B L 00
`
`OCTOBER,
`
`1968
`
`D
`
`The
`
`Journal
`
`of Hematology
`VOL.
`XXXII,
`NO.
`
`4
`
`Arabinosyl
`
`Cytosine
`of
`Acute
`
`: A Useful
`Leukemia
`
`in
`Agent
`in Adults
`
`the
`
`Treatment
`
`By
`LAT,
`
`ROSE
`
`Rum
`
`ELLISON,
`
`MICHEL
`
`BomoN,
`
`GUSSOFF,
`
`RICHARD
`
`JEAN
`T.
`
`JAMES
`
`F.
`BERNARD,
`
`HOLLAND,
`
`MARISE
`
`WEn(cid:1),
`
`CLAUDE
`
`JACQUIL-
`
`ARThUR
`
`SAWITSKY,
`
`FRED
`
`ROSNE.R,
`
`BER-
`
`NARD
`L.
`HAURANI,
`
`SPURR,
`
`SILVER,
`
`ARTHUR
`
`KARANAS,
`
`DONALD
`
`ROBERT
`
`M.
`KYLE,
`
`HAYES,
`
`J. L.
`
`JOHANNES
`HUTCHISON,
`
`BLOM,
`JACKSON
`
`R.
`
`CUTTNER,
`JANET
`Louis
`A.
`FORCIER
`
`LEONE,
`AND
`
`CHARLES
`
`FARID
`H.
`
`JOHN
`
`MOON
`
`A RABINOSYL
`
`in
`
`and
`inhibits
`against
`Talley
`These
`
`synthetic
`is
`CYTOSINE
`(ara-C)
`the
`normal
`from
`moiety
`the
`sugar
`differing
`to mammalian
`cytotoxic
`(Fig.
`deoxycvtidine.
`It
`is
`1).
`shows
`in
`vivo
`viruses,2’3’4
`and
`of DNA
`a
`number
`a variety
`of
`transplanted
`rodent
`and
`L12103’6
`leukemia
`reported
`series
`of
`13
`patients
`Vaitkevicius#{176}
`and
`investigators
`administered
`drug
`intravenously
`
`a
`
`a
`
`the
`
`pyrimidirie
`metabolites
`cells
`antitumor
`neoplasms.7’8
`treated
`with
`rapidly
`with
`
`nucleoside
`cytidine
`culture,1
`activity
`
`in
`
`ara-C.
`doses
`
`B
`Group
`Cooperative
`Leukemia
`From
`8, 1968.
`March
`publication
`for
`accepted
`12,
`1967;
`September
`First
`Institute,
`Memorial
`Park
`A,
`Roswefl
`of Medicine
`Department
`ELLI50N:
`ROSE
`(CA
`F.
`Institute,
`Memorial
`Park
`Roswell
`York.
`Buffalo,
`02599):
`HOLLAND
`Lesic#{233}mies, H#{244}pital
`Les
`Sur
`de
`Recherches
`Y.
`Buffalo,
`Institut
`WEaL:
`MARISE
`Recherches
`Sur
`Les
`de
`itut
`Inst
`France.
`Xe,
`Paris
`Saint-Louis,
`CLAUDE
`JACQUILLAT:
`Saint-Louis,
`Paris
`Leuc#{233}mies, Hdpital,
`Institut
`Recher-
`France.
`Xe,
`B0IR0N:
`MICHEL
`France.
`Paris
`Leuc#{233}mies,
`H#{244}pital Saint-Louis,
`ches
`Stir
`Les
`Xe,
`BERNARD:
`JEAN
`Paris
`H#{244}pital Saint-Louis,
`it ut
`Inst
`Recherches
`Sur
`Les
`Leuc#{233}mies,
`de
`France.
`Xe,
`Hospital,
`Hyde
`New
`Island
`Jewish
`S.U.N.Y.,
`Long
`(CA
`05923):
`SAWITSKY
`ARTHUR
`(CA
`05923):
`Hospital
`Brooklyn,
`Y.
`Park,
`N.
`Maimonides
`S.U.N.Y.,
`R05NEII
`FRED
`05923):
`(CA
`of
`Brooklyn,
`Brooklyn,
`Hospital
`Jewish
`N.
`S.U.N.Y.,
`BERNARD
`CUSSOFF
`(CA
`07968):
`Cornell
`Medical
`Center,
`Hospital,
`York
`N.
`New
`RIcJs.Aiw
`T.
`Su.vms
`Cornell
`Medical
`Center,
`Hospital,
`York
`New
`York.
`New
`(CA
`07968):
`ARTHUR
`KARANAS
`(CA
`York,
`N.
`Y.
`New
`York.
`Mt.
`Sinai
`Hospital,
`04457):
`CHARLES
`CUTTNER
`JANET
`L.
`(CA
`Winston-Salem,
`N.
`Gray
`School
`Medicine,
`of
`S(cid:1)ums
`Bowman
`03927):
`Bowman
`Gray
`School
`of Medicine,
`Winston-Salem,
`03927):
`DONALD
`HAYES
`Walter
`Reed
`Medical
`Center,
`Cancer
`Chemotherapy
`N.
`C.
`A.
`(CA
`Clinic,
`Rhode
`Island
`Hospital,
`Provi-
`08025):
`Louis
`LEONE
`05462):
`dence,
`Jefferson
`Medical
`College
`Hospital,
`Phila-
`J. L.
`delphia,
`Mayo
`Clinic,
`Rochester,
`Minn.
`HUTCHINSON:
`R.
`(CA
`04326):
`Montreal
`P. Q.,
`Canada.
`JACKSON
`FORCIER
`Dartmouth
`Hospital,
`Hitchcock
`Hospital,
`Hanover,
`N.
`H. MOON
`College
`of Virginia,
`Richmond,
`Va.
`JOHN
`
`de
`
`of
`
`New
`
`C.
`
`H.
`
`Acute
`the
`submitted
`Rum
`New
`N.
`
`JAMEs
`
`Y.
`Y.
`
`Army
`
`(CA
`BLOM:
`C.
`D.
`HAURANI
`
`M.
`JOHANNES
`Washington,
`R.
`I.
`FARaD
`Pa.,
`KYLE
`ROBERT
`Hospital,
`General
`School
`Medical
`(CA 03735):
`
`(CA
`(CA 04646):
`Montreal,
`Affiliated
`Medical
`
`BLOOD,
`
`VoL.
`
`32,
`
`No.
`
`4
`
`(OCTOBER).
`
`1968
`
`507
`
`

