Comparison
`Strategies
`
`of Three
`for
`
`Remission
`Treatment
`the
`A Cancer
`and
`
`Induction
`of Acute
`Leukemia
`
`and
`
`Regimens
`Nonlymphocytic
`Group
`B Study
`
`Two
`
`Postinduction
`Leukemia:
`
`By Harvey
`Samuel
`
`Preisler,
`Kopel,
`
`Kirshner,
`Jeffrey
`Roger B. Davis,
`Carey,
`Robert
`N. Levy, Robert
`and the Cancer
`
`Eloise Dupre,
`Phillip
`Schulman,
`and Leukemia
`
`Richards
`Frederick
`Arlan
`J. Gottlieb,
`Group
`
`B
`
`Ill, H. Clark Hoagland,
`0. Ross McIntyre,
`
`Patients
`domized
`of
`seven
`daunorubicin
`intensified
`extension
`ten
`days.
`receive
`phylaxis
`increase
`prophylaxis
`patients
`
`T HE
`
`leukemia
`nonlymphocytic
`therapy
`remission
`induction
`three
`and
`cytosine
`arabinoside
`same
`the
`+
`3”)
`to
`receive
`((cid:1)7
`6-thioguanine
`either
`the
`addition
`of
`by
`the
`administration
`of cytosine
`arabinoside
`of
`Additionally.
`all
`patients
`were
`randomized
`not
`to
`receive
`cotrimoxazole
`antibacterial
`or
`during
`the
`remission
`induction
`phase.
`Neither
`in intensity
`of chemotherapy
`the
`antibacterial
`increased
`the
`remission
`above
`the
`53% for
`treated
`with
`the
`standard
`3”
`regimen.
`
`ran-
`were
`consisting
`days
`regimen
`or
`
`of
`
`by
`to
`to
`pro-
`an
`
`acute
`with
`to
`receive
`days
`of
`
`or
`
`nor
`rate
`“7
`
`+
`
`of
`
`acute
`
`nonlymphocytic
`
`leukemia
`
`a
`
`the
`
`the
`
`of
`
`+
`
`of
`
`by
`
`the
`
`of
`
`for
`increase
`therapy.
`in
`
`study
`this
`part
`second
`The
`maintenance
`of
`long-term
`utility
`randomized
`patients
`were
`end.
`8 months
`of maintenance
`after
`maintenance
`therapy
`tinue
`was
`a
`transient
`there
`who
`discontinued
`patients
`the
`remitters
`was
`identical
`term
`of
`Additionally.
`there
`is a suggestion
`for
`patients
`randomized
`to
`discontinue
`months.
`a 1987
`
`the
`addressed
`chemotherapy.
`to discontinue
`chemotherapy
`a total
`of 3 years.
`in
`the
`relapse
`the
`proportion
`two
`patient
`a survival
`all
`
`issue
`
`of
`
`all
`
`To
`treatment
`or
`to
`con-
`Although
`for
`rate
`long-
`of
`groups.
`advantage
`therapy
`at
`
`the
`this
`
`8
`
`by Grune
`
`& Stratton.
`
`Inc.
`
`they
`
`Patients
`Although
`mg/dL
`patients
`Although
`study,
`they
`whose
`mg/dL
`neoplastic
`
`if
`ineligible
`were
`specified
`the
`protocol
`for BUN and
`I .5 mg/dL
`who
`had
`were
`entered
`ineligible,
`technically
`analyses
`being
`careful
`with
`differences
`in
`any
`showed
`>40
`mg/dL
`was
`BUN
`excluded
`from
`was
`disease
`and
`associated
`
`had
`maximum
`for
`creatinine
`levels
`slightly
`these
`patients
`performed
`response
`or whose
`analysis.
`cytotoxic
`
`function.
`inadequate
`levels
`of 30
`permissible
`a number
`o1
`levels,
`these
`limits.
`above
`included
`in the
`were
`to determine
`whether
`toxicity.
`patient
`or
`Any
`creatinine
`level was
`>2.0
`Patients
`a
`history
`of
`therapy
`not
`eligible
`
`renal
`
`with
`were
`
`for
`
`randomization
`
`(See
`
`Statistical
`
`Methods).’#{176}”
`
`in
`
`Treatments
`
`Under
`
`Study
`
`the
`
`schema
`random-
`(cytosine
`seven
`days,
`therapy
`
`TREATMENT
`(ANLL)
`phase
`induction
`remission
`of
`consists
`and
`a postinduc-
`to normal
`hematopoiesis
`to return
`designed
`The
`first
`part
`remission.
`to
`prolong
`designed
`tion
`phase
`determine
`to
`was
`designed
`here
`reported
`to
`be
`the
`study
`standard
`seven
`intensity
`of
`the
`increase
`in
`an
`whether
`of
`daunorubicin
`and
`three
`days
`arabinoside
`cytosine
`days
`induction
`regimen
`used
`3”)
`remission
`(“7
`(DNR)
`B (CALGB)
`since
`Leukemia
`Group
`and
`Cancer
`197412
`cotrimoxazole
`antibacterial
`of
`administration
`the
`and/or
`an
`increase
`the
`complete
`in
`result
`would
`prophylaxis3’5
`second
`phase
`the
`study
`was
`of
`The
`rate.
`(CR)
`remission
`prolonged
`maintenance
`ther-
`whether
`to determine
`designed
`the
`postinduction
`was
`during
`apy
`of moderate
`intensity
`all
`patients
`received
`necessary.6
`Accordingly,
`chemotherapy
`for
`8 months,
`at which
`time
`domized
`discontinue
`all
`therapy
`the
`to
`continue
`monthly
`courses
`of maintenance
`therapy
`of 3 years.
`in this
`described
`The
`data
`intensity
`in the
`increase
`an
`administration
`nor
`here,
`in the
`CR
`improvement
`8 months
`beyond
`therapy
`that
`reinforce
`are
`presented
`may
`occur
`kemic
`relapse
`biologic
`processes.7’8
`
`the
`
`demonstrate
`paper
`of
`3
`therapy,
`+
`7
`cotrimoxazole
`of
`that
`maintenance
`and
`rate
`is unnecessary.
`In
`addition,
`an
`earlier
`hypothesis
`a
`result
`at
`least
`
`as
`
`of
`
`neither
`that
`described
`as
`results
`in an
`chemo-
`data
`leu-
`that
`distinct
`
`two
`
`phase
`maintenance
`ran-
`half
`were
`to
`other
`half
`a total
`
`for
`
`and
`
`induction
`Remission
`phase
`the
`induction
`for
`therapy
`to induction
`ized
`arabinoside,
`100 mg/m2/d
`and DNR,
`45 mg/m2
`on days
`
`Figure
`therapy.
`Patients
`study.
