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`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 1
`
`

`

`CANCER
`Principles 6} Practice
`ofOncology
`
`
`
`
`‘IIII
`Ill-ll...
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`“III
`lull-III.
`
`“In
`IIIIIII.
`
`Illllll‘.
`din-ll
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`
`
`
`5th Edition
`
`L Lippincott - Raven-
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`5
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`Philadelphia . New York
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`Project Editor: Grace R. Caputo
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`5th Edition
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`Copyright © 1997 by Lippincott—Raven Publishers.
`Copyright © 1993.
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`Library of Congress Cataloging-in—Publication Data
`
`Cancer: principles and practice ol'ot'tcology/[etlitetl 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.
`III. Rosenberg, Steven A.
`
`1. DeVita, Vincent T., Jr.
`
`11. Hellman, Samuel.
`
`Care has been taken to confirm the accuracy of the iniortnation presented and It)
`describe generally accepted practices.
`l-lowm'er. the authors. editors. and publisher are
`not. responsible for errors or omissions or for any consequences from application of the
`information in this book and make no warranty. express or implied. with respect to the
`contents of the publication.
`The authors, editors, and publisher have exerted every eii‘ort to ensure that drug
`seiection and dosage set. forth in this text are in accordance with current. recommendations
`and practice at the time of publication. i-Iowever. in view of ongoing research. changes in
`government regulations. and the constant flow of information relating to drug therapy
`and tlrug reactions, the reader is urged to check the package insert for each drug for
`any change in indications and dosage and for added warnings and precautions. This is
`particularly important at hen the reconrunended agent is a new or infrequently employed
`drug.
`Some drugs and medical devices presett ted in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
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`planned for use in their clinical practice.
`
`9
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`7
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`5
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`1
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`DR. REDDY’S LABS., INC. EX. 1039 PAGE 3
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`

`

`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
`22 74
`New Drugs and Biologies in Hodgkin’s Disease
`
`2274
`
`22 74
`
`........................................... 2285
`
`45
`Leukemias
`
`SECTION 1
`
`2285
`
`2285
`2287
`
`MoIeoular Biology of the Leukemias
`ISSA KHOURI
`FELIX GARCIA SANCHEZ
`ALBERT B. DEISSEROTH
`Chronic Myelogenous Leukemia
`Acute Myelogenous Leukemia
`Changes in 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
`Application of the Structural Information Derived From the Study
`of Chromosomal Translocations to the Therapy of Leukemia and
`Solid Tumors
`2292
`
`2291
`
`Summary
`
`2292
`
`SECTION 2
`
`Acute Loukemias
`DAVID A. SCHEINBERG
`PETER MASLAK
`MARK WEISS
`
`2293
`
`2296
`
`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 Management of Acute Leukemia
`Treatment of Newly Diagnosed Acute Myelogenous Leukemia
`Treatment of Relapsed Acute Myelogenous Leukemia
`23 08
`Acute Promyelocytic Leukemia
`2310
`General Principles for the Treatment of Adult Acute Lymphoblastic
`Leukemia
`231 0
`2311
`Prognostic Features in Adult Acute Lymphoblastic Leukemia
`Treatment of Newly Diagnosed Adult Patients With Adult Lymphoblastic
`Leukemia
`2312
`Treatment of Relapsed or Refractory Adult Patients With Acute
`Lymphoblastic Leukemia
`231‘ 3
`Central Nervous System Relapse in Adult Acute Lymphoblastic
`Leukemia
`2314
`Bone Marrow Transplant for Adult Acute Lymphoblastic
`Leukemia
`23 I 4
`
`2304
`
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`DR. REDDY’S LABS., INC. EX. 1039 PAGE 4
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`