`

`508
`
`ELLISON
`
`ET
`
`AL.
`
`NH2
`
`HOH2CV0.s..,J
`
`HO
`
`NH2
`
`020
`
`HO(cid:1)(cid:1)
`
`ARABINOSYL
`
`CYTOSINE
`
`1*12
`
`(cid:1)
`
`CYT((cid:1)INE
`
`Fig.
`1.-Structures
`deoxycytidine.
`
`and
`
`RIBOSIDE
`of arabinosyl
`
`CYTOS1NE
`
`DEOXYRIBOSIDE
`
`cytosine
`
`and
`
`the
`
`normal
`
`metabolites
`
`cytidine
`
`for
`daily
`10 mg./Kg.
`than
`of
`not more
`intervals.
`to
`10
`day
`at
`three
`with
`lymphosarcoma.
`patients
`(which
`had
`thrombocytopenia
`megaloblastic
`dogs),
`marked
`in
`of mitosis
`of
`hematopoietic
`
`to
`3
`from
`injections)
`daily
`repeated
`in
`and
`
`7
`
`study
`
`a
`
`leukemic
`in
`intraperitoneal
`animals
`of
`the
`
`in
`
`in
`
`in
`
`of
`
`mice
`dose
`
`with
`ara-C
`
`a
`4
`
`in
`
`the
`
`a
`
`is
`
`a
`
`days.
`9
`to
`4
`50 mg./Kg.
`There
`
`or
`was
`
`been
`changes
`(which
`
`cells
`
`gave
`They
`single
`a
`transient
`The
`patients
`expected
`in
`had
`
`the
`not
`
`dose
`30-50
`
`of
`
`total
`a
`of
`dose
`regression
`developed
`pharma-
`from
`marrow
`and
`been
`in
`
`seen
`
`ranging
`(with
`mg./Kg.
`adenopathy
`leukopenia
`cologic
`abnormalities
`animal
`studies).
`the
`varied
`ara-C
`of
`toxicity
`and
`The
`effectiveness
`pro-
`of
`A daily
`administration.
`schedule
`of
`drug
`L1210
`leukemia
`bearing
`survival
`increase
`duced
`greater
`single
`than
`did
`disease)
`course
`the
`late
`early
`or
`(treated
`either
`times
`given
`ara-C
`that
`demonstrated
`also
`was
`dose.5
`It
`large
`weekly
`more
`leukemia
`advanced
`with
`of
`animals
`time
`the
`survival
`daily
`increased
`to
`be
`was
`found
`Ara-C
`schedule.5
`dosage
`frequent
`other
`less
`the
`than
`any
`of
`intravenous
`continuous
`pharmacology
`vivo.1#{176}The
`in
`rapidly
`deaminated
`cancer
`advanced
`with
`patients
`studied
`in
`humans
`was
`infusion
`of
`ara-C
`better
`ara-C
`yielded
`of
`that
`more
`frequent
`administration
`based
`the
`finding
`on
`continuous
`administra-
`or
`in mouse
`leukemia.
`Frequent
`administration
`results
`tion
`at
`active
`blood
`levels
`hopefully
`would
`maintain
`pharmacologically
`used
`the
`ara-C
`at
`doses
`times
`(recognizing
`inability
`to
`detect
`circulating
`dose
`the
`found
`that
`total
`by
`available
`methods).
`Using
`day
`course,
`we
`7
`with
`continuous
`infusion
`of
`ara-C
`producing
`hematologic
`depression
`less
`than
`that
`reported
`with
`single
`daily
`injections.”
`, ‘(cid:1) The
`hematologic
`abnor-
`
`

`

`ARABINOSYL
`
`CYTOSINE
`
`developing
`malities
`infusion
`tinuous
`total
`greater
`Preliminary
`cated
`that
`adults
`with
`then
`initiated
`at
`several
`by
`a
`study
`ported
`in
`
`doses
`of
`
`this
`
`dose
`work
`ara-C
`acute
`a
`
`in
`
`four
`
`by
`
`of
`
`for
`Talley
`
`7
`
`days
`after
`
`by
`
`509
`
`by
`a
`
`con-
`7-fold
`
`study
`activity
`B (ALE),
`with
`ara-C
`followed
`be
`
`mdi-
`in
`
`re-
`
`was
`will
`described.14
`
`in
`
`been
`
`30 mg./m.2/day
`reported
`daily
`injections.
`of
`the
`pharmacologic
`had
`antileukemic
`Leukemia
`Group
`leukemia
`adults
`This
`infusion.13
`Both
`studies
`previously
`
`receiving
`patients
`those
`to
`comparable
`were
`to nine
`into
`divided
`the
`course
`during
`done
`continuous
`infusion
`given
`leukemia.
`The
`Acute
`myelocytic
`treatment
`of
`acute
`the
`study
`of
`continuous
`intravenous
`given
`by
`daily
`infusions
`of
`varying
`durations.
`paper.
`Some
`these
`patients
`have
`
`acute
`type,
`
`or
`
`with
`
`in
`ALB
`30
`
`in
`
`leukemia
`clinical
`other
`three
`at
`contributed
`patients
`
`were
`was
`
`a
`
`It
`day.
`(with
`
`in
`status,
`considerations.
`institutions.
`cases.
`randomized
`intended
`Because
`54
`
`METHOD
`relapse
`previous
`
`OF
`were
`
`STUDY
`eligible
`treatment,
`first
`second
`
`the
`
`In
`
`In
`
`the
`
`the
`
`for
`
`study,
`study,
`
`two
`
`inclusion
`elevation
`ALB
`ALB
`
`in
`
`of
`6503,
`6606,
`
`study
`leukocyte
`nearly
`13
`
`of
`
`regardless
`count,
`the
`of
`in.sti-
`
`all
`the
`
`daily
`treated
`
`a
`drug
`for
`
`10
`
`mg./m2/day
`continuous
`population
`a
`
`12
`
`than
`
`between
`all
`patients
`that
`problems
`in
`of
`cases)
`hours.
`Provision
`leukocyte
`level
`the
`production
`downward
`modification
`dependent
`solely
`remission
`a
`count
`if marrow
`production
`resumed.
`intervals
`marrow
`aim
`the
`without
`
`on
`
`of
`cent
`24
`
`per
`for
`the
`(and/or
`such
`be
`
`drug
`that
`than
`unless
`white
`1/2
`
`to
`and/or
`was
`
`adults
`All
`morphologic
`of
`degree
`bleeding,
`of
`patients
`were
`treated
`the
`Group
`ttstions
`In
`6503,
`mg./m.2/day.
`for
`24
`hours
`institution
`clinic
`
`rather
`based
`the
`
`of
`
`fall
`of
`
`group
`the
`
`to
`
`at
`
`dose
`week
`the
`The
`to
`
`and
`fusion
`one
`patients,
`the
`period
`dose
`daily
`fication
`by
`caused
`depression
`it was
`stipulated
`tion),
`but
`cellularity
`rather
`of
`marrow
`discontinued
`drug
`was
`not
`of
`the
`peripheral
`gressive
`the
`daily
`dose
`decrease
`of
`leukopenia
`progression
`after
`week,
`full
`one
`if
`cent
`one
`by
`per
`50
`was
`level
`and
`the
`original
`throughout
`followed.
`not
`regularly
`point
`of
`phase
`ing
`the
`induction
`the
`of
`marrow
`hypocellulanty
`of
`proceeded,
`As
`the
`study
`first
`in
`continued.
`subsequent
`All
`response
`marrow
`duction
`Once
`phase.
`phase.
`maintenance
`patients
`the
`entered
`and
`no
`drug
`one
`receiving
`drug
`maintenance
`When
`use
`of
`changed
`30
`mg./m.2
`subcutaneously
`In
`second
`study,
`designated
`period
`for
`daily
`drug
`others)
`and
`or
`by
`between
`doses
`30
`over
`given
`a
`point,
`end
`cut
`improvement
`no
`relatively
`less
`allow
`three
`over
`hours.
`
`the
`this
`
`one
`
`patients
`
`one
`was
`
`the
`made
`of
`evidence
`gastrointestinal
`be
`monitored
`peripheral
`marrow
`
`be
`hospitalizing
`gave
`was
`and
`
`the
`
`of
`
`to
`
`of
`
`The
`the
`not
`
`doses,
`with
`large
`during
`downward
`definite
`tract
`by
`counts.
`resulted.
`followed
`If
`
`an
`more
`
`was
`leukemic.
`not
`had
`increase
`than
`however,
`administration
`i.e.,
`the
`and/or
`mg./m.2,
`
`in
`
`a
`
`dis-
`in-
`
`was
`
`on
`hypoplastic
`or
`below
`1000/mm3
`levels
`still
`cellular
`was
`and
`marrow
`hypocellularity
`protocol
`also
`specified
`white
`count
`remained
`hypocellular.
`This
`continue
`was
`to
`maximum
`tolerable
`development
`of
`drug
`initial
`two
`study
`received
`occurred
`and
`At
`first
`receiving
`shown
`once
`
`in-
`of
`hour
`modi-
`platelet
`ulcera-
`estimates
`Thus,
`Pro-
`by
`further
`occurred
`in
`dose
`one-half
`at
`was
`provision,
`drug
`dur-
`production
`amount,
`bleeding.
`fatal
`sepsis
`was
`doses,
`10
`the
`30
`mg./m.2/day
`cleared,
`marrow
`hypocellularity
`groups,
`two
`were
`randomized
`into
`mg./m.2
`weekly
`subcutaneously.
`effective,
`the
`randomization
`twice
`weekly
`for
`maintenance.
`vs.
`attempted
`to
`determine
`whether
`somewhere
`between
`minutes
`patients
`were
`over
`the
`again
`was
`found
`bone
`100
`or
`hypocellularity
`
`they
`
`30
`be
`
`we
`fell
`
`to
`weekly
`6606,
`
`Initially
`given
`we
`
`50
`
`the
`optimal
`the
`tested
`(as
`randomized
`same
`larity
`mg./m2
`level
`changed
`mg./m2/day
`
`dose
`as
`
`was
`
`an
`if
`
`to
`
`for
`4
`
`4
`
`off
`was
`active
`groups
`The
`
`aim
`
`ALB
`administration
`hours.
`24
`12
`mg./m.2/day
`of
`While
`period.
`hour
`treatment
`further
`from
`When
`we
`noted.
`in
`depressing
`the
`receiving
`of marrow
`
`entering
`one
`hour
`a
`aimed
`at
`a
`allowed
`at
`that
`one
`marrow,
`the
`mg./m.2/day
`
`the
`
`was
`
`the
`period
`marrow
`dose
`total
`dose
`hour
`randomization
`in
`one
`hour,
`again
`stressed
`
`10
`study
`
`and
`hypocellu-
`1000
`of
`at
`this
`was
`30
`this
`
`or
`
`at
`
`