`of
`the
`the standard
`with
`by continuous
`I, 2, and
`
`1A provides
`were
`initially
`7 + 3 regimen
`infusion
`for
`3) or with
`induction
`
`the
`ofPublic
`Science
`
`Roswell
`Health
`and
`School
`MN;
`Jewish
`General
`Manhasset,
`Cotton
`May
`in
`
`From
`School
`Frontier
`Bowman-Gray
`Clinic,
`Rochester,
`NY;
`Long
`Island
`Massachusetts
`Hospital.
`and
`Norris
`Submitted
`Supported
`04326
`awarded
`tutes
`ofHealth.
`from
`a
`grant
`additional
`grant
`Address
`reprint
`of Hematologic
`Elm St. Buffalo,
`The publication
`charge
`payment.
`“advertisement”
`fact.
`indicate
`this
`& Stratton,
`© 1 987
`by Grune
`0006-4971/87/6905-0027$3.00/0
`
`Buffalo;
`Institute,
`Memorial
`Park
`Institute,
`Cancer
`Dana-Farber
`and
`Foundation,
`Technology
`Research
`of Medicine,
`Winston-Salem,
`Maimonides
`Medical
`Medical
`Center,
`Hospital,
`Boston;
`NY;
`Upstate
`Medical
`Cancer
`Center,
`Hanover,
`19,
`1986;
`accepted
`December
`part
`by
`Grants
`CA-02599,
`the
`by
`National
`Cancer
`Department
`ofHealth
`the
`T.J. Martell
`support
`information.)
`requests
`to Harvey
`Oncology,
`Roswell
`NY
`14263.
`costs
`ofthis
`This
`article
`in
`accordance
`
`Harvard
`Boston;
`Buffalo,-
`Mayo
`NC;
`Brooklyn,
`Center,
`NY;
`Park,
`Hyde
`University
`Shore
`Syracuse,
`NY,’
`
`New
`North
`Center,
`NH.
`
`1986.
`13,
`CA-33601,
`Institute,
`National
`Human
`Services
`(See
`Appendix
`
`and
`
`CA-
`Insti-
`and
`by
`for
`
`and
`Foundation.
`
`D. Preisler,
`Park
`Memorial
`
`MD,
`
`Department
`Institute,
`
`666
`
`article
`must
`with
`
`defrayed
`were
`therefore
`be
`18
`U.S.C.
`
`in part
`hereby
`§1734
`
`by page
`marked
`solely
`
`to
`
`Inc.
`
`CELGENE 2108
`APOTEX v. CELGENE
`IPR2023-00512
`
`1441
`
`MATERIALS
`
`AND
`
`METHODS
`
`Study
`
`Design
`
`CALGB
`study
`closed
`to accrual
`
`was
`7921
`in November
`
`activated
`1982.
`
`in November
`
`1979
`
`and
`
`was
`
`Eligibility
`
`patient
`Any
`to
`according
`(FAB)
`British
`life-threatening
`infections.
`study.
`
`acute
`with
`criteria
`the
`working
`infections
`Informed
`consent
`
`nonlymphocytic
`established
`was
`
`eligible
`eligible
`required
`
`was
`
`party
`were
`
`by
`
`the
`for
`only
`
`(ANLL)
`leukemia
`French-American-
`study.9
`Patients
`upon
`control
`prior
`entry
`
`with
`such
`the
`
`of
`into
`
`to
`
`Blood,
`
`Vol 69.
`
`No
`
`5 (May),
`
`1987:
`
`pp
`
`144
`
`1-1449
`
`

`

`PREISLER
`
`ET AL
`
`DAyS (cid:1)
`
`I
`
`LIV
`
`fguIII
`
`LiY(cid:1)
`
`DAYS I-?
`
`(cid:1)I
`
`(cid:1)1III
`
`R A N 0 0 N
`
`(cid:1)1IIV
`
`DAYS 1-10
`
`1
`
`III
`
`Days
`
`I
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`R A N 0 0 N z C
`
`DNR 45 MG /M2
`
`I V. Days
`
`1,2,3
`
`A- Co-Tr,moxozo$s
`Sulfamethozozole)
`
`(80 MG Tr,methoprwni’400
`P0. B (cid:1) 0
`
`MG
`
`1442
`
`I
`
`I
`
`lv
`
`I ARA-C 100 MG /M(cid:1)/0
`
`Conhnuotm
`
`IV hfusion
`
`(cid:1)%V(cid:1)16-TGIO0NG/M2
`
`PQql2h,
`
`Days 1-7
`
`...
`
`B- No Co-Tr,moxozols
`Bone Morrow
`Biopsy
`End
`of First Counie
`
`I
`
`(cid:1) (cid:1)
`
`Second Course
`
`and DapErole 7 Days After
`
`Dacontmue
`Therapy
`
`AND
`
`OBSERVE
`
`Continue
`Treatment
`Cycles
`
`Until Relapse
`
`/
`
`R A D 0 N z(cid:1)
`
`CYCLE I
`
`CYCLE 2
`
`V=
`
`I
`
`H
`
`V=I
`
`V=
`
`42
`
`14
`
`Ii
`16
`
`II
`
`V =
`
`WEEKS
`
`0
`
`2
`
`S K r(cid:1)J
`
`(cid:1)I(cid:1)(cid:1)(cid:1)(cid:1)1(cid:1)
`8
`
`10
`
`4
`
`6
`
`MONTHS
`
`I
`
`4
`
`me
`
`I
`20
`
`6
`
`22
`
`24
`
`26
`
`28
`8
`
`T E S T N C
`
`(cid:1)ARA-C
`
`OOMG/M2SC
`
`(0
`
`2H.tO)
`
`6-’rG,00MG/N2
`
`P0
`
`(R ‘
`
`‘(cid:1),
`
`I
`
`1DNR45MG/N2.
`FOR DNR DOSING
`(MAXIMUM
`500
`
`iv DAYS I S 2
`BEYOND
`CYCLE
`MG /M2)
`
`2.
`
`V VCR 2 MG IN2
`
`PRED4OMG/M(cid:1)/DAV,5
`
`I V (MAX
`
`2 MG)
`PO(MAX
`
`100MG)
`
`Cycle
`‘Each
`Each Course
`
`Consisls
`is Given
`
`ci Chemotherapy,
`4 Courses
`of
`at 2e Day Intervals
`
`1 .
`Fig
`Remission
`(A)
`(B) Maintenance
`
`Treatment
`induction
`phase.
`
`schema.
`phase.
`
`administration
`the
`by extending
`either
`increased
`of
`or by the
`addition
`I 0 + 3”)
`to ten days
`(“
`100 mg/m2
`every
`12 hours
`for
`seven
`TAD)
`at
`cytosine
`arabinoside.
`These
`two modifications
`that
`were
`based
`upon
`reports
`the
`literature
`of our
`standard
`regimen
`might
`be
`improved
`arabinoside
`administration
`to ten
`days12
`or
`
`by
`
`in
`
`was
`intensity
`whose
`of cytosine
`arabinoside
`6-thioguanine
`(6-TG;
`days
`concurrent
`with
`of
`the
`7 +
`3 regimen
`the
`therapeutic
`efficacy
`by extending
`cytosine
`the
`addition
`of 6-TG.’3”5
`A second
`in Fig
`indicated
`as
`administered,
`was
`therapy
`course
`of
`only
`The
`remission.
