging, with a cure rate of
`at least 50%.
`Treatment of relapse: Thefirst relapse
`after initial chemotherapy is almost always
`treated with stem cell transplantation. Pa-
`tients must be physiologically = 65 yr and
`have responsive disease, good performance
`status, and a source of uncontaminated and
`adequate number CD34* stem cells. Tumor
`response is usually assessed with a second-
`line salvage chemotherapy regimen. Stem
`cells are harvested from peripheral blood or
`bone marrow.Thestem cell product may be
`purged (cleared of tumor cells by in vitro
`methods) or positively selected (collecting
`CD34* cells), and soon the stem cell pool
`may be expanded in vitro. Consolidation
`myeloablative therapy may include chemo-
`therapy with or without whole-bodyirradi-
`ation. Posttreatment immunotherapy(eg, in-
`terferon, IL-2) is being studied.
`Autologous
`transplantation (stem
`cells from the self ) is recommendedas sal-
`vage therapy for all eligible patients with
`chemosensitive relapse. If an HLA-compati-
`ble donoris available, allogeneic (stem cells
`from a related donor) transplantation may
`be considered for those with high-grade lym-
`phomas, bone marrow or blood involvement,
`or low-grade lymphomas.Theallotransplant
`stem cell product is free of contaminating
`tumorcells and may provide a theoretically
`beneficial graft-vs.-lymphomaeffect. These
`advantages must be balancedbythe signifi-
`cantly increased risks of the allotransplant
`procedure.
`A cure may be expected in 30 to 50% of
`eligible patients with intermediate- and high-
`grade lymphomas undergoing myeloablative
`therapy. In low-grade lymphomas,it remains
`uncertain whether cure may be obtained
`with transplantation, althoughsurvivalis su-
`perior to secondary palliative therapy alone.
`The mortality rate of myeloablative trans-
`plantation has decreased dramatically to 2
`to 5% for most autologous procedures and
`< 15% for most allogeneic procedures.
`A newarea ofinvestigation is the role of
`autologoustransplantationas first treatment
`at initial diagnosis. Using the IPI, high-risk
`patients may be identified and selected for
`dose intensification. Preliminary data sug-
`gest an increased rate of cure.
`A late sequela of standard and high-dose
`chemotherapy is the occurrence of second
`
`i,
`
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`962 /
`
`SECTION 11 ~ HEMATOLOGY AND ONCOLOGY
`
`neoplasms, especially myelodysplasias and
`acute myelogenous leukemia. Chemother-
`apy combined with radiotherapy increases
`this risk, althoughits incidenceis still only
`about 3%. A special late event in young
`women with Hodgkin’s disease treated with
`radiotherapy is an increased incidence of
`breast cancer.
`
`BURKITT’S LYMPHOMA
`(Small Noncleaved Cell Lymphoma)
`Although rare in the USA, Burkitt’s lym-
`phomais endemic in Central Africa. It may
`present in childhood as a rapidly enlarging
`jaw or ovarian mass. More frequently, it ap-
`pears as bulky abdominal disease, often aris-
`ing in the region of the ileocecal valve. In
`adults,it may be bulky and generalized, often
`with massive involvement of liver, spleen,
`and bone marrow. CSF andbrain disease are
`often found at diagnosis or with relapsing
`lymphoma.
`The pathology reveals a high mitotic rate
`and a starry sky pattern of rapidly prolifer-
`ating malignant lymphocytes. The diseaseis
`closely associated with Epstein-Barr virus
`(EBV) in the endemic lymphoma; however,
`it is uncertain whether EBV plays an etio-
`logic role. Burkitt’s lymphoma has charac-
`teristic cytogenetics, usually t(8;14), involv-
`ing the C-myc oncogene. Staging includes CT
`of the torso, bone marrow biopsy, CSF cy-
`tology, and gallium scanning.
`Treatment must beinitiated urgently and
`staging studies expedited because of rapid
`tumor growth. With treatment, tumorlysis
`syndrome may be a complication of rapid
`cell death. A high LDH level predicts for this
`complication, and patients must receive hy-
`dration,allopurinol, alkalinization and atten-
`tion to electrolytes (to preventor treat hy-
`perkalemia), possible uric acid nephropathy,
`and acute renal dysfunction, hypocalcemia,
`and hyperphosphatemia. High-dose, short-
`course combination chemotherapy may be
`highly curative (> 75 %). Meningeal prophy-
`laxis is essential. Occasionally, the disease
`
`is completely resected prior to chemother.
`apy, but aggressive therapyisstill indicated,
`
`MYCOSIS FUNGOIDES
`An uncommon chronic T-cell lymphoma
`primarily affecting the skin and occa.
`sionally the internal organs.
`Mycosis fungoidesis rare compared with
`Hodgkin's disease and non-Hodgkin’s lym.
`phoma (NHL) and, unlike most other lym.
`phomas,is insidious in onset.It may appear
`as a chronic, pruritic rash that is difficult to
`diagnose. Initially plaquelike,it may spreaq
`to involve mostof the skin, become nodular,
`and eventually become systemic. Lesions
`may becomeulcerated. Pathologic diagnosis
`is delayed because sufficient quantities of
`lymphomacells appear in the skin lesions
`very gradually. Immunophenotyping studies
`show that the malignantcells are mature T
`cells (T4*, T11*, T12*). Characteristic Pay.
`trier’s microabscesses are present in the epi-
`dermis. Most patients are > 50 yr at diagno-
`sis,
`from which time the average life
`expectancy is 7 to 10 yr, even withouttreat.
`ment. In somecases, aleukemic phase called
`Sézary syndromeis characterized by the
`appearanceofmalignantT cells with serpen-
`tine nuclei in the peripheral blood.
`Treatment
`in which
`Electron beam radiothera