`

`510
`
`ELLISON
`
`ET
`
`AL.
`
`Table
`
`1.-Study
`
`of Arabinosyl
`
`Crtosine
`
`in Acute
`
`Leukemia
`
`of Adults
`
`12
`
`24
`or
`ALB
`
`hr.
`6503
`
`infus.
`
`4 hr.
`1 or
`ALB
`
`infus.
`6606
`
`Cases
`Randomized
`Cases
`Invalidated
`given
`drug
`before
`died
`study
`of
`out
`transferred
`of dosage
`alteration
`gross
`response
`previous
`ara-C
`not
`of
`cause
`response
`following
`acute
`leukemia
`no records
`received
`Evaluated
`in Paper
`acute
`myelocytic
`acute
`lymphoblastic
`acute
`unclassified
`
`Cases
`
`regimen
`and
`relapse
`clear
`
`polycyth.
`
`vera
`
`117
`
`1
`
`116
`
`to
`
`be
`and
`study
`
`days
`
`of
`
`117
`
`101
`
`3
`2
`3
`1
`3
`1
`3
`
`98
`9
`9
`
`82
`14
`5
`
`to
`
`increased
`the
`leukocyte
`consisted
`ara-C
`
`of
`given
`
`100
`then
`and
`60
`stable
`was
`level
`30 mg./m2
`either
`intravenously
`
`( at
`
`4-hour
`yet
`
`dose
`decreased
`in
`this
`
`and
`
`if
`
`for
`had
`
`or
`
`was made
`cellularity
`Maintenance
`subcutaneously,
`produced
`both
`indicated
`the
`three
`this
`supportive
`the
`study
`first
`were
`evaluated
`only
`complete
`peripheral
`
`blood
`
`the
`not
`treatment
`5
`consecutive
`every
`4 weeks.
`remission)
`supportive
`therapy,
`studies,
`feasible.
`and
`Multiple
`institutions
`contributing
`measure,
`the
`were
`treated
`more
`criteria
`by
`the
`or
`(CR)
`remission
`
`platelet
`the
`bulk
`possibility
`exists
`vigorously
`Acute
`(PR)
`the
`
`of
`
`partial
`in
`
`than
`Leukemia
`remission
`presence
`
`of
`
`platelet
`including
`transfusions
`of
`the
`that
`
`cases
`a
`
`transfusions,
`were
`more
`in
`first
`the
`higher
`proportion
`study.
`in
`second
`the
`many
`results
`B.#{176}In
`the
`Group
`considered
`significant.
`are
`progression
`persistence
`
`was
`readily
`study.
`
`of
`
`or
`
`time
`allowance
`mg/rn.2
`if marrow
`leukopenic.
`even
`weekly
`twice
`the dose which
`Throughout
`used
`where
`available
`in
`Because
`of
`patients
`in
`Responses
`be
`discussed,
`to
`Marrow
`and/or
`
`Park
`Paris,
`
`Memorial
`France;
`
`Institute,
`New
`York
`
`Buffalo,
`Hospital,
`
`York;
`
`New
`Cornell
`
`Institut
`Medical
`
`de
`Center,
`
`Recherches
`New
`
`sur
`
`les
`New
`
`York,
`
`#{176}Roswell
`Leuc#{233}mies,
`York.
`#{176}Disease
`per
`cent
`5
`lymphocytic
`cytoid
`in
`acute
`contain
`karyopoiesis
`a
`complete
`(11
`Gm.
`mm.
`in
`cluding
`A (“no
`sponse
`Disease
`any
`3
`in
`leukemia
`
`cells
`
`per
`the
`physical
`evident
`be
`
`to
`
`for
`
`A requires
`status
`cells,
`blast
`and
`leukemia,
`and
`or
`other
`elements
`myelocytic
`leukemia.
`qualitatively
`and
`(except
`for
`must
`remission,
`with
`cent
`A patient
`peripheral
`symptoms
`signs
`and
`there
`disease”),
`a complete
`considered
`status
`B implies
`a
`rating
`category.
`For
`such
`a
`must
`contain
`from
`a hemoglobin
`least
`500
`and
`no more
`
`as
`must
`remission.
`of
`2
`rating,
`5.1
`at
`
`the
`40
`no
`
`per
`more
`which
`Bone
`quantitatively
`drug
`induced
`adult
`males
`females),
`blood.
`and
`
`following:
`cent
`than
`cannot
`marrows
`normal
`changes,
`also
`least
`must
`well
`be
`
`or
`
`at
`
`5
`be
`
`marrow
`the
`In
`lymphocytes
`fewer
`cent
`blast
`per
`classified
`as
`qualifying
`for
`erythropoiesis,
`such
`as
`at
`least
`have
`mature
`1500
`a
`rating
`have
`marrow
`and
`as
`improvement
`
`no
`be
`cells
`blast
`promyelocytes,
`cells,
`mature
`normal
`more
`Ml
`ratings
`such
`granulopoiesis,
`megaloblastosis).
`12
`Gm.
`neutrophilic
`of
`1
`blood)
`disease
`
`there
`
`must
`and
`
`per
`
`in
`
`to
`
`all
`
`a
`for
`status
`
`than
`acute
`mono-
`elements
`must
`and
`classify
`hemoglobin,
`cent
`granulocytes/cu.
`categories
`disease
`A
`
`more
`in
`
`also
`mega-
`
`as
`
`(in-
`status
`a
`re-
`
`for
`
`To
`
`of
`cytic
`hemogram
`to
`transfusion),
`platelets/cu.
`
`implies
`
`at
`
`mm.,
`
`of
`
`mature
`than
`
`in
`the
`
`one
`bone
`per
`25
`7 Gm.
`
`categories,
`4
`or more
`with
`patient
`a
`marrow
`cells.
`A rating
`blast
`cent
`not
`maintenance
`of
`this
`(with
`granulocytes/cu.
`mm.,
`25,000
`in
`the
`blood.
`
`of
`
`the
`in
`
`but
`acute
`of
`
`no
`
`rating
`myelo-
`for
`the
`2
`attributable
`100,000
`to
`
`blasts
`
`peripheral
`
`to
`least
`neutrophilic
`5 per
`cent
`
`

