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`VincentT. DeVita,Jr:
`Samuel Hellman
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`DR. REDDY’S LABS., INC. EX. 1039 PAGE 1
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`
`
`CANCER
`Principles & Practice
`of Oncology
`
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`
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`CLL.
`naa
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`BERR eee,
`Za
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`BER ERE em
`Ze
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`ERR Eee Of
`One EEE
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`5th Edition
`
`LY Lippincott - Raven
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`E
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`U BL tI
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`Philadelphia « New York
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`5th Edition
`Copyright © 1997 by Lippincott—Raven Publishers.
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`Library of Congress Cataloging-in-Publication Data
`Cancer:principles and practice of oncology/[edited by] Vincent T. DeVita, Jr.,
`Samuel Hellman, Steven A. Rosenberg; 290 contributors.—5th ed.
`.
`cm,
`Includes bibliographical references.
`Includes index.
`ISBN 0-397-51573-1 (one-vol. ed.)
`ISBN 0-397-51574-X (two-vol. set)
`ISBN 0-397-51575-8 (vol. 1)
`ISBN 0-397-51576-6 (vol. 2)
`ISSN 0892-0567
`1. Cancer. 2. Oncology.
`I. DeVita, Vincent T., Jr. I. Hellman, Samuel.
`III. Rosenberg, Steven A.
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`any changein indications and dosage andfor added warnings andprecautions. This is
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`
`
`45
`Leukemias
`SECTION 1
`
`SECTION 2
`
`Contents
`
`lv
`
`2243
`
`Pathology and Biologic Features
`Diagnosis and Staging
`2249
`2252
`Patterns of Clinical Presentation
`Immunologic Abnormalities
`2254
`Treatment
`2255
`Hodgkin's Disease in HIV-Positive Patients
`Complications of Therapy
`2274
`New Drugs andBiologies in Hodgkin’s Disease
`
`2274
`
`2274
`
`2285
`2287
`
`eee Rae ne we ew ew ng ee BERG Be ES Ha wm ee we ee ee 2285
`Molecular Biology of the Leukemias
`2285
`ISSA KHOURI
`FELIX GARCIA SANCHEZ
`ALBERT B. DEISSEROTH
`Chronic Myelogenous Leukemia
`Acute Myelogenous Leukemia
`Changesin CML
`2289
`Genetic Changes in ALL: Enumerative Chromosomal Abnormalities of
`Leukemic Syndromes
`2289
`2290
`Chimeric Transcriptional Regulatory Proteins in ALL
`Translocations Resulting in Lineage-Specific Patterns of Transcriptional
`Regulatory Proteins
`2290
`Leukemic Syndromes Organized by the Chromosomes Involved
`2291
`Application of the Structural Information Derived From the Study
`of ChromosomalTranslocations to the Therapy of Leukemia and
`Solid Tumors
`2292
`Summary
`2292
`
`2293
`
`2296
`
`2304
`
`Acute Leukemias
`DAVID A. SCHEINBERG
`PETER MASLAK
`MARK WEISS
`2293
`Epidemiology and Etiology
`2295
`Biology of Acute Leukemias
`Diagnosis and Classification of Acute Leukemias
`Principles of Therapy for Acute Leukemia
`2300
`2303
`Principles of Clinical Managementof Acute Leukemia
`Treatment of Newly Diagnosed Acute Myelogenous Leukemia
`Treatment of Relapsed Acute Myelogenous Leukemia
`2308
`Acute Promyelocytic Leukemia
`23/0
`General Principles for the Treatment of Adult Acute Lymphoblastic
`Leukemia
`2310
`Prognostic Features in Adult Acute Lymphoblastic Leukemia
`2311
`Treatment of Newly Diagnosed Adult Patients With Adult Lymphoblastic
