Prednisone
`Treatment
`Prolonged
`
`Azathioprine
`and
`of Chronic
`Thrombocytopenia
`
`Compared
`Graft-v-Host
`After
`
`With
`Disease:
`Allogeneic
`
`Prednisone
`Prognostic
`Marrow
`
`Placebo
`and
`Influence
`Transplantation
`
`for
`
`of
`
`Sullivan,
`By K.M.
`K.C. Doney,
`H.M.
`
`R.P. Witherspoon,
`F.R. Appelbaum,
`Shulman,
`G.E.
`Sale,
`
`R. Storb,
`R. McGuffin,
`C. Anasetti,
`
`S. Dahlberg,
`N. Flournoy,
`P. Weiden,
`G.B. McDonald,
`J. Meyers,
`M.M.
`T.P.
`Loughran,
`S. Strom,
`J. Nims,
`
`H.J.
`Schubert,
`and
`E.D.
`
`Sanders,
`J.E.
`Deeg,
`J. Gauvreau,
`Thomas
`
`conducted
`We
`prednisone
`prine
`extensive
`with
`platelet
`apy
`with
`received
`other
`thoxazole
`1 980
`patients
`randomized
`well
`matched
`group
`III
`(n
`progressive
`therapy
`(5%).
`and
`nated
`
`day)
`
`and
`
`were
`
`comparison
`double-blind
`a randomized.
`I) v prednisone
`(group
`and
`azathio-
`placebo
`and
`treatment
`II)
`as
`early
`(1 .5 mg/kg/day)
`(group
`disease
`(GVHD).
`Patients
`chronic
`graft-v-host
`were
`placed
`into
`ther-
`counts
`<100.0O0/(cid:1)sL
`III).
`All
`three
`groups
`(group
`prednisone
`alone
`(1 mg/kg
`every
`prednisone
`of
`identical
`doses
`trimethoprim-sulfame-
`one
`and
`double-strength
`January
`daily.
`Between
`twice
`(TMP-SMX)
`tablet
`untreated
`previously
`1 79
`December
`1 983.
`Patients
`evaluable.
`1 64 were
`enrolled
`and
`63) were
`63)
`and
`group
`II
`(n -
`group
`(n =
`I
`factors;
`those
`placed
`into
`for
`prognostic
`frequent
`acute
`GVHD
`and
`38)
`had
`more
`-
`GVHD.
`Median
`duration
`of
`onset
`of
`chronic
`2
`years.
`Complications
`included
`diabetes
`was
`(5%)
`and
`infection.
`For
`groups
`I,
`necrosis
`aseptic
`respective
`incidence
`of
`infection
`was
`dissemi-
`the
`varicella.
`1 1 %.
`24%.
`bacteremia,
`6%.
`11%.
`
`of
`
`of
`
`II.
`
`to
`
`34%;
`
`Ill,
`
`1 8%.
`1 4%,
`pneumonia.
`interstitial
`and
`34%;
`did
`of death
`cause
`the most
`frequent
`was
`malignancy
`mor-
`Nonrelapse
`groups.
`significantly
`across
`the
`not
`differ
`I. 40%
`in group
`tality,
`however.
`did
`differ:
`21 % in group
`and5s%ingrouplll(l
`vlI.P=
`vlll.P=-
`Forty
`.003;l
`.001).
`patients
`in group
`in group
`II, and
`10
`in group
`Ill survive
`I, 30
`with
`a minimum
`follow-up
`of
`3.8
`years.
`Karnofsky
`perfor-
`for
`68
`survivors
`are
`90%
`to 1 00%,
`scores
`mance
`scores
`five
`seven
`survivors
`are
`70%
`89%
`and
`scores
`for
`after
`years
`survivors
`are
`<70%.
`Actuarial
`survival
`at
`5
`26%
`and
`I, 47%
`is 61 % in group
`in group
`II,
`transplant
`with
`III
`group
`(I v II. P =
`.03;
`I v III. P =
`). Treatment
`.0001
`better
`prednisone
`alone
`results
`in
`fewer
`infections
`and
`survival
`prednisone
`and
`azathioprine
`in standard-risk
`than
`chronic
`Treatment
`with
`prednisone
`alone
`is
`GVHD.
`in high-risk
`patients
`with
`thrombocytopenia.
`effective
`other
`strategies
`are
`required.
`a 1988
`by Grune
`& Stratton.
`
`5%.
`
`Recurrent
`and
`
`II,
`
`in
`
`less
`and
`
`for
`
`to
`
`Inc.
`
`after
`
`when
`times
`recent
`in more
`and
`care
`supportive
`better
`and
`benefits
`the
`Because
`grafting
`marrow
`therapy
`trial
`double-blind
`randomized,
`prednisone
`compared
`with
`placebo
`GVHD.
`of
`chronic
`treatment
`as
`a
`contraindication
`function
`< 100,000/zL)
`were
`counts
`alone. We
`the
`report
`nisone
`which
`has
`a minimum
`trial,
`transplant.
`
`and
`diagnosis
`earlier
`used.
`were
`closer
`follow-up
`cytotoxic
`long-term
`toxicities
`of
`studied
`in
`are
`unclear,
`we
`the
`use
`prednisone
`and
`of
`and
`azathioprine
`in early
`Patients
`with
`poor
`marrow
`to
`azathioprine
`(platelet
`into
`treatment
`with
`pred-
`placed
`of
`this
`controlled
`clinical
`results
`follow-up
`of
`3.8
`after
`
`therapy,
`
`a
`
`years
`
`MATERIALS
`
`AND METHODS
`
`with
`
`exten-
`179 patients
`1983,
`to December
`1980
`From January
`Seventy
`the
`study.
`entered
`chronic
`GVHD
`sive
`(multiorgan)
`placebo
`prednisone
`and
`to receive
`were
`randomized
`enrolled
`patients
`and
`receive
`prednisone
`7 1 were
`randomized
`to
`(group
`I),
`and
`azathioprine
`(group
`II). An
`additional
`38 patients
`with
`thrombocy-
`(group
`topenia
`III)
`were
`placed
`into
`treatment
`with
`prednisone
`alone. When
`interim
`analysis
`showed
`an
`increased
`mortality,4
`an
`group
`III was
`closed
`and
`treatment
`was modified
`to include
`alternat-
`ing
`cyclosporine
`and
`prednisone.
`Results
`of
`subsequent
`study
`were
`presented
`in another
`report.5
`I and
`to groups
`randomized
`patients
`Fifteen
`(1 1%) of 141 enrolled
`not
`and were
`treatment
`protocol
`II had violations
`of
`the double-blind
`after
`enroll-
`refused
`treatment
`evaluable
`for
`response.
`Five
`patients
`required.
`Five
`therapy
`was
`not
`ment
`because
`they
`considered
`that
`open-label
`azathioprine
`because
`refused
`the
`study
`drug
`and
`two took
`they
`or
`their
`physicians
`wished
`to choose
`the
`specific
`drug
`regimen.