`

`Ait(cid:1)t.rnNosm
`
`crrosr(cid:1)
`
`511
`
`Table
`
`2.-Response
`
`of Adults
`Infusions
`
`Acute
`with
`of Arabinosyl
`
`Leukemia
`Cytosine
`
`to 12
`
`or 24 Hour
`
`Daily
`
`PR
`
`-
`
`-
`
`2
`
`5
`
`1 (cid:1)
`
`1
`
`- - - -
`
`CR
`
`2
`10*
`
`2 2
`
`1*
`
`1 1 1
`
`-
`
`-
`
`-
`
`#
`Evaluable
`
`12
`41
`9
`36
`
`1 3 5
`
`1 5 1 2
`
`Total
`#
`Rxed
`
`12
`41
`9
`36
`
`1 4 5
`
`1 5 1 2
`
`Dx
`
`AML
`
`ALL
`
`AUL
`
`Infus.
`time
`hrs./day
`
`Daily
`dose
`mg/rn.2
`
`12
`
`24
`
`12
`
`24
`
`12
`
`24
`
`10
`30
`10
`30
`
`10
`30
`
`30
`
`10
`30
`10
`30
`
`*
`
`=
`
`1 patient
`
`with
`
`complete
`
`remission
`
`except
`
`for hemoglobin
`
`level.
`
`involvement,
`
`hepatosplenomegaly,
`
`etc.
`
`is
`
`not
`
`included
`
`elsewhere,
`disease
`of
`among
`remissions.
`In
`some
`instances
`ara-C,
`patients
`received
`when
`response
`of
`the
`a
`most
`instances,
`when
`not
`necessary
`disqualify
`to
`kemia
`in
`absence
`of
`study,
`nor
`the
`such
`patients.
`overall
`Table
`studies
`two
`entered
`includes
`leukemia
`monocytic,
`elomonocytic,
`leukemia,
`with
`acute
`were
`studied,
`leukemia
`described.
`two
`protocols
`chronic
`myelocytic
`of
`30 mg./mnl/day
`
`an
`
`in
`
`1
`
`gives
`the
`(AML)
`
`a
`
`the
`
`leukemia
`given
`during
`
`i.e.,
`
`node
`
`where
`
`severe
`adrenal
`leukemia
`steroid
`
`bleeding
`corticosteroid
`occurred
`was
`used,
`cases
`sign
`
`developed
`therapy.
`patients
`in
`remission
`this
`from
`relapse
`of
`mnethotrexate
`
`the
`Special
`were
`who
`occur
`not
`Development
`not
`remove
`systemic
`
`in
`
`course
`notation
`also
`and
`
`of
`
`treatments
`will
`
`be
`steroid.
`
`of
`
`with
`made
`
`In
`it was
`leu-
`the
`in
`
`from
`factor
`
`given
`therefore
`meningeal
`patient
`the
`citrovorum
`
`did
`study.
`did
`with
`
`such
`other
`intrathecal
`
`the
`
`did
`
`any
`of
`
`use
`
`summary
`described
`patients
`all
`erythro-leukemia.
`or
`number
`of
`adults
`with
`dose
`Following
`this,
`were
`entered
`4 or
`12
`hours.
`
`the
`
`of
`above.
`diagnosed
`
`of
`
`the
`
`to
`phase
`during
`
`patients
`number
`designated
`The
`group
`as
`myeloblastic,
`addition
`In
`“acute”
`the
`nonrandomly
`group
`of
`a
`
`patients
`in
`
`which
`
`with
`
`study
`
`with
`as
`acute
`217
`of
`
`leukemia
`acute
`myelocytic
`acute
`myelocytic,
`evaluable
`chronic
`the
`
`my-
`adults
`myelocytic
`of
`phase
`consisted
`
`the
`of
`
`course
`“acute”
`treatment
`
`in
`chosen
`a
`small
`into
`
`ALB
`
`6503
`
`RESULTS
`
`first
`
`The
`received
`acute
`with
`responded
`fell
`only
`responded.
`AUL
`3 with
`10 mg./m.2/day,
`dose
`level,
`
`the
`of
`results
`30 mg./m.2/day,
`unclassffied
`with
`complete
`slightly
`short
`A similar
`or ALL)
`with
`relatively
`
`are
`
`per
`
`as
`
`per
`smaller
`responses
`responses
`
`the
`
`summarized
`study
`cent
`of
`77 with
`25
`or
`(AUL)
`acute
`leukemia
`remission.
`partial
`or
`being
`classifiable
`of
`response
`rate
`(19
`seen
`was
`in
`the
`the majority
`of
`more
`of
`
`in Table
`AML
`lymphocytic
`These
`partial
`complete.
`All
`cent
`of
`21 with
`group
`of
`patients
`being
`complete.
`were
`complete
`
`the
`2. Of
`per
`and
`20
`leukemia
`remissions
`types
`AML
`
`adults
`cent
`
`who
`of
`15
`(ALL)
`usually
`leukemia
`of
`and
`all
`treated
`with
`At
`the
`higher
`in
`the
`group
`
`of
`
`