`Leukemia
`2312
`Treatment of Relapsed or Refractory Adult Patients With Acute
`Lymphoblastic Leukemia
`23/3
`Central Nervous System Relapse in Adult Acute Lymphoblastic
`Leukemia
`2314
`Bone Marrow Transplant for Adult Acute Lymphoblastic
`Leukemia
`23/14
`
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`
`
`Wi
`
`Contents
`
`SECTION 3
`
`2314
`Treatment of Mature B-Cell Acute Lymphoblastic Leukemia
`Granulocyte Sarcomas, Leukemia Cutis, and Other Extramedullary
`Leukemic Involvement
`2315
`i
`Biological and Immunological Therapies of Acute Leukemias
`2315
`Conclusion
`2316
`
`2321
`
`Chronic Leukemias
`ALBERTB. DEISSEROTH
`HAGOP KANTARJIAN
`MICHAEL ANDREEFF
`MOSHE TALPAZ
`MICHAEL J. KEATING
`ISSA KHOURI
`RICHARD B. CHAMPLIN
`Chronic Lymphocytic Leukemia
`Prolymphocytic Leukemia
`2327
`Hairy Cell Leukemia
`2327
`T-Cell Chronic Lymphocytic Leukemia
`Chronic Myelogenous Leukemia
`2328
`Summary
`2338
`
`2321
`
`2328
`
`SECTION 4
`
`SECTION 5
`
`2344
`
`Plasma Cell Neoplasms
`SYDNEY E. SALMON
`J. ROBERT CASSADY
`History
`2344
`Incidence and Mortality
`Pathogenesis
`2347
`Pathology
`2349
`Diagnosis and Clinical Staging of Myeloma
`Treatment
`2355
`Complications and Special Problems
`2369
`Other Plasma Cell Neoplasms
`23 7)
`Perspective
`2379
`
`2346
`
`2352
`
`2388
`
`Myelodysplastic Syndromes
`DAVID A. SCHEINBERG
`PETER MASLAK
`MARK WEISS
`2388
`Incidence, Etiology, and Classification
`2389
`Biology of Myelodysplastic Syndromes
`Diagnosis
`2389
`2390
`Prognosis in Myelodysplastic Syndromes
`Specific Syndromesof Myelodysplastic Syndromes
`Chronic Myelomonocytic Leukemia
`2391
`Treatment of Myelodysplastic Syndromes
`2391
`Hematopoietic Growth Factors
`2392
`Drug Therapy of Myelodysplastic Syndromes Including
`Chemotherapy
`2393
`Allogeneic Bone Marrow Transplantation for Myelodysplastic
`Syndromes
`2394
`
`2391
`
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`
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`2388
`
`Chapter 45.5 Leukemias
`
`DAVID A. SCHEINBERG
`PETER MASLAK
`SECTION 5»
`MARK WEISS
`
`Myelodysplastic Syndromes
`
`
`
`INCIDENCE, ETIOLOGY,
`AND CLASSIFICATION
`
`The myelodysplastic syndromes (MDS) are a heterogeneous
`groupofclonal neoplastic hematologic disorders characterized
`by varying degrees of bone marrowfailure, abnormal hemato-
`poiesis, andproliferation ofmyeloidblast cells. Although cer-
`tain types of MDS have been termed “preleukemia”! or“smol-
`dering leukemia’* and are often considered low-grade
`neoplasms, the clinical courses of the subtypes exhibiting ex-
`cess blasts are highly malignant, and complete remissions are
`difficult to achieve with chemotherapy. One fifth of patients
`with MDS, usually among those in the high-risk group (see
`below), will progress to acute myeloid leukemia (AML). As with
`AML,morbidity and mortality in patients with MDSare a con-
`sequence of bone marrowfailure, leading to anemia,bleeding,
`andinfection. Unlike the leukemias, however, only a small frac-
`tion of patients with MDS die as a consequence of leukemic
`transformation; most die as a direct consequence of marrow
`failure.* Many of the distinctions between cases of MDS with
`excess levels of blasts and true AML,particularly certain cases
`of secondary AML, are semantic; whereas the origins, chromo-
`somal abnormalities, and clinical courses of both diseases are
`often similar, an arbitrary level of at least 30% bone marrow
`blasts is used to denote those patients with AML as opposed
`to those with MDS, who have fewerblasts.