`The
`remaining
`three
`patients
`discontinued
`treatment
`before
`com-
`pleting
`the
`9-month
`schedule.
`The
`results
`in these
`I 5 inevaluable
`patients
`were
`as
`follows.
`In group
`I, three
`refused
`therapy
`(two
`died
`and
`one
`survived
`with
`40% performance);
`one
`stopped
`treatment
`after
`3 months
`and died;
`one
`refused
`study
`drug,
`took
`prednisone
`and
`azathioprine,
`and
`died;
`and
`two
`refused
`study
`drug
`and
`took
`
`that
`
`C
`
`marrow
`
`chronic
`(cid:18)7O%.(cid:1)
`
`is a major
`(GVHD)
`disease
`HRONIC
`graft-v-host
`of
`allogeneic
`in 25% to
`45% of
`survivors
`complication
`patients
`with
`transplantation.’3
`Less
`than
`20% of
`extensive
`GVHD
`survive
`with
`Karnofsky
`untreated
`scores
`Therapy
`with
`antithymocyte
`performance
`corticosteroids
`given
`late
`in the
`course
`of disease
`or
`globulin
`in little
`benefit.2
`In a pilot
`study
`of combined
`immu-
`results
`nosuppression
`with
`cytotoxic
`agents
`and
`corticosteroids,
`compari-
`of 21
`patients
`survive
`free
`of disability.2
`However,
`to
`of
`son
`therapy
`with
`azathioprine
`prednisone
`previous
`experience
`with
`prednisone
`was
`complicated
`by
`the
`fact
`that
`patients
`given
`the
`were
`treated
`
`late
`
`I 6
`
`our
`
`and
`alone
`combination
`
`From
`
`the
`
`Fred
`
`Hutchinson
`
`Cancer
`
`Research
`
`Center
`
`and
`
`the
`
`1988.
`No. CA 18221.
`Cancer
`Insti-
`Lung
`and
`
`of
`
`Seattle.
`ofMedicine,
`School
`of Washington
`University
`29.
`accepted
`March
`1987;
`12.
`August
`Submitted
`by US Public
`Health
`Service
`Grants
`Supported
`CA 09515,
`CA
`15704
`from
`the National
`18029.
`CA
`and HL 36444from
`the National
`Institute
`ofHeart.
`tute.
`Department
`ofHealth
`and Human
`Services.
`Blood,
`the American
`Presented
`in part
`at
`the
`29th
`Annual
`Meeting
`ofHematology.
`Washington.
`DC. December
`1987.
`Society
`5-8.
`02425
`Award
`Al
`Dr Thomas
`is a recipient
`of Research
`Career
`the
`National
`Institute
`of
`Allergy
`and
`Infectious
`Diseases,
`Dr.
`Loughran
`is
`a Fellow
`of
`the
`Leukemia
`Society
`
`from
`DHHS.
`America.
`requests
`reprint
`Address
`Cancer
`Research
`chinson
`ofOncology,
`I 124 Columbia
`The publication
`costs
`of:his
`charge
`payment.
`This
`article
`“advertisement”
`in accordance
`fact.
`indicate
`this
`& Stratton.
`© 1988
`by Grune
`0006-4971/88/7202-0019$3.00/0
`
`of
`
`Fred Hut-
`Division
`
`MD.
`Sullivan.
`to Keith M.
`Center,
`Department
`ofMedicine.
`St. Seattle,
`WA 98104.
`article
`defrayed
`were
`must
`therefore
`be
`with
`18 U.S.C.
`section
`
`in part
`hereby
`1 734
`
`by page
`marked
`solely
`
`to
`
`Inc.
`
`546
`
`Blood,
`
`Vol
`
`72, No 2 (August),
`
`1988:
`
`pp 546-554
`
`

`

`PREDNISONE
`
`± AZATHIOPRINE
`
`IN CHRONIC
`
`GVHD
`
`547
`
`100% performance).
`with
`survive
`(both
`three
`refused
`study
`(both
`died);
`therapy
`and
`one
`survived
`50% performance,
`with
`with
`treatment
`and
`complied
`poorly
`one
`and
`azathioprine,
`took
`prednisone
`drug,
`treatment
`after
`6 months
`and
`survived
`
`two
`II,
`In group
`one
`died,
`(one
`drug
`100% perfor-
`with
`one
`refused
`died;
`and
`died;
`and
`one
`with
`100% perfor-
`
`prednisone
`refused
`survived
`mance);
`study
`stopped
`mance.
`Demographic
`
`data
`
`of 164 evaluable
`
`patients
`
`are
`
`listed
`
`in Table
`
`1.
`
`aplastic
`
`for
`
`with
`Patients
`cyclophosphamide,
`Patients
`with
`phosphamide
`body
`irradiation
`fractionated
`marrow
`from
`
`transplant
`prepared
`were
`anemia
`successive
`four
`each
`of
`on
`50 mg/kg
`high-dose
`hematologic
`malignancies
`received
`followed
`or
`other
`chemotherapy
`regimens
`lO-Gy
`dose
`a
`(TBI)
`given
`as
`single
`14 patients
`to
`I 7.5-Gy
`dose.7’8 All
`but
`I 2-
`14 received
`HLA-identical
`siblings;
`those
`from
`HLA-nonidentical
`donors.’
`Three
`HLA-identical
`
`with
`days.’
`cyclo-
`total
`by
`as
`or
`received
`marrow
`recipients
`
`a
`
`Table
`
`1 . Patient
`
`Characteristics
`
`at Study
`
`Entry
`
`Randomized
`
`Prednisone
`(Group
`
`+ Placebo
`
`I)
`
`Prednisone
`
`+ Azathioprine
`II)
`(Group
`
`Placed
`
`Alone
`Prednisone
`(Group III)
`
`38
`
`2 0
`
`/0
`1/3
`2/8
`1 1/1
`
`4 4 2
`
`/0
`
`6 (16)
`(58)
`22
`10(26)
`23 (3-47)
`28/10
`6 (16)
`
`5
`
`63
`
`7 4
`
`/0
`8/6
`1/3
`12/3
`
`8 7 2
`
`/2
`
`5 (8)
`44(70)
`14 (22)
`
`(1-48)
`24
`47/16
`
`4 (6)
`
`0 6 4
`
`9
`
`63
`
`9 2
`
`/0
`
`6/6
`1/10
`
`13/3
`
`4 7 2
`
`/0
`
`8(13)
`42 (66)
`13 (21)
`23 (2-43)
`44/19
`
`4 (6)
`
`Characteristic
`
`No.
`
`of evaluable
`
`patients
`
`Diagnosis
`
`Aplastic
`
`Refractory
`
`anemia
`ANL/ALL
`
`ANL/ALL
`Relapse
`Remission
`2nd+
`1st Remission
`Accelerated
`
`ANL/ALL
`ANL/ALL
`o(cid:1)’ blast
`crisis CML
`
`CML
`
`No.