`

`512
`
`ELLISON
`
`ET
`
`AL.
`
`Table
`
`3.-Toxic
`Arabinosyl
`
`Effects
`Cytosine
`
`or
`12
`of
`in Adults
`
`24 Hour
`with
`
`Daily
`Acute
`
`infusions
`Leukemia
`
`of
`
`30 mg./m.2/day
`%
`
`10 mg./m.2/day
`%
`
`FalltoWBCl.0-1.9
`
`<1.0
`fall
`
`platelet
`hypocellularity
`tract:
`effects
`other
`diarrhea,
`
`Definite
`Marrow
`Gastrointestinal
`(cid:1) or
`ulcers
`N & V and/or
`Phlebitis
`
`Total
`*Numbern
`
`no. patients
`represent
`
`9
`45
`42
`39
`
`3
`1
`8
`
`92
`
`no ulcers
`
`8
`21
`29
`29
`
`0
`4
`8
`
`24
`
`a minimum
`
`figure.
`
`Information
`
`on
`
`this
`
`not
`
`always
`
`recorded.
`
`12
`
`hours
`as
`
`an
`
`the
`
`of
`Two
`remissions
`4,
`footnotes)
`
`patients
`may
`actually
`that
`
`so
`
`in
`
`it
`
`is
`
`hour
`the
`been
`have
`difficult
`
`24
`
`group
`complete
`whether
`say
`
`who
`re-
`
`to
`
`remissions
`complete
`previously
`were
`28
`and
`weeks
`agents
`other
`response
`in
`administered
`produced
`12
`instances
`inadequate,
`
`remissions
`partial
`plus
`or whose
`previous
`untreated
`the
`25 who
`were
`in
`per
`cent
`receiving
`ara-C.
`Thus
`prior
`to previous
`treatment.
`related
`the
`induction
`phase
`during
`than
`200
`or more
`than
`less
`retrospective
`review
`the
`i.e.,
`more
`could
`have
`
`in
`
`73
`the
`treat-
`treated
`there
`
`varied
`1000
`data
`been
`
`to
`
`of
`
`drug
`
`with
`
`In
`was
`
`degree
`
`greater
`was
`toxicity
`drug
`of
`related
`those
`being
`effects
`and
`prominent
`was
`at
`the
`treatment
`stopped
`some
`“overshoot”
`been
`leukopenia
`occurred.
`doses
`than
`reported
`
`than
`30
`at
`to marrow
`platelet
`transfusions
`first
`evidence
`with
`the
`higher
`The
`gastrointestinal
`by
`others
`using
`
`10 mg./
`at
`depression
`were
`of marrow
`dose
`due
`effects
`daily
`
`once
`
`that
`
`116
`
`randomized
`analysis.
`for
`of
`disappeared
`They
`liver
`42
`with
`the
`3. Of
`bilirubin
`7 had
`significant
`normal,
`platelet
`to
`hemolytic
`reaction
`a
`elevation
`(1),
`5 had
`bilirubin
`continued
`drug
`administration,
`
`cases,
`Abnormalities
`in
`normal
`
`4
`
`data
`
`function
`liver
`concerning
`before
`in
`were
`present
`unchanged
`these
`and
`remained
`before
`ara-C,
`function
`tests
`either
`elevations
`coincident
`with
`transfusion
`(1),
`or widespread
`<3
`mg.
`cent
`with
`return
`had
`minor
`variations
`in
`SGOT
`
`7
`
`tests
`ara-C
`
`in
`25
`
`to
`
`to
`
`4
`
`per
`
`day.
`a
`for
`treated
`partial
`categorized
`were
`(see
`Table
`however,
`missions,
`difference.
`important
`this
`is
`cent
`per
`were
`22
`There
`who
`with
`AML
`patients
`two
`lasted
`less
`than
`ment
`with
`two
`weeks
`or more
`for
`no
`appreciable
`difference
`was
`The
`total
`amounts
`of
`ara-C.
`widely.
`Few
`responses
`were
`mg./m.2
`total
`drug
`dose.
`suggests
`that
`drug
`trial
`tolerated.
`The
`with
`
`and
`incidence
`predominant
`the
`Platelet
`depression
`used.
`Since
`we
`there
`may
`have
`already
`given
`before
`frequent
`at
`both
`less
`administration.
`49
`of
`the
`adequate
`are
`administration.
`the
`other
`remained
`sepsis
`hemorrhage
`normal
`
`rn.2
`(Table
`frequently
`depression,
`to
`drug
`were
`drug
`In
`
`3).
`
`(5),
`
`on
`
`

`

`and/or
`treatment,
`after
`ara-C.
`has
`not
`had
`during
`the
`acute
`leukemic
`tic
`leukemia
`quently
`there
`The
`
`ARABINOSYL
`
`CYTOSINE
`
`513
`
`and/or
`marked
`the
`
`with
`
`that
`courses
`
`of
`of
`
`during
`2 months
`and
`arabinoside
`diagnoses
`myelocy-
`2 was
`subse-
`jaundice.
`Thus
`
`he
`
`of
`
`of
`
`normal
`to
`return
`bilirubin
`phosphatase
`alkaline
`tests
`three
`all
`abnormalities
`1 developed
`and
`hepatitis,
`serum
`picture
`was
`this
`last
`patient,
`In
`of
`cytosine
`subsequent
`recurrence
`during
`a
`cases
`(with
`Two
`nonrandomized
`ensuing
`18 months.
`phase
`of
`chronic
`phase
`of
`lymphosarcorna
`and
`acute
`) also
`one
`those
`developed
`a
`similar
`picture.
`Only
`with
`ara-C
`and
`there
`was
`no
`recurrence
`of
`retreated
`no
`evidence
`of hepatotoxicity.
`definite
`in marrow
`rating
`improvement
`in
`a median
`of
`4 weeks
`with
`earlier
`evidence
`of
`response
`hour
`41/2
`infusion
`group
`(31/2
`vs.
`with
`to
`range
`of
`drug
`a
`120
`of
`3 times
`many
`as
`days
`infusion
`i.v.
`equal
`an
`produce
`effect.
`to
`improvement
`of marrow
`seen
`appeared
`dose
`but
`drug
`because
`of marrow
`in
`
`was
`both
`
`This
`during
`had
`those
`
`of
`drug
`was
`the
`after
`depression)
`
`1 to
`noted
`groups.
`dose
`12
`hour
`the
`in
`However,
`wks).
`945 mg.
`was
`were
`necessary
`also
`indicates
`the
`course
`already
`who
`
`after
`may
`
`at
`
`the
`have
`group
`total
`both
`lower
`first
`at
`
`of
`
`9 weeks
`There
`infusion
`a median
`necessary
`the
`at
`the
`that
`treatment
`discontinued
`the
`higher
`
`been
`received
`
`was
`first
`ara-C,
`of
`start
`slightly
`a
`been
`the
`24
`in
`than
`480 mg./m.2
`of
`doses.
`Thus,
`daily
`dose
`evidence
`the
`lower
`(usually
`dose.
`Table
`used
`
`4 gives
`in
`
`details
`
`these
`
`the
`(predominantly
`
`responsive
`
`was
`
`of
`use
`
`timing
`the
`to
`occurred
`is
`
`patients.
`bleeding
`responses
`
`during
`the
`
`Where
`
`prednisone
`episodes)
`did
`
`not
`
`appear
`
`the
`
`such
`
`that
`
`levels
`the
`
`were
`
`doses
`steroid.
`all
`age
`with
`treated
`was
`There
`100,000/cu.
`leukopenic
`indicates
`
`age
`with
`only
`
`the
`When
`treated.
`all
`of
`distribution
`relationship
`ara-C,
`no
`one
`response
`in
`skewing
`not
`
`but
`
`age
`the
`
`in
`
`of
`
`with
`re-
`an
`
`the
`
`concerning
`patients
`the
`or
`amount
`to be
`of
`related
`distribution
`at
`Responses
`patients
`compared
`responders
`the
`to
`of
`age
`leukemia
`myelocytic
`acute
`with
`patient
`a
`be
`seen.
`rate
`can
`sponse
`distribution
`the
`of
`mm.
`of
`over
`white
`count
`initial
`Analysis
`of
`occur.
`did
`patients
`the
`of
`responders
`towards
`the
`markedly
`level
`rate
`response
`equal
`an
`pretreatment
`platelet
`a higher
`but
`rate
`in
`those
`response
`patients
`and
`moderately
`thrombocytopenic
`was
`started.
`time
`ara-C
`at
`the
`greater
`or
`100,000/mm.3
`whose
`platelets
`were
`in ALB
`98
`Four
`patients
`included
`in
`the
`as AML
`designated
`and
`evaluated
`by
`the
`contributing
`institu-
`ervthroleukemia
`diagnosed
`cases
`as
`remission
`(comnlete
`for
`a
`partial
`of
`these
`sustained
`4
`per
`cent).
`additional
`An
`11 Gm.
`which
`rose
`above
`never
`red
`blood
`cells
`in
`nucleated
`had
`per
`cent
`31-61
`abnormal
`numbers
`as
`well
`as
`ara-C
`treatment
`occurred.
`marrow
`remission
`and
`partial
`one
`of
`the
`erythroid
`and
`with
`at
`expense
`this
`response
`rate
`of
`patients
`The
`differ
`from
`that
`of AML
`not
`induced,
`patients
`were
`was
`30 mg./m.(cid:1)
`ara-C
`subcutaneously
`of
`remission
`
`of
`
`were
`6503
`One
`tions.
`hemoglobin
`group
`this
`in
`start
`at
`the
`complete
`One
`occurred
`only
`blood
`improvement.
`of
`12)
`therefore
`Once
`remission
`either
`drug
`increase
`duration
`
`no
`
`in
`
`of
`
`of
`
`except
`8 patients
`marrows
`their
`mvelohlasts.
`improvement
`no
`peripheral
`(25
`per
`
`cent
`
`at
`
`random
`week.
`a
`administration.
`
`receive
`to
`A marked
`
`All
`
`Other
`elements
`of
`group
`a whole.
`as
`allocated
`
`once
`drug
`
`by
`
`was
`
`produced
`
`the
`
`did
`
`or
`
`