`failed
`to enter
`leukemia
`IA,
`if
`the
`patient’s
`and
`in
`achieved
`a partial
`remission
`exceptions
`were
`patients
`who
`was
`during
`first
`course
`of
`therapy
`the
`whom the
`severity
`of
`toxicity
`course
`2. Half
`of
`the
`patients
`felt
`to
`preclude
`administration
`to receive
`cotrimoxazole,
`two
`on
`each
`program
`were
`randomized
`regular-strength
`tablets
`(80 mg trimethoprim
`and
`400 mg sulfame-
`thoxazole),
`by mouth
`twice
`a
`day
`starting
`on
`the
`day
`before
`initiation
`chemotherapy
`and
`continuing
`until
`remission
`occurred
`or
`until
`patient
`removed
`from the
`study
`as
`treatment
`failure.
`The
`study
`in all
`three
`years
`old.
`
`the
`
`of
`
`of
`the
`
`was
`
`a
`
`amended
`was
`was
`regimens
`This
`modification
`
`1980
`in November
`reduced
`to 30 mg/m2/d
`was
`introduced
`
`as
`
`the DNR
`so that
`patients
`for
`a consequence
`
`over
`of
`
`dose
`60
`the
`
`previous
`would
`patients.2
`CR or partial
`who entered
`Patients
`induction
`therapy
`advanced
`course
`of
`patients
`were
`considered
`remaining
`were
`removed
`from the
`study.
`permitted
`were
`interruptions
`Dose
`reductions
`of 50% and/or
`or
`renal
`hepatic
`dysfunction,
`severe
`gastrointestinal
`toxicity,
`for
`prior
`to
`day
`performed
`on the
`dysfunction.
`A lumbar
`puncture
`was
`If any
`the
`initiation
`ofchemotherapy
`every
`6 months
`for 5 years.
`and
`leukemic
`cells were
`seen
`on a cytocentrifuge
`preparation,
`the patient
`received
`50 mg of cytosine
`arabinoside
`intrathecally
`four days
`until
`leukemic
`cells
`were
`no
`longer
`detectable
`in the
`and
`this
`was
`followed
`by the
`same
`dose
`of cytosine
`arabinoside
`4 weeks
`for 8 months.
`Maintenance
`therapy
`consisted
`tion
`chemotherapy.
`Sequential
`courses
`sine
`arabinoside
`tine
`(courses
`
`CALGB
`increase
`
`protocol
`the CR
`
`in ANLL
`rate
`and
`
`that
`reduce
`
`suggested
`the
`death
`
`that
`rate
`
`this
`
`change
`for
`older
`
`following
`remission
`to the maintenance
`to
`be
`treatment
`
`the second
`phase.
`The
`failures
`and
`
`dose
`
`every
`CSF,
`every
`
`therapy.
`of a series
`Each
`consisted
`together
`2 and
`4),
`
`with
`or DNR
`
`of
`
`in
`indicated
`As
`five-day
`of monthly
`cycle
`was
`composed
`five
`days
`of
`6-TG
`(course
`(course
`3)
`
`Fig
`
`I B, maintenance
`courses
`of combina-
`of
`four
`such
`courses.
`administration
`of
`cyto-
`1 ), prednisone/vincris-
`administered
`on a rotating
`
`(cid:1)
`(cid:1)
`

`

`TREATMENT
`
`OF ANLL
`
`1443
`
`a
`
`was
`
`of DNR
`500 mg/m2
`of
`dose
`cumulative
`When
`schedule.
`by replacement
`cycle was modified
`course
`of each
`the
`third
`reached,
`for
`ten times.
`orally
`every
`12 hours
`100 mg/m2
`with
`6-TG,
`of DNR
`Following
`two cycles
`of maintenance
`therapy
`(8 months),
`marrow
`aspiration
`biopsy
`were
`performed.
`Patients
`who were
`in CR
`and
`still
`at
`this
`time were
`randomized
`either
`to stop maintenance
`chemother-
`apy
`immediately
`or
`to continue
`maintenance
`for an additional
`seven
`cycles
`(for
`a
`duration
`of maintenance
`therapy
`of
`3 years)
`or
`until
`the
`time
`relapse
`occurred
`the
`seven
`cycles
`were
`completed.
`Bone marrow
`all
`patients
`
`total
`of
`
`if
`
`that
`
`before
`
`aspiration
`regardless
`
`was
`of
`
`every
`repeated
`their
`maintenance
`
`4 months
`treatment
`
`until
`
`relapse
`assign.
`
`for
`ment.
`
`Evaluation
`
`of Response
`
`previously
`criteria
`by the
`A CR was defined
`to contain
`had
`In brief,
`a bone marrow
`aspirate
`granulopoiesis,
`with
`a normal
`cellularity
`and
`normal
`and
`erythropoiesis.
`Additional
`requirements
`count
`within
`normal
`limits
`and
`blood
`symptoms
`attributable
`to leukemia.
`Relapse
`was defined
`as a return
`excess
`of 25%.
`
`of
`
`leukemic
`
`et al.’
`cells,
`
`by Rai
`reported
`<5% abnormal
`thrombopoiesis,
`a peripheral
`all
`signs
`and
`
`included
`clearing
`of
`
`cells
`
`to the marrow
`
`in
`
`Statistical
`
`Methods
`
`were
`who
`
`to
`
`this
`the
`data
`were
`to
`
`the
`
`from
`excluded
`were
`ineligible
`clearly
`who
`Patients
`prior
`but
`withdrawn
`registered
`were
`Patients
`analysis.
`follow-up
`with
`no
`patients
`and
`therapy
`of
`protocol
`initiation
`with
`prior
`cancer
`Patients
`also excluded.
`after
`registration
`were
`not
`eligible
`for
`randomization
`but were
`nonrandomly
`assigned
`treatment
`with
`7 +
`3 without
`cotrimoxizole
`and
`have
`been
`excluded
`from this
`report.
`Seven
`hundred
`forty-nine
`patients
`were
`registered
`in the
`study.
`Their
`study
`status
`is shown
`in Table
`1 . Six
`hundred
`of
`the
`697
`patients
`with
`primary
`leukemia
`were
`(95.8%)
`sixty-eight
`eligible
`evaluable.
`and
`of
`points
`The
`primary
`end
`and
`duration
`were
`response
`rates
`by
`age
`(60
`points
`were
`stratified
`regimens
`of
`the
`three
`induction
`ized
`assignment
`of cotrimoxazole,
`crobial
`agent
`were
`stratified
`For
`the maintenance
`and
`were
`time
`to relapse
`from the date
`of CR and
`tion
`(ie,
`after
`two
`cycles
`stratified
`by
`the
`induction
`maintenance
`randomization
`All
`P values
`reported
`as
`duration
`curves
`as well
`were
`calculated
`by
`using
`
`questions
`induction
`for
`interest
`these
`end
`of
`Analysis
`of survival.