`
`yr
`
`age
`
`in years
`
`MTX
`
`phase
`Chronic
`Lymphoma/other
`(%) of patients
`<10
`yr
`10-30
`yr
`>30
`(range)
`Median
`(M/F)
`Sex
`(%)
`donor
`HLA-nonidentical
`Bone marrow T-ceII
`depletion
`GVHD prophylaxis
`Acute
`None
`ShortMTX(11
`Standard
`Cyclosporine
`MTX/cyclosporine
`Grade
`of Acute GVHD
`
`d)
`(102
`(180
`
`d)
`
`d)
`( 1 1 / 1 80
`
`d)
`
`0 I
`
`I
`III
`IV
`
`Total
`
`Type
`
`grade
`of onset
`De novo
`
`(%)
`ll-lV
`of chronic
`
`GVHD
`
`(%)
`
`Quiescent
`
`Progressive
`
`Presentation
`
`of
`
`chronic
`
`GVHD
`
`(%)
`
`No.
`
`Subclinical
`
`always
`clinical
`
`-‘
`
`Subclinical
`always
`Clinical
`treatment
`(%) Entering
`transplant
`(cid:1)4 mo after
`5- 1 2 mo after
`transplant
`> 1 2 mo after
`transplant
`Median
`(range)
`values
`at entry
`to treatment
`(months
`Time
`Karnofsky
`(%)
`score
`bilirubin
`Serum
`(mg/dI)
`WBC count
`(x 1034iL)
`Platelet
`count
`(x
`103/s1)
`
`after
`
`transplant)
`
`3 (2-38)
`70(60-95)
`0.9
`(0.2-14.0)
`5.4 (1.6-19.0)
`
`170(100-442)
`
`4 (2-33)
`100)
`70 (30-
`0.7
`(0.2-39.0)
`5.4
`(2.2-20.0)
`168(100-600)
`
`0 3
`
`2 0
`
`8 6 9 1
`
`4
`
`24
`
`(63)
`
`8 (21)
`17 (45)
`13 (34)
`
`5 (13)
`9 (24)
`24 (63)
`
`33 (87)
`5 (13)
`
`0 3
`
`(3-8)
`70(30-90)
`(0. 1-14.0)
`1.0
`4.3
`(1.5-14.8)
`39 (6-80)
`
`5 3 2
`
`4
`12
`
`11
`
`16
`
`0 2
`
`7 (43)
`
`24 (38)
`27
`(43)
`12 (19)
`
`8 (13)
`17 (27)
`38 (60)
`
`34 (54)
`26
`(41)
`3 (5)
`
`0 5 4
`
`6
`
`9 3 2
`
`1 1
`
`3
`19
`10
`
`0 2
`
`9 (46)
`
`21 (33)
`31 (49)
`11
`(17)
`
`6(10)
`18 (28)
`39 (62)
`
`35 (56)
`21 (33)
`
`7(11)
`
`Abbreviations:
`
`disease;
`
`MTX,
`
`acute
`ALL,
`methotrexate.
`
`lymphoblastic
`
`leukemia;
`
`ANL,
`
`acute
`
`nonlymphoblastic
`
`leukemia;
`
`CML,
`
`chronic myelogenous
`
`leukemia;
`
`GVHD,
`
`graft-v-host
`
`

`

`548
`
`SULLIVAN
`
`ET AL
`
`received
`and
`treat-
`
`it
`
`of T lymphocytes.’#{176} All others
`purged
`given marrow
`were
`marrow.
`The
`prophylaxis,
`grading,
`unmodified
`allogeneic
`were
`reported
`ment
`ofacute
`GVHD
`as a direct
`followed
`if
`onset
`a progressive
`had
`Chronic
`GVHD
`developed
`GVHD
`chronic
`GVHD.
`Quiescent
`extension
`of
`acute
`GVHD
`de novo
`chronic
`after
`resolution
`of acute
`GVHD,
`whereas
`upon
`was
`established
`was
`not preceded
`by acute GVHD.
`Diagnosis
`data
`by
`previously
`review
`of
`clinical,
`laboratory,
`and
`histologic
`as
`published
`criteria.2”
`Subclinical
`chronic
`GVHD
`was
`defined
`oral
`histologic
`evidence
`ofchronic
`GVHD
`on both
`the blind
`skin and
`biopsies
`without
`signs
`or
`symptoms
`of
`clinical
`disease.
`Clinical
`chronic
`GVHD
`was defined
`as both
`histologic
`and
`clinical
`evidence
`of chronic
`GVHD.
`At
`study
`entry,
`all patients
`were
`in hematologic
`remission
`with
`donor
`marrow
`engraftment
`and
`had
`not
`received
`prior
`treatment
`for
`chronic
`GVHD.
`Previous
`GVHD
`prophylaxis
`was discontinued
`upon
`study
`entry.
`Institutional
`by the
`approved
`Protocols
`and
`consent
`forms
`were
`All
`Center.
`Research
`Cancer
`Review
`Board
`of
`the Fred Hutchinson
`for
`doses
`given
`in oral
`divided
`three
`groups
`received
`prednisone
`2).
`(Table
`weeks
`I and
`2 and
`thereafter
`as a single
`oral morning
`dose
`to
`addition
`Patients
`in
`groups
`I and
`II
`received
`study
`drug
`in
`of a
`prednisone.
`Study
`drug was
`assigned
`by random
`permutations
`supplied
`set of numbers
`known
`only
`to the protocol
`registrar
`and was
`as unmarked
`50-mg
`scored
`tablets
`of either
`placebo
`or azathioprine.
`Study
`drug was
`given
`as a single
`evening
`dose
`of 1.5 mg/kg/day.
`Patients
`in
`all
`three
`treatment
`groups
`received
`prophylactic
`Adults
`received
`one
`double-strength
`(160 mg TMP)
`TMP-SMX.
`and
`tablet
`twice
`daily,
`children
`received
`75 mg/m2
`TMP
`twice
`daily.
`Patients
`with
`life-threatening
`allergies
`received
`prophy-
`TMP-SMX
`penicillin
`or
`cephalexin.
`Patients
`with
`severe
`allergic
`less
`lactic
`histories
`were
`rechallenged
`with
`TMP-SMX.
`Patients
`received
`supportive
`care
`with
`artificial
`tear
`replacements,
`sun-blocking
`creams,
`oral
`caloric
`and
`protein
`supplements
`required.
`and
`as
`9 months
`of
`treatment,
`patients
`were
`reevaluated
`in Seattle
`After
`with
`physical
`examination,
`assessment
`of Karnofsky
`performance
`score,
`laboratory
`studies
`(blood
`urea
`nitrogen,
`serum
`creatinine,
`complete
`blood
`count,
`and
`liver
`function
`tests),
`pulmonary
`function
`tests,
`Schirmer’s
`test
`and
`biomicroscopy,
`nutritional
`status,
`and
`routine
`skin
`oral
`mucosa
`biopsies
`and
`other
`biopsies
`as
`and
`drug
`code
`was
`not
`broken
`and
`response
`to
`The
`The
`determined
`in
`a
`blinded
`manner.
`following
`was
`treatment
`were
`used
`to judge
`treatment
`response.
