OCtober II, 2000
`
`HEALTH SCIENCES
`IJBRAR1ES
`
`)
`
`for the Prevention of
`rhIL-ll
`Chemotherapy-Induced
`Thrombocytopenia
`
`by
`With an introduction
`Ruzelle Kurzrock, MD
`The University of Texas
`M. D. Anderson Cancer Center
`
`Withpresentations by:
`
`Tomas Berl, MD
`University of Colorado
`Health Sciences Center
`
`Ullrich Schwertschlag, MD, PhD
`Genetics Institute,
`Inc.
`
`Mitchell S. Cairo, MD
`Columbia University
`Babies and Children's Hospital
`
`Craig H. Reynolds, MD
`US Oncology
`Ocala Oncology Center
`
`John W. Smith D, MD
`Earle A. Chiles
`Research Institute
`Providence Portland
`Medical Center
`
`For ONCOLOGY on the Web. VISit www canccrietwork
`
`corn
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 1
`
`

`

`the opinions of the editors or the publisher
`reflect
`expressed in articles are those of the authors and do not necessarily
`Clinical opinions
`strives
`to select knowledgeable,
`experienced
`authors
`and reviewers
`for articles
`and to answer clinical queries
`from readers. However,
`guarantee
`the clinical advice offered.
`of the patient and are based only on the infonnation
`are formulated without benefit of personal examination
`to clinical questions
`that answers
`Readers must
`take into account
`supplied by the physician making the inquiry. As our readers must surely appreciate, our editorial advisors, consultants,
`and reviewers cannot diagnose or prescribe
`for a particular
`patient without actually seeing the patient. Thus,
`the general comments
`in this journal arc based on the clinical experience of the authors,
`reviewers,
`and consultants
`and shouldnot
`be construed as a formal consultation
`or specific recommendation
`fur a particular patient.
`errors can QCt:1II.
`typographical
`are precise and accurate. However,
`The authors, editors, and publisher
`take extreme care to be certain that drugs and dosage recommendations
`infonnation
`data. Also, dosages
`and methods of administration of
`Therefore,
`be sure to double-check
`all dosage
`schedules
`in articles
`against
`the manufacturer's
`package
`pharmaceutical
`products mentioned
`by authors may not necessarily be the same as rhose listed in the package insert. Such dosages and delivery methods may reflect
`the clinical
`experience
`of the author or authors and/or may reflect
`the experience
`of other clinical
`investigators.
`
`and officers of PRR, Inc. ONCOLOGY
`neither
`the editors nor publisher can
`
`The Association
`Medical Publications,
`
`of
`
`Inc.
`
`2000 by PRR, Inc., 48 South Service Road. Melville, NY 11747. James F. McCarthy, Senior Vice President, Editorial;
`copyrighted
`ONCOLOGY(ISSN 0890-9091}-Contenls
`Louis Morris, Senior Vice President
`and Regulatory Affairs Editor; Edwin S. Geffner, Vice President
`and Consulting Editor; Robert C. Canale, Vice President
`and Director of
`Information Aids may be reproduced
`Marketing; Fay Symons, President. All rights reserved. Special Patient
`by an individual physician for distribution in his or her own practIce
`without specific request
`to the publisher. One or two copies of articles for personal or internal use may be made at no charge. Copying beyond that number
`for personal orintema[
`use is granted by PRR, Inc., provided that a fee of9¢ per page per copy is paid directly to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01970 (telepho?c:
`978-750-8400).
`Such permission
`does not extend to copying for general distribution,
`for advertising
`or promotional
`use, or for resale, which require specific written perrrussio»
`from the publisher. ONCOLOGY is included in Index Medicus, Excerpta Medica, EMBASE,SciSearch, Research Alert, Current Contents/Clinical Medicine,
`and the CancerLit and
`Cancer Line databases
`at the National Cancer
`Institute.
`issues in May, July, and November by PRR,
`offices at 48 South Service Road, Melville, NY 11~47
`Inc., with publication
`ONCOLOGY is published monthly with additional
`(telephone:
`631-777-3800).
`Subscription
`rates: domestic $99 per year; Canada, $105 per year; foreign, $121 per year; nurses $84 per year; students, $84 per year; single copies.
`$16 each. Periodicals
`postage paid at Huntington
`Station, NY 11746 and at additional mailing offices.
`Please notify PPS Medical Marketing Group,
`Inc. promptly ofchange~f
`address
`(send old mailing label and new address). Postmaster:
`Please send address changes
`(fonn 3579)
`to ONCOLOGY, c/o PPS Medical Marketing Group,
`Inc., 264 Passaro
`Avenue, Fairfield, NJ 07004-2595.
`ONCOLOGY is included in Index Medicus
`
`2
`
`ONCOLOGY. VOLUME 14 • NUMBER 9 • SUPPLEMENT NO 8
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 2
`
`