`v over
`60). Comparisons
`and
`under
`stratified
`by the
`random-
`were
`also
`evaluations
`of
`this
`antimi-
`and
`the
`regimen
`assigned.
`induction
`by the
`points
`the
`primary
`end
`the
`study,
`of
`phase
`points
`were measured
`Both
`end
`survival.
`time
`of maintenance
`randomiza-
`from the
`of maintenance).
`These
`comparisons
`were
`chemotherapy
`regimen
`assigned
`the
`was
`stratified
`in that way.
`and
`are
`two
`sided.
`Survival
`any
`rates
`computed
`from these
`the
`life
`table
`method
`(product
`
`since
`
`response
`curves
`limit
`
`and Meier.’6
`(log
`used
`
`Survival
`rank)
`test)7
`for
`overall
`
`was
`
`comparisons
`The
`chi-square
`comparisons
`
`evaluable
`
`were
`
`made
`test
`for
`response
`
`of
`
`of Kaplan
`estimator)
`using
`the Mantel-Haenszel
`contingency
`tables
`rates
`across
`strata.’5
`response,”
`for
`“not
`deemed
`were
`A number
`of patients
`of marrow
`status
`documentation
`inadequate
`usually
`as
`result
`of
`comparing
`response
`of estimating
`and
`posttreatment.
`For
`purposes
`used
`rates,
`a
`conservative
`approach
`was
`with
`respect
`to
`these
`patients.
`They were
`assumed
`to have
`been
`treatment
`failures,
`ie,
`they
`were
`included
`in
`the
`denominators
`of
`the
`rates,
`but
`not
`in
`the
`numerators.
`A number
`grams
`prior
`transplantation
`sidered
`censored
`lation
`of
`the
`survival.
`study
`under
`treatments
`the
`of
`Toxicity
`criteria.2
`toxicity
`CALGB
`reported
`previously
`and
`the cotrimoxazole-treated
`between
`rates
`of
`infection
`to determine
`the
`efficacy
`of prophylactic
`used
`were
`groups
`tration
`of cotrimoxazole.
`
`a
`
`of patients
`to
`completion
`programs
`at
`the
`remission
`
`entered
`of
`while
`date
`of
`duration
`
`bone marrow
`this
`study.
`in
`their
`initial
`entry
`into
`that
`but
`continued
`
`transplantation
`Patients
`who
`remission
`program
`to be
`
`pro-
`entered
`were
`con-
`for
`calcu-
`followed
`for
`
`assessed
`was
`Specific
`
`using
`by
`comparisons
`the
`control
`adminis-
`
`RESULTS
`
`Remission
`
`Induction
`
`Therapy
`
`The Outcome
`
`ofRemission
`
`Induction
`
`Therapy
`
`of
`
`7
`
`enter
`of
`
`+
`
`CR,
`thera-
`1% were
`studies.
`were
`.6).
`of
`
`(10
`
`or
`
`entered
`patients
`eligible
`668
`the
`percent
`Fifty-six
`during
`24% expired
`remission,
`a partial
`4% achieved
`and
`remission,
`did
`not
`py,
`14% survived
`but
`marrow
`definitive
`of
`a
`lack
`inevaluable
`because
`3 regimens
`rates
`and
`10
`3, TAD,
`The
`CR
`for
`+
`(P =
`and
`57.3%,
`(Table
`2)
`respectively
`52.6%,
`56.9%,
`courses
`3 required
`two
`patients
`with
`10
`Fewer
`treated
`+
`( 1 5%
`responders)
`of
`complete
`enter
`to
`therapy
`remission
`with
`or TAD
`(28%)
`3 (29%)
`patients
`did
`than
`treated
`7 +
`.011),
`(P =
`median
`to
`remission
`was
`not
`but
`the
`time
`for
`the
`3,
`regimens
`4.8
`significantly
`different
`three
`+
`TAD,
`The
`weeks;
`7 + 3, 4.4 weeks;
`4.1 weeks).
`toxicity
`of
`identical,
`the
`three
`regimens
`was
`with
`all
`patients
`experienc-
`ing
`life-threatening
`hematopoietic
`toxicity,
`and
`7% to
`I 1% of
`patients
`experiencing
`severe
`life-threatening
`renal,
`he-
`patic,
`and/or
`cardiac
`toxicity.
`Three
`hundred
`twenty-three
`345
`receive
`cotrimoxazole,
`and
`receive
`no antimicrobial
`prophylaxis
`tion
`therapy.
`The
`rate
`was
`CR
`patient
`received
`cotrimoxazole.
`
`patients
`patients
`
`to
`to
`
`randomized
`were
`randomized
`were
`induc-
`remission
`during
`not
`the
`56%
`whether
`or
`addition,
`cotrimoxazole
`
`In
`
`1 . Study
`
`of Patients
`
`Table
`
`2. Outco mes
`
`of Remissio
`
`n Induction
`
`Therapy
`
`Table
`
`Status
`With
`
`in the Study
`Without
`
`Cotrimoxazole
`
`Cotrimoxazole
`
`7+3
`
`TAD
`
`10+3
`
`7+3
`
`TAD
`
`10+3
`
`Total
`
`Patients
`
`entered
`cancer
`Patientsrandomized
`
`Prior
`
`Ineligible
`
`Cancelled
`
`No
`
`follow-up
`
`106
`
`110
`
`119
`
`116
`
`111
`
`135
`
`1
`1
`
`2
`
`2
`1
`
`0
`
`2
`3
`
`0
`
`5
`1
`
`1
`
`2
`0
`
`0
`
`5
`1
`
`2
`
`749
`
`-(cid:1)
`
`697
`
`17
`7
`
`5
`
`Casesanalyzed
`
`102
`
`107
`
`114
`
`109
`
`109
`
`127
`
`668
`
`Numberofpatients
`CR
`Partial
`
`remissiont
`
`Noresponsealivet
`
`Expired(cid:1)
`evaluable
`Not
`
`“7+3”
`
`211
`111(53)
`13
`(6)
`
`38(18)
`
`(21)
`45
`4 (2)
`
`TAD
`
`“10+3”
`
`216
`123(57)
`6 (3)
`
`31(14)
`
`55
`
`(26)
`1 (0.5)
`
`241
`138(57)
`10
`(4)
`
`26(11)
`
`(26)
`63
`4 (2)
`
`‘Number
`
`of patients
`
`(%).
`
`tPatients
`administered.
`
`whose
`
`leukemia
`
`proved
`
`to be resistant
`
`to the
`
`chemotherapy
`
`$Death
`
`during
`
`remission
`
`induction
`
`therapy.
`
`

`

`1444
`
`PREISLER
`
`ET AL
`
`had
`with
`
`no effect
`each
`of
`
`survival
`on patient
`the
`chemotherapy
`
`or on the
`treatment
`
`toxicity
`arms.