`

`514
`
`‘4
`
`(cid:1) .u
`
`+
`
`+
`
`00
`
`++
`
`++
`
`+
`
`a
`
`a a I
`
`.a
`
`ELLISON
`
`ET AL.
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`++
`Co
`
`CO
`
`Co
`
`Co
`
`Co
`
`++
`
`C-
`C.1
`t-
`
`Co
`-
`(cid:1)
`
`Co
`eq
`-
`
`eq
`0
`Co
`
`C-
`Co
`eq
`
`-
`Co
`-
`
`(cid:1)
`
`II.(cid:1)
`
`0
`
`5
`
`Co
`
`--
`
`Cocoeqeq(cid:1)
`
`--
`
`‘-v’
`
`-
`
`I
`
`](cid:1) I: :(cid:1)(cid:1):(cid:1)
`
`I
`
`I
`
`(cid:1)000
`(cid:1)
`
`Co
`
`(cid:1)
`Co
`
`Co
`
`0-
`
`Co
`Co
`
`C
`
`I
`
`Ct2
`
`*
`
`(cid:1)I
`o
`
`I(cid:1)I
`(cid:1)
`
`Cl)
`
`C,’---
`
`-
`
`(cid:1)eq(cid:1)(cid:1)eqeq
`
`2 (cid:1)
`
`004
`
`0
`
`EEEEEEEEEEEEEEEE
`
`04
`
`0.
`
`.fJ
`
`‘4
`
`0-.
`
`‘4
`
`(cid:1)
`
`‘4
`
`(cid:1)
`
`C-
`
`-
`
`‘0
`
`.(cid:1)
`
`0
`
`eq
`
`‘00
`
`00(cid:1)(cid:1)
`
`CO
`
`-
`
`eq
`
`CO
`
`-04-
`
`(cid:1)
`
`Co
`
`C-
`
`I
`
`I I I .(cid:1)
`
`Co
`
`CoCoCo
`
`(cid:1)
`
`01
`eq
`
`Co
`
`(cid:1)
`
`0
`
`Coe(cid:1)
`
`-
`Co
`Co Co
`
`Co
`
`eq
`
`0
`(cid:1)0
`0
`
`0 0 a
`
`‘a
`a
`
`‘(cid:1)
`
`I
`a
`‘a
`
`0
`
`Co.(cid:1)02
`
`0 4a
`
`.5
`
`0
`
`I
`
`I
`
`I
`
`(cid:1) ,-(cid:1)
`
`I
`
`I
`
`I
`
`I
`
`00
`Co
`
`0-
`
`Co
`000
`
`000
`
`Co
`
`Co
`
`eq
`
`(cid:1)
`
`eq
`
`eq
`
`(cid:1)
`
`eq
`(cid:1)
`
`000000
`
`.(cid:1) (cid:1)
`
`I
`
`..‘(cid:1)
`o
`
`222!(cid:1)(cid:1)
`
`.0
`
`.5
`
`aa a
`
`.(cid:1)
`
`I.a
`0,
`
`a
`
`(cid:1)
`
`-
`
`eq eq Co CO
`
`eq
`
`eq
`
`-
`
`eq
`
`Co C(cid:1) Co
`
`eq
`
`eq
`
`Co
`
`-
`
`Co
`
`Co
`
`eq
`
`eq
`
`-
`
`Co
`
`Coeq-Co
`
`C.(cid:1))
`
`(cid:1)
`
`eq
`
`eq
`
`-
`
`e*
`
`co
`
`eq
`
`-
`
`eq
`
`-
`
`eq
`
`eq
`
`eq
`
`co
`
`eq
`
`eq
`
`eq
`
`-
`
`eq
`
`Co
`
`cq
`
`eq
`
`eq
`
`eq
`
`-
`
`eq
`
`eqeqeqeq
`
`.(cid:1);2
`
`(cid:1)(cid:1)
`
`(cid:1)
`
`.5 .(cid:1)(cid:1).(cid:1)0
`2-(cid:1).(cid:1)0
`
`$.??.0
`
`1(cid:1)1
`
`(cid:1)eq(cid:1)eq(cid:1)o
`
`-(cid:1)
`
`0.
`
`4
`
`-
`
`:::::::::::::::::::::::
`‘q . Co
`
`II’4I
`
`IIIIIIIII”II(cid:1)”I(cid:1)(cid:1)(cid:1)I
`
`00
`
`(cid:1)
`
`00
`
`eq
`
`(cid:1)‘
`
`Co
`
`CoCo
`
`(cid:1)‘
`
`(cid:1)
`
`(cid:1)
`
`(cid:1)
`
`0
`
`-(cid:1)
`
`