`

`ONCOLOGY®
`
`':::'{'SEPTEMBER 2000 (SUPPLEMENT :,,0 R\
`
`···",,~"-·__'''~'·R.~.,~","..__,,',
`
`.
`
`(. -
`
`9
`
`12
`
`21
`32
`41
`
`Ruzelle Kurzrock, MD
`The University of Texas
`M. D. Anderson Cancer Center
`Houston
`
`Tomas Berl, MD
`University of Colorado
`Health Sciences Center
`Denver
`Ullrich Schwertschlag, MD, PhD
`Genetics Institute, Inc.
`
`Mitchell S. Cairo, MD
`Columbia University
`Babies and Children's Hospital
`New York
`
`Craig H. Reynolds, MD
`US Oncology
`Ocala Oncology Center
`Ocala, Florida
`
`John W. Smith II, MD
`Earle A. Chiles Research Institute
`Providence Portland Medical Center
`
`P_o_rt_l_an_d_,_O_re_g_o_n
`
`-----
`
`SUPPLEMENT NO 8 • SEPTEMBER 2000 • ONCOLOGY
`
`7
`
`,I
`
`IiII
`
`,
`Vntroduction
`hIL-ll
`for the
`revention of
`Dose-Limi ting
`Induced
`hemotherapy-
`, hrombocytopenia
`
`~reclinical
`bharmaCOIogiCBasis
`'orClinical Use
`as an Effective
`Df rhIL-ll
`latelet-Support Agent
`~
`J)
`and
`DoseReductions
`Delays:Limitations of
`'~yelosuppressive
`fhemotherapy
`
`-------------------------_._--
`
`.-
`
`1
`
`1
`f,linical Efficacy of
`,!hIL-ll
`I
`fu] olerability and
`Bide-Effect Profile of
`~hIL-ll
`1
`
`lIl r
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 3
`
`

`

`MITCHELL S. CAIRO, MD
`Columbia Uuiversity
`Babies and Children's Hospital
`New York, New York
`
`Dose Reductions and
`Delays: Limitations of
`Myelosuppressive
`Chemotherapy
`
`Thrombocytopenia
`
`in patients
`with cancer has multiple origins.
`Disease-related
`causes
`include
`reduced thrombopoiesis
`in cancers with
`bone marrow involvement and tumor-
`induced disseminated intravascular co-
`agulopathy
`as
`seen
`in mucinous
`prostatic, lung, ovarian, and gastrointes-
`tinal adenocarcinomas.[I] However,
`the
`use of chemotherapy with or without
`radiation therapy is the most common
`cause of clinically significant
`thrombo-
`cytopenia.[l,2]
`The National Cancer
`Institute offers a grading system for de-
`termining the severity based on platelet
`counts (Table 1).
`retrospective
`Data from two large,
`studies conducted at the Baltimore
`(n = 1,274)
`Cancer Research Center
`and The University of Texas M. D.
`Anderson Cancer Center
`in Houston
`(n = 3,682) indicate that clinically sig-
`nificant reductions in platelet counts to
`nadirs < 50,000/flL occur in approxi-
`mately 20% to 25% of patients receiv-
`ing dose-intensive myelosuppressive
`chemotherapy for solid tumors or lym-
`phoma.Bvl]
`In approximately
`10% to
`15% of these patients, platelet counts
`fall below 20,000/JlL.
`of
`The risk of
`the development
`thrombocytopenia
`is aggravated by the L
`
`ABSTRACT
`
`occurs at various grades of severity in patients with
`Thrombocytopenia
`nonmyeloid malignancies undergoing chemotherapy with myelosuppres-
`it is the major dose-limiting hematologic toxicity,
`sive agents. Frequently,
`especially in the treatment of potentially curable malignancies
`such as
`leukemia, lymphomas,andpediatric cancers. Thisisbecomingincreasing-
`ly important given the recent
`trend toward the use of dose-intensive
`combination chemotherapy regimens facilitated by supportive hematopoi-
`etic colony-stimulating
`factors
`to prevent chemotherapy-induced febrile
`neutropenia.
`The standard preventive measure against chemotherapy-
`induced depression of platelets in subsequent
`treatment cycles has been
`dose reduction and/or dose delay. However.follow-up
`data from studies in
`various populations of patients with cancer suggest a correlation between
`delivery of lower than intended doses and poor outcomes, including reduced
`disease-free periods and overall survival. Other consequences of thromb-
`ocytopenia
`include the need for platelet
`transfusions and subsequent
`exposure to the risk of numerous complications,
`including bacterial and
`viral infections; febrile, nonhemolytic
`transfusion reactions; and transfu-
`sion-induced
`immunosuppression.
`Furthermore,
`a large proportion of
`multitransfused
`patients become refractory to subsequent
`infusions. Re-
`fractoriness
`to platelet
`transfusions
`is quickly becoming more prominent.
`The availability of a platelet growth factor-recombinant
`human interleu-
`kin-l I (rML-II, also known as oprelvekin [Neumega J)-provides
`an effec-
`tive means of preventing chemotherapy-induced
`thrombocytopenia
`and
`acceleratingplatelet
`recovery, thereby facilitating the administration offull
`doses of chemotherapy during subsequent cycles and avoiding the needfor
`rescue with platelet
`transfusions.
`
`.
`
`~ __
`
`One or two copies of this article for personal
`or internal use may be made at no charge. Copies
`beyond that number require that a 9¢ per page per
`copy fee be paid to the Copyright Clearance Cen-
`ter, 222 Rosewood Drive. Danvers, MA 01970.
`Specify ISSN 0890-9091. For
`further
`informa-
`tion, contact
`the CCC at 508-750-8400. Write
`publisher
`for bulk quantities.
`
`chemotherapy,
`use of dose-intensive
`with or without
`the support of hemato-
`poietic colony-stimulating
`factors for
`the amelioration
`of chemotherapy-
`associated febrile neutropenia.[5-7] Pro-
`viding hematopoietic
`support with pe-
`
`ripheral blond stem-cell transplantation
`during multiple cycles of high-dose che-
`motherapy does not prevent cumulative
`thrombocytopenia
`or enhance platelet
`recovery .[8] In fact, Spitzer et al[8] re-
`ported a significant delay in platelet re-
`
`SUPPLEMENT NO 8 • SEPTEMBER 2000 • ONCOLOGY
`
`21
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 4
`
`