`Theincidence of MDSis difficult to define precisely because
`of the heterogeneity of the syndromes, the presence of the
`more benign subtypes, which often go untreated, and theclini-
`cal and pathologic overlap of the more malignant syndromes
`with AML. Theincidence of MDSis 50% to 70% that of AML..*
`This translates into approximately 5000 new cases of MDSdi-
`agnosedeachyearin the United States. Males are more often
`affected than females, and there is a clear age-relatedrise in
`incidence. MDSis rarely seen before the age of 50 but rapidly
`increasesin incidence in older populations and may equalthe
`incidence of AML by the eighth decade." The prevalence in
`persons over 65 years old has been estimatedat 0.1%.> The
`median age is about 70.°
`A numberofrisk factors have been associated with the devel-
`opment of MDS; theseare largely the same factors as those
`causing AML, such as ionizing radiation, benzene, cigarette
`smoke, and chemotherapeutic drugs.’ Alkylating agents and
`radiation therapy used in the treatment of Hodgkin’s disease,
`non-Hodgkin’s lymphomas, myeloma, breast cancer, in bone
`marrowtransplantation, and in other malignancies are impli-
`cated as etiologic agents, associated with frequentlossesofall
`or parts of chromosomes 5 and 7.8 Risks are increased in pa-
`tients who were treated with combined chemotherapy and ra-
`diotherapy as comparedwith thosetreated with either modality
`alone.®!° Lower doses of cyclophosphamide, however, such as
`those used in the adjuvant therapy of breast cancer, may not
`significantly increase the risk of secondary MDS.!! Increased
`
`calttitfative doses of alkylating agents results in increag,d
`risks.”
`:
`In patients with Hodgkin’s and non-Hodgkin's lymphomag
`whoreceive high-dose cyclophosphamide or total-body irra.
`diation as preparation for an autologous bone marrowtray.
`plant or autologousstemcell transplant, there is a Significayy
`risk for developing a treatment-related MDS or AML!5.14
`Actuarial risks are estimated at 11% to 18%over a 5 to 6
`year period, Factors predicting increased risks are use of
`irradiation, age greater than 38 years, a longer time between
`initial treatment and the transplant, and decreased platelet
`counts at the time of transplant. Ten of 15 patients wih
`secondary MDS whohadcytogenetic analyses performed haq
`abnormalities of chromosome 7. In addition,
`it was noteq
`that cytogenetic abnormalities were present in approximately
`50%of patients who underwent transplant but had no ey.
`dence of MDS at the time ofanalysis."
`The timefrom the end of cancer therapy to the beginning
`of treatment-related MDSis typically 3 to 6 years but varies
`from 1.5 to 13 years.®’? Approximately one third ofpatients
`developing a treatment-related secondary leukemia (whichis
`myeloid in more than 90% ofcases) have a preceding myelodys-
`plastic phase.®!? When MDSoccurs after chemotherapy,it is
`generally a high-risk subtype associated with increased blasts
`(see later). MDS does not generally result from treatment with
`topoisomerase II inhibitors (etoposide, doxorubicin, and oth-
`ers), which typically cause translocations involving chromo.
`some 11q23 or other balanced translocations. Moreover, AML
`carrying these balanced translocationsis rarely precededby an
`antecedent MDS.!® Viruses or other infections have not been
`associated with MDS. The risk of MDS may be increased in
`families of patients with MDS.!” In addition, thereis a rare,
`familial form of MDS and AMLseenin association with mono-
`somy 7.'®%!9 These MDScases are associated with frequent
`transformation to leukemia at a young age.
`The various pathologic entities of MDS wereclassified by
`the French-American-British (FAB) group into five subtypes
`(refractory anemia (RA), refractory anemia with ringed si-
`droblasts (RARS), refractory anemia with excess blasts (RAEB),
`refractory anemia with excess blasts in transformation (RAEB-
`T), and chronic myelomonocytic leukemia (CM ML)“ (Table
`45,5-1), These classes are generally divided according to the
`numberof blasts in the blood and marrow and the presence
`of monocytosis; bone marrowswithat least 30%blasts are classi-
`fied as acute leukemia. The pathologic diagnosis is difficult,
`however, due to the heterogeneity offindings. Cytochemical
`staining (1) forirontoidentify ringedsideroblasts, (2) for pel
`oxidase to identify abnormal granulation of myeloid cells, (3)
`for periodicacid-schiffstain to identify abnormal erythroblasts,
`(4) for reticulin forfibrosis, and (5) with antiplatelet antibodies
`to mark micromegakaryocytes can sometimes be helpful.*! Gy-
`togenetic analysis is necessary toassistin diagnosis andto assess
`prognosis (see later). Forty to seventy percent ofpatients have
`abnormal
`findings.'©?2-24 ‘The incidence of an abnorm’
`karyotypeis even higherin patients with MDS secondary 1
`cytotoxic agents.” In practice,
`the MDS subtypes may be
`grouped into three main categories, ‘The low-risk subtype
`whichrarely progress to AML, the high-risk subtypes, which
`carry a far worse prognosis, and CMML,which behaves like #
`myeloproliferative disorder and has a variable prognosis.