`Progressive
`disease
`criteria
`2 months
`of
`treatment
`or
`stable
`disease
`with
`persisting
`after
`Karnofsky
`scores
`<50% after
`9 months
`of
`treatment
`was
`considered
`no response.
`The
`drug
`code was
`broken
`at
`study
`failure.
`Clinically
`inactive
`chronic
`GVHD,
`but
`biopsies
`showing
`continued
`GVHD
`activity
`with
`no new organ
`involvement
`after
`9 months
`therapy
`of
`was
`considered
`partial
`response.
`Clinically
`inactive
`disease
`and
`biopsies
`showing
`no GVHD
`activity
`after
`9 months
`therapy
`was
`
`of
`
`Table
`
`2. Alterna
`
`te-Day
`
`Predn
`
`isone
`
`Regimen
`
`Prednisone
`(mg/kg/(cid:1)aIly)
`
`WeekofTherapy
`
`1
`2
`
`3
`4
`
`5
`6
`7
`8
`9-36
`
`DayA
`
`1.0
`1.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`1.5
`1.25
`1.0
`
`DayS
`
`1.0
`1.0
`
`0.5
`0.25
`
`0.12
`
`0
`0
`0
`0
`
`stopped
`treatment
`When
`response.
`complete
`considered
`disease
`histologic
`and
`but
`clinical
`response
`complete
`flare
`a
`to
`have
`was
`considered
`the
`patient
`returned,
`reinstituted
`for another
`9 months.
`Therapy
`was
`GVHD.
`a complete
`response,
`therapy
`was
`discontinued.
`with
`a partial
`response,
`treatment
`continued.
`If
`with
`symptoms
`were
`clinically
`active
`disabling
`after
`and
`treatment,
`patients
`were
`declared
`a failure.
`Results
`were
`analyzed
`as of
`June
`1, 1987.
`by the Kaplan-Meier
`method,
`and
`estimated
`(two-sided
`significance
`levels)
`were
`calculated
`and
`stratified
`log-rank
`tests.’9’(cid:1)#{176}
`
`was
`
`after
`activity
`chronic
`of
`For patients
`For
`patients
`chronic
`GVHD
`18 months
`
`a
`
`of
`
`Survival
`comparison
`using
`
`were
`rates
`statistics
`log-rank
`
`the
`
`RESULTS
`
`I
`
`in
`
`Entry
`groups
`prognostic
`(40%)
`treatment
`four
`(70%)
`diagnosis
`ment.
`chronic
`Patients
`ized
`patients
`pretreatment
`
`sL.
`
`had
`were
`
`to
`
`III
`at
`was
`and
`
`II,
`
`randomized
`treatment
`in group
`III
`
`at
`
`treat-
`did
`
`to
`and
`I, 25
`started
`Forty-
`disease
`during
`patients
`therapy.
`random-
`from
`prophylaxis,
`or
`time
`<100,000/
`group
`in
`<2,000/zL
`cellularity
`in group
`
`1 , patients
`in Table
`shown
`As
`data.
`well
`matched
`for
`II were
`and
`Twenty-four
`(38%)
`patients
`factors.
`II,
`and
`(37%)
`in
`group
`group
`14
`chronic
`was
`still
`subclinical.
`while
`GVHD
`these
`with
`subclinical
`of
`patients
`63
`developed
`chronic
`GVHD
`clinical
`Only
`in
`19
`the
`164
`evaluable
`of
`(12%)
`GVHD remain
`subclinical
`throughout
`in group
`III
`did
`not
`to differ
`appear
`in
`diagnosis,
`age,
`GVHD
`acute
`Karnofsky
`scores
`values,
`or bilirubin
`definition,
`all
`counts
`By
`platelet
`treatment.
`leukocyte
`counts
`lower
`slightly
`The
`but
`only
`two
`patients
`had
`leukocytes
`patients,
`Median
`pretreatment
`bone
`marrow
`entry.
`80% of
`normal
`in group
`I, 80% of
`normal
`50% of normal
`in group
`III.
`47 (29%)
`therapy,
`starting
`after
`Nine
`months
`Response.
`of 164 evaluable
`(16%)
`had
`or
`relapsed,
`26
`died
`had
`patients
`and
`50
`a partial
`response
`had
`(25%)
`failed
`therapy,
`and
`41
`(30%)
`had
`a complete
`to
`treatment
`(Table
`3).
`response
`Complete
`responses
`occurred
`in 21 (33%)
`patients
`ofgroup
`I,
`23
`(37%)
`ofgroup
`II,
`and
`(16%)
`ofgroup
`III.
`six
`surviving
`Among
`I I 7 patients
`Long-term
`follow-up.
`of
`therapy
`hematologic
`remission
`completed
`9 months
`who
`(Table
`3), 50 (93%)
`(89%)
`of
`of 54 patients
`in group
`I, 40
`II, and
`in group
`patients
`in group
`I 5 (83%)
`of
`1 8 patients
`returned
`one or more
`times
`to Seattle
`for
`reevaluation.
`evalu-
`Thirty
`(18%)
`of
`the
`Toxicity
`and
`infection.
`listed
`patients
`developed
`or more
`of
`the
`toxicities
`one
`3. Twenty-nine
`patients
`in group
`I, 39 (62%)
`(46%)
`(74%)
`III
`and
`28
`in group
`developed
`one
`or more
`in Table
`listed
`3. Disseminated
`varicella
`zoster,
`and interstitial
`were
`pneumonia
`more
`frequent
`randomized
`to receive
`azathioprine
`as
`compared
`recipients.
`Patients
`in
`group
`III
`had
`more
`than
`did
`patients
`in group
`I who
`received
`
`in
`
`45
`III
`
`in
`in
`
`164
`
`II,
`
`able
`Table
`group
`infections
`bacteremia,
`in patients
`with
`placebo
`
`frequent
`identical
`Among
`pneumococcus
`SMX),
`phi/us
`Twenty
`pneumoniae,
`lovirus
`
`infections
`treatment.
`of
`28
`episodes
`occurring
`(five
`six
`Staphylococcus,
`three
`and
`influenzae,
`episodes
`interstitial
`of
`four
`varicella,
`one
`Legionella,
`
`owing
`eight
`bacteremia,
`off TMP-
`patients
`when
`five
`six
`Pseudomonas,
`Hemo-
`organisms.
`other
`gram-negative
`pneumonia
`(six
`Pneumocystis
`idiopathic,
`three
`cytomega-
`and
`herpes
`simplex)
`
`were
`were
`
`to
`
`one
`
`five
`
`(CMV),
`
`(cid:1)
`(cid:1)
`

`

`PREDNISONE
`
`± AZATHIOPRINE
`
`IN CHRONIC
`
`GVHD
`
`549
`
`Table
`
`3. Results
`
`of Treatment
`
`Result
`
`Randomized
`
`Placed
`
`Prednisone
`(Group
`
`+ Placebo
`I)
`
`Prednisone
`
`+ Azathioprine
`(Group
`II)
`
`Prednisone
`(Group
`
`Alone
`Ill)
`
`No.
