`
`SEVENTEENTH EDITION
`I
`THE
`
`MERCK
`
`MANUAL
`
`OF
`
`DIAGNOSIS AND THERAPY
`
`MARK H. BEERS, M.D., and ROBERT BERKOW, M.D.
`
`Editors
`
`Senior Assistant Editors
`ROBERT M. BOGlN, M.D., and
`ANDREW]. FLETCHER, M.B., B.Chir.
`
`Editorial Board
`
`Philip K. Bondy, M.D.
`Preston V. Dilts, Jr., MD.
`Douglas A. Drossman, M.D.
`L. Jack Faling, M.D.
`Eugene P. Frenkel, M.D.
`Glen 0. Gabbard, MD.
`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 & C0,, lNC.
`Whitehouse Station, NJ.
`
`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 chemotherapy is sim—
`ilar to that of AML, after age and karyotype
`are considered.
`
`139 / LYMPHOMAS
`A heterogeneous group of neoplasms arising in the reticutoen—
`dothetiat and lymphatic systems.
`
`The major types are Hodgkin‘s disease 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 malezfemale ratio is
`1.4:1. Hodgkin’s disease is rare before age 10
`and has a bimodal age distribution that peaks
`at ages 15 to 34 andafter age 60. However,
`the second peak may be 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 Ilodg—
`kin’s disease appear to 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
`Reedeternberg cells
`(large, binucleated
`cells) in lymph nodes or other sites. 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‘r 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-l anaplastic large
`cell NHL.
`
`R TABLE 139—l .
`\Type
`
`HISTOI’ATHOLOGIC SUBTYPES OF HODGKIN'S DISEASE
`
`Appearance
`
`Incidence
`
`Progression
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`LymDhocy’te-
`Predominant
`NOduLar
`Sclerosis
`
`Few Reed-Stemberg Cells and
`many lymphocytes
`Dense fibrous tissue*
`surrounds nodules of
`Hodgkin’s tissue
`
`A moderate number of Reed-
`Stemberg cells with a
`mixed background infiltrate
`
`Numerous Reed—Sternberg
`cells and extensive fibrosis
`
`3%
`
`Relatively slow or indolent
`
`67%
`
`25%
`
`Intermediate or moderately
`progressive; relatively slow
`or indolent (occasionally)
`Intermediate or moderately
`progressive; aggressive
`
`5%
`
`Aggressive
`
`
`Mixed
`
`Cellularity
`
`LymDhocyte-
`
`depleted
`*ShOWs characteristic birefringence with polarized light.
`
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`956 /
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`SECTION I] — HEMATOLOGY AND ONCOLOGY
`
`Symptoms and Signs
`Symptoms and signs primarily relate to
`the site, amount, and extent of nodal mass
`involvement. Most patients 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 contiguous sites. The rate of progres-
`sion varies according to histopathologic sub—
`type (see TABLE 139—1). Intense pruritus may
`occur early; fever, night sweats, and weight
`loss are frequent when internal nodes (bulky
`mediastinal or
`retroperitoneal), viscera
`(liver), or bone marrow is 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.
`Bone involvement 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. Homer’s syndrome and
`laryngeal paralysis may ' result when en-
`larged lymph nodes compress the cervical
`sympathetic and recurrent laryngeal nerves,
`respectively. Neuralgic pain follows nerve
`root compression. Intracranial, gastric, and
`cutaneous lesions 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 may result 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 common bacterial and un-
`usual fungal, viral, and protozoa] 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-
`phjlia 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 or liver 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 node en-
`largement (especially cervical) and medias-
`tinal adenopathy, with or without fever,
`night sweats, and weight loss, suggests lym-
`phoma; however, Hodgkin’s disease can be
`definitively diagnosed by lymph node biopsy
`that reveals Reed-Stemberg 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—Ml [CD15] and CD30 [Ber-HZD are
`important in cases that 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 spleno'megaly 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 must first be delin-
`eated. The Ann Arbor staging system is com-
`monly used (see TABLE 139—2). The CDTS'
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`77%
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`CHAPTER 139 — LYMPHOMAS / 957
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`TABLE 139—2. ANN ARBOR STAGING OF
`HODGKIN'S DISEASE AND NON-
`
`HODGKIN’S LYMI’HOMA
`Slage*
`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 may be falsely 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 and liver should be considered when
`therapeutic decisions will be significantly af-
`fected. However, staging laparotomy indi-
`cations have been narrowed significantly in
`recent years. Only patients whose clinical
`stage is IIA or less and in whom mantle ra-
`diation is planned may be considered. If the
`patient is to receive chemotherapy, staging
`laparotomy is 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 (extended field) to 3600 cGy is stan-
`dard because the disease spreads by lym-
`phatic contiguity. Patients with subclassifi-
`cation E may also respond to radiotherapy,
`although combined chemotherapy and radio—
`therapy is often recommended. Treatment is
`blased mainly on pathologically staged pa-
`tients, although selected patients may be
`Considered for primary radiotherapy with-
`OUt pathologic staging.