`
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`re
`
`Diagnosis
`
`2389
`
`TABLE 45.5-1. Clinical and Pathologic Features of Myelodysplastic Syndromes®16?0-49
`Bone ProgressionpeeAN)osMDS
`
`
`Marrow
`(% of Cases)
`to AML(%)
`Range
`Median
`
`LOW-RISK MDS
`
`HIGH-RISK MDS
`
`15-30
`10-15
`25-30
`20
`10-20
`NA
`
`10
`10
`45
`60
`15
`NA
`
`<5% blasts
`.
`Refractory anemia
`<5% blasts*
`Refractory anemiawith ringed sideroblasts
`5-19% blasts
`Refractory anemia with excess ofblasts
`20-29%
`Refractory anemtia with excess ofblasts in transformation
`<20%+
`CHRONIC MYELOMONOCYTIC LEUKEMIA
`230% blasts
`ACUTE MYELOID LEUKEMIAWITH HISTORY OF MDS
`NA, not applicable; MDS, myelodysplastic syndromes; AML,acute myeloid leukemia.
`«> 15% oferythroblasts are “ringed” sideroblasts.
`Blood monocyte counts must be over 10°/L.BeesanhersON
`
`1-5
`1-5
`0.5-2
`<i
`1-5
`<I
`
`4
`4
`|
`0.5
`0.5
`
`all three lineages, with the highest rates in RAEB-T.Increased
`apoptosis of marrowstroma was also seen.**
`Genetic abnormalities in MDSare becoming increasingly im-
`portant in understanding the pathophysiology ofthe disease,
`in determining diagnosis, andin assigning prognosis. Approxi-
`matelyonehalfofall cases have nonrandom abnormalities that
`can be associated with one or more of the MDS types®° (Table
`45.5-2). One of the most common changes is the loss of part
`of the long arm ofchromosome5 (5q-), Thisis of consicerable
`interest since a number of genes involved in hematopoiesis
`have been mappedto 5q,”" including M-CSF, GM-CSF, in-
`terleukin (IL)-4, IL-5, CD14, interferon regulatory factor-1
`(IRF-1), a potential tumor suppressor,*?"" early growth re-
`sponse gene- 1, the receptors forplatelet-derived growthfactor
`and M-CSF(fms), and others.”® The loss of fms gained impor-
`tance because fmsis a tyrosine kinase protooncogene; a viral
`form of fms (v-fms) has wansforming properties. Oncogenic
`point mutations have been found in fms in patients with MDS
`and AML.27"8 In addition to these findings, fms mutations
`have been observed in patients who have received cytotoxic
`chemotherapy,leading to speculation as to its role in the patho-
`genesis of MDS and AM {.2" The role of fms remains unclear,
`however, because the loss of 5q implies the presence of an
`important tumor suppressor gene rather than a dominantly
`acting mutated oncogene.
`Mutations in ras genes (N-ras, K-ras, H-ras) have also been
`found in 10 to 25% ofpatients with MDS.248° Therefore,it is
`possible that ras gene activation may play a role in progression
`ofMDSin some patients, particularly those with CMML, where
`there is the highest association.*°
`
`BIOLOGY OF MYELODYSPLASTIC
`. SYNDROMES
`The presence of nonrandom chromosomal abnormalities in
`the blast cells of patients with MDS demonstrates that the dis-
`ease is a Clonal neoplasm.?*° X-chromosome inactivation
`studies have been conducted oncells of different
`lineages
`within the same patient to ascertain whetherearly hematopoi-
`etic progenitors with multipotent capability are involvedin the
`MDS clone.2%2? Both polymorphonuclear leukocytes and B
`lymphocytes were shown to be involved in some patients, sug-
`gesting the involvementofa primitive multipotent progenitor.