`

`Table I
`National Cancer Institute Grading System for Severity of Thrombocytopenia
`
`4 <
`
`10.0 x 109/L
`< 10,000/~L
`< 10.0 x 10'/L
`< 10,000/~L
`
`1
`
`x 10'/L
`< LLN-75.0
`< LLN- 75,000/~L
`
`2
`~ 50.0 - < 75.0 x 10e/L
`~ 50,000 -< 75,000/~L
`
`3
`
`~ 10.0 - < 50.0 x 10'/L
`~ 10,000-<50,000/~L
`
`~ 50.0 - < 75.0 x 10'/L
`~ 50,000 - < 75,000/~L
`
`~ 20.0 - < 50.0 x 10'/L
`~ 20,000 - < 50,000/~L
`
`10'/L
`~ 10.0-<20.0x
`~ 10,000 - < 20,000/~L
`
`10% - < 25% decrease
`from baseline
`
`25% - < 50% decrease
`from baseline
`
`50% - 75% decrease
`from baseline
`
`2': 75% decrease
`from baseline
`
`Adverse Event
`Platelets
`
`For BMT studies
`
`For leukemia studies or
`bone marrow infiltrativel
`myelophthisic
`process
`
`0
`
`WNL
`
`WNL
`
`WNL
`
`risk
`etoposide) as one of the strongest
`factors for interruption of radiotherapy
`due to thrombocytopenia
`(odds ratio:
`45.5; P < .001 vs controls).
`of
`The total cumulative percentage
`bone marrow irradiated was also a strong
`risk factor. The relative contributions
`of chemotherapy and radiation therapy
`to thrombocytopenia
`depeud on the
`amount of bone marrow in the radiation
`field. For example, chemotherapy would
`be the primary contributing factor
`in
`patients receiving small-field radiation
`therapy. Using the results of the multi-
`variate analysis and regression analy-
`sis, the authors estimated that 49% (22/
`45) of patients would be at high risk for
`thrombocytopenia. They also suggest-
`ed that these high-risk patients may he
`candidates
`for clinical
`trials of a plate-
`let growth factor.
`
`Increased Severity With Dose-
`Intensive Chemotherapy
`there
`Over the past 10 to 15 years,
`has been a trend toward escalation of
`chemotherapy
`dose intensity with the
`intent of achieving cure or prolonged
`remission in patients with hernatolog-
`ic[l3]
`and solid tumor malignancies,
`including
`ovarian
`cancer,[6,14,15]
`small-cell
`lung cancer,[ 16] testicular
`cancer,[17,18]
`and
`breast
`can-
`cer.[1O,19,20]
`(For breast cancer,
`re-
`cent trials have suggested no benefit in
`clinical
`outcomes
`from such dose
`escalation; however,
`longer follow-up
`and subset analyses are required.) This
`trend has been accompanied by an in-
`creased incidence of severe, prolonged
`thrombocytopenia, which has now be-
`come a major dose-limiting hematoh~g-
`ic toxicity .[5,6, 15,21 ,22] In two studies
`of patients with previously untreated
`
`II
`
`jI ~
`
`---l
`
`BMT = bone marrow transplant;
`
`LLN = lower
`
`limit of normal; WNL '" within normallimi1s.
`
`covery after the second cycle compared
`with that seen following the first cycle
`of high-dose myelotoxic chemotherapy
`(cyclophosphamide
`[Cytoxan, Neosar],
`carmustine
`[BiCNU], etoposide)
`in pa-
`tients with lymphoma, despite infusion.
`After cycle 2, the platelet recovery time
`to 100,000/flL ranged from 10 to 267
`days vs 12 to 53 days after cycle I; 8 to
`267 days to 50,000/flL vs 9 to 53 days
`after cycle
`I; and 8 to 101 days
`to
`20,000/flL vs 8 to 28 days after cycle 1.
`Thrombocytopenia Associated
`With Myelosuppressive
`Chemotherapy
`
`and
`suppression
`Megakaryocytic
`recovery occur rapidly following treat-
`ment with cell-cycle-specific
`chemo-
`therapeutic
`agents.
`In contrast, with
`cell-cycle-nonspecific
`agents-such
`as
`husulfan (Myleran), nitrosourea, mito-
`mycin (Mutamycin), and platinum com-
`plexes-suppression
`occurs more
`gradually but
`is more persistent. With
`the latter agents, recovery from myelo-
`suppression may take up to 50 days or
`longer, depending on the extent of sup-
`pression.[9] These agents affect prolif-
`erating platelet precursors
`rather
`than
`mature platelets. Therefore,
`thrombocy-
`topenia gradually develops over 7 to 10
`days, and platelet counts < 20,000/flL
`generally occur by about day 10 after
`the start of myelotoxic chemotherapy.[8]
`It should be noted, however,
`that be-
`cause
`changes
`in peripheral
`platelet
`counts lag behind changes in bone mar-
`row production,
`at a given point in time
`the platelet
`count does not reflect
`the
`level ofmegakaryocytopoietic
`activity.
`Chemotherapy-induced
`thrombocy-
`topenia
`increases
`in severity with in-
`
`creased intensity oftreatment,[IO] with
`the combined use of cycle-specific
`and
`cycle-nonspecific
`chemotherapeutic
`agents (which is often the case [Table
`2]), and with the adjuvant use of radia-
`tion therapy and highly myelosuppres-
`sive drugs.[2] The combined
`use of
`cycle-specific
`and cycle-nonspecific
`agents also produces thrombocytopenia
`of more prolonged duration. Moreover,
`particular
`treatment regimens appear to
`be associated with high rates of severe
`thrombocytopenia. For example, World
`Health Organization grades 3/4 throm-
`(platelet counts < 50,000/
`bocytopenia
`flL) have been reported at rates of 48%
`among patients treated with doxorubi-
`cin 20 mg/m'/d,
`ifosfamide (Ifex) 2,500
`mg/mvd,
`and dacarbazine
`(DTlC-
`Dome) 300 mg/mvd (MAID)
`for ad-
`> 50% with
`vanced
`sarcoma;[ll]
`ifosfamide 5 g/m', carboplatin (Parapl-
`atin) 400 mg/m-, and etoposide at doses
`ranging from 300 to 1200 mg/m' for non-
`small-cell
`lung cancer;[5] and 24% to
`33% with paclitaxel (Taxol) 135 mg/m'
`(one dose),
`ifosfamide 1,200 rng/mvd,
`and cisplatin (Platinol) 30 mg/m'/d for
`ovarian cancer.[12]
`also interferes
`Thrombocytopenia
`with other modalities of cancer
`treat-
`ment, such as radiation therapy.
`In a
`case-control study involving 45 patients
`with malignant disease, MacManus
`et
`al retrospectively evaluated risk factors
`for unscheduled interruptions
`in radio-
`therapy associated with platelet counts
`< 50,000/flL or significant
`neutrope-
`nia.[2] Multivariate
`analysis identified
`concurrent administration of myel at ox-
`ic chemotherapeutic
`agents
`(most
`commonly in this study cisplatin, meth-
`otrexate,
`fluorouracil,
`vincristine,
`cy-
`clophosphamide,
`doxorubicin,
`and
`
`22
`
`ONCOLOGY· VOLUME 14 • NUMBER 9 • SUPPLEMENT NO 8
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 5
`
`