`

`lvi
`
`Contents
`
`2314
`Treatment of Mature B-Cell Acute Lymphoblastic Leukemia
`Granulocyte Sarcomas, Leukemia Cutis, and Other Extramedullary
`Leukemic Involvement
`2315
`Biological and Immunological Therapies of Acute Leukemias
`2315
`Conclusion
`2316
`
`2321
`
`SECTION 3 Chronic Leukemias
`ALBERT B. DEISSEROTH
`HAGOP KANTARIIAN
`MICHAEL ANDREEFF
`MOSHE TALPAZ
`MICHAEL I. 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 Plasma 06]] Neoplasms
`SYDNEY E. SALMON
`]. ROBERT CASSADY
`
`2344
`
`2346
`
`2344
`History
`Incidence and Mortality
`Pathogenesis
`2347
`Pathology
`2349
`Diagnosis and Clinical Staging of Myeloma
`Treatment
`2355
`Complications and Special Problems
`Other Plasma Cell Neoplasms
`23 75
`Perspective
`23 79
`
`23 69
`
`2352
`
`SECTION 5 Myelodysplastic Syndromes
`DAVID A. SCHEINBERG
`PETER MASLAK
`MARK WEISS
`
`2388
`
`2388
`2389
`
`Incidence, Etiology, and Classification
`Biology of Myelodysplastic Syndromes
`Diagnosis
`2389
`2390
`Prognosis in Myeiodysplastic Syndromes
`Specific Syndromes of Myelodysplastic Syndromes
`Chronic Myelomonocytic Leukemia
`2391
`Treatment of Myelodysplastic Syndromes
`Hematopoietic Growth Factors
`2392
`Drug Therapy of Myelodysplastic Syndromes Including
`Chemotherapy
`2393
`Allogeneic Bone Marrow Transplantation for Myelodysplastic
`Syndromes
`2394
`
`2391
`
`2391
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 5
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`DR. REDDY’S LABS., INC. EX. 1039 PAGE 5
`
`