`Cytogenetic analyses of colony-forming units from pat ients
`with MDS demonstrate involvementofboththe erythroid and
`granulocytic-monocytic lineages” but also the residual pres-
`ence of normal pluripotentcells. In patients in whom a remis-
`sion can be achieved, polyclonal hematopoiesis can return202"
`The ability of progenitorcells from patients with MDS to
`form colonies in vitro is reduced.289°! Thefailure ofin vitro
`colony formation has been correlatedwith survival.! Hemato-
`Poietic growth factors, such as erythropoietin (Epo), granulo-
`cyte colony stimulating factor (G-CS F), and granulocyte-mono-
`yte colony stimulating factor
`(GM-CSF),
`can promote
`increased, but still subnormal, colony formation in vitro2°"!
`GM-CSFappears moreeffectivein growth promotion, whereas
`G-Cs¥ appears to have greater differentiating activity. Cyto-
`kine and growthfactor production in cells from patients with
`MDs is defective as well? Despite this observation, levels of
`Epoin the serumare inversely related to the degree of ane-
`mia." —Phese abnormalities in both the production and re-
`‘Ponse to growth anddifferentiating factors in MDS have sup-
`Portedthe use of hematopoietic growthfactors as a therapeutic
`DIAGNOSIS
`Strategy (see later).
`The observation that MDSis typically characterized by pan-
`. Patients with MDSare typically 50 to 80years of age. They
`Ytopenias, in the setting of bone marrow hypercellularity, has
`may present with pallor, fatigue, fever, petechiae, bruising, or
`€d
`to the proposal that the dysplastic cells are undergoing
`bleeding, as a consequence of bone marrowfailure, or with an
`mute, programmed, cell death (apoptosis). An insitu
`abnormalfinding on a routine complete blood count. Exposure
`10d for detection of apoptosis in the bone marrows from
`totoxic chemotherapy may produce MDS in a younger
`to c
`patients with MDS demonstratedhighlevels pi ,0ptosis 11
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`
`
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`
`
`
`
`
`
`
`
`
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`
`2390
`
`Chapter 45.5 Leukemias
`
`TABLE 45.5-2. Chromosomal Abnormalities
`in Myelodysplastic Syndromes?®*”
`Clinical Syndromes Associated With Specific
`Karyotypic Changes
`% of
`MDS
`Cases
`
`Associated Syndromes
`
`Abnormality
`
`del (5q)
`+8
`
`27
`19
`
`RA > RARS
`All MDS types; secondary MDS;
`AML
`
`—7 (& rarely del 7q)
`
`15-20
`
` RAEB and RAEB-T; secondary
`MDS and AML
`
`t/del (11q)
`(del (12p)
`del (20q)
`-Y
`
`7
`5
`5
`5
`
`RARS(andothers)
`CMML, RAEB, and RAEB-T
`MPD,PV, RAEB, and AML
`Normal males; RAEB; CMML
`
`Specific Karyotypic Changes Associated With Different
`Disease Subgroups
`Most Common Associated
`Change*
`
`Disease Type
`
`RA
`RARS
`RAEB and RAEBT
`
`CMML
`
`AML (de novo)
`
`5q-
`+8, 5q-, —7,t/del(11), 20q—
`5q-, —7, +8, +5, 7q~-, 20q-,
`+21, -Y
`—7, +8, t/del (12p), fms
`mutations, +21, —Y, 7q~
`(8:21), t(15:17), t(9:11), inv(16)
`
`RA, refractory anemia; RARS, refractory anemia with ringed sider-
`oblasts; MDS, myelodysplastic syndromes; AML, acute myeloid leuke-
`mia; RAFR, refractory anemia with excess blasts; RAEB-T, refractory
`anemia with excessblasts in transformation; CMML,chronic myelomo-
`nocytic leukemia; MPD, myeloproliferative disorder; PV, polycythemia
`vera.
`
`* Listed in orderoffrequency.
`
`with large, abnormally granular platelets or hypogranulay
`platelets; in the marrow, micromegakaryocytes are frequen,
`Blood chemistries are usually not helpful, although Big and
`folate levels should be evaluated to exclude nutritional ane.
`mias. Serumandurinarylysozyme maybe increased in CM My
`Examination of the marrow and blood should distinguish
`MDS from carcinomatous or lymphomatous replacement of
`the bone marrow, toxic damage to the marrow, paroxysmay
`nocturnal hemoglobinuria, hypersplenism, autoimmuneane.
