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`
`Tbalidomide for treatment of patients with chronic graft-versus-host disease
`.
`Sibel Koc We d L .
`Robert P 'w- n Y eisennng, Mary E. D. Flowers, Claudio Anasetti, H. Joachim Deeg, Richard A. Nash, Jean E. Sanders,
`1therspoon, Frederick R. Appelbaum, Rainer Storb, and Paul J. Martin
`·
`
`In a rand
`·
`omized, placebo-controlled
`d b
`'
`·
`le-bl"
`OU
`ind trial, thalidomide or placebo
`t
`Coger ther With glucocorticoids and either
`.
`ye osporin
`e or tacrolrmus was adminis-
`t
`ered as · •.
`m,t,al therapy for clinical exten-
`S •
`lVe chro ·
`me graft-versus-host disease
`(cGV
`n. HD). All patients had thrombocytope(cid:173)
`,a or cGVHO
`that evolved directly from
`a
`.
`.
`cute GVHD
`as an indicator of a poor
`Introduction
`
`prognosis. The study drug (thalidomide
`or placebo) was administered initially at a
`dose of 200 mg orally per day, followed by
`a gradual increase to 800 mg/d if side
`effects were tolerable. Treatment with the
`study drug was discontinued before reso(cid:173)
`lution of cGVHD in 23 (92%) of the 25
`patients who received thalidomide and in
`17 (65%) of the 26 patients who received
`
`placebo (P ::::; .02). Neutropenia and neuro(cid:173)
`logic symptoms were the most frequent
`reasons for early discontinuation of treat(cid:173)
`ment with thalidomide. The duration of
`treatment with thalidomide was too short
`in controlling
`to assess its efficacy
`cGVHD. (Blood. 2000;96:3995-3996)
`
`© 2000 by The American Society of Hematology
`
`,
`.
`.
`.
`.
`.
`,
`d
`Case reports h·
`c1ve escnbed the use of thalidomide for treatment of
`chro .
`1-
`I
`nic graft-vers
`us- 1ost c 1sease (cGVHD), 1-4 and preclinical
`stuct·
`.
`. .
`t d
`ies demonst
`act1V1ty m a rat model of cGVHD.5 In a
`ra e
`sub .
`sequent pfr1se II 1 · . 1 ..
`Ina! 8 (38 %) of 'JI patients with
`c 1mca
`'
`.
`hl.gh
`.
`.
`-
`.
`'
`.
`·
`-risk cGVH
`D improved after pnmary treatment with thahdo-
`lllide 6 1
`·
`·
`t d
`11 the sam
`e 8 u Y, improvement was also observed after
`.
`'
`.
`treatm
`·
`·
`ent with th 1'!
`'
`a Jc om1de m 18 (78%) of 23 patients with cGVHD
`Who 1
`•
`d d
`lad not res
`previously to other treatment. In a
`. pon e
`confirmator
`cGVHo . Y Slu~y, 16 (20%) of 80 patients with refractory
`To evaJ _showed improvement after treatment with thalidomide. 7
`Pati·e111 t" 1'.e the efficacy of thalidomide as primary treatment for
`s Wllhh" h .·
`,g -usk cGVHD, we conducted a phase III, random-
`izect tr" 1
`tion w'.~ comparin~ thalidomide versus placebo, given in combina-
`1 cyclosponne (or tacrolimus) and prednisone.
`
`4 times uaily (3 mg/kg 4 times daily for children), if sedation was tolerable.
`If sedation was intolerable, the dose of study drug was decreased by 25% to
`50%. After sedation resolved, the dose was re-escalated by 25 % to 50%
`increments as tolerated. A monthly patient sci t~assessment for symptoms of
`weakness, dysesthesias, or clumsiness was used for interim neurologic
`evaluations, and administration of the study drug was discontinued if
`neuropathy was documented at any time after starting treatment. Treatment
`with the study drug was suspended if the absolute _neutrophil count was 500
`to 1000/µL on 2 consecutive occasions or less than 500/µL on a single
`occasion , Treatment was resumed with a 50% reduction in dose when the
`absolute neutrophil count surpassed 1500/µL, and the dose was gradually
`increased as allowed by toxicity. If neutropcnia recurred, treatment with
`study drug was discontinued permanently.