`

`2338
`
`Chapter 45.5 Leukemias
`
`DAVID A. SCIIEINBERG
`PETER MASLAK
`MARK WEISS
`SECTION 5
`
`
`Myelodysplastic Syndromes
`
`
`INCIDENCE, ETIOLOGY,
`AND CLASSIFICATION
`
`The myelodysplastic syndromes (MDS) are a heterogeneous
`group ol'cloiial neoplastic hematologic disorders characterized
`by varying degrees ol‘hone marrow failure. abnormal hemato~
`poiesis. and proliferation of myeloid blast cells. Although cer-
`tain types of MDS have been termed "prelenkemia"' or “smol—
`clering |eukemia"'"' 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 MDS are a con-
`sequence of bone marrow failure, leading to anemia, bleeding,
`and infection. 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.3 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 fewer blasts.
`The incidence of MDS is difficult to define precisely because
`of the heterogeneity of the syndromes, the presence of the
`more benign subtypes, which often go untreated, and the clini-
`cal and pathologic overlap of the more malignant syndrr mics
`with AMI... The incidence of MDS is 50% to 70% that ol'AML.4
`This translates into approximately 5000 new cases of MDS di-
`agnosed each year in the United States. Males are more often
`affected than females, and there is a clear age-related rise in
`incidence. MDS is rarely seen before the age of 50 but rapidly
`increases in incidence in older populations and may equal the
`incidence of AMI. by the eighth decade." The prevalence in
`persons over 65 years old has been estimated at 0.1%.5 The
`median agr is about 70.6
`A number of risk factors have been associated with the devel-
`
`opment of MDS; these are largely the same factors as those
`causing AML, such as ionizing radiation. benzene, cigarette
`smoke, and chemotherapeutic drugs.7 Alkylating agents and
`radiation therapy used in the treatment of Hodgkin’s disease,
`non—Hodgkin’s lymphomas, myeloma, breast cancer, in bone
`marrow transplantation, and in other malignancies are impli»
`cated as etiologic agents, associated with frequent losses of all
`or parts of chromosomes 5 and 7.8 Risks are increased in pa-
`tients who were treated with combined chemotherapy and ra—
`diotherapy as compared with those treated with either modality
`alone.9‘10 Lower doses of cyclophosphamide, however, such as
`those used in the adiuvanl therapy of breast cancer, may not
`significantly increase the risk of secondary MDS.” Increased
`
`cumulative doses of alkylating agents results in increased
`risks."*12
`
`In patients with Hodgkin’s and non-I—Iotlgkiu's lle’hnlnas
`who receive high—dose cyclophosphamide or total-body “Ta-
`diation as prei'iai'ation for an autologons bone marrow ”mm
`plant or antologous stem cell transplant. there is a signilicanl
`risk for developing a treatmerit—related MDS or AMLJJtli
`Actuarial risks are estimated at II% to 18% over a 5 to 6
`year period. Factors predicting increased risks are use of
`irradiation, age greater than 38 years, a longer lime between
`initial treatment and the transplant, and decreased Platelet
`counts at the time of transplant. Ten of 15 patients with
`secondary MDS who had cytogenetic analyses performed had
`abnormalities of chromosome 7. In addition,
`it was noted
`tltal tytogenetic abnormalities were present in approximately
`50% of patients who underwent transplant but had no Wt
`deuce oi MDS at the time of analysis.”
`The time front the end of cancer therapy to the beginning
`of treatment-related MDS is typically 3 t0 6 years but varies
`from 1.5 to 13 years.9'12 Approximately one third of patients
`developing a treatment—related secondary leukemia (which is
`myeloid in more than 90% of cases) have a preceding myelodys.
`plastic phasef”15 When MDS occurs 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 translocations is rarely preceded by an
`antecedent MDS.16 Viruses or other infections have not been
`associated with MDS. The risk of MDS may be increased in
`families of patients with MDS.l7 In addition, there is a rare,
`familial form of MDS and AML seen in association with mono-
`
`somy 7.18'19 These MDS cases are associated with frequent
`transformation to leukemia at a young age.
`The various pathologic entities of MDS were classified by
`the French—American-British (FAB) group into five subtypes
`(reli'actoiy anemia (RA). refractory anemia with ringed si-
`ilroblasts (RARS). reli'actoty anemia with excess blasts (RAEB),
`i‘eli'actory anemia with excess blasts in transloriuation {RAKE-
`'I"), and chronic myelon'ionocytic leukemia ((Ih-IMI.)3” ('l'able
`‘11-).5-1). These classes are generally divided according to the
`number of blasts in the blood and marrow and the presence
`ol‘nionocytosis; hunt: mar-rows with at least 30% blasts arc classi-
`fied as acute leukemia. The pathologic diagnosis is tlilliL'lllli
`however. due to the heterogeneity of findings. (Iytochemicfll'
`staining ( l) for iron to identify ringed sidet‘ohlasts, (‘2) for [18!"
`oxidase to identify abnormal granulation of myeloid cells, {3)
`for periodic acid—schift‘stain to identify abnormal eiythrohlastsi
`(4) ful‘ i'eticttiin for Iibrosis. and [5) with antiplatelet antibodies
`to mark microtnegakai'yocytes can sometimes he helpful.zl Cl"
`togenetic analysis is necessary to assist in diagnosis and to assess
`prognosis (see later). Forty to seventy percent inpatients have
`abnormal
`findings."3’22“2'1 The incidence ol an abnormal
`Itai‘yot'ypc is even higher in patients with MDS secondary l”
`cytotoxic r-igentsF‘2 In practice.
`the MDS subtypes may be
`grouped into three main categories. The ion-risk sulnypfiSI
`which rarely progress to AML, the high-risk subtypes. Wlllfl'
`carry a far worse prognosis. and CMMI., which behaves him a
`myeloproliferative disorder and has a variable prognosis-
`
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`DR. REDDY’S LABS., INC. EX. 1039 PAGE 6
`
`