`

`ovarian cancer and residual disease af-
`ter primary laparotomy,
`combination
`therapy with high-dose carboplatin and
`cisplatin, and ifosfamide therapy for six
`cycles (n ~ 37),[6] and cisplatin, carbo-
`platin, and cyclophosphamide
`for up to
`eight cycles
`(n ~ 44),[15]
`resulted in
`platelet nadirs < 50,000/flL in 100%
`and 66% of patients, respectively.
`Furthermore,
`the increasing use of
`granulocyte colony-stimulating
`factor
`(G-CSF,
`filgrastim [Neupogen])
`and
`granulocyte-macrophage
`colony-stimu-
`lating factor
`(GM-CSF,
`sargramostim
`[Leukine]) to reduce the risk of chemo-
`therapy-induced
`severe
`neutropenia
`during dose-intensive
`cancer chemo-
`therapy regimens[5,21,23]
`appears
`to
`be associated with more severe and
`protracted
`thrombocytopenia,[7,22]
`likely because the chemotherapy toler-
`ance is improved. Whereas neutropenia
`would have previously been dose limit-
`ing, now it is no longer so. This is well
`illustrated by findings in 37 young adult
`and pediatric patients newly diagnosed
`with sarcoma who received intensive
`combination chemotherapy
`and radia-
`tion therapy
`either with or without
`GM-CSF support.[7] Patients
`treated
`concomitantly
`with GM-CSF
`had
`significantly lower median platelet na-
`dirs (29,500/~L vs 59,000/flL,
`respec-
`tively; P < .0001)
`and required
`a
`significantly longer median time to re-
`covery to platelet count > 75,000/~L
`(16 days vs 14 days,
`respectively;
`p < .0001), compared with patients not
`treated with GM-CSF.
`In a study of patients with advanced
`breast cancer, dose-intensive chemother-
`apy with G-CSF support was associat-
`ed with a 17% incidence of low platelet
`counts «
`50,000/mL)
`compared with
`0% among patients who received a less
`intensive regimen without G:.CSF sup-
`port (P < .002).[21] Depressed platelet
`counts contributed to a higher incidence
`of treatment delays in the higher dose-
`intensive group, compared with the lat-
`ter group (21 % vs 8%, respectively; P <
`.0001).[21]
`
`to:
`
`Address all correspondence
`Mitchell S. Cairo, MD
`Columbia University
`Babies and Children's Hospital, HP5
`New York, NY 10032
`e-mail: mcI319@columbia.edu
`
`Treatment Delays
`During the use of combination che-
`motherapeutic regimens for nonmyeloid
`malignancies,
`the standard response of
`physicians to the development of throm-
`bocytopenia
`is dose reductions and/or
`delayed administration of the next cy-
`cle of chemotherapy (Table 2). This is
`also the response of treating physicians
`for patients receiving combined-modal-
`ity therapy (chemotherapy
`and radia-
`tion therapy). In the study conducted by
`MacManus
`et al,
`thrombocytopenia
`forced the interruption of radiation ther-
`apy for 3 days or more in 98% (44/45)
`of patients, 27% (12/45) of whom had
`at
`least one measurement
`of platelet
`count < 25,OOO/~L.[2] In addition to
`treatment
`interruption,
`the planned ra-
`diation dose was reduced by > 10% in
`51% of the cases, vs 11% of controls
`(radiation therapy only).
`chemo-
`During myelosuppressive
`of subse-
`therapy,
`the administration
`quent cycles is routinely delayed until
`the platelet
`count has recovered
`to
`100,000l~L, as mandated by almost all
`of the protocols
`for investigations of
`chemotherapeutic
`regimens
`seen in
`Table 2.[5,11,12,24-27]
`In these stud-
`ies,