`
`associated
`
`Prognostic
`Induction
`
`Table
`ated
`for
`induction
`significantly
`
`Factorsfor
`Therapy
`
`the
`
`3 lists
`possible
`therapy.
`related
`
`the Outcome
`
`of Remission
`
`patient
`relationship
`of
`Only
`five
`to
`treatment
`
`characteristics
`to
`the
`these
`
`evalu-
`were
`of
`remission
`outcome
`20
`characteristics
`were
`outcome,
`and
`was
`of
`
`that
`
`one
`
`significance
`borderline
`important
`factor,
`most
`old
`entering
`years
`s60
`years
`patients
`was
`serum
`tant
`factor
`with
`a creatinine
`level
`as
`compared
`56%
`
`was
`Age
`41% of
`compared
`The
`Only
`
`4).
`(Table
`only
`with
`as
`remission
`(P <
`.00001).
`old
`levels.
`creatinine
`of
`I .6 to 2.0 mg/dL
`for
`patients
`whose
`SGOT
`of
`
`An
`
`level
`
`with
`.006).
`
`was
`
`<1.6
`
`(P =
`with
`whose
`
`(cid:18)40
`
`by
`104
`
`single
`>60
`of
`
`the
`far
`patients
`with
`65%
`impor-
`most
`next
`36% of patients
`entered
`remission
`creatinine
`level
`mU/mL
`was
`59% for
`with
`count
`A WBC
`rate
`with
`a CR
`with
`a count
`or gingival
`sign,
`being
`with
`a CR
`extramedullary
`
`compared
`47%
`<40 mU/mL.
`associated
`for
`patients
`58%
`The
`presence
`ofskin
`good
`prognostic
`68% as
`compared
`without
`such
`
`of
`rate
`a CR
`level was
`SGOT
`100,0O0fi(cid:1)L
`was
`>
`with
`compared
`(P =
`.041).
`an
`unexpectedly
`a CR
`rate
`of
`for
`patients
`(P =
`.032).
`percent
`patients
`patients
`at
`
`These
`57%
`
`fever
`CR
`
`a
`
`without
`higher
`and/or
`(60%
`
`Table
`
`4.
`
`Factors
`
`of Prognostic
`
`Significance
`
`Remission
`Outcome
`Induction
`
`Remission
`
`Duration
`
`5urvival
`
`Age
`WBCcount
`Infection
`
`Skin
`
`or gingival
`
`involvement
`Creatinine
`SGOT
`Hemoglobin
`
`<.00001
`.041
`.057
`
`.032
`.006
`.018
`
`NS
`
`.023
`NS
`NS
`
`NS
`NS
`NS
`
`.001
`
`<.0001
`.013
`.008
`
`NS
`.016
`.0001
`
`.008
`
`are P values
`Results
`Abbreviation:
`NS.
`
`univariate
`using
`not
`significant.
`
`analysis.
`
`patients
`Bacterial
`infections.
`infections
`group
`
`received
`who
`infections
`Fungal
`and
`than
`
`receive
`not
`did
`or
`predominant
`the
`were
`were
`frequent
`infections
`the
`common
`in
`were
`more
`in the
`control
`group
`(29%).
`
`(50%)
`
`cotrimoxazole.
`first
`cause
`of
`of
`causes
`second
`cotrimoxazole
`
`Miscellaneous
`Remission
`
`Observations
`Induction
`Therapy
`
`Regarding
`
`the Outcome
`
`of
`
`study
`the
`after
`year
`>60
`patients
`so that
`than
`rather
`of DNR
`group
`patients
`in this
`age
`whereas
`I 39
`patients
`the CR
`rates
`were
`respectively),
`fewer
`died
`during
`therapy
`
`One
`modified
`mg/m2/d
`eleven
`dosage,
`Although
`43%
`V
`dosage
`P=
`
`.028).
`
`was
`30
`
`the
`the
`
`protocol
`the
`initiated,
`was
`receive
`age would
`years
`of
`hundred
`45 mg/m2/d.
`One
`DNR
`received
`higher
`dosage.
`received
`lower
`(39%
`significantly
`different
`not
`lower
`patients
`treated
`at
`the
`(3 1% v
`respectively,
`45%
`
`=
`
`Without
`
`Table
`
`5.
`
`Types
`
`of
`
`Induction
`
`Infections
`
`associated
`patients
`of
`at
`diagnosis
`of only
`38% as
`below
`this
`value
`involvement
`was
`associated
`with
`rate
`of
`54%
`involvement
`or
`presented
`of patients
`Forty-three
`rate
`a
`to
`have
`tended
`infection.
`had
`were
`febrile
`who
`of
`than
`the
`of diagnosis
`time
`the
`infection
`documented
`v 52.6%
`P =
`severe
`of
`The
`presence
`.07).
`respectively,
`CR
`rates
`asso-
`being
`significance,
`prognostic
`of
`was
`also
`infection
`a CR
`with
`40% as
`compared
`of
`only
`rate
`a CR
`with
`ciated
`severe
`infection
`without
`for
`patients
`of
`rate
`(P
`.057).
`57%
`on
`the
`effect
`had
`no
`cotrimoxazole
`administration
`The
`whether
`of
`patients
`on
`the
`survival
`outcome
`of
`treatment
`infected
`or not
`or
`febrile,
`infected
`or not
`were
`afebrile
`infec-
`of
`severe
`or
`life-threatening
`diagnosis.
`The
`incidence
`afebrile
`therapy
`for
`patients
`who were
`tion
`during
`induction
`adminis-
`at
`diagnosis
`was
`reduced
`from
`73% to
`59% by
`the
`(P =
`tration
`ofcotrimoxazole
`.01 3),
`but
`as noted
`earlier,
`this
`no
`had
`effect
`on
`treatment
`outcome.
`Table
`provides
`5
`information
`regarding
`the
`of
`infection
`experienced
`
`at
`
`by
`
`With
`
`Cotrimoxazole
`323)
`(n -
`
`Cotnimoxazole
`(n -
`345)
`
`Severe
`Infection
`
`Life-Threatening
`Infectiont
`
`Severe
`Infection
`
`Life-Threatening
`Infection
`
`First
`
`induction
`
`infections
`
`Bacterial
`Fungal
`
`Viral
`Multiple
`FUO
`Type
`
`not
`
`reported
`
`induction
`Second
`infection
`Bacterial
`Fungal
`Viral
`
`Multiple
`
`FUO
`Type
`
`not
`
`reported
`
`14
`6
`3
`2
`37
`54
`
`3
`9
`0
`0
`4
`19
`
`20
`11
`0
`3
`5
`25
`
`20
`14
`0
`3
`0
`5
`
`14
`5
`1
`1
`49
`66
`
`4
`6
`1
`0
`7
`23
`
`40
`9
`1
`5
`6
`13
`
`28
`7
`0
`3
`1
`12
`
`Abbreviation:
`
`LocaI
`38#{176}C.