`

`r
`
`TABLE 45.5-1.
`
`Clinical and Pathologic Features of Myelodysplastic Syndromes
`
`'
`
`Bone
`Marrow
`
`MDS
`(% of Cases)
`
`Progression
`in AMI. (%)
`
`6,16,20,49
`
`Diagnosis
`
`2 389
`
`Survival (y)
`
`Range
`
`Median
`
`Low.RISK MDS
`
`.
`Reli‘Eit‘torY anemia
`Refractory anemia with ringed sideroblasts
`
`momma MDs
`
`Rctimnm)‘ anemia with excess of blasts
`Refmlilmfi' anemia with excess ofblasts in transformation
`CHRONIC MYELOMONOCYTIC LEUKEMIA
`ACUTE MYELOID LEUKEMIA WITH HISTORY OF MDS
`
`<5% blasts
`<5% blasts*
`
`549% blasts
`20—29%
`<20%’r
`230% blasts
`
`15—30
`10—15
`
`25—30
`20
`10—20
`NA
`
`10
`10
`
`45
`60
`15
`NA
`
`1—5
`1—5
`
`0.5—2
`<1
`1—5
`<1
`
`4
`4
`
`l
`0.5
`
`0.5
`
`/N
`
`A, not applicable; MDS. ntyelotlysplastic syndromes; AML, acute Inyeloid leukemia.
`as >15% of etythroblasts are "ringed" sidet'olilasts.
`Blood monocyte counts must be over 10“i'l..
`L///——
`
`all three lineages, with the highest rates in RAEB-T. Increased
`apoptosis of marrow strouta was also seen.34
`Genetic alinortmtlities in MDS are becoming increasingly im-
`portant in understanding the pathophysiology of the disease,
`in determining diagnosis, and in assigning prognosis. Approxi-
`mater one ltali'ol'all cases have nonrandom abnormalities that
`can be associated with one or more of the MDS types25 (Table
`45.52). One of the most common changes is the loss of part
`ofthe long arm ol'cbromosonie 5 (Sq-J. This is ol'considerable
`interest since a number of genes involved in heinatopoiesis
`have been mapped to 5o?“ including M—(ISl-‘, GM-('.11'il". in-
`terleukin [lLl-fil. 114-5, (.ll)l£l-. interferon regulatory factor—1
`(IRF-l). a potential tumor fill})p‘t'€§$(tl‘.$5'im earlyf growth re-
`sponse gene- 1 _. the receptors for platelet-dct’iVed growth factor
`and M-(ZS'F (fins). and (itl'iei's.9fi'l‘lie loss of fins gained impor-
`tance because fms is a tyrosine kinase protooncogene; a viral
`form of fins (v-fms) has transforming properties. Oncogenic
`point mutations have been found in {ms in patients with M05
`and AMLM'” In addition to these findings, fms mutations
`have been obsetved in patients who have received Cytotoxic
`chemotherapy, leading to speculation as to its role in the patho—
`genesis of M US and .t\l\'ll...2‘1 The role of fins remains unclear,
`however, because the loss of 5c; 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 If] to 25% of patients with l\JIl)S.3‘1‘3‘l3 Therefore, it is
`possible that ras gene activation may play a role in progression
`ofMDS in some patients. particularly those with CMML, where
`there is the highest association.40
`
`DIAGNOSIS
`
`The presence of nonrandom chron'tosomal abnormalities in