`treatment was delayed for I to 4
`weeks if this platelet
`threshold was not
`reached.
`Elting et al retrospectively reported
`that
`among 500 patients
`receiving
`chemotherapy for solid tumors or lym-
`phoma,
`reduction
`in platelets
`to
`< 50,000l~L resulted in the delay of a
`chemotherapy cycle by more than 7 days
`in 8% of patients.[28]
`
`Dose Reductinns
`The practice of reducing doses in
`response to prolonged myelosuppres-
`sion is demonstrated in the studies in
`Table 2. In the event of slow platelet
`recovery[I1,24,26,27,29,30]
`or persis-
`tence of platelet counts < 50,000/~L
`[11,24,30-32]
`or even 75,000/~L to
`I00,000/~L,[22,27]
`chemotherapy
`was significantly deescalated, often by
`reducing drug doses by up to 50% .
`In the breast cancer
`study of Fetting
`et ai, no chemotherapy
`was to be
`administered if the platelet count was
`< 50,000/~L.[25]
`In a dose-escalation study in 24 pa-
`tients with
`solid
`tumors
`or non-
`Hodgkin's
`lymphoma,
`cumulative
`thrombocytopenia
`(defined as platelet
`count < 25,OOO/~L)was the major dose-
`
`study was
`limiting toxicity.[5] This
`conducted to evaluate the feasibility of
`escalating the dose of etoposide from
`300 mg/rn? to 600, 900, or 1,200 mg/m'
`in a dose-intensive ifosfamide, carbopl-
`atin, and etoposide (ICE) regimen with
`GM-CSF support. At all dose levels of
`etoposide,
`clinically
`significant
`thrombocytopenia
`developed
`after
`multiple treatment cycles; by cycle 3,
`'" 50% of patients required platelet trans-
`fusions
`to maintain a platelet
`count
`> 20,OOO/~L.
`in conjunction
`Thrombocytopenia
`with neutropenia led to dose reductions
`in most patients who received more than
`three cycles of therapy. Cumulative
`thrombocytopenia was the major factor
`limiting the escalation of etoposide dos-
`es above 900 mg/m'. Continued decline
`in nadir platelet counts over successive
`cycles and subsequent dose limitation
`have been reported in other studies in
`which GM-CSF support was provid-
`ed.[22] These findings support the pre-
`dictability
`of
`low platelet
`nadirs
`following successive cycles in patients
`who develop thrombocytopenia during
`the first cycle.
`
`Clinical Consequences of Low
`Platelets and Thrombocytopenia
`
`Compromised Chemotherapy
`Outcome
`The standard practice of reducing
`the dose of chemotherapeutic
`drugs
`and/or delaying treatment
`to avoid the
`risk of clinicalJy significant bleeding
`secondary to thrombocytopenia
`could
`result
`in suboptimal outcome,
`includ-
`ing reduced antitumor efficacy and/or
`reduced survival rates or shorter dura-
`tion of remission.[1 0, 13,33-35]
`The study of Bonadonna et al has
`provided the longest follow-up data for
`analysis of the relationship between
`delivered
`dose
`and survival
`out-
`come.[33]
`In this
`study,
`patients
`received either 12 cycles of adjuvant
`CMF (cyclophosphamide, methotrex-
`ate, fluorouracil) chemotherapy or no
`chemotherapy
`after radical mastecto-
`my for primary breast
`cancer with
`positive axillary lymph nodes. Chemo-
`therapy doses were reduced in older
`patients (> 60 years) and if myelosup-
`pression was present. A total of 386
`women,
`including 179 who received
`no chemotherapy
`after mastectomy
`(control group) and 207 who received
`
`SUPPLEMENT NO 8 • SEPTEMBER 2000 • ONCOLOGY
`
`23
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 6
`
`