`.Stage I and HA disease can be treated
`Wlth radiotherapy alone to an extended field
`that includes all lymph node—bearing areas
`. abOIVe the diaphragm and, in most cases, the
`Denaomc lymph nodes to the aortic bifur—
`gram“ and spleen or splenic pedicle. Such
`r efitment cures about 80% of patients. Cure
`t1elfers to being disease-free at 5 years post—
`eFaDY. after which relapse is very rare. In
`fiftiems with bulky mediastinal disease, ra-
`mOtherapy alone has a high relapse rate; che—
`motherapy followed by radiotherapy results
`a prolonged relapse-free survival in about
`
`1
`
`2
`
`I
`H
`
`III
`
`In one lymph node only
`In two or more lymph nodes on the
`same side of the diaphragm
`In the lymph nodes, spleen, or both
`and on both sides of the
`diaphragm
`Above the renal vessels (eg, spleen;
`splenic, hilar, celiac, and portal
`nodes)
`In the lower abdomen (periaortic,
`pelvic, or inguinal nodes)
`IV
`Extranodal involvement (eg, bone
`
`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 (weight loss, 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 may suffice.
`For stage IIIAl 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 IIIAl, chemo-
`therapy and radiotherapy are indicated. For
`stage IIIA2 disease, combination chemo—
`therapy is generally used with or without ra-
`diotherapy of bulky nodal sites. Cure rates
`of 75 to 80% have been achieved.
`Because radiotherapy 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,
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`958 / SECllON ll - HEMATOLOGY AND ONCOLOGY
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`1
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`|
`
`
`
`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 become the
`standard regimen for most cases based on
`the results of recent randomized studies. A]-
`ternating MOPP and ABVD or hybrid com-
`binations have not proven superior to ABVD
`in prospective studies. Other effective drugs
`include nitrosoureas, ifosfamide, cisplatin or
`carboplatin, and etoposide. Patients who fail
`to achieve complete remission or who re—
`lapse within 6 to 12 mo have a poor progno—
`sis. Autologous transplantation using bone
`marrow or peripheral cell products has been
`carried out in selected patients; conven—
`tional salvage regimens are generally not cu—
`rative. Autologous transplantation can cure
`up to 50% of patients 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 oflym-
`phoid cells in sites ofthe immune system,
`including lymph nodes, bone marrow,
`spleen, liver, and GI tract.
`
`Pathologic classification of non—Hodgkin’s
`lymphomas (NHLs) continues to evolve,
`reflecting new insights into the cells of origin
`and the biologic bases of these heteroge-
`neous diseases. The course of NHL varies
`from indolent and initially well tolerated to
`rapidly fatal. A leukemia-like picture may
`develop in up to 50% of children and about
`20% of adults with some types of NHL.
`
`Incidence and Etiology
`NHL occurs more often than Hodgkin's
`disease. In the USA, about 50,000 new cases
`are diagnosed annually in 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-
`lymphoma Virus (HTLV—l) has been isolated
`and appears to be endemic in southern Ja—
`
`pan, the Caribbean, South America, and the
`southeastern USA. The acute illness of adlllt
`T-cell leukemia-lymphoma is characten'zed
`by a fulminating clinical course with Skin
`infiltrates, lymphadenopathy, hepatOSplenQ
`megaly, and leukemia. The leukemic Cells
`are malignant T cells, many with 00,11V01uted
`nuclei. Hypercalcemia often develops, re
`lated to humoral factors rather than to diffict
`bone invasion.