`the blast cells of patients with MDS demonstrates that the dis-
`ease is a clonal
`JIGOPlEISHIF'I’ufi X-cln'omosotne inactivation
`studies.
`ltave been conducted on cells of different
`lineages
`within the same patient to ascertain whether early hematopoi-
`eticprogenitors with mnltipotent capability are involved in the
`MDS Lfltlllc.2fi'2? Both polymtirpltonttclear leukocytes and B
`lymphocytes were shown to be involved in some patients. sug—
`gesting the involvement of a primitive multipotent progenitor.
`Cytogct'tetic analyses of colony-im'ming units from patients
`with MDS demonstrate it'ivolveinem ol'both the erythroid and
`grantulocytic-monocytic lineages” but also the residual pres-
`ence of normal pluripotent cells. In patients in whom a remis-
`sion can be achieved. polyclonal hematopoiesis can return?““"""
`The ability of progenitor cells from patients with MDS to
`furm colonies in vitro is I'etlnc't-rcl?“"mill The failure of in vitro
`C91011}F formation has been correlated with survival.1 l‘lematow
`lt'uictic growth factors, such as eiythropoietin (lipo), gl'tlllllltt~
`Eyre colony stimulating [actor ((;'(:S F). and gt'antllocyte-mono—
`9'19 colony stimulating factor
`[GM—(28F).
`can promote
`Increased, but still subnormal, colony iortnation in viii-0.30““
`Girl-(151" appears more effective in growth promotion. whereas
`9'ng appears to have greater tlill‘erentiating activity. ('jyto-
`him: and growth factor production in cells from patients with
`MDS is defective as well?2 Despite this observation, levels of
`£P°Illt the serum are inversely related to the degree of ane-
`mil-ta 'llhese abnt‘irtnalities in both the production and re-
`Sponge to growth and tliiTerenliating factors in MDS have sup-
`ported the use ol'bematopoietic growth factors as a therapeutic
`{5“}?ng (see later).
`lhe observation that MDS is typically characterized by pan—
`v, Patients with MDS are typically 50 to 80 years of age. Theyr
`Ell"Peltias, in the setting ofboue marrow Itypet'ccllttlarity, has
`may present with pallor, fatigue. fever. petecliiae, bruising. or
`“(i to the proposal that the dysplastic cells are undergoing
`bleeding, as a consequence of bone marrow failure, or with an
`Erapzltnre, programmed. cell death (apoptosis). An in‘sitn
`abnormal finding on a routine complete blood count. Exposure
`kid [or detection ol apoplosts tn the bone tnarrotvs from
`to cytotoxic chemotherapy may produce MDS in a younger
`Patients with MDS demonstrated high levels of zfioptosis in
`. REDDY’S LABS., INC. EX. 1039 PAGE 7
`
`BIOLOGY OF MYELODYSPLASTIC
`:t-.. SYNDROMES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`