`
`or
`
`tFulminant
`system
`failure.
`of
`(cid:1)Type
`
`FUO,
`visceral
`
`of undetermined
`fever
`infection
`with
`systemic
`
`origin.
`signs
`
`and/or
`
`a fever
`
`of
`
`local
`
`or
`
`visceral
`
`infection
`
`with
`
`sepsis,
`
`shock,
`
`or
`
`other
`
`infection
`
`documented
`
`by culture
`
`or by biopsy.
`
`of
`
`or
`
`they
`
`types
`
`Table
`
`3.
`
`Characteristics
`Patient
`for Potential
`Prognostic
`
`at Diagnosis
`Significance
`
`Evaluated
`
`Age
`
`Sex
`
`Race
`
`WBC count
`
`Infection
`CNS involvement
`
`Skin
`
`gingival
`
`involvement
`
`Hepatomegaly
`
`Splenomegaly
`
`Number
`
`of circulating
`
`Ieukemic
`
`cells
`
`Lymphadenopathy
`
`Hematocrit
`
`Hemoglobin
`
`level
`
`Platelet
`
`count
`
`Bleeding
`
`Temperature
`
`BUN
`
`Creatinine
`
`SGOT
`
`Bilirubin
`
`(cid:1)
`

`

`TREATMENT
`
`OF
`
`ANLL
`
`Remission
`
`Duration
`
`of
`two
`weeks
`remission
`patient
`
`no
`
`v
`
`45.4
`partial
`with
`
`curve
`weeks;
`52.4
`at 3 years.
`in remission
`induction
`to the
`number
`who
`required
`than
`durations
`
`for
`
`all
`22%
`There
`dura-
`arms.
`
`of
`a
`
`of
`
`those
`
`Patients
`.02).
`a median
`at
`status
`beyond
`
`who
`of 20.7
`100
`
`or
`to
`
`before
`died
`or
`stop
`patients,
`were
`duration
`The
`randomi-
`still
`to be
`also
`provides
`randomized
`diverged
`3 months
`
`to
`
`no
`
`to
`
`to
`
`The
`
`duration
`remission
`the
`2A provides
`Figure
`was
`The
`median
`CR.
`who
`entered
`patients
`to be
`in remission
`were
`projected
`of patients
`statistically
`significant
`difference
`was
`no
`three
`tion
`between
`patients
`treated
`on
`the
`The
`overall
`remission
`duration
`was
`related
`courses
`necessary
`induce
`a CR.
`Patients
`to
`single
`course
`longer
`remissions
`had
`therapy
`who
`required
`(median
`remission
`courses
`P =
`respectively,
`55.9
`entered
`status
`relapsed
`weeks,
`remaining
`in this
`weeks.
`relapsed
`patients
`forty-eight
`hundred
`One
`randomization
`second
`point
`of
`the
`reaching
`remaining
`Of
`the
`therapy.
`maintenance
`continue
`not.
`There
`73 were
`and
`randomized,
`1 5 1 were
`remission
`in
`differences
`significant
`statistically
`randomized.
`not
`were
`or were
`patients
`who
`between
`after
`patients
`duration
`of
`remission
`for
`all
`median
`was
`67 weeks,
`with
`38% of patients
`projected
`zation
`in
`remission
`3 years
`later
`(Fig
`2b).
`This
`figure
`the
`remission
`duration
`curve
`for
`patients
`continue
`or
`stop
`therapy.
`curves
`
`1445
`
`converged
`but
`randomization
`after
`after
`75 weeks
`superimposable
`after
`randomization
`time
`to
`relapse
`discontinued
`was
`therapy
`was
`weeks
`in patients
`who
`continued
`of
`remission
`induction
`therapy
`the
`effect
`on
`time
`to relapse
`or
`to continue
`maintenance
`
`became
`and
`randomization.
`patients
`for
`compared
`45 weeks
`(P =
`therapy
`.62).
`had
`no statistically
`patients
`randomized
`for
`chemotherapy.
`
`in
`
`persistently
`The
`median
`whom
`71
`with
`type
`The
`significant
`to stop
`
`Toxicity
`
`Associated
`
`With Maintenance
`
`Chemotherapy
`
`were
`data
`Toxicity
`cycle
`of maintenance
`second
`cycle.
`Seventy-five
`severe
`or worse
`hematologic
`a
`cycle
`1 with
`reduction
`count
`threatening
`levels
`(WBC
`ulocyte
`count
`to
`<500/giL,
`to
`occurring
`<25,O00/,.(cid:1)L)
`patients
`percent
`of
`who
`severe
`hematologic
`toxicity,
`ing
`reductions
`in blood
`counts
`Death
`in
`remission
`occurred
`was
`clearly
`related,
`and
`remission
`for
`patients
`<40
`years
`years
`old,
`and
`14% for
`patients
`
`available
`therapy
`
`the
`for
`patients
`for
`on
`220
`patients
`and
`patients
`experienced
`percent
`at
`some
`time
`during
`toxicity
`blood
`counts
`to
`life-
`of
`the
`to < 1,000/(cid:1)tL,
`gran-
`reduced
`platelet
`count
`and/or
`patients.
`Sixty-six
`of
`in
`51%
`2
`of
`therapy
`had
`cycle
`received
`3 1% having
`life-threaten-
`with
`to the
`levels
`just
`described.
`and
`only
`during
`cycles
`I
`with
`a
`3% death
`rate
`old,
`9% for
`patients
`41
`(P =
`>60
`years
`old
`.03).
`
`329
`for
`of
`
`first
`the
`
`2
`in
`to 60
`
`age
`
`56
`
`20C
`
`260
`
`B’#{176}
`
`.9
`.8
`
`.7
`
`.6
`.5
`.4
`.3
`
`.2
`
`)
`
`>-
`
`-J
`
`0 0
`
`.
`
`0
`
`52
`
`104
`
`56
`
`208
`
`260
`
`AIM
`
`WEEKS
`
`52
`
`04
`
`WEEKS
`
`-RESPONDERS
`
`CNSR
`106
`
`RLAPS
`266
`
`TOTAL
`372
`
`MEDIAN
`52.4
`
`-ALLPTS
`
`CENSORED RELAPSED
`57
`94
`
`TOTAL MEDIAN
`151
`670
`
`l(cid:1)l-
`
`(cid:1)l,
`
`, ,,,
`
`Dl.0 .9
`.8
`
`>-
`I-#{149}
`.6
`_J
`.5
`.4
`
`.3
`.2
`
`0(cid:1)
`
`a.
`
`cl.(cid:1)(cid:1)
`
`.4
`.3
`
`52
`
`04
`
`56
`
`208
`
`260
`
`0
`
`52
`
`04
`
`156
`
`208
`
`260
`
`WEEKS
`
`WEEKS
`
`MAINTENANCE
`STOP
`CONTINUE
`
`------
`
`-
`
`CENSORED
`29
`28
`
`RELAPSED
`48
`46
`
`TOTAL
`77
`74
`
`MEDIAN
`45.4
`70.9
`
`AGE
`
`41-60
`
`-14-40
`
`----61+
`
`CENSORED
`29
`47
`30
`
`RELAPSED
`90
`102
`74
`
`TOTAL
`119
`149
`04
`
`MEDIAN
`42.7
`68.3
`49.9
`
`2.