`mia, and autoimmune thrombocytopenia. The 20%ofpatients
`with a hypocellular bone marrowcan be distinguished from,
`aplastic anemia by careful evaluation of the morphology ang
`by use of cytogenetics.*! HIV infection and AIDS can result in
`many of the hematopoietic and hematopathological features
`of MDS**; this diagnosis should be excluded in appropriate
`patients. AMLis distinguished from RAEB and RAEB-T based
`on the percentageofblasts in the marrow; MDS musthaveless
`than 30%. CML andother myeloproliferative disorders may
`be distinguished based on morphology andcharacteristic cyto-
`genetic abnormalities.
`Abnormalities in serum immunoglobulins are common in
`MDS.*44 Polyclonal gammopathies are observed in up to
`one third of patients. Monoclonal gammopathy and hypo-
`gammaglobulinemia are also seen. Autoimmune antibodies
`have an increased incidence.** B cell numbers appear normal,
`but T cells are frequently reduced, with CD4-positive cells
`more often affected than CD8 cells.*° These abnormalities
`in B and T cell function, however, do not appear to have
`significant clinical impact. Interestingly, there are reports of
`an increased risk of having both a lymphoid neoplasm and
`MDSsimultaneously.”*° However, transformation from MDS
`to a lymphoid neoplasm is rare. Therefore,
`the association
`between B lineage neoplasms and MDS maynotbea directly
`causal one.
`
`PROGNOSIS IN MYELODYSPLASTIC
`SYNDROMES
`
`F
`
`cohort than in those with de novo disease. Splenomegaly is
`seen in one fifth of patients, especially those with CMML; hepa-
`tomegaly is seen less often.
`‘Lhe blood smear and bone marrowaspirate smear and bi-
`opsy should be examinedin all patients. Anemia is essentially
`always present, and neutropenia and thrombocytopenia are
`common. If the peripheral blood monocyte count is greater
`than 1 x 10°/L in the setting of other features of MDS, CMML
`is diagnosed. The hone marrow and peripheral blood smears
`typically demonstrate evidence of dysplasia of all three line-
`ages. Blasts, when present in excess, are typically myeloid by
`histochemistry (Sudan black- or myclopcroxidase-positive) and
`by flow cytometry (expressing CD13 or CD33). In rare circum-
`stances, the blasts are ofB lineage (expressing CD19 or CD10).
`Blasts with biphenotypic features have also been reported.
`The marrow biopsy and smearis often hypercellular but may
`be normocellular or hypocellular. The morphology is notable
`for variable degrees of hypogranulation and hyposegmenta-
`tion (Pelger-Huet-like) of neutrophils, anisocytosis, poikilocy-
`70
`48
`0-1 point
`tosis, and macrocytosis of red cells in the blood, and marked
`50
`44
`2 points
`dyserythropoiesis in the marrow,including ringed sideroblasts,
`10
`8
`4 points
`asynchronous maturation, abnormal nuclear shapes, and chro-
`—aaa
`matin clumping. Dysplasia of platelets is noted in the blood,
`
`'
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 8
`
`An initial evaluation of potential prognostic features predict-
`ing survival in 141 patients with MDS showed bone marrow
`blasts and the degree of cytopenias to be most important
`(the Bournemouth score).? One point is assigned for each
`of the following poor prognostic features: bone marrow blasts
`over 5%; platelets below 100 x 10°/L, neutrophils below 2.5
`x 10°/L; and hemoglobin below 10 g/dL (Table 45.5-3).