`

`————_——___—_—_—
`
`Table 2
`
`Reported Occurrence of Thrombocytopenia and Subsequent Treatment Reduction in
`Patients Receiving Combination Chemotherapy Regimens for Nonmyeloid Malignancies
`
`Regimen
`
`Cancer
`Type
`
`Thrombocytopenia
`Grade“
`Incidence Treatment Modification
`
`Reference
`
`If day 1 platelet count < 100,000/uL, treatment
`delayed up to 2 weeks
`
`Fetting et al[25]
`
`if platelet count < 50,000, chemotherapy
`delayed
`
`Osborne et al[22]
`
`lf platelet counts between 50,000 and 75,000,
`planned doses reduced by 50%
`
` Chemotherapeutic
`
`Cyclophosphamide,
`doxorublcm,
`fluorouracil (CAF)
`
`Breast
`
`Cyclophosphamide,
`doxorublctn,
`vincristine,
`
`Breast
`(advanced)
`‘
`
`methotrexate,
`tluorouractl,
`leucovorin
`
`1
`2
`3
`
`4
`
`4
`
`45%
`8%
`3%
`
`1%
`
`70%
`
`lfosfamide,
`doxorubicin (Al)
`
`Sarcoma
`
`2
`
`5%
`
`Mesna, doxorubicin,
`ifosfamide,
`dacarbazine (MAID)
`
`Sarcoma
`
`Cisplatin, etoposide
`(EP)
`
`Small-cell
`lung
`
`1/2
`3/4
`
`1
`2
`3
`4
`
`68%
`48%
`
`12%
`5%
`7%
`2%
`
`If platelets < 40,000/uL, dose of both drugs
`reduced by 20%; if platelets < 100,000 at
`next scheduled treatment, further therapy
`delayed for 1 week; if treatment delayed
`for > 1 week for two consecutive courses,
`dose reduced by 20%
`
`if treatment delayed for > 3 weeks without
`hematologic recovery, treatment
`discontinued
`
`Cycle delayed until platelets at 100,000;
`if platelet nadir < 50,000, dacarbazine dose
`reduced by 50%
`
`If platelets < 100,000, dose delayed 1 week;
`if platelets 75 to 100,000 at 4 weeks,
`doses of both drugs reduced by 50%
`
`Schutte et al[24]
`
`Elias et al[11]
`
`Boni et al[27]
`
`lfosfamide,
`carboplatin, etoposide
`(ICE)
`
`Non—small- 4
`cell lung
`
`> 50%
`
`If platelets < 100,000, treatment delayed
`1 week
`
`Krigel et a|[5]
`
`Cyclophosphamide,
`cisplatin or carboplatin
`
`Ovarian
`
`Paclitaxel, carboplatin
`
`Ovarian
`
`Paclitaxel,
`ifosfamide, cisplatin
`
`Ovarian
`
`Cisp/atin
`2
`3
`4
`Carboplatin
`2
`3
`4
`
`1
`2
`4
`
`'
`
`4
`
`Platelet
`nadir: day
`12—25
`
`9%
`6%
`2%
`
`21%
`17%
`7%
`
`8%
`8%
`4%
`
`If platelets < 100,000, treatment delayed
`for 2 weeks; if no recovery by day 42
`but platelets > 50,000, cyclophosphamide
`and carboplatin dose reduced by 50%,
`cisplatin dose by 40%
`1
`
`Hannigan et al[26]
`
`If platelet recovery required 2 weeks, next
`courses repeated every 4 weeks with
`,
`carboplatin dose reduced by 25%;
`if grade III or IV thrombocytopenia occurred,
`dose of both drugs reduced by 25% or 50%,
`respectively
`
`Skarlos et al[30]
`
`24%~33% lf platelets < 100,000, next dose postponed for Veldhuis et a|[12]
`up to 4 weeks; ifgrade IV thrombocytopenia ,
`occurred, paclitaxel and ifostamide dose
`reduced
`
`Continued
`
`24
`
`ONCOLOGY ° VOLUME 14 ' NUMBER9 ' SUPPLEMENT N08
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 7
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 7
`
`