`Fig
`subsequent
`cessation
`
`duration.
`Remission
`to randomization
`continuation
`
`Remission
`(A)
`or continue
`to stop
`of chemotherapy
`beyond
`
`or
`
`curve
`duration
`maintenance
`8 months.
`
`all
`for
`therapy-all
`(D) Relationship
`
`whose
`patients
`patients-and
`between
`
`leukemia
`(C)
`age and
`
`entered
`relationship
`remission
`
`Remission
`(B)
`CR.
`remission
`duration
`of
`duration.
`
`duration
`to the
`
`(cid:1)
`(cid:1)
`(cid:1)
`(cid:1)
`

`

`1446
`
`PREISLER
`
`ET AL
`
`Clinical
`
`Prognostic
`
`Factorsfor
`
`Remission
`
`Duration
`
`are
`
`at
`with
`the
`
`The
`3 years.
`a characteristic
`steepest
`slope,
`therapy.
`The
`to
`relapse
`third
`component
`earlier,
`the
`the
`first
`two
`related.
`were
`provided
`data
`important
`remission
`
`curve
`The
`
`has
`survival
`first
`slope.
`death
`represents
`second
`component
`during
`the
`first
`represents
`seen
`deaths
`only
`cycles
`of mainte-
`
`late
`in
`
`2
`
`prognostically
`seen
`it can
`be
`their
`because
`of
`induction
`therapy.
`
`the
`
`important
`that
`relation-
`Figure
`
`alive
`patients
`1 8% of
`each
`three
`components,
`has
`component,
`which
`during
`induction
`remission
`subsequent
`represents
`death
`and
`the
`years
`of
`remission,
`As
`noted
`relapses
`and
`death.
`during
`remission
`occurred
`nance
`therapy
`and were
`age
`Table
`4 lists
`the
`factors
`that
`survival.
`From
`the
`for
`of
`majority
`factors
`were
`the
`ship
`to
`outcome
`of
`3B illustrates
`tion
`increases,
`becomes
`greater,
`remission
`induction
`
`only
`evaluated,
`factors
`were
`statistically
`level
`remission
`duration
`patients
`between
`remission
`durations
`longest
`and
`younger
`individuals
`and
`(medians
`of
`49.9
`Patients
`with
`a hemoglobin
`remission
`duration
`values
`<8
`had
`a median
`of
`I 2 to
`1 8 had
`values
`
`at diagnosis
`age
`significantly
`(Table
`4).
`and
`60
`41
`(median,
`significantly
`months
`value
`57.6
`of
`
`Figure
`years
`68.3
`
`and
`prog-
`2C
`age
`of
`weeks).
`shorter
`respectively,
`of 8 to
`1 2 g/dL
`weeks;
`those
`with
`5 1 weeks,
`and
`those
`a median
`of 36 weeks
`
`had
`42.7
`
`of
`
`for
`that
`
`various
`the
`Of
`hemoglobin
`initial
`factors
`nostic
`demonstrates
`had
`the
`Older
`remissions
`P =
`.026).
`had
`a median
`hemoglobin
`with
`hemoglobin
`(P=
`.002).
`
`this
`the
`
`effect.
`fall
`thus
`
`Note
`in the
`indicating
`therapy.
`
`that
`first
`
`as
`part
`increasing
`Once
`the
`
`the
`of
`
`severity
`the
`survival
`mortality
`period
`of
`
`of
`
`infec-
`curve
`during
`induction
`
`Survival
`
`Figure
`patients.
`
`the
`3A presents
`The median
`
`able
`
`survival
`duration
`
`for
`curve
`of
`survival
`
`evalu-
`668
`the
`is 41 .2 weeks;
`
`I .0
`
`.8
`
`5
`
`.4
`
`.3
`.2
`
`A(cid:1)
`
`>-
`
`5-..:
`
`4(cid:1)
`
`0(cid:1)
`
`0.
`
`SURVIVAL
`MAINTENANCE
`
`FROM
`RANDOMIZATION
`
`1.0
`.9
`
`.8
`
`.7
`6
`.5
`
`.4
`.3
`.2
`
`D
`
`-J
`
`4 a
`
`.
`
`52
`
`104
`
`156
`
`208
`
`260
`
`WEEKS
`
`ALIVE
`II?
`
`DEAD
`551
`
`TOTAL
`668
`
`MEDIAN
`41.2
`
`-ALL
`
`PTS
`
`B’#{176}
`
`.9
`.8
`.7
`.6
`
`I-
`
`-J
`
`4 0 a
`
`-
`
`Survival
`(A)
`Survival.
`3.
`Fig
`entered
`into
`for all patients
`curve
`study.
`(B) Relationship
`be-
`this
`severity
`of
`infection
`and
`tween
`mild
`infection.
`mild
`cu-
`survival:
`or
`upper
`respiratory
`taneous
`without
`fever;
`moder-
`infection
`ate
`infection.
`evidence
`infec-
`tion
`with
`temperature
`>38#{176}C;
`severe
`infection,
`local
`or visceral
`infection
`with
`systemic
`signs
`temperature
`>38#{176}C.(C)
`and/or
`Relationship
`between
`age
`and
`(D)
`survival.
`Survival
`after
`ran-
`domization-all
`patients-and
`(E)
`survival
`randomization
`by treatment
`
`after
`arm.
`
`of
`
`52
`
`104
`
`156
`
`208
`
`260
`
`WEEKS
`
`0
`
`0
`
`52
`
`104
`
`156
`
`208
`
`260
`
`-ALL
`
`PTS
`
`ALIVE
`76
`
`DEAD
`75
`
`TOTAL
`151
`
`MEDIAN
`150.7
`
`E
`
`>-5-.
`
`_J
`
`4.
`
`0’
`a..
`
`I .0
`.9
`
`.8
`
`.7
`
`.6
`
`4
`.3
`.2
`
`.1
`0
`
`SURVIVAL
`MAINTENANCE
`
`BY
`ASSIGNMENT
`
`“(cid:1)-I4lI1.4H
`
`0
`
`‘
`52
`
`‘
`104
`
`‘
`56
`
`I
`208
`
`260
`
`WEEKS
`
`WEEKS
`
`ALIVE
`82
`13
`18
`2
`
`DEAD
`348
`80
`86
`33
`
`TOTAL
`430
`93
`04
`35
`
`MEDIAN
`45.4
`33.3
`36.5
`8.6
`
`-
`
`SEVERITY
`NONE
`- MILD
`-
`-
`-
`-
`---MODERATE
`SEVERE
`
`C’0
`
`-
`
`260
`
`(cid:1)1(cid:1)4(cid:1)44.ff.