`Morel and colleagues*’ expandedthis approach by evaluating
`408 cases of de novo MDS for clinical features, pathology,
`and cyogenetics,
`to construct additional prognostic models
`for survival and progression to AML. Survival could be pre-
`
`TABLE 45.5-3. Survival in Myelodysplastic Syndromes:
`Bournemouth Score®
`
`Score
`Patients With Score
`2-Year Survival Rate
`Subgroup
`(%)
`(%)
`
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 8
`
`
`
`r-
`
`Asi5 45.5-4. Factors Predicting Survival: Lille Score*”
`0 points
`1 Point
`2 Points
`z5sb bone marrow
`5-10% bone marrow
`>10% bone
`lasts
`blasts
`marrow blasts
`platelets >75 & 10°/L
`Platelets <75 X 10°/L
`‘Normal or single
`Complex karyotype
`. ‘paryouPle change
`pisk group: 0 points, low; 1-2 points, inter
`
`mediate; 3-4 points, high.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dicted based on examination ofthe karyotype; the percentage
`of blasts in the bone marrow, and the platelet count (Table
`45.5-4). ‘The low-risk group (score of 0) representing one
`third of patients had a median survival of 55 months, One
`halfof patients constituted the intermediate-risk group (score
`of 1 or 2), who had a median survival of 24 months. The
`high-risk group (score of 3 or 4) had a median survival of6
`months. Progression to AML. was predicted by other features
`(Table 45,5-5), notably the percentage of bone marrow blasts
`and the karyotype. Low-risk patients with no adverse features
`shad a 2-year freedom from AML. of 92%; patients with one
`ofthese two factors had a 2-year freedom from AML.of 60%;
`and patients with more than 10% blasts in the bone marrow
`and complex karyotypes had a 68% incidence of AMLby2
`years.Models based on combinations of the hemoglobin level,
`platelet count, and bone marrow or bloodblast percentages
`have been repeatedly demonstrated to predict both survival
`and leukemic transformation.**? A study of 401 patients in
`Japanalso confirmed the prognostic importance of karyotype
`for survival and progression fo AML.°° In this study, a score
`based on the Bournemouthscore (seeearlier) and thecomplex-
`ity of the karyotypic changes yielded three prognostic groups
`with 2-year survivals of 25%, 60%, and 80%, respectively.
`The importance ofkaryotype as an independent prognostic
`feature has been reported in other smaller studies.!0"25!?
`Clonal evolution with additional chromosomal abnormalities
`may occur frequently” andconfers a poor prognosis with sur-
`vival of only 2 months.”
`
`2391
`Treatment ofMyelodysplastic Syndromes
`Other reports have demonstrated the exceptionally poor
`survival of patients with treatment-related Mps.® Median sur-
`vival was less than 1 year and did not significantly vary with
`age, SEX, initial neoplasm, orits therapy. This poor prognosis
`was similar in patients with treatment-related AML andtreat-
`ment-related MDS that progressed to AML.
`SPECIFIC SYNDROMES
`OF MYELODYSPLASTIC SYNDROMES
`5q- SYNDROME
`The 5q— syndrome, typically foundin olderwomen, is charac-
`terized by an indolent course that seldom leads to AMLA
`‘Three quarters of patients are womens the median age is 66
`years. Morphologically, this syndrome presents as RAor RARS
`with monolobulated megakaryocytes. Cytogenetics demon-
`strate 5q- as the sole abnormality. The bloodis characterized
`by a macrocytic anemia, modest leukopenia, and normal to
`increased numbers of platelets. In one study, eight of nine
`patients with MDSand (1) signs of macrocytic anemia, (2) nor-
`mal or high platelet counts, and (8) hypolobular megakaryo-
`cytesdemonstrated 5q-asasole abnormality when cytogenetics
`were obtained.** The presence of additional chromosomal
`changes denotes patients with a much poorer progneysis. This
`syndrome must also be distinguished from treatment-related
`AML with a 5q-; these latter patients have @ poor prognosis.
`CHRONIC MYELOMONOCYTIC LEUKEMIA
`Chronic myelomonocytic leukemia has been classified as an
`MDSbecauseofits prominent bone marrowdysplastic features.
`Patientswith CMMLalsohavecharacteristicsofmyeloprolifera-
`tive disorders suchas monocytosis, splenomegaly, and hepato-
`megaly. The typical ageofpresentation is65 to 75 years; males
`outnumberfemales by almost 9: | 4955.58 Most patients present
`with anemia, 25 to 50%present with hepatomegaly or spleno-
`megaly (and a quarter ofpatients are febrileatdiagnosis.”” De-
`spite elevated monocyte countsin the peripheral blood andin-
`volvement of extramedullary sites, gingival infiltration is not
`usuallyseen.2®Onethirdofpatientshavemonocytelevelsabove
`5 x 10°7L.Thebonemarrowis typicallyhypercellularwith mye-
`loid hyperplasia andtrilineagedysplasia.Serumandurinary ly-
`soryme is elevated in 40% to 80%ofpatients.°*°? Monosomy 7,
`trisomy 8, and structural changes involving chromosome 12p
`are the most common cytogenetic abnormalities.”°
`Median survival from diagnosis is 18 to 30 months, with a
`range of | monthto 10 years.°”°” Poor prognosis is predicted
`by increased bone marrow blasts, markedly elevated mono-
`cytosis (more than 10 * 1O°vL), and evidence of either In-
`creased proliferation and neoplastic cell burden or increased
`dysplasia and cytopenias.