`

`ARABINOSYL
`
`CYTOSINE
`
`515
`
`o All
`entered with <2wks.
`#{149}No Response
`(57)
`#{149}CR or PR (16)
`
`prior Rx
`
`(73)
`
`.#{149}
`(cid:1)
`
`20
`WEEKS
`diagnosis
`of
`12
`or
`24
`had
`either
`than
`survival
`
`50
`
`40
`30
`FROM DIAGNOSIS
`73
`previously
`untreated
`hour
`daily
`infusions
`a
`complete
`remission
`did
`those
`no
`response.
`
`with
`
`60
`
`adults
`arabinosyl
`of
`(CR)
`or
`
`a
`
`with
`
`acute
`cytosine
`partial
`
`re-
`
`0
`
`l0
`
`> > C
`
`l)
`
`Fig.
`myelocytic
`(ALB
`mission
`
`2.-Survival
`leukemia
`Those
`a
`longer
`
`#6503).
`(PR)
`
`had
`
`from
`given
`who
`
`a
`
`have
`patients
`the
`13
`patients
`this
`for
`became
`
`(median
`were
`of
`not
`
`and
`to
`before
`of
`the
`
`of
`
`relapsed,
`unmaintained
`the
`of
`of
`5 weeks.
`One
`treated
`of
`group
`median
`days;
`the
`577
`obvious,
`remission
`maintenance
`subcutaneous
`receiving
`include
`group
`duration
`gave
`results
`This
`poor
`entered
`patients
`five
`in this
`study
`treatment
`assessing
`In
`the
`results
`sufficient
`response
`the
`rate
`is
`of
`must
`also
`of
`survival
`the
`group
`The
`in
`those
`cent
`response
`rate
`seen
`per
`does
`were
`previously
`treated
`who
`little
`patients
`who
`had
`received
`in
`least
`at
`former
`group
`had
`had
`the
`receiving
`ara-C
`thus
`represented
`priate,
`therefore,
`analyze
`separately
`or
`no
`treatment
`ara-C.
`Nine
`alive.
`The
`survival
`the
`patients
`of
`that
`the
`rest
`group
`(Fig.
`whole
`is
`disturbingly
`short.
`We
`by
`with
`others
`obtained
`the
`Leukemia
`of
`In
`leukemia.
`a
`group
`855
`such
`the
`cooperating
`institutions
`where
`
`is
`
`on
`in
`to
`
`not
`or
`one
`a
`
`of
`with
`2).
`therefore
`Group
`patients
`previously
`
`of
`
`with
`the
`As
`acute
`the
`
`duration
`remission
`a median
`with
`remission
`still
`in
`is
`weekly
`once
`advantage
`the
`When
`30 weeks.
`changed
`was
`the
`randomization
`twice
`weekly.
`ara-C
`30
`mg./m.2
`remission
`of
`9 weeks),
`but
`only
`of
`dose.
`this
`patients
`indicate
`considered.
`be
`patients
`with
`differ
`from
`no
`treatment
`on
`remission
`group.
`selected
`patients
`the
`73
`responders
`the
`16
`remissions
`However,
`attempted
`B in
`(which
`treated
`
`at
`of
`to
`
`28
`
`of
`to
`
`a
`
`by
`
`enumeration
`drug
`effect.
`noted,
`the
`leukemia
`rate
`noted
`Most
`prior
`appro-
`little
`still
`than
`as
`data
`
`leukemia,
`extent
`akeady
`myelocytic
`per
`cent
`22
`to
`ara-C.
`prior
`therapy
`other
`It
`seemed
`who
`had
`in
`this
`markedly
`the
`of
`compare
`with
`acute
`all
`those
`an
`age
`
`are
`
`more
`received
`group
`longer
`group
`these
`myelocytic
`seen
`related
`
`was
`survival
`to
`
`adults
`included
`or
`
`not),
`
`

`

`516
`
`ELLISON
`
`ET
`
`AL.
`
`prior
`
`#{163}2weeks
`o 6-49
`Years
`Years
`ar
`0
`50
`
`Rx
`
`old
`older
`
`(27)
`(46)
`
`0
`
`10
`
`from
`3.-Survival
`leukemia
`given
`#6503):
`comparison
`
`Fig.
`myelocytic
`(ALB
`older.
`
`20
`WEEKS
`diagnosis
`24
`or
`12
`of
`results
`
`of
`
`30
`FROM
`73
`hour
`in
`
`two
`
`40
`DIAGNOSIS
`previously
`untreated
`daily
`infusions
`age
`groups,
`
`50
`
`70
`
`adults
`arabinosyl
`and
`
`with
`
`50
`
`acute
`cytosine
`years
`
`or
`
`of
`16-49
`
`was
`time.
`adults
`(Fig.
`
`difference
`survival
`untreated
`first
`study
`nonresponsive
`on
`survival
`although
`however,
`The
`does
`We
`studied
`the
`time
`patients,
`dying
`evidence
`probably
`out
`response,
`tion,
`more
`3 to
`6 weeks,
`ly
`related
`died
`during
`
`not
`
`in
`
`was
`time
`
`to
`
`6
`
`with
`demonstrated,
`related
`Similar
`age
`myelocytic
`with
`acute
`differences
`3).
`Such
`When
`compared
`patients.
`younger
`previously
`the
`time,
`younger
`ara-C
`entire
`the
`equivalent
`is completely
`older
`in
`the
`rate
`early
`death
`previously
`that
`differ
`from
`to
`therefore,
`attempted,
`between
`the
`relationship
`nonresponsive
`the
`of
`death
`in
`than
`study
`for
`less
`32 were
`on
`less
`than
`3 weeks.
`Three-quarters
`deaths
`of
`drug
`toxicity,
`whereas
`2
`In
`related
`to
`drug
`effects.
`those
`who
`were
`however,
`and
`who
`subjected
`seen.
`marrow
`depression
`Thus,
`on
`the
`19 died
`during
`study
`18
`Among
`drug
`toxicity.
`patients
`this
`to
`12 week
`interval
`with
`
`patients
`differences
`leukemia
`were
`noted
`with
`untreated
`was
`to
`
`median
`longer
`a
`having
`50
`under
`previously
`73
`the
`in
`occurred
`ara-C
`in
`received
`who
`responsive
`in
`the
`both
`earlier
`accumulated
`ara-C
`patients
`did
`comparable.
`Neither
`the ALB
`control
`experience.
`untreated
`patients
`given
`
`the
`
`the
`and
`data
`poorly,
`group,
`
`ara-C
`
`in
`
`group
`content
`previously
`obtained.
`determine
`the
`
`the
`production
`patients.
`3 weeks,
`29
`of
`these
`were
`possibly,
`continued
`to
`continued
`among
`36
`with
`9 of
`on
`study
`two
`deaths
`
`the
`of
`cause
`hematologic
`of
`Among
`the
`87
`of
`with
`29
`patients
`and
`study
`drug
`patients
`these
`deaths
`for
`6
`to
`probably
`
`early
`
`deaths
`toxicity
`nonresponsive
`these
`patients
`no
`showed
`was
`1 death
`with-
`longer
`administra-
`on
`study
`apparent-
`12 weeks,
`related
`
`and
`and
`
`for
`
`9
`to
`
`on
`
`

