Dlin.web.unc.edu

Cyclosporine or Cyclosporine Plus Methylprednisolone for Prophylaxis of
Graft-Versus-Host Disease: A Prospective, Randomized Trial
By H. Joachim Deeg, Danyu Lin, Wendy Leisenring, Michael Boeckh, Claudio Anasetti, Frederick R. Appelbaum, Thomas R. Chauncey, Kristine Doney, Mary Flowers, Paul Martin, Richard Nash, Gary Schoch, Keith M. Sullivan, Patients with a lymphohematopoietic malignancy consid-
difference was seen for grades III-IV GVHD. However, chronic
ered to be at high risk for posttransplant relapse were en-
GVHD occurred somewhat more frequently in patients re-
rolled in a study to compare the use of cyclosporine (CSP)
ceiving CSP plus MP (44%) than in patients receiving only
as a single agent with a combination of methylprednisolone
CSP (21%; P ! .02). The incidence of de novo chronic GVHD
(MP) and CSP for graft-versus-host disease (GVHD) prophy-
was marginally higher in patients receiving CSP plus MP (P
!
laxis after marrow transplantation from an HLA-identical sib-
.08). No significant differences in the risk of infections
ling donor. Sixty patients were randomized to receive CSP
were observed. There was a suggestion that the risk of re-
only and 62 were randomized to receive CSP plus MP. Daily
lapse was lower in patients receiving CSP plus MP (P ! .10)
CSP was started on day Ï1 (5 mg/kg/d intravenously) and
and, although the overall survival in the two groups was not
administered at gradually reduced doses until day 180. MP
different (P ! .44), there was a slight advantage in favor of
was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/
CSP plus MP-treated patients for relapse-free survival (P !
kg/d on day 15, started on a taper schedule on day 29, and
.07). These results suggest that prophylactic MP, when com-
discontinued on day 72. All 104 evaluable patients (surviving
bined with CSP, has only limited efficacy in acute GVHD
ı28 days) had sustained engraftment. The incidence rates
prevention and may increase the probability of chronic
of grades II-IV acute GVHD were 73% and 60% for patients
receiving CSP and CSP plus MP, respectively (P ! .01). No
᭧ 1997 by The American Society of Hematology.
CYCLOSPORINE (CSP) HAS been used clinically for infection,10 although this was not the case in an earlier
almost 2 decades. Although introduced with high ex- study.11 The combination of CSP plus prednisone has never pectations into the practice of marrow transplantation, the been compared in a prospective randomized study to single- efficacy of CSP as a single agent for the prevention of graft- agent CSP. Such a study is of interest for several reasons.
versus-host disease (GVHD) was not superior to that of a (1) Although the addition of methylprednisolone (MP) to then standard regimen of intermittent methotrexate (MTX).1-3 CSP may decrease the incidence of GVHD, it may add to However, second generation studies showed a significant toxicity and, as a result, fail to improve overall outcome.12 reduction in the incidence of acute GVHD and improved (2) Earlier noncontrolled studies suggested that the use of survival when CSP was administered in combination with MP increased the probability of developing chronic MTX.4-6 One disadvantage of the combined regimen was that GVHD.12,13 (3) At least one study comparing CSP plus MTX the myelosuppressive effect of MTX delayed hematopoietic to CSP combined with MTX plus MP showed a decreased recovery as compared with results with CSP alone.4,5 In addi- incidence of relapse with the incorporation of MP.12 There- tion, it has been suggested that prevention of acute GVHD fore, we performed a prospective randomized study compar- may be associated with an increased probability of leukemic ing a combination of CSP plus MP with single-agent CSP relapse.7 Other investigators combined CSP plus predni- for GVHD prophylaxis in patients considered at high risk sone.8,9 This combination allowed for more rapid hematopoi- of recurrent malignancy posttransplant.