`

`1
`
`2390
`
`Chapter 45.5 Leukemias
`
`TABLE 45.5-2. Chromosomal Abnormalities
`
`in Myelodysplastic Syndromes25’97
`
`Clinical Syndromes Associated With Specific
`Karyotypic Changes
`
`% of
`MDS
`
`Abnormality
`Cases
`Associated Syndromes
`
`del (Bq)
`+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 (l lq)
`t/del (12p)
`del (20q)
`—Y
`
`7
`5
`5
`5
`
`RARS (and others)
`CMML, RAEB, and RAEB—T
`MPD, PV, RAEB, and AML
`Normal males; RAEB; CMML
`
`Specific Kaiyotypic Changes Associated With Different
`Disease Subgroups
`Most Common Associated
`
`Disease Type
`
`RA
`RARS
`RAEB and RAEBT
`
`CMML
`
`AML (de novo)
`
`Change*
`
`5q—
`+8, 5qa, —7,t/del(11), 20q—
`5q*, —7, +8, +5, 7q—, 20q—,
`+21, —Y
`—7, +8, Udel (121)), fms
`mutations, +21, —Y, 7q—
`t(8;21), [(15;17), t(9;ll), inv(l6)
`
`RA, refractoty anemia; RARS, refractory anemia with ringed sider-
`oblasts; MDS, myelodysplastic syndromes; AML, acute myeloid leuke—
`mia; RAEB, refractory anemia with excess blasts; RAEB-T, refractory
`anemia with excess blasts in transformation; CMML, chronic myelomo-
`nocytic leukemia; MPD, myeloproliferative disorder; PV, polycythemia
`vera.
`
`* Listed in order of frequency.
`
`cohort than in those with de novo disease. Splenomegaly is
`seen in one fifth ofpatients, especially those with CMML; hepa-
`tomegaly is seen less often.
`The blood smear and bone marrow aspirate smear and bi-
`opsy should be examined in all patients. Anemia is essentially
`always present, and neutropenia and thrombocytopenia are
`common. If the peripheral blood monocyte count is greater
`than 1 X lOg/L in the setting of other features of MDS, CMML
`is diagnosed, The bone 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 cytometly (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 smear is 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-
`tosis, and macrocytosis of red cells in the blood, and marked
`dyserythropoiesis in the marrow, including ringed sideroblasts,
`asynchronous maturation, abnormal nuclear shapes, and chro—
`matin clumping. Dysplasia of platelets is noted in the blood,
`
`with large. abnormally granular platelets or hypogranuIal.
`platelets; in lhc marrow, Inicmmcgakaryocytes are “miner“
`Blood chctnisu'ics are usually not helpful, although Big and
`Foiate levels should be evaluated to exclude nutritional illlc-
`mias. Serum and urinary lysozymc may he increased in (ZMMI
`Examination of the tnarrm-r and blood should distinmljsi‘:
`MDS from carcinomalous or Iymphoniaious replace-mum of
`:tl
`the bone marrow, toxic damage to [11C marrow, pai‘oxysm
`nocturnal hemoglobinuria, laypcmplenisnt, autoin'nnunc ane.
`mia, and autoimmune thromlmcytopenia. The 20% of patients
`with a hypocellular bone marrow can be distinguished from
`aplastic anemia by careful evaluation of the morphology and
`by use ofcymgenetics.“ HIV infection and AIDS can result in
`many of the hematopoietic and hematopathological features
`of MDS“; this diagnosis should be excluded in appropriate
`patients. AML is distinguished from RAEB and RAEB—T based
`on the percentage of blasts in the marrow; MDS must have less
`than 30%. CML and other myeloproliiterative disorders may
`be distinguished based on morphology and characteristic Cy“)-
`genetic abnormalities.
`Abnormalities in serum immunoglobulins are common in
`MDS.43’44 Polyclonal gammopathies are. observed in up to
`one third of patients. Monoclonal gammopathy and hypo-
`gammaglobulincmia are also seen. Autoimmune antibodies
`have an increased incidence.43 B cell numbers appear normal,
`but T cells are frequently reduced, with CD4—positive cells
`more often affected than CD8 cells.45 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
`MDS simultaneously.“16 However, transformation from MDS
`to a lymphoid neoplasm is rare. Therefore,
`the association
`between B lineage neoplasms and MDS may not be a directly
`causal one.
`
`PROGNOSIS IN MYELODYSPLASTIC
`SYNDROMES
`
`.
`
`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).3 One point is assigned for each
`of the following poor prognostic features: bone marrow blasts
`over 5%; platelets below 100 X 109/L, neutrophils below 2.5
`X lOg/L; and hemoglobin below 10 g/dL (Table 45.5—3).
`Morel and colleagues47 expanded this approach by evaluating
`408 cases of de novo MDS for clinical features, pathology,
`and cyogenetics,
`to construct additional prognostic models
`for suwival and progression to AML. Survival could be pre-
`
`TAISIJS 45.5-3. Survival in Myelodysplastic Syndromes:
`BOLII‘IICIIHnJLl‘I SCOI‘C3———___.——-'-
`Score
`Patients With Score
`2-Year Survival Rd”
`Subgroup
`(%)
`(%)
`
`70
`48
`0—1 point
`50
`44
`2 points
`10
`8
`4 points
`——____.—--"
`
`-
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 8
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 8
`
`