`
`The incidence of NHL, particularly inum,‘
`noblastic and small noncleaved (Burkjws
`lymphoma) cell types, is increased in HIV
`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-myc
`gene rearrangements are characteristic of
`some AIDS—associated
`lymphomas. Re-
`sponse to chemotherapy is possible, but tox.
`icity is common and opportunistic infections
`continue to occur, resulting in short survival
`Pathology
`The Working Formulation classifies
`NHL into prognostic categories having ther-
`apeutic implications as follows (NOTE: The
`prognostic designations are based on sur-
`vival data of patients treated before 1980 and
`may not accurately reflect outcomes in pa-
`tients undergoing modern therapy, as dis-
`cussed under Treatment, below):
`
`0 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.
`
`Imrnu—
`' High-grade lymphomas (20%):
`noblastic lymphoma; lymphoblastic lym—
`phoma; small noncleaved cell lymphoma
`(Burkitt’s and non—Burkitt’s type).
`0 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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`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
`tumor tissue, 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 major role in treatment strategy.
`
`Symptoms and Signs
`Although various clinical manifestations
`exist, many patients present with asymp-
`tomatic peripheral
`lymphadenopathy. En-
`larged lymph nodes are 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 lymphomamay cause a mal—
`absorption syndrome). The skin and bones
`are initially involved in 15% of patients with
`diffuse large cell lymphoma and 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. Weight loss,
`fever, night sweats, and asthenia indicate
`disseminated disease.
`Two problems are common in NHL, but
`rare in Hodgkin’s disease: (1) Congestion
`and edema of the face and neck can result
`from pressure on the superior vena cava (su—
`periorvenacavaor superiormediastinalsyn—
`drome), and (2) ureteral compression from
`pelvic lymph nodes may interfere with uri-
`nary flow and cause secondary renal failure.
`
`Anemia is initially present in about 33% of
`patients and eventually develops in most. It
`may be caused by bleeding from GI involve-
`ment or low platelet levels, hemolysis from
`hypersplenism or Coombs’—positive hemo-
`lytic anemia, bone marrow infiltration from
`lymphoma, or marrow suppression from
`chemotherapy or radiotherapy. A leukemic
`phase develops in 20 to 40% of lymphocytic
`lymphomas and rarely in intermediate-grade
`lymphomas. High—grade lymphomas may fre-
`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-l 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 lymphoma is heterogeneous; im-
`munophenotyping shows that 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 be of the small non-
`cleaved cell (Burkitt’s lymphoma), diffuse
`large cell, or lymphoblastic type. Childhood
`lymphomas present special problems (eg, G1
`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 and superior vena cava
`syndrome. Follicular lymphomas rarely oc-
`cur in 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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`960 / SECI'lON 11 — HEMATOLOGY AND ONCOLOGY
`
`ture and invasion ofthe capsule and adjacent
`fat by characteristic neoplastic cells are the
`usual histologic criteria. Immunophenotyp-
`ing studies to determine the cell of origin will
`identify specific subtypes and help define
`prognosis and may aid in management deci—
`sions (see below). Demonstration of the leu-
`kocyte common antigen CD45 by immuno-
`peroxidase rules out metastatic carcinoma,
`which is often in the differential diagnosis of
`“undifferentiated” malignancies. The test for
`leukocyte common antigen can be done on
`fixed tissues. Most surface marker studies
`can also be done on fixed tissue with immu—
`noperoxidase methods. Gene rearrange—
`ment (to document B—cell or T-cell clonality)
`and cytogenetics require fresh tissue.
`
`Staging
`
`Localized NHL does occur, but the disease
`is disseminated in about 90% of follicular
`lymphomas and 70% of diffuse lymphomas
`when first recognized. Clinical staging pro-
`cedures similar to those for Hodgkin’s dis-
`ease (see above) are indicated, except that
`laparotomy and splenectomy are 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 NHL than in Hodgkin’s
`disease and do not usually alter prognosis.
`
`Organ infiltration is more Widespread, and
`the bone marrow and peripheral blood “lay
`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 radia.
`tion alone for
`localized low—grade lym.
`phoma, considering intrathecal therapy for
`intermediate—grade lymphoma, determining
`the International Prognostic Index [IPI]).