`
`of evaluable
`
`patients
`
`Response
`
`(%)
`
`after
`
`9-mo
`
`therapy
`
`Complete
`
`response
`
`response
`
`Partial
`Failed
`treatment
`before
`Died or Relapsed
`Median
`(range)
`Karnofsky
`
`9 mo
`score
`
`after
`
`9-mo
`
`therapy
`
`(%)
`
`responders
`Complete
`responders
`Partial
`treatment
`Failed
`of therapy
`Toxicity
`Diabetes mellitus
`necrosis
`Aseptic
`< 1 ,000/ML
`< 100.00O/(cid:1)L
`Gastrointestinal
`hemorrhage
`Severe
`osteoporosis
`Psychosis
`
`Neutrophils
`
`Platelets
`
`percentage
`
`of patients)
`
`63
`
`21
`18
`
`(33)
`(29)
`
`1 5 (24)
`9 (14)
`
`(90-100)
`100
`(80-100)
`95
`70 (30-95)
`
`3
`4
`0
`
`1
`1
`1
`1
`
`63
`
`23
`17
`
`(37)
`(27)
`
`5 (8)
`18 (29)
`
`100
`
`(80-100)
`
`(80-100)
`90
`30 (30-90)
`
`5
`3
`4
`3
`
`2
`0
`0
`
`38
`
`6 (16)
`
`6 (16)
`
`6 (16)
`20 (52)
`
`100
`
`(90-100)
`
`100)
`(80-
`90
`70 (50-90)
`
`1
`
`1
`
`2
`
`-
`
`2
`1
`0
`
`(no.
`
`of patients,
`
`(total)
`
`of
`
`Episodes
`Varicella
`Localized
`
`infection
`zoster
`
`Disseminated
`
`Bacteremia
`Interstitial
`Noninterstitial
`
`pneumonia
`pneumonia
`
`18
`
`(18,
`
`29%)
`
`1 1 (1 1.
`
`17%)
`
`7(7.
`
`11%)
`
`6%)
`4 (4,
`3 (3. 5%)
`13 (10,
`
`16%)
`
`25
`
`(25.
`
`40%)
`
`10(10,
`
`16%)
`
`15(15,24%)
`
`1 1%)
`7 (7.
`14%)
`9 (9.
`14 (10,
`16%)
`
`17
`
`(15,
`
`39%)
`
`2 (2.
`
`5%)
`
`15(13,34%)
`
`34%)
`(13,
`17
`8 (7,
`18%)
`17 (13,
`34%)
`
`of Pneumocystis
`six episodes
`All
`observed.
`were
`or
`not
`given
`patients
`either
`31
`developed
`in
`of
`noninterstitial
`episodes
`TMP-SMX.
`Forty-four
`owing
`unknown
`organisms
`21
`to
`nia
`developed,
`( 1 1 ),
`owing
`remainder
`to
`Pneumococcus
`fungus
`(four),
`(four),
`gram-negative
`influenzae
`staphylococcus
`(two).
`and
`(two)
`9 months
`first
`in the
`given
`was
`Prednisone
`dosage.
`Drug
`remaining
`the
`patients;
`(86%)
`dose
`to
`141
`schedule
`full
`in
`toxicities
`to the
`owing
`had
`modifications
`dose
`some
`patients
`dose
`prednisone
`in
`in Table
`3. Permanent
`reduction
`listed
`99%,
`to
`75% to
`three
`observed
`in eight
`(5%)
`patients:
`was
`dose.
`two
`to
`to 74%,
`and
`to 25% to 40% protocol
`three
`(6%)
`in
`Azathioprine
`was
`given
`reduced
`dose
`in
`four
`patients:
`to 75% to 99% and
`two
`to 50% to 74% protocol
`dose.
`TMP-SMX
`was
`not
`given
`or was
`discon-
`tinued
`effects
`in nine
`(14%)
`patients
`in group
`to side
`nine
`II,
`and
`I 3 (34%)
`in group
`Twelve
`III.
`in group
`received
`no
`additional
`antibiotics.
`patients
`these
`remaining
`19 received
`cephalexin
`(nine),
`penicillin
`ampicillin
`(two).
`or
`
`pneumoniae
`discontinuing
`pneumo-
`and
`Hemophilus
`organisms
`
`the
`
`I,
`of
`The
`(eight),
`
`50%
`
`two
`Prophylactic
`owing
`( 14%)
`3 1
`
`Clinical
`patients
`hepatic
`(16%),
`(6%),
`frequent
`included
`globulinemia
`production
`
`manifestations.
`with
`clinical
`(73%),
`oral
`myofascial
`and
`serosal
`in patients
`rheumatoid
`(IgG
`(8%).
`
`of
`
`disease
`were
`
`145
`in
`noted
`Sites
`(79%),
`dermal
`GVHD
`chronic
`intestinal
`(47%),
`ophthalmic
`(72%),
`esophageal
`(1 1%),
`pulmonary
`(11%),
`was more
`GVHD
`(2%).
`Intestinal
`chronic
`abnormalities
`in group
`Laboratory
`III.
`hypogamma-
`factor
`reactivity
`(16%),
`autoantibody
`650
`mg/dL,
`15%)
`and
`<
`Scleroderma
`with
`joint
`contractures
`devel-
`
`in
`
`1 1 (8%)
`GVHD.
`
`of
`
`145
`
`evaluable
`
`patients
`
`with
`
`clinical
`
`I,
`
`III
`
`in
`died
`cause
`
`the
`
`and
`
`=
`
`I,
`
`to
`
`oped
`chronic
`33
`group
`patients
`(37%)
`Twenty-three
`Mortality.
`4).
`(Table
`in group
`(74%)
`II,
`and
`28
`(52%)
`in group
`of death.
`the most
`common
`Recurrent
`malignancy
`was
`were
`26%
`recurrent
`malignancy
`Kaplan-Meier
`estimates
`of
`III
`(I
`II,
`and
`39% in
`group
`in group
`I, 33% in group
`II,
`v
`P = .95;
`P = .23).
`common
`Infection
`was
`the most
`I v III,
`The
`remaining
`deaths
`were
`cause
`of
`nonrelapse
`mortality.
`without
`infection,
`hemorrhage,
`owing
`to progressive
`GVHD
`with
`a
`long
`pretransplant
`or
`organ
`failure.
`One
`patient
`of paranoia
`refused
`psychiatric
`therapy
`and
`commit-
`history
`ted
`suicide.
`1 shows
`nonrelapse
`from
`of death
`probability
`Figure
`By
`causes.
`actuarial
`in
`group
`21% of
`patients
`estimate,
`40% in group
`II,
`in group
`III
`died
`of nonmalignant
`58%
`(P = .0001).
`Among
`causes
`randomized
`patients,
`nonrelapse
`mortality
`was
`significantly
`increased
`azathioprine
`recip-
`in
`(P = .003).
`ients
`When
`I was
`compared
`to group
`III,
`group
`the
`increase
`in nonrelapse
`mortality
`in patients
`with
`throm-
`bocytopenia
`was
`significant
`(P
`.0001).