etic recovery compared with MTX-containing regimens, al- beit at the price of a higher incidence of GVHD than seenwith MTX plus CSP.5,6 Also, evidence has been presented that the addition of prednisone may increase the risk of From September 1991 through July 1994, 123 patients considered at high risk for posttransplant relapse were registered on this proto-col. This included patients with lymphoid and myeloid malignancies From the Fred Hutchinson Cancer Research Center, Seattle, WA; who were not in remission (relapse or resistant disease) and with the Veterans Administration Medical Center, Seattle, WA; and the lymphoid malignancies in third or subsequent remission or with Departments of Medicine and Biostatistics, University of Washing- myeloid leukemia in second or subsequent remission. One patient (unique patient number 7559) declined a transplant after randomiza- Submitted September 30, 1996; accepted January 8, 1997. tion. Characteristics of the remaining 122 patients (followed for 17.5 Supported by Public Health Service Grants No. CA15704, to 59 [median, 41] months) are shown in Table 1. Seven stratification CA18029, CA18221, and HL36444 from the National Institutes of variables were considered: diagnosis (myeloid v lymphoid), disease Health, Department of Health and Human Services, Bethesda, MD. stage (remission v relapse or accelerated phase), age (õ25 years v Address reprint requests to H. Joachim Deeg, MD, Fred Hutchin- ¢25 years), donor/patient gender, high risk v low risk for posttrans- son Cancer Research Center, 1124 Columbia St, M318, Seattle, WA plant relapse,14 conditioning regimen (1,200 cGy total body irradia- tion [TBI] or none v ú1,200 cGy TBI), receiving intravenous (IV) The publication costs of this article were defrayed in part by page Ig (yes v no), and treatment in laminar air flow room (yes v no). As charge payment. This article must therefore be hereby marked shown in Table 1, the study arms were balanced with respect to ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to these risk factors. Protocol and consent forms were approved by the Institutional Review Board of the Fred Hutchinson Cancer Research ᭧ 1997 by The American Society of Hematology. Center (Seattle, WA). Risks and benefits of treatment regimens were explained to each patient in detail before hospital admission.
Blood, Vol 89, No 10 (May 15), 1997: pp 3880-3887 Table 1. Patient and Transplant Characteristics
patients who were discharged to the Outpatient Department receivedoral CSP at a dose of 5 mg/kg twice daily. This dose was continued through day 83 if no toxicity developed; it was tapered to 4 mg/kg on day 84, to 3 mg/kg on day 98, to 2 mg/kg twice a day on day120, and continued through day 180. Downward dose adjustments were made if renal toxicity developed. MP was started on day 7 and administered through day 14 at a dose of 0.25 mg/kg IV twice daily.
On day 15, the MP dose was increased to 0.5 mg/kg twice daily and then decreased again to 0.25 mg/kg orally on day 29, to 0.15 mg/kg on day 43, and to 0.1 mg/kg on day 57 through day 72, when Assessment, grading, and treatment of acute GVHD have been reported previously.16-19 Acute GVHD was treated by increasing the dose of MP to 2 mg/kg in patients who had been randomized to CSP plus MP or by instituting MP in patients randomized to receive CSP only. The plan was to treat patients for 14 days at the full dose and then begin to taper steroids. Patients who did not respond to MP as primary therapy were generally treated with antithymocyte Patients were evaluated for the presence of chronic GVHD before discharge from the center as described.17,20,21 Studies included hema- topoietic and chemical parameters, skin and lip biopsies, Schirmer’s test, pulmonary function tests, and other examinations as indicated.
Patients with clinical extensive chronic GVHD were treated with Abbreviations: LAF, laminar air flow room; ALL, acute lymphoblas- continued immunosuppression. Patients with subclinical disease or tic leukemia; ANC, acute nonlymphoblastic leukemia; CML, chronic without evidence of GVHD were observed at regular intervals, and myelogenous leukemia; NHL, non-Hodgkin lymphoma; MDS, myelo- therapy was instituted if clinical disease developed.
dysplastic syndrome; CY, cyclophosphamide; BU, busulfan.
* Patients were stratified by disease status.
† Numbers of patients in remission are in parenthesis.
‡ Refractory anemia with excess blasts (RAEB) or RAEB in transfor- All patients received prophylactic systemic antiviral and antibacte- rial antibiotics and trimethroprim-sulfamethoxazole for Pneumo- cystis carinii prophylaxis as described.5 Twelve patients were placed in a laminar air flow room for protective isolation. Ten patients received intermittent IVIg as part of a concurrent study. In the re- maining patients, IVIg was administered only when serum IgG levels The infection data for this analysis were collected prospectively All donors were HLA-genotypically identical relatives. Serologi- on coded data sheets for the time interval from day 0 through day cal (class I) and molecular typing (class II) were performed according 100 and categorized in a blinded fashion (M.B.) as described.10,22 Briefly, bacteremia was defined as one or more positive blood cul-tures with any bacterial organism regardless of associated symptoms.