`

`r’
`
`Treatment ofMyelodystlastic Syndromes
`
`2391
`
`OFS Predicting Survival: Lille SCOTCH
`1 Point
`2 Points
`5-10%bone marrow
`>10%bone
`Platelets <75 X 10%
`blasts
`marrow blasts
`Complex karyotype
`
`TJ‘BI'H 45.5-4. Fact
`
`_/""0Fowl-i
`“more>75 >< log/L
`blasts
`(5% bone marrow
`'
`1‘
`ifioflliill or single
`Mrs-(rtylrir' c ange
`
`Other reports have demonstrated the exceptionally poor
`h treatmerit-related M 1'35.“ Median sur-
`vival was less than 1 year and did not srgrnlrcamly vary wnh
`strrwrlvaloi patrentswit
`.
`’
`.
`‘
`.-
`..
`1
`-
`‘
`age, sex, initial neoplasm, or its therapy.This poor prognosis
`was similar in patients with treatincur-related AML and treat-
`merit-related MDS that progressedtoAML.
`SPECIFIC SYNDROMES
`OF MYELODYSI’LASTIC SYNDROMES
`
`5q—SYNDROME
`'I‘he 5q— syndrome, typicallyr found in olderwomen, is charac-
`teriaed by an indolent course that. seldom leads to AM1“
`lhrce quarters 01. patients are women; the median age is be
`years. Mor'plrologrcaliv. thissyndrome presentsas RAor RARS
`with monolobulared irregakawocytes. (Ivlogenetics demon-
`slrate5(1- as thesole abnormality.The blood rscharacterrrtetl
`by a rnacrocyilc anenua. modest leukopenra. and not-trialLo
`lucreasednumbers of platelets. in one study, eight oi nrne
`patients\vuh M135“"din“Eli's0i ““‘CTUCY‘Wanemia, l2) “0‘“
`ma" 0“ high plateletcounts, and {3) hypolobular megakarvo-
`cytesdemonstratedoq-asasoleabnormalitywhencyrogeneucs
`”it presence 0* arldnronal Ci‘1‘0'llf’5‘fli‘él
`r
`'___
`_
`_
`.
`changesdenotes patientswith a much poorer prognosis. 11115
`syndrome must also be distinguished from treatment-related
`.
`AML with a fiq-t these latter patients hav
`ELOMONOCYTIC LEUKEMIA
`
`were obtained."‘
`
`C II. IJQOI’ prognosrs.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Risk group: 0 points, low; 1—2 points, intermediate; 3-4 points, high.
`.-—-""'"""""""""—-"'""_'__‘
`tion ofthe kerlyotype, the percentage
`arrow, and ‘1“: platelet count (Table
`core of 0) representing one
`dicted based on esamina
`a" of 55 months. One
`of blasts in the bone in:
`hall'01—patientsconstitutedtheintermediate-riskgroup(score
`455-4]. The low-risk group (s
`third of patients had a median snwiv
`of l or 2}, who had a median survival of :24 months. The
`high-risk group (score of3 or 4} had a “redian survival 01'5
`months. Progression to AMLwas predicted by other features
`able 455-5}, notably the percentage ofbone marrow blasts
`'-risk patientswith no adverse Features
`..had a 2vyear freedom from AMl. of 92%; patients with one
`and the karyotype. Low
`“ftl'rese twofactorshada 2-year freedom from AMI.01-(50%;
`a $095 blasts in the bone marrow
`and patients with more that
`anti complex karyotypes had a ("18% incidence of AMI; by 2
`years
`hemoglobin level,
`Models based on corrrbinations of the
`platelet count. and bone marrow or blood blast percentages
`have been repeatedly demonstrated to predict both survival
`and leukemic transi'ormationfimflg A study of 40] patients in
`Japan also confirmed the prognostic importance of karyorype
`lirr survival and progression to AMLF” in this study. a score
`ll? ofllre kar‘votypic changesyielded three prognostic groups
`based on the Bournemouth score (see earlier) and the complex—
`with ‘2»year survivals of25%. 60%. and 80%. respectively.
`The importanceofliaryotypc asan independent prognostic
`feature has been reported in other smaller studies.“3‘22"r’l'52
`(Ilonal evolution with additional chromosomal abnormalities
`“ml“ "(Tl-It frequently”and
`Vtral ofoniv 2 months.”
`_
`conl'ers a poor prognosis with sur-
`
`CHRONIC MY