`The original study design specified that the primary end point was death
`from any cause other than reclment malignancy. Enrollment of 66 patients
`in each arm was projected to have 90% power and 95% confidence for
`detecting a decrease from 35% transplant-related mortality at 2 years
`among patients treated with placebo to 10% among patients treated with
`thalidomide. An interim analysis by an independent data and safety
`monitoring committee was planned after the first 15 transplant-related
`deaths had occurred, and the study was to be terminated if the P value for
`the difference between the 2 iinns was less than .0051. Results of the
`interim analysis did not show a significant transplant-related mortality
`difference between the 2 arms. Moreover, the results indicated less than
`42% probability of reaching statistical significance for this end point if the
`study was continued to its originally planned enrollment, assuming that the
`original hypothesis was correct for the remaining patients. Because it had
`taken nearly 5 years to enroll the first 51 patients, and because there was
`little chance of a positive result, the study was closed prematurely. In the
`analysis summarized below; survival was evaluated with the use of
`Kaplan-Meier estimates, and all other time-to-event end points were
`evaluated with the use of cumulative incidence estimates to account for
`competing risk events.8 Time-to-event data were compared by log-rank
`tests, and other outcomes were compared by Mann-Whitney tests, x2 tests,
`or Fisher exact tests.
`
`study design
`.
`Fifty-t
`\Vo patients w · th 1 · ·
`1 c 11ucal extensive cGVHD consented to participate.
`Twenty-,•
`.
`d
`SIX were 'l SS.
`to receive thalidomide and 26 were assigned to
`• · igne
`I·
`receive
`from ti p acebo. One patient assigned to receive thalidomide withdrew
`.
`.
`le study befor b
`e cgmmng treatment and was excluded from further
`evnlunt·
`'IOn.
`• .
`Prednisone w· , ,
`<ts ,idm1mstered orally at a dose of 1.0 mg/kg per day for the first
`2 week 1.
`.
`.
`d
`8, oliowecl b
`Y gm ual reducuon to 0.5 mg/kg eve1y other day by week 22.
`.
`Cyclo,
`and t·l sponne was administered orally at a dose of 12 mg/k> " per day if tolerated
`•
`•
`"'
`.
`1en g-- d
`. 1d ual!y decreased after 22 weeks to 6 mg/kg per day. Alternatively,
`tacror
`. .
`.
`Ulllls Was a I • • '
`l mm1ste1ed orally at a dose of0.12 mg/kg per day, 1t tolerated
`and th
`•
`en gradually d
`ecreased after 22 weeks to 0.06 mg/kg per day.
`Th e .
`suppliecls~ucl~ d:ug (thalidomide or placebo with identical appearance) was
`40758 . Y runenthal GmbH (Stoiber", Germany), dispensed under IND
`daily for ch·t 1mstered initially at 200 mg orally once daily (3 mg/kg once
`"'
`· ·
`<1nd ncl
`Weight) TI I dren less than 12 years of age and less than 67 kg of body
`ie dose was gradually increased to reach a target dose of 200 mg
`·
`F=rorn the~D-.- . - . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`Reprints: Paul J. Martin, Fred Hutchinson Cancer Research Center, 1100
`;vision of Clinical Research, Freel Hutchinson Cancer Research
`Center S
`Fairview Ave North, D2-100, PO Box 19024, Seattle, WA 98109-1024; e-mail:
`Seattl~. :::. lie, WA, and Department of Medicine, University of Washington,
`pmartin@fhcrc.org.
`s
`The publication costs of this article were defrayed in part by page charge
`'
`Ubrnitted A
`Pnl 17, 2000; accepted August 1, 2000.
`S
`payment. Therefore, and solely to indicate this fact, this article is hereby
`H Upported by gr
`t H
`ans L36444 and CA18221 from the National Institutes of marked "advertisement" in accordance with 18 U.S.C. section 1734.
`ealth D
`Stolbe;g :artment of Hearth and Human Services, and Griinenthal GmbH,
`© 2000 by The American Society of Hematology
`' ermany.
`
`BLooD 1
`' DECEMBER 2000 • VOLUME 96, NUMBER 12
`
`3995
`
`

`

`3996
`
`KOC et al
`
`BLOOD, 1 DECEMBER 2000 • VOLUME 96, NUMBER 12
`
`Thalidomide
`
`1.00
`
`0.75
`
`>(cid:173)
`:!:
`:0
`1J 0.50
`e a..