`appear
`not
`Mortality
`did
`Prognostic
`factors.
`to
`gender,
`acute
`GVHD
`time
`prophylaxis,
`or
`from
`Table
`5 lists
`factors
`in relation
`to mortality
`(P = .02),
`through
`Age
`>20
`years
`prior
`grade
`II
`(P = .03),
`of
`chronic
`the
`progressive
`onset
`GVHD
`(P = .0001),
`and
`failure
`to respond
`to 9 months
`of
`(P = .04)
`were
`associated
`with
`increased
`mortality
`rank
`analyses
`stratified
`treatment
`group.
`Actuarial
`mortality
`19
`patients
`
`related
`study
`entry.
`all
`causes.
`IV acute
`GVHD
`treatment
`in
`
`log-
`
`by
`in
`
`in
`
`whom
`
`chronic
`
`

`

`550
`
`Table
`
`4. Causes
`
`of Death
`
`Randomized
`
`Cause
`
`Prednisone
`(n-63)
`
`+
`
`Placebo
`
`Prednisone
`
`+ Azathioprine
`(n-63)
`
`Bacterial
`
`infection
`
`Interstitial
`
`pneumonia
`
`zoster
`Varicella
`Cytomegalovirus
`Idiopathic
`Pneumocystis
`
`Other
`Infection
`infection
`Fungal
`Progressive
`GVHD
`Respiratory
`failure
`
`without
`without
`
`infection
`IP
`
`Heart
`Varicella
`
`failure
`zoster
`
`without
`
`IP
`
`Hemorrhage
`Myasthenia
`Suicide
`Recurrent
`Total
`
`gravis
`
`malignancy
`
`2
`
`1
`0
`0
`0
`
`1
`1
`1
`1
`0
`1
`0
`0
`1
`14
`23
`
`1 0
`
`1
`0
`2
`1
`
`1
`3
`1
`1
`1
`1
`1
`0
`0
`10
`33
`
`SULLIVAN
`
`ET AL
`
`Placed
`
`Prednisone Alone
`(n-38)
`
`6
`
`2
`2
`0
`0
`
`0
`3
`1
`1
`1
`0
`1
`1
`0
`10
`28
`
`Abbreviations:
`
`GVHD,
`
`graft-versus-host
`
`disease;
`
`IP,
`
`interstitial
`
`(nonbacterial,
`
`nonfungal)
`
`pneumonia.
`
`100
`
`80
`
`0
`/0 40
`
`2:
`
`p<00001
`
`Th,’ornbocylopenio,
`
`p/OCed:
`
`-1(cid:1)(cid:1)
`
`P’ednisone(n-38)
`Prednisone
`
`#Azothioprine(n(cid:1)63)
`
`GVHD
`
`remained
`
`subclinical
`
`throughout
`
`therapy
`
`was
`
`58% as
`
`compared
`, clinical
`
`clinical
`with
`sustained
`
`50% mortality
`with
`patients
`in 46
`chronic
`GVHD
`and
`52% mortality
`GVHD at
`diagnosis.
`chronic
`GVHD
`had
`
`chronic
`subclinical
`
`subclinical
`with
`in 99
`patients
`
`with
`Patients
`higher mortality
`
`Randomized:
`‘P,edn,sone#P/oceboj’n:63)
`
`owing
`shows
`
`increased
`to an
`the
`probabilityofrelapse
`
`rate
`
`of
`
`relapse
`in
`146
`
`leukemia.
`of
`patients
`
`with
`
`Figure
`hemato-
`
`2
`
`0
`
`1
`
`2
`
`4
`
`7
`6
`Transplant
`
`8
`
`9
`
`10
`
`11
`
`of
`
`3
`Years
`
`5
`after
`
`Fig 1 .
`of death
`
`Kaplan-Meier
`from nonrelapse
`
`estimates
`limit
`product
`(ie.
`transplant-related)
`
`the probability
`of
`causes.
`
`relation
`in
`malignancies
`logic
`statistical
`Three-way
`GVHD.
`malignancy
`was significantly
`chronic
`GVHD
`remained
`.0003).
`(P
`
`to
`analysis
`increased
`subclinical
`
`=
`
`course
`the
`that
`showed
`in patients
`throughout
`
`chronic
`relapse
`in whom
`observation
`
`of
`
`Factor
`
`GVHD
`
`age
`
`yr
`acute
`
`Patient
`(cid:1)20yr
`>20
`Grade
`0
`
`I
`
`II
`
`Ill
`
`IV
`Type
`
`of chronic
`
`GVHD
`
`onset
`
`Denovo
`Quiescent
`Progressive
`Presentation
`Subclinical
`
`of chronic
`always
`
`GVHD
`
`clinical
`
`Subclinical
`-.
`always
`Clinical
`9-mo
`after
`Response
`response
`Complete
`Partialresponse
`Failed treatment
`Died or relapsed
`
`therapy
`
`before
`
`9 mo
`
`Table
`
`5. Mortality
`
`Risk
`
`Factors
`
`No. of Dead/No.
`
`of Evaluable Patients
`
`Groupl
`(n-63)
`
`8/31
`15/32
`
`6/21
`
`5/13
`
`6/19
`
`6/10
`
`0/0
`
`6/21
`12/31
`5/11
`
`3/6
`
`7/ 1 8
`13/39
`
`2/21
`5/18
`7/1 5
`9
`
`Groupll
`(n-63)
`
`6/17
`27/46
`
`10/24
`
`7/12
`
`6/11
`
`10/16
`
`0/0
`
`10/24
`14/27
`9/12
`
`4/8
`
`1 7
`6/
`23/38
`
`7/23
`4/17
`4/5
`1 8
`
`Grouplll
`(n-38)
`
`11/17
`17/21
`
`4/8
`
`4/6
`
`8/9
`
`11/14
`
`1/1
`
`4/8
`12/17
`12/13
`
`4/5
`
`7/9
`17/24
`
`1/6
`4/6
`3/6
`20
`
`Total(%)
`(n-
`164)
`
`25/65
`59/99
`
`(38)
`(60)
`
`20/53
`
`(38)
`
`16/31
`
`(52)
`
`20/39
`
`(51)
`
`27/40(68)
`
`1/1
`
`(100)
`
`20/53
`38/75
`26/36
`
`(38)
`(51)
`(72)
`
`1 1/1
`
`9 (58)
`
`20/44
`53/101
`
`(45)
`(52)
`
`(20)
`(31)
`(54)
`
`10/50
`13/41
`14/26
`47
`
`(cid:1)
`(cid:1)
`

`

`PREDNISONE
`
`± AZATHIOPRINE
`
`IN CHRONIC
`
`GVHD
`
`551
`
`0J
`‘0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`C
`
`p(O.0003
`
`CIWOyS
`
`(n(cid:1)/9)
`
`(C//fl/CO/
`
`0/wayS
`
`(n(cid:1)85)
`
`Years
`
`after
`
`Transplant
`
`100
`
`80
`
`60
`
`40
`
`20
`
`C
`
`0
`
`p<o.oo1
`
`1
`
`2
`
`Rondomized
`Prednisone
`
`# Placebo
`
`(n(cid:1)63)
`
`Randomized
`
`Prednisone
`
`#Aza/fliopnne
`
`(n:63)
`
`rh(ombocy/openio,
`Prednisone
`(n(cid:1)38)
`
`placed
`
`4
`
`3
`Years
`
`5
`after
`
`7
`6
`Transplant
`
`8
`
`9
`
`10
`
`11
`
`of
`estimates
`limit
`product
`Kaplan-Meier
`Fig 2.