`
`N \
`
`.9
`.8
`7
`.6
`.5
`
`.2
`
`I.
`
`0
`
`52
`
`104
`
`156
`
`208
`
`WEEKS
`
`>-
`I-.:i
`4(cid:1)
`
`0 a
`
`..
`
`AGE
`AND
`
`41-60
`
`UNDER
`
`-40
`
`---61+
`
`ALIVE
`36
`56
`25
`
`DEAD
`38
`185
`228
`
`TOTAL
`174
`241
`253
`
`MEDIAN
`52.0
`62.5
`5.7
`
`MAINTENANCE
`-STOP
`
`CONTINUE
`
`ALIVE
`44
`32
`
`DEAD
`33
`42
`
`TOTAL
`77
`74
`
`MEDIAN
`UNDEF
`95.7
`
`(cid:1)
`(cid:1)
`(cid:1)
`(cid:1)
`

`

`TREATMENT
`
`OF ANLL
`
`1447
`
`curves
`the
`all
`is passed,
`death
`has
`at diagnosis
`infection
`that
`remission.
`entering
`the
`patient
`to
`prognostically
`is
`other
`hand,
`the
`remission
`duration.
`relationship
`to
`curves
`for
`patients
`with
`different
`nosis
`are
`virtually
`identical
`for
`but
`diverge
`thereafter
`(data
`not
`for
`patients
`treated
`with
`the
`three
`tion
`regimens
`were
`virtually
`identical.
`importance
`In contrast,
`age was
`of prognostic
`induction
`both
`the
`outcome
`of
`remission
`demonstrates
`3C
`to survive
`remission
`whereas
`patients
`likely
`to die
`early
`rate
`during
`the
`
`which
`parallel,
`are
`no effect
`on events
`The
`hemoglobin
`important
`because
`In this
`the
`hemoglobin
`levels
`the
`first
`of
`shown).
`survival
`different
`remission
`
`case,
`
`phase
`The
`
`on
`its
`
`indicates
`subsequent
`level,
`of
`survival
`at
`diag-
`the
`curve
`curves
`induc-
`
`with
`therapy
`that
`
`respect
`and
`patients
`induction
`over
`in therapy
`first
`year
`
`to
`
`remission
`<40
`years
`therapy
`years
`but
`
`of
`also
`
`Figure
`duration.
`old
`are more
`likely
`than
`are
`older
`patients,
`age
`are
`not
`only
`more
`have
`a higher
`death
`
`60
`
`of
`the
`
`these
`When
`remission.
`in Fig
`data
`presented
`at
`are
`a disadvantage
`higher
`death
`rate
`and
`subsequent
`have
`a higher
`is
`likely
`that
`offsets
`any
`years
`of
`age
`durations.
`Figure
`randomized
`the
`first
`is
`1 50.7
`years
`survival
`therapy.
`those
`
`considered
`are
`data
`is apparent
`2C,
`of a higher
`because
`remission
`during
`both
`relapse.
`Although
`rate
`than
`patients
`greater
`ability
`to
`advantage
`have
`had
`
`it
`
`that
`from
`
`together
`that
`older
`relapse
`induction
`younger
`patients
`40
`to 60 years
`survive
`after
`the
`patients
`their
`longer
`
`with
`patients
`rate
`and
`therapy
`also
`old,
`relapse
`to
`40
`remission
`
`a
`
`it
`
`60
`
`to
`relapse
`their
`survival
`might
`
`gives
`to stop
`32 weeks
`weeks,
`after
`curves
`There
`stopped
`
`3D
`
`survival
`the
`or
`to continue
`of maintenance.
`48%
`of
`patients
`with
`randomization.
`Figure
`for
`patients
`randomized
`appears
`to be
`a trend
`therapy,
`but
`the
`
`the
`
`of
`curve
`maintenance
`The median
`projected
`3D
`
`to
`
`patients
`after
`time
`at
`the
`
`3
`
`for
`
`151
`therapy
`survival
`be
`alive
`provides
`or
`to continue
`survival
`is . I I.
`
`also
`to stop
`greater
`P value
`
`for
`current
`
`who
`
`+
`
`3”
`in
`
`have
`mens,’3’5
`
`arabinoside
`that
`might
`
`and
`“7
`regimens
`differences
`due
`to
`dose/schedules
`observations
`confirm
`antimicrobial
`reduces
`the
`
`previous
`
`associated
`the
`latter
`treatment
`extent
`tion
`
`remission
`schedules
`from
`
`that
`efficacy
`would
`cytosine
`to
`the
`with
`that
`
`regi-
`TAD
`with
`rates
`the
`cytosine
`for
`used
`differences
`Any
`used.
`these
`TAD
`between
`appear
`to be most
`likely
`arabinoside
`and
`DNR
`addition
`6-TG.
`The
`of
`respect
`cotrimoxazole
`to
`of
`the
`administration
`patients
`granulocytopenic
`to be
`appears
`infections3’5
`and
`Perhaps
`in fungal
`infections.21’22
`with
`the
`fact
`that
`cotrimoxazole
`a modest
`infections
`only
`to
`of
`cotrimoxazole
`administra-
`
`the
`
`high
`very
`reported
`and
`doses
`the
`differ
`and DNR
`exist
`in therapeutic
`therapy
`the
`than
`rather
`here
`reported
`observations
`agent
`to
`severely
`incidence
`of
`severe
`an
`increase
`with
`together
`reason
`bacterial
`reduced
`the
`failure
`for
`accounts
`the CR
`rate.
`to improve
`duration
`of
`The median
`here
`was
`52.4 weeks,
`remission
`at
`3
`years.
`suggest
`that
`patients
`do
`therapy
`and
`who
`have
`entered
`remission
`range
`7 months.2325
`of
`those
`patients
`randomized
`therapy
`began
`to
`diverge
`randomization
`due
`to an
`patients
`in whom
`therapy
`curves
`then
`began
`to converge
`as
`a
`result
`of
`a
`significant
`patients
`whose
`therapy
`became
`superimposable
`remained
`so thereafter.
`inflection
`indicative
`a
`lower
`relapse
`earlier
`in patients
`tinued.
`Once
`the
`tinued
`administration
`Hence,
`rate
`relapse.
`that
`administration
`therapy
`for
`3 years
`years
`administration
`relapse
`thereafter
`term
`remission
`therapy.
`Patients
`months
`appear
`receive
`3 years
`advantage
`after
`The
`relatively
`chemotherapy
`consolidation
`Institute
`chemotherapy
`maintenance
`1 7 months,
`beyond
`or
`four
`maintenance
`lar
`results
`reported
`
`patients
`for
`remission
`projected
`22% of patients
`with
`presented
`contrast,
`data
`In
`remission
`receive
`similar
`who
`after
`therapy
`receive
`any
`not
`of
`remissions
`median
`duration
`duration
`curves
`The
`remission
`to continue
`maintenance
`to stop
`or
`afte