`
`0.25
`
`6
`12
`18
`Months After Starting Study Drug
`
`24
`
`Figure 1. Duration of treatment. The lime to discontinuation of study drug was shorter
`for patients who received thalidomide than for those who received placebo. One
`patient who received lhalidomide and 5 patienls who received placebo continued
`treatment with study drug until the onset of their terminal illness. These patients were
`categorized as not having discontinued treatment with the study drug before death.
`
`thalidomide and 47% for those who received placebo (P = .35).
`The cumulative incidence of discontinuation of all immunosuppres(cid:173)
`sive medications after resolution of cGVHD is projected to reach
`39% at 4 years for patients who received thalidomide and 23% for
`those who received placebo (P = . 12). These trends support
`7 suggesting that thalidomide might have limited
`previous results6•
`efficacy for treatment of cGVHD. At 3 years after enrollment in the
`study, the product limit estimate of survival was 49% for patients
`treated with thalidomide and 47% for those who received placebo
`(P = .87). The most frequent causes of death were infection,
`cGVHD, and recurrent malignancy.
`The duration of treatment with thalidomide in our study was
`quite short. Treatment with thalidomide might promote the develop(cid:173)
`ment of tolerance, thereby explaining how such a limited interven(cid:173)
`tion might improve the longer-term prospects of resolving cGVHD
`during continued immunosuppressive treatment. Our results sug(cid:173)
`gest that a regimen of 100 mg/d might be well tolerated, especially
`if given as a single dose at night. With this regimen, it would be
`possible to determine whether administration of thalidomide for 9
`to 12 months has any benefit for patients with cGVHD.
`
`Acknowledgments
`
`We thank the physicians and nurses who cared for patients, Aurora
`Brandvold and Terese Ajer for help with data collection and data
`management, Alison Sell and Jennifer Brackensick for editorial
`assistance.
`
`Table 1. Maximum dose of study drug, according to treatment arm
`
`Percent of
`prescribed dose
`
`Thalidomide no.
`(%)
`
`25
`50
`75
`100
`
`13 (52)
`4 (16)
`1 (4)
`7 (28)
`
`Placebo no.
`(%)
`
`2 (8)
`9 (35)
`1 (4)
`14 (54)
`
`The maximum administered daily dose at any time after randomization was
`calculated as a percentage of the prescribed daily target dose. Three of the 7 patients
`who reached 100% of the prescribed target dose of thalidomide later had to reduce
`the dose because of toxicity. None of the 14 patients who reached 100% of the
`prescribed target dose of placebo had toxicity that led to reduction of the dose. The p
`value for trend was .005.
`
`Results and discussion
`
`The maximum administered dose of the study drug was signifi(cid:173)
`cantly lower for patients who received thalidomide as compared to
`those who received placebo (P = .005) (Table I). Only 4 (16%) of
`25 patients were able to tolerate thalidomide at the prescribed daily
`target dose, whereas 14 (54%) of 26 patients were able to tolerate
`placebo at the prescribed daily target dose. Thirteen patients (52%)
`in the thalidomide group and 2 (8%) in the placebo group received
`only 25% of the prescribed daily target dose. Neutropenia occurred
`in 64% of the patients treated with thalidomide and in 23% of those
`who received placebo (P = .003). Numbness occurred in 48% of
`the patients treated with thalidomide and in 23% of those who
`received placebo (P = .08). After treatment with thalidomide, 17
`patients reported sedation, and 10 had constipation. After treatment
`with placebo, 5 patients reported sedation, and 2 had constipation
`(P = .001 and .009, respectively).
`· The median duration of treatment with thalidomide was 53 days
`(range, 1-411) compared to 245 days (range, 9-654) for placebo (Figure
`1 ). Administration of study drug was discontinued before resolution of
`cGVHD in 23 (92%) of the patients assigned to receive thalidomide and
`in 17 (65%) of those assigned to receive placebo (P = .02). Treatment
`with study drug was discontinued before resolution of cGVHD because
`of neutropenia in 14 patients who received thalidomide and in 4 patients
`who received placebo (P = .002). Treatment with study drug was
`discontinued because of neurologic symptoms in 11. patients who
`received thalidomide and in 3 patients who received placebo (P = .01).
`We suspect that patients who enrolled in previously published studies6
`
`required considerable encouragement and suppo1t to sustain compliance
`with a regimen of thalidomide at doses of 200 mg or greater per clay.
`The cumulative incidence of secondary therapy for cGVHD is
`projected to reach 28% at 4 years for patients treated with
`
`-7
`
`References
`
`2.
`
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