`Chronic rnyeiornonocytic leukemia has been classified as an
`MDS because ofits prominent bone marrow clysplastic features.
`Patientswith GMMLalso havecharacteristics ofrnveloprolifera-
`live disorders such as monocytosis, splenomegaly, and hep-ato-
`megaiy. The typical age ofpresentation is 65 to 75 years; males
`outnumberfemalesbyalmost ‘2'.1.4”‘55‘5'3Most patientspresent
`with anemia,25 to 50%presentwith hepalonregaly orspleuo-
`rnegalv[andaquarterofpatientsarefebrile.atdiagnosis.“De-
`spite elevatednronot.=tecourrtsin the peripheralblood antihi-
`volvernerrt ofextrzunerlullary sites, gingival infiltration is not
`usuallyseen.55Onethirdol‘parienrshavenronotytelevelsabove
`5 X to”:L.Thebonernarrowistypicallylrvpercellularwithmye-
`d trilineage clyspiasia. Serum and urinary lyA
`loid hyperplasia an
`soryme is elevated iii 40% to 80% of patients.”“'f"_’ Monosomv 7.
`trisomy 8, and structural changes involving chromosome 12p
`are the most common cytogenetic abnormalities?“
`diagnosis is 18 to 30 months, with a
`Medran srmuval from
`“a“
`‘
`~
`.
`range ol 1 month to 10 years; ‘ " - Poor prognosis is predicted
`by increased bone marrow blasts. markedly elevated mono-
`cytosrs (more‘than ill X lll"r'l.}, and evidence of erther rn—
`creased pr'olrleratton and neoplastic cell burden or Increased
`_
`dysplasia and cytopenias.
`TREATMENT OF MYELODYSPLASTIC
`SYNDROMES EMENT AND SUI’PORTIVE CARE
`
`GENERAL MANAG
`OF MYELODYSPLA
`
`sion to Acute
`
`TABLE 45.5-5. Factors Predicting Progres
`P001‘ Risk Factor
`Myeloid Leukemia
`210% blasts
`Better Risk Factor
`Circulating blasts
`RAEB, RAEB-T
`WBC <4 X 10%
`Complexzkaryotypes
`Hgb <10 g/dL
`
`Bone marrow blasts <10%
`N0 circulating blasts
`RA, RARS, CMML
`WBC >4 X 109/L
`1:“lekaryotypeor
`Hgb >10 g/dL
`’7q—- (seen alone)
`(1—, +8, —Y, —-'7,
`-
`STIC SYNDROMES
`“A.
`refractoryr anemia; RARS. refractory anemla with ringed si-
`{Egnlllasm (ZMML. chronic myelmnonocyric leukemia: RAE“, refrac-
`MDS are primarily related to bone mar-
`The complications ol
`.
`.
`_
`‘l anemia with excess blasts; mantra refractory anemia with excess
`progress to overt
`‘55
`r.
`’ o
`'i
`‘
`he er aiens
`Y 5 Laos. «we. E33. ibsi l’AtGE 9
`'0;
`.
`t
`.
`Ill-l5 rn transforrrraruru; WBC. whrte blond‘cells; fl herno lobrn.
`
`
`
`
`DR. REDDY’S LABS., INC. EX. 1039 PAGE 9
`
`

`

`2392
`
`Chapter 45.5 Leukemias
`
`AML. Ideally, the goal of treatment is the eradication of the
`malignant clone with the restoration of normal hematopoiesis.
`Although transient responses to 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 MDS is
`related to both the biology of the disease and the characteristics
`of the host. The malignant cell appears to be an early hemato-
`poietic progenitor or stem cell, and the association of this early
`phenotype with intrinsic drug resistance may play a role in
`treatment
`failures/’7 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 ntat‘t'ows of many patients.“ This implies that eradi-
`cation of the neoplastic clone would not reestablish polyclonal
`hematopoiesis. As a consequence, following cytotoxic chemo-
`therapy, patients succumb to 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.59 In addition, other comorbid conditions often com-
`plicate clinical management. Since MDS is 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 may have
`a smoldering clinical course in which the only therapeutic inter-
`vention required is 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 limit its applica—
`tion to patients who can no longer be sustained with supportive
`measures.
`
`Currently, the standard of ca