`of
`with
`subclinical
`in 1 9 patients
`of malignancy
`relapse
`cal chronic
`subclinical
`GVHD.
`42 patients
`with
`clinical
`chronic
`GVHD.
`Eighteen
`GVHD.
`and 85 patients
`with
`clinical
`evaluable
`patients
`(16 with
`clinical
`and
`2 with
`subclinical
`164
`transplants
`for
`nonmalignant
`clinical
`chronic
`GVHD)
`receiving
`disorders
`were
`excluded
`from this
`analysis.
`
`the
`
`-‘
`
`probability
`subclini-
`chronic
`of
`the
`
`-‘
`
`Status
`
`(48%)
`
`and
`
`I, 30
`in group
`patients
`(63%)
`patients
`in group
`(26%)
`10
`is 45 months
`after
`follow-up
`complete
`response
`with
`(5%)
`in group
`III
`two
`of 2 months
`(range
`one
`and
`were
`retreated.
`liver
`(four),
`mouth
`(ten),
`Currently,
`65
`(81%)
`and
`are
`chronic
`of
`scores
`80 surviv-
`
`in
`had
`to
`
`of
`
`free
`the
`
`of
`
`Forty
`ofsurvivors.
`II,
`patients
`in group
`survive
`(Table
`6). Minimum
`III
`transplant.
`Nine
`(14%)
`patients
`and
`(10%)
`in group
`II,
`group
`I, six
`flares
`of
`chronic
`GVHD
`a median
`after
`1 1 months)
`stopping
`therapy
`of
`flare
`Primary
`sites
`included
`skin
`(one),
`eye
`(one),
`and muscle
`(one).
`the
`survivors
`continue
`off
`treatment
`GVHD.
`The
`Karnofsky
`performance
`ing
`patients
`are
`shown
`in Table
`6.
`Figure
`3 shows
`the
`actuarial
`survival.
`were
`61% in group
`I, 47% in group
`II,
`(P = .001
`). When
`randomized
`patients
`compared,
`survival
`was
`reduced
`(P = .03).
`When
`groups
`I
`was
`impaired
`in
`patients
`.0001).
`
`were
`ients
`survival
`(P=
`
`and
`
`III
`II
`
`estimates
`Survival
`26% in group
`groups
`I and
`in
`in azathioprine
`recip-
`III
`were
`compared,
`thrombocytopenia
`
`and
`with
`
`DISCUSSION
`
`estimates
`limit
`product
`Kaplan-Meier
`Fig 3.
`patients
`evaluable
`among
`survival
`patients
`evaluable
`+ placebo).
`in
`and 38 patients
`in group
`+ azathioprine),
`represent
`40 group
`I, 30 group
`II, and
`as of June
`1 #{149}1 987.
`Minimum
`follow-up
`
`63
`
`63
`
`of
`sone
`sone
`marks
`surviving
`transplant.
`
`at
`
`the
`
`and
`
`in
`
`probability
`the
`of
`I
`(predni-
`group
`(predni-
`II
`group
`Tic
`Ill
`(prednisone).
`10 group
`Ill patients
`is 3.8
`years
`after
`
`long-
`We
`
`only
`With
`
`increasing
`assumes
`center
`investigators
`and
`cian
`of marrow
`transplantation
`use
`as
`the
`success
`importance
`is vital
`in
`conducting
`This
`collaboration
`increases.2’
`such
`as we
`describe.
`trials
`term,
`double-blind
`clinical
`education
`and
`responsiveness,
`found
`that
`with
`appropriate
`only
`was
`enthusiastic
`and
`and
`patient
`compliance
`physician
`not
`in
`the
`study
`were
`15
`(8%)
`of
`179
`patients
`enrolled
`recip-
`evaluable.
`Moreover,
`although
`80% of our
`transplant
`of
`I I 7
`ients
`reside
`outside
`Pacific
`Northwest,
`I 05
`(90%)
`the
`patients
`completing
`9 months
`of protocol
`therapy
`returned
`to
`Seattle
`for
`long-term
`follow-up
`evaluation.
`With
`joint
`and
`early
`treatment,
`runting,
`scleroderma,
`most
`Indeed,
`contractures
`now uncommon
`developments.
`are
`(6%)
`of
`five
`have
`patients
`normal
`Karnofsky
`scores,
`and
`improved
`80
`survivors
`function
`at <70%
`performance.
`chronic
`of
`disability-free
`survival,
`new
`manifestations
`and myasthenia
`such
`as obliterative
`bronchiolitis2225
`with
`minimum
`may
`be
`observed.
`Nevertheless,
`of
`survivors
`80
`of
`3.8
`years
`and
`with
`65
`(81%)
`appears
`suffi-
`all
`treatment,
`the
`present
`study
`off
`mature
`to detect
`causes
`of disability.28
`most
`allowed
`double-blind,
`placebo-controlled
`design
`of
`the
`of
`azathioprine
`in early
`treatment
`GVHD.
`clinical2
`and
`experimental29
`studies
`
`role
`Prior
`
`of
`
`The
`on events
`plant
`center.
`
`graft
`the marrow
`well-being
`the
`long
`after
`developing
`Collaboration
`between
`
`of
`
`recipient
`patient
`leaves
`the
`primary
`
`may
`the
`care
`
`depend
`trans-
`physi-
`
`GVHD,
`gravis,26’27
`follow-up
`currently
`ciently
`The
`assessment
`chronic
`
`Placed
`
`Alone
`Prednisone
`(n - 38)
`
`10
`
`(45-89)
`66
`6 1 (42-85)
`
`24 (9-57)
`1 (10)
`
`10
`
`9
`(2-64)
`
`33
`
`8 0
`
`2 (20%)
`
`5tatus
`
`of surviving
`No.
`Median
`(range)
`Months
`after
`
`patients
`follow-up
`transplant
`
`Months
`
`after
`
`study
`
`entry
`
`Treatment
`
`characteristics
`
`Median
`(range)
`No. of patients
`No.
`of patients
`
`duration
`of
`therapy
`still on therapy
`(%)
`stopping
`therapy
`
`(mo)
`
`No.
`
`of patients
`
`still
`
`off
`
`Median
`
`(range)
`
`duration
`
`therapy
`off
`
`therapy
`
`(mo)
`
`Current
`
`Karnofsky
`
`score
`
`100%-90%
`
`89%-70%
`
`<70%
`
`Table
`
`6.