`Prognosis and Treatment
`
`The histopathology, stage of disease, and
`(in some reports) results of surface marker
`studies significantly influence the prognosis
`and response to 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. Other fac—
`tors that adversely affect prognosis are poor
`performance status, age > 60 yr, elevated
`LDH level, 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 imrnunoblastic
`lymphomas has been reported. The IPI con-
`siders five categories: age, performance
`status, LDH level, number of extranodal
`sites, and stage. Prognostic groups of low,
`low intermediate, high intermediate, and
`high risk may be 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-
`5-Yr
`2-Yr
`Free
`Free
`Complete
`Bisk
`Survival
`Survival
`Survival
`Survival
`Palienls” Response
`Factors
`Risk
`
`
`
`
`
`
`(n) (%) (%) (%) (%) (%)Group (%)\
`
`Low
`0 or 1
`35
`87
`79
`70
`84
`73
`Low—
`2
`27
`67
`66
`50
`66
`51
`Intermediate
`
`High—
`Intermediate
`
`3
`
`22
`
`55
`
`59
`
`49
`
`54
`
`43
`
`4 or 5 16 44 58 40 34High 26
`
`
`
`
`
`
`
`*Patients total 2031, including 1385 in the training sample and 646 in 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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`Treatment oflocalized disease (stages
`I and II): 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,
`lyrnphoblastic 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
`(lyrnphoblastic), 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 under study. 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—
`Doside, cytarabine), has been reported to re-
`Sult in a cure rate of > 90% for children and
`adults.
`Patients with T-cell lymphoblastic lym-
`Dhoma are managed in a similar fashion to
`Phose with acute childhood T—cell leukemia,
`19, 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: The first relapse
`after initial chemotherapy is almost always
`treated with stem cell transplantation. Pa—
`tients must be physiologically s 65 yr and
`have responsive disease, good performance
`status, and a source of uncontaminated and
`adequate number CD344 stem cells. Tumor
`response is usually assessed with a second-
`line salvage chemotherapy regimen. Stem
`cells are harvested from peripheral blood or
`bone marrow. The stem 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-body irradi-
`ation. Posttreatment immunotherapy (eg, in-
`terferon, IL-2) is being studied.
`Autologous
`transplantation (stem
`cells from the self) is recommended as sal-
`vage therapy for all eligible patients with
`chemosensitive relapse. If an HLA—compati—
`ble donor is available, allogeneic (stem cells
`from a related donor) transplantation may
`be considered for those with high—grade lym-
`phomas, bone marrow orblood involvement,
`or low-grade lymphomas. The allotransplant
`stem cell product is free of contaminating
`tumor cells and may provide a theoretically
`beneficial graft-vs.-lymphoma effect. These
`advantages must be balanced by the 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, although survival is 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 new area of investigation is the role of
`autologous transplantation as 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
`
`.1
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`962 / SECI'lON ll — HEMATOLOGY AND ONCOLOGY
`
`a
`
`neoplasms, especially myelodysplasias and
`acute myelogenous leukemia. Chemother-
`apy combined with radiotherapy increases
`this risk, although its incidence is 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.
`
`BURKITI’S LYMPHOMA
`
`(Small Noncleaved Cell Lymphoma)
`Although rare in the USA, Burkitt’s lym—
`phoma is 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 and brain 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 disease is
`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;l4), involv-
`ing the C-myc oncogene. Staging includes CT
`of the torso, bone marrow biopsy, CSF cy—
`tology, and gallium scanning.
`Treatment must be initiated urgently and
`staging studies expedited because of rapid
`tumor growth. With treatment, tumor lysis
`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 prevent or 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 therapy is still indicated,
`
`MYCOSIS PUNGOIDES
`An uncommon chronic T—cell Lymphoma
`primarily affecting the skin and 0000,
`sionally the internal organs.
`Mycosis fungoides is 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 spread
`to involve most of the skin, become nodular,
`and eventually become systemic. Lesions
`may become ulcerated. Pathologic diagnosis
`is delayed because sufficient quantities of
`lymphoma cells appear in the skin lesions‘
`very gradually. Immunophenotyping studies
`show that the malignant cells are mature T
`cells (T4 +, T11 +, T12 Jr). Characteristic Pau—
`trier’s microabscesses are present in the epi—
`dermis. Most patients are > 50 yr at