`TREATMENT OF MYELODYSPLASTIC
`SYNDROMES
`GENERAL MANAGEMENT AND SUPPORTIVE CARE
`OF MYELODYSPLASTIC SYNDROMES
`The complications of MDSare primarily related to bone mar-
`YSLABS.LINC® he 03SPAC progress to overt
`PAGE9
`
`TARLE 45.5-5. Factors Predicting Progression to Acute
`Myeloid Leukemia
`Better Risk Factor
`Poor Risk Factor
`Bone marrow blasts <10%
`=10% blasts
`No circulating blasts
`Circulating blasts
`RA, RARS, CMML
`RAEB, RAEB-T
`WBC >4 x 10°/L
`WBC <4 X 10°/L
`Heb >10 g/dL
`Hgb <10 g/dL.
`Normal karyotype or
`Complex-karyotypes
`5q-, +8, -Y, —7, 7q— (seen alone)
`eeeRa, refractory anemia; RARS, refractory anemia with ringed si-
`atsCMML, chronic myelomonocytic leukemia; RAEB,refrac-
`cnnwithexcessblasts;RAEB-T,refractoryanemiawith excess
`lasts in transformation; WBC, white bloodcells; p hemoglobin.
`
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 9
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`
`
`2392
`
`Chapter 45.5 Leukemias
`
`AML.Ideally, the goal of treatment is the eradication ofthe
`malignantclone with the restoration of normal hematopoiesis.
`Althoughtransient responsesto cytotoxic therapy are occasion-
`ally seen, true eradication of the malignant clone with durable
`remissions are rare.
`The failure of current therapy to successfully treat MDSis
`related to both the biology of the disease and the characteristics
`of the host. The malignantcell appears to be an early hemato-
`poietic progenitoror stem cell, and the association ofthis early
`phenotype with intrinsic drug resistance may play a role in
`treatment
`failure.°’? The dominant nature of the malignant
`clone and the profound effect on normal hematopoiesis have
`led to speculation that normal stem cells may not remain in
`the bone marrows of many patients.” ‘This implies that eradi-
`cation of the neoplastic clone would notreestablish polyclonal
`hematopoiesis. As a consequence, following cytotoxic chemo-
`therapy, patients succumbto infection or hemorrhage associ-
`ated with prolonged pancytopenia.
`The sequalae of marrow failure are more pronounced in
`older patients. This experience has already been established
`in the treatment of older patients with AML. Advanced age
`confers an increased risk of death during attempted remission
`induction therapy, since older patients have a limited reserve
`to deal with the multiple-organ toxicities of intensive chemo-
`therapy.°* In addition, other comorbid conditions often com-
`plicate clinical management. Since MDSis primarily a disease
`of older patients, these factors have confounded attempts at
`aggressive therapeutic intervention.
`Further complicating therapy of MDS is the heterogenous
`nature of these disorders. Patients with low-risk MDS mayhave
`asmolderingclinical course in which the only therapeutic inter-
`vention requiredis intermittent transfusion. Alternatively, pa-
`tients with high-risk MDS may present with a picture similar
`to acute leukemia. This wide clinical spectrum necessitates that
`the patient care be individualized. The disappointing results
`achieved with cytotoxic chemotherapy often Jimit its applica-
`tion to patients who can no longerbe sustained with supportive
`measures.
`
`Currently, the standard of care in MDSis supportive therapy.
`Anemia is the most common problem, and patients should
`be transfused with packed red cells in response to symptoms.
`Patients often become dependent on blood product support,
`and the initial period of observationis helpful in determining
`the optimal time interval between transfusions. Some patients
`with low-risk MDS may require transfusional support over pro-
`longed periods of time, and an assessment of the need for
`chelation therapy with desferroxamine should be part of the
`early evaluation and follow-up.
`Thrombocytopenia may also complicate the clinical course
`of patients with MDS. Generally, platelet transfusions are re-
`served for episodes of bleeding or prophylaxis in anticipation
`of surgery or otherinvasive procedures. The degreeof alloim-
`munization ma