`
`Status
`
`of Survivi
`
`ng Patients
`
`Randomized
`
`Prednisone
`(n -
`
`+ Placebo
`63)
`
`Prednisone
`
`+ Azathioprine
`(n - 63)
`
`40
`
`68
`
`(48-125)
`
`63
`
`(42-88)
`
`24 (9-72)
`8 (20)
`35
`
`32
`(3-78)
`
`48
`
`34
`
`4
`
`2 (5%)
`
`30
`
`72
`
`64
`
`(51-95)
`
`(44-90)
`
`22 (9-90)
`6 (20)
`28
`
`24
`(2 1 -74)
`
`46
`
`26
`
`3
`1 (3%)
`
`(cid:1)
`

`

`552
`
`SULLIVAN
`
`ET AL
`
`suggested
`current
`and with
`uncontrolled
`toxic
`therapy
`ly, with
`early
`in
`recipients
`thioprine.
`
`was
`
`The
`GVHD.
`against
`activity
`has
`azathioprine
`that
`of chronic
`GVHD,
`study
`randomized
`is the
`first
`trial
`its design
`to
`immunodeficiency
`owing
`effect
`of
`the
`and
`immunodeficiency
`to
`cyto-
`owing
`GVHD
`analyzed.
`be dissociated
`and
`Surprising-
`could
`was
`the
`control
`ofGVHD
`equivalent
`treatment
`and
`prednisone
`plus
`aza-
`alone
`of
`prednisone
`bacterial
`infections
`were more
`and
`However,
`viral
`treatment.
`The
`nonrelapse
`mor-
`with
`combination
`frequent
`in
`increased
`standard-risk
`patients
`significantly
`tality
`(21%
`azathioprine
`in group
`I v 40% in
`additional
`receiving
`appeared
`pneumonia
`to be
`increased30
`Interstitial
`II).
`group
`but
`significant
`and
`myelosuppression
`abnormalities3’
`hepatic
`were not more
`in azathioprine
`recipients.
`common
`The study
`contribu-
`the
`allowed
`assessment
`of
`also
`design
`malignancy
`in preventing
`recurrent
`of cytotoxic
`therapy
`tion
`significantly
`did
`relapse
`rates
`not
`differ
`transplant.
`The
`after
`in placebo
`and
`azathioprine
`recipients.
`previous
`studies,
`In
`the
`contribution
`of chronic
`GVHD
`to an
`antileukemic
`effect
`had
`been
`less
`clear
`since
`patients
`with
`more
`severe
`chronic
`were
`usually
`treated
`with
`azathioprine.32’33
`The
`pres-
`fails
`to show
`an
`antileukemic
`effect
`of azathioprine
`
`GVHD
`ent
`
`study
`
`treated
`untreated
`otics)
`
`infection.(cid:1)’
`prevent
`to test
`ress
`this
`treatment
`of
`the
`Because
`of
`prompt
`treatment
`warranted.47
`Prognostic
`
`without
`prednisone
`with
`TMP-SMX
`no immunosuppression
`patients
`(ie,
`treated
`with
`prednisone
`v 8% in
`patients
`(P = .001).”
`Because
`patients
`with
`SMX
`immunoglobulin
`demonstrate
`impaired
`resembling
`that
`pattern
`infection
`of
`primary
`immunodeficiencies,
`long-term
`globulin
`intravenous
`(IV)
`immune
`may
`Controlled
`studies
`hypothesis.
`Finally,
`varicella
`zoster
`can
`seriousness
`varicella
`of
`with
`acyclovir
`
`and
`
`v
`
`no
`and
`
`I 5%
`antibi-
`TMP-
`GVHD
`and
`with
`
`in
`
`a
`
`the
`of
`to
`
`chronic
`regulation
`associated
`administration
`be another
`method
`are
`currently
`in prog-
`prompt
`recognition
`and
`also
`lower
`mortality.
`in
`these
`patients,
`appears
`be
`fully
`
`IV
`
`to
`
`age,
`failure
`
`acute
`
`to
`The
`
`cvi-
`of
`
`or
`
`could
`vitro
`
`patient
`included
`study
`in this
`factors
`GVHD,
`chronic
`of
`onset
`progressive
`GVHD,
`respond
`thrombocytopenia.
`and
`of
`therapy,
`to 9 months
`for
`reason
`patients
`with
`thrombocyto-
`in
`mortality
`increased
`penia
`is poorly
`Pretreatment
`thrombocytope-
`understood”
`impaired
`marrow
`function,
`as
`with
`nia was
`associated
`megakaryocyte
`cellularity
`50%
`of
`denced
`by
`a median
`to 80% median
`megakaryocyte
`cellularity
`normal
`(compared
`in
`patients
`normal
`platelet
`counts).
`Viral-induced
`with
`suppression
`of megakaryocytopoiesis
`cell-mediated49
`persisting
`thrombocytopenia.
`account
`for
`in
`Recent
`immune-mediated
`defects
`in
`hematopoietic
`studies
`suggest
`function
`in patients
`progenitor
`cell
`with
`chronic
`GVHD.5#{176}
`The
`use of cyclosporine
`in this
`setting
`of
`thrombocytopenia
`and
`appears
`to be of value
`is
`the
`subject
`of another
`report.5
`with
`in
`We
`conclude
`that
`patients
`with
`chronic
`GVHD
`normal
`marrow
`function,
`prednisone
`led
`to
`fewer
`infections
`and
`better
`survival
`than
`therapy
`prednisone
`and
`aza-
`thioprine.
`Early
`treatment
`abated
`disabling
`natural
`history
`clinical
`extensive
`chronic
`Patients
`with
`not
`benefit
`due
`to
`an
`subclinical
`GVHD
`did
`increased
`leukemia.
`thrombocy-
`rate
`of
`recurrent
`topenia
`identified
`a group
`of
`patients
`response
`and
`frequent,
`often
`fatal,
`Improved
`prednisone
`supportive
`care
`and
`treatment
`are
`high-risk
`chronic
`patients
`who
`poor
`function
`who fail
`therapy.
`
`with
`
`the
`
`GVHD.
`therapy
`from
`Persisting
`with
`poor
`infection.
`needed
`marrow
`
`for
`
`have
`
`to
`
`or
`
`of
`
`GVHD
`initial
`
`and
`with
`
`ACKNOWLEDGMENT
`
`of
`
`the
`for management
`physicians
`to referring
`indebted
`are
`We
`and
`physicians,
`nurses,
`outpatient
`inpatient
`and
`as well
`as
`patients
`and
`Research
`Center
`Fred Hutchinson
`Cancer
`staff
`of
`the
`support
`of
`Medical
`Center.
`We
`appreciate
`support
`the
`Hospital
`Swedish
`Park,
`Burroughs
`Wellcome,
`Research
`Triangle
`Pelkey
`and
`Jack
`for
`their
`support
`and
`supply
`of
`the
`study
`drug. We
`especially
`NC,
`Deborah
`Gayle
`and Marianne
`Hansen
`for superb
`assistance
`thank
`long-term
`follow-up.