`

`Thrombocytopenia
`Incidence
`Grade"
`
`Treatment Modification
`
`Reference
`
`Table 2, Continued
`
`Chemotherapeutic
`Regimen
`
`Etoposide,
`doxorubicin,
`cisplatin(EAP)
`
`Cancer
`Type
`
`Gastric
`
`1
`2
`3
`4
`
`36%
`19%
`21%
`7%
`
`Etoposide,
`methylprednisolone,
`cisplatln, cytarabine
`(ESHAP)
`Prednisone,
`doxorubicin,
`cyclophosphamide,
`etoposide, cytarabine,
`bleomycin, vincristine,
`methotrexate,
`leucovorin
`(ProMACE-CytaBOM)
`
`Lymphoma Median
`platelet
`(refractory
`and
`nadir
`70,000
`relapsing)
`7% of
`Lymphoma
`patients
`required
`platelet
`transfusion
`
`If platelets < 50,000lj.,lL,etoposide dose reduced Preusser et al[31)
`by20%
`
`If platelets s; 20,000, cytarabine dose reduced
`by 50% and etoposide dose by 20% for all
`future courses
`
`Velasquez et al[29]
`
`If platelets 50,000 to 99,000, etoposide and
`cytarabine doses reduced by 50%,
`cyclophosphamide and doxorubicin by 25%
`
`If platelets < 50,000, methotrexatedose reduced
`by 50%
`
`Lonqoetal[32J
`
`Etoposide, ifosfamide,
`cisplalin(VlhP)
`
`Germ-cell
`
`4
`
`ifosfamide
`Up to 48% If severe myelotoxicity occurred,
`and etoposide dose reduced by 30%
`
`Ghosnet al[33a]
`
`according to the World Health Organization
`a Grade of thrombocytopenia
`2 = 50,000-74,000;
`4 = < 25,000.
`3 =: 25,000-49,000;
`1 :;:75,000-99,000;
`
`classification
`
`system based on platelet count
`
`(/IJL): 0 = >100,000;
`
`;;~!lj!j;;;;;;~!j!j~:;,;;;;;;;rn;;;j;ij;;;@
`
`••••
`
`1.0
`0.s
`0.8
`0.7
`
`> 85% 01 optimal dose (n '" 42)
`
`65-84% 01 optimal dose (n '" 94)
`
`< 65% 01 optmal dose (n '" 71l
`
`Control (n " 179)
`
`..
`>.~
`"•
`f
`0.6
`0.6
`c;
`~ 0.'
`•"'e
`:0
`0.3
`0.2
`
`chemotherapy,
`combination
`adjuvant
`~~;;;;.;.;
`20 I·
`were followed
`for approximately
`years.
`the 20-year
`at
`outcomes
`Survival
`analysis showed a disease (relapse)-free
`survival
`rate of .49% and an overall
`survival rate of 52% in 42 women who
`received 85% or more of the planned
`dose of CMF.
`In comparison, women
`who received
`less
`than 85% of the
`planned dose had markedly
`inferior
`survival
`rates (Figure 1)', Disease-free
`and overall survival rates were 30% and
`25%, respectively,
`among women who
`received < 65% of the optimal CMF
`dose, and 33% and 32%, respectively,
`among women who received 65% to
`84% of the optimal dose. The overall
`survi val
`rate
`among women who
`..=:,:;:...;;.=::=::=::..=...=.,=====~
`or more (ie, < 65% ofthc optimal CMF 1rt~B2123:2:;:S::EiG::::;;TIZ:;;"=··'[···=·'="·=·"=·'=·'G'i::··=;;"'Ji="=
`received CMF at doses reduced by 35%
`dose) was identical
`to the rate in the
`Figure 1: Overall Survival-Superior
`20-year overall survival rates among women
`control group (25%). Myelosuppression
`with node-positive breast cancer who received 85% or more of the optimal doses of
`was the main reason for dose reduction
`adjuvant cyclophosphamide, methotrexate, and fiuorouracil followingmastectomy,
`in this study. Of course, other confound-
`compared with women who received less than 85% of the optimal chemotherapy
`ing factors of comorbidity and disease
`dose. Survival was estimated by Kaplan-Meier method. (Reprinted with permission
`severity cannot be excluded by this
`from Bonadonna et aL[33])
`retrospective
`subset analysis.
`Results consistent with Bonadonna's
`findings were provided
`by a large
`(n = 1,572)
`randomized
`prospective
`study (Cancer and Leukemia Group B
`[CALGB]
`study 8541)
`that evaluated
`outcome
`effects
`following
`treatment
`
`0.1
`
`0.0
`
`0
`
`6
`
`'0
`Years after mastectomy
`
`16
`
`20
`
`~0
`
`c,
`
`dose levels of
`with three different
`doxorubicin,
`and
`cyclophosphamide,
`fluorouracil.[lO] This study observed
`significantly (P S; .05) longer disease-
`
`free survival and overall survival rates
`after a median of 3.4 years among
`women treated with "high" or "moder-
`ate" dose intensity regimens, compared
`
`SUPPLEMENT NO 8 • SEPTEMBER 2000 • ONCOLOGY
`
`25
`
`DR. REDDY’S LABS., INC. EX. 1037 PAGE 8
`
`