`

`517
`
`PR
`
`1 1 1
`
`1
`
`- - -
`
`- -
`
`being
`during
`steep
`
`group,
`lower
`the
`
`17
`and
`deaths
`were
`to
`be
`
`more
`
`than
`drug
`of
`account,
`of
`per
`
`before
`deaths
`for
`
`the
`
`of
`
`entire
`
`and
`
`dose
`
`but
`
`15
`2 of
`causes.
`deaths
`to
`drug
`those
`
`the
`
`bleed-
`of
`infection
`In
`9
`resulting
`toxicity.
`in whom
`
`related
`
`of
`
`for
`
`was
`
`12 weeks
`study
`related
`occurrence
`however,
`not
`does
`treatment.
`first month
`the
`the
`cent
`responders,
`20
`the
`received
`3 weeks
`less
`died
`in
`than
`of
`2
`only
`that
`worth
`noting,
`however,
`depression
`ever
`developed
`hematologic
`the
`early
`of
`such
`depression.
`Thus,
`later
`deaths
`drug
`levels,
`the
`daily
`the
`lower
`were
`more
`apt
`with
`30 mg./m.2/day.
`study:
`on
`while
`died
`patients
`infection,
`sepsis,
`4 of pulmonary
`and
`4 of miscellaneous
`a preponderance
`was
`death
`seemed
`to
`be
`infection
`smaller
`
`ARABINOSYL
`
`CYTOSINE
`
`Table
`
`5.-Response
`
`of Adults
`Infusions
`
`Acute
`with
`of Arabinosyl
`
`Leukemia
`Cytosine
`
`to
`
`1 or 4 Hour
`
`Daily
`
`Daily
`Dose
`mg./m2
`
`CR
`3*
`6(cid:1)
`
`53
`
`1 - -
`
`it
`
`--
`
`#
`Evaluable
`
`16
`20
`20
`26
`
`3 119
`
`23
`
`Total
`#
`Rxed
`
`18
`20
`24
`31
`
`3 219
`
`24
`
`level.
`administration.
`
`Infus.
`time
`hrs./day
`
`1
`
`4
`1
`
`4
`
`14
`
`with
`
`Dx
`
`AUM
`
`ALL
`
`AUL
`
`0
`
`= (cid:1) pts.
`f =
`response
`
`related
`
`30
`50
`100
`30
`30
`50
`100
`30
`30
`30
`Hgb
`CR except
`to prednisone
`
`toxicity.
`
`ing
`and
`cause
`from
`The
`death
`
`One
`other
`to
`twelfth
`survival
`per
`
`cent
`(10
`
`drug
`transferred
`to
`the
`third
`the
`slope
`of
`Twenty-five
`27
`per
`and
`dose
`daily
`nonresponders
`these
`neither
`of
`to
`were
`due
`disease
`related
`drug
`related
`Fifty-one
`(9 CNS,
`bleeding,
`of
`death
`infection
`proportion
`was
`not
`
`patient
`The
`therapy.
`study
`of
`week
`during
`curve
`the
`of
`cent
`29 who
`the
`of
`mg./m.2).
`It
`is
`dose
`lower
`on
`the
`result
`as
`a
`died
`at
`both
`disease
`treated
`in
`those
`with
`in those
`treated
`of
`the
`nonresponsive
`87
`2 GI,
`4 other),
`14 of
`3 of
`renal
`dysfunction,
`is
`not
`known.
`There
`in
`the
`cases
`where
`of
`deaths
`due
`related
`to drug
`
`was
`
`on
`
`to
`toxicity.
`
`6606
`second
`
`1
`
`ALB
`The
`administered
`used
`in ALB
`or
`hour.
`was
`delayed.
`kemic
`patients
`hour
`24
`infusion,
`Therefore,
`we
`
`study
`doses
`6503,
`With
`Since
`when
`we
`
`the
`
`planned
`was
`ara-C.
`Initially,
`of
`30 mg./m.2/day,
`1
`hour
`infusion
`knew
`that
`drug
`is
`that
`new
`
`to
`
`but
`
`test
`we
`we
`
`the
`a greater
`given
`once
`increase
`in
`an
`randomization
`
`we
`
`the
`felt
`
`set
`
`up
`
`a
`
`the
`used
`gave
`appearance
`dose
`total
`than
`daily
`the
`1 hour
`described
`as
`
`it
`was
`
`of more
`effectiveness
`total
`dose
`the
`same
`for
`either
`the
`drug
`of marrow
`is
`tolerated
`when
`dosage
`under
`
`is
`
`rapidly
`as
`that
`4
`hours
`depression
`in
`nonleu-
`given
`indicated.
`Method
`
`by
`
`of
`
`

`

`518
`
`ELLISON
`
`ET
`
`AL.
`
`6.-Toxic
`Table
`Arabinosyl
`
`Effects
`Cytosine
`
`or 4 Hour
`oil
`in Adults
`with
`
`Daily
`Acute
`
`Infusions
`Leukemia
`
`of
`
`4
`
`30
`
`%3
`
`7
`16
`61
`
`18
`
`8
`
`13
`
`38
`
`100
`
`%1
`
`4
`24
`57
`
`48
`
`10
`
`19
`
`21
`
`1
`
`50
`
`%5
`
`19
`62
`
`33
`
`10
`
`14
`
`21
`
`30
`
`%2
`
`4
`38
`86
`
`48
`
`10
`
`14
`
`21
`
`Time
`Infusion
`Hrs./day
`
`Daily Dose-mg./m.2
`
`Fall
`
`to WBC
`
`1.0-1.9
`<1.0
`
`Definite Platelet Fall
`
`Marrow
`
`Hypocellularity
`
`Gastrointestinal Tract
`Ulcers
`c or s other effects
`diarrhea
`N & V and/or
`sulcers
`
`Total
`
`Number
`
`of
`
`Patients
`
`study
`
`in
`
`the
`765
`
`that
`age
`
`The
`5.
`longer
`was
`definitely
`daily
`
`response
`infusions,
`somewhat
`higher
`and
`
`dose
`
`study
`and
`
`re-
`
`with
`patients
`
`the
`in
`through
`to
`
`start
`
`two
`a
`
`10.
`
`Table
`in
`summarized
`are
`with
`the
`that
`obtained
`from
`period
`induction
`during
`and
`mg./m.2)
`(median
`with
`50 mg./m.2
`950 mg./m.2
`study.
`the
`previous
`first
`seen
`similar
`to
`in
`76
`18
`of
`the
`from
`mm.
`184,000/cu.
`from
`ranged
`level
`1700
`complete
`1
`remission
`remission,
`complete
`(1
`of AML
`the
`5
`cases
`among
`remission)
`partial
`1
`additional
`institutions.
`An
`contributing
`the
`by
`blood
`cells
`nucleated
`red
`cent
`33-55
`per
`had
`6606
`the
`of
`of myeloblasts
`at
`numbers
`abnormal
`one
`complete
`remission
`and
`remissions
`com-
`level
`among
`these
`Thus,
`response
`rate
`of
`of
`group
`15 patients.
`of
`toxicity
`are
`shown
`frequently
`than
`did
`period
`of
`
`this
`of
`significantly
`dose
`given
`infusion
`(median
`than
`was
`
`results
`differ
`total
`hour
`4
`infusion
`daily
`of
`
`dose)
`response
`in
`patients
`leukocyte
`responses
`and
`
`The
`
`for
`
`Study.
`does
`rate
`although
`higher
`in
`the
`2300
`The
`missions
`whose
`There
`except
`labelled
`10
`patients
`in
`their
`ara-C
`plete
`40
`per
`The
`
`inal
`dose
`was
`
`on
`The
`weekly
`
`as
`
`4
`
`not
`the
`the
`in
`1 hour
`mg./m.2
`pattern
`occurring
`pretreatment
`three
`were
`hemoglobin,
`erythroleukemia
`treated
`in ALB
`as
`marrow
`as well
`were
`treatment.
`There
`for
`except
`hemoglobin
`was
`cent
`seen
`in this
`incidence
`and
`types
`effects
`occurred
`more
`spread
`out
`over
`a
`longer
`not
`any more
`marked.
`were
`function
`Adequate
`data
`on
`hepatic
`initial
`abnormalities
`7 with
`cases.
`One
`among
`while
`the
`other
`had
`clearing
`on
`treatment.
`6
`remained
`so,
`developed
`significant
`abnormalities
`SGOT
`and/or
`alkaline
`phosphatase
`changes
`which
`still
`drug.
`maintenance
`subcutaneous
`
`in Table
`those
`while
`
`the
`
`6. The
`after
`the
`marrow
`
`gastrointest-
`same
`daily,
`depression
`
`time,
`
`available
`showed
`Of
`the
`
`in
`
`50
`an
`43
`with
`reverted
`
`the
`of
`increase
`initially
`sepsis
`to
`
`randomized
`in
`SGOT
`normal,
`and
`normal
`
`37
`had
`while
`
`2
`
`course
`ara-C
`
`was
`and
`
`randomized
`10
`receiving
`
`in
`
`patients,
`23
`intensive
`
`13
`intravenous
`
`twice
`receiving
`treatment,
`
`

`

`ARABINOSYL
`
`CYTOSINE
`
`days
`five
`maintenance
`still
`p