`

`Table 3
`Potential Complications
`(Incidence, Where Data Are
`Available) of Platelet
`Transfusions'
`
`Refractoriness to platelet
`(30%-70%)
`Alloimmunization (20%-70%)
`
`transfusion
`
`Infection
`
`Hepatitis A
`Hepatitis B (1/200,000 units)
`HepatitisC (1/100,000 units)
`Hepatitis non-AlBIC
`Hepatitis G/GB
`HIV [1/450,000 to 11660,000]
`Cytomegalovirus(CMV)30%]'
`Bacterial (0.4%)
`Graft-vs-host disease
`Immunomodulation
`of tumor biology
`Transfusion reactions (30%)
`
`-Data from references 1,41,42.
`~Riskfrom unscreened blood products for CMV-
`seronegative recipient of a CMV-seronegative
`graft.[41]
`
`with women treated with less intense
`doses,
`the doses used in the study
`However,
`were within the conventional
`range,
`including those used in the high dose
`intensity regimen
`(cyclophosphamide
`600 mg/m' and doxorubicin 60 mg/m'
`on day I, and fluorouracil 600 mg/m-
`on days
`I and 8). This study clearly
`demonstrates, however,
`that clinical
`benefit
`is
`significantly
`reduced
`if
`administered
`chemotherapy
`doses
`are less than the standard doses. The
`3-yeardisease-free
`survival rate associ-
`ated with a low-intensity
`regimen
`(ie, 50% lower
`than the doses in the
`high-intensity
`regimen)
`was
`II %
`less than that seen in the high-intensity
`regimen.
`Several other studies that evaluated
`the outcomes
`of different
`doses
`of
`chemotherapeutic agents have shown
`significantly (P < .05) superior overall
`survival rates at conventional
`doses
`compared with reduced doses in patients
`with various solid tumors. These include
`studies of variable doses of cisplatin
`and cyclophosphamide
`in conjunction
`with unchanged
`doses of doxorubicin
`and etoposide
`for treatment of small-
`cell lung cancer (43% vs 26% at 2 years;
`P ~ .02);[16] variable doses of cisplatin .
`
`doses of cyclophos-
`and unchanged
`phamide
`(32% vs 27% at 4 years;
`P ~ .04)
`for
`advanced
`ovarian
`cancer;[14].
`and variable
`doses
`of
`cisplatin
`combined with unchanged
`doses of vinblastine
`and bleomycin
`(83% vs 58% at 2 years; P ~ .009; rates
`estimated
`from graph)
`for
`testicular
`cancer. [17]
`A third study also showed a statisti-
`cally
`significantly
`decrease
`in the
`2-year overall
`survival
`rate among
`patients who received an ACVB (doxo-
`rubicin, cyclophosphamide,
`vindesine,
`bleomycin)
`induction
`regimen
`for
`aggressive
`lymphoma
`at a relative
`dose intensity less than 70% of
`the
`optimum dose intensity (61 % vs 72%;
`P ~ .02).[35] This study differs from
`the previously described studies in that
`the reduction in relative dose intensity
`was due to toxicity-dependent
`treatment
`delays rather than dose reduction.
`Data from radiotherapy studies also
`support
`the importance
`of delivering
`the total planned treatment
`to a given
`patient to achieve maximum benefit.
`An analysis of pooled data from trials
`performed
`by the Radiation Therapy
`Oncology Group (RTOG)
`showed re-
`duced local
`tumor control and reduced
`long-term survival rates in patients with
`nonresectable non-small-cell
`lung can-
`cer as a result of unscheduled
`interrup-
`It is speculated
`tions in treatment.[36]
`that
`treatment
`interruption
`allows
`for
`the repopulation of tumor cells. [37]
`Data from several small
`trials sug-
`gest improvement
`in survival benefit
`with the use of higher
`than standard
`doses of chemotherapy in patients with
`solid tumor malignancies,
`including
`adults with metastatic breast cancer[19]
`or ovarian cancer[14] and children with
`Burkitt's
`lymphoma[38]
`or neuro-
`blastoma.[39] Although the benefit of
`higher than standard doses remains high-
`ly controversial.] 13AO]
`the consensus
`regardless of the type of malignancy is
`that the use of lower than standard dos-
`es is associated with poorer outcomes.
`Taken together,
`these data underline
`importance
`of avoiding
`both
`the
`treatment delays and dose reductions
`if maximum benefit is to be achieved.
`
`Platelet Transfusions
`Platelet
`transfusions have been the
`mainstay
`of
`treatment
`for
`thrombo-
`cytopenia for decades. They are recog-
`nized as an effective
`short-term "rescue"
`
`26
`
`ONCOLOGY· VOLUME 14 • NUMBER 9 • SUPPLEMENT NO 8
`
`induced
`for chemotherapy-
`treatment
`severe thrombocytopenia
`and are wide-
`ly used for this indication.[41] Howev-
`er, platelet transfusions are associated
`with clinically relevant risks of several
`immunologic
`and nonimmunologic
`complications
`(Table 3).[1,41,42]
`
`Immunologic Complications
`transfu-
`After one or more platelet
`sions, a high percentage of patients (30%
`to 70%)
`risk becoming
`refractory
`to
`subsequent transfusions, the main cause
`to class I HLA
`being alloimmunization
`antigens on platelets and, less common-
`Iy, to platelet-specific
`antigens.[ 1,41 ]
`Approximately
`20% to 70% of patient