Conditioning Regimens and Transplantation Any culture record for a given organism within 21 days of an initial Conditioning regimens are summarized in Table 1. Fractionated positive blood culture for that organism was considered to represent irradiation was delivered from two opposing 60Co sources at an the same infection and was not considered to indicate a new bacter- exposure rate of 7 cGy/min. Within 4 hours of the last TBI exposure emia. Blood culture records for a different organism occurring any or 36 hours after the last dose of chemotherapy, donor marrow was time after a positive culture for another organism was considered to infused IV. The marrow cell dose ranged from 0.5 to 6.1 (median, be a separate bacteremia. Blood culture records for multiple organ- 1.8) 1 108 cells/kg. The day of marrow infusion was designated day isms on the same day were considered to be a single polymicrobial 0. Engraftment was defined as the first of at least 3 consecutive bacteremia. Culture records for a micrococcus or non-JK corynebac- days on which the neutrophil count surpassed 0.5 1 109/L after the terium species or aerobic diphtheroids were not included in the pres- ent analysis because they were considered to be contaminants. Organsite infections were identified as positive bacterial cultures from GVHD Prophylaxis, Assessment, and Treatment normally sterile sites (eg, sinuses). Fungemia was defined as occur- All patients received CSP and, in addition, were randomized to rence of one or more positive blood cultures with any fungal organ- receive or not to receive MP in a nonblinded fashion; regimens for ism regardless of associated symptoms. Invasive mold infections both drugs were identical to those previously described by others.8,15 were defined as biopsy-proven tissue invasion or positive cultures CSP was administered at doses of 5 mg/kg/d as a continuous IV as described.22 Analyses were performed considering all infections, infusion on days 01 through 3 and at 3 mg/kg/d on days 4 through bacterial infections, fungal infections, and combined invasive fungal, 14. On days 15 through 35, 3.75 mg/kg/d was administered IV; gram-negative, and polymicrobial infections.
Table 2. Incidence of Acute GVHD
The primary response variable in the study design was the incidence of grades II-IV acute GVHD. Secondary responses tobe analyzed included the development of chronic GVHD, incidence of infections, relapse, and survival. The CSP arm was expected to show a 50% incidence of grades II-IV GVHD. For purposes of this study, reduction to 25% would have been considered clinically significant. For a test with .05 statistical significance and with power 90% a maximum sample size of 92 patients per arm would be required.23 An interim analysis was performed as planned upon en-rollment of 71 patients. The estimated incidence rates of acute GVHD for patients receiving CSP or CSP plus MP were 60% and 44%, respectively, yielding a one-sided P value of .092. These in- terim results suggested a beneficial effect of the drug combination but were not strong enough to terminate the study early. Patient enrollment was therefore continued, but the goal of accruing 92 patients had to be abandoned as a consequence of competing clinical Log-rank test statistics and Cox models were used in an analysis by intent to treat for time to event data including acute and chronic GVHD, survival, relapse, nonrelapse mortality, relapse- free survival, and infection. A second analysis was performed by actual treatment, excluding 8 patients in the CSP arm and 7 patients in the CSP plus MP arm who failed to receive the prescribed treat- ment based on decisions by the attending physician. For additional * Log-rank test for overall grading; x2 test for grading by organ.
analysis of the infection data, the Anderson-Gill counting processmodel24 was used, which is an extension of the Cox model thataccommodates multiple events (infection episodes) in the same indi-vidual. Cumulative incidence and conditional probability esti- risk of developing acute GVHD among patients on CSP was mates25,26 were used in the analysis of acute and chronic GVHD.
significantly higher than for patients on CSP plus MP for Kaplan-Meier estimates are presented for disease-free survival. Soft- any grade (P Å .001) and for grades II-IV (P Å .01) but not ware package S-plus 3.3 (Mathsoft Inc, Seattle, WA) was used for for severity grades III-IV (P Å .28). As shown in Table 3, the Anderson-Gill model, and SAS (SAS Institute Inc, Cary, NC), results were basically the same in the analysis by actual Stata (Stata Statistical Software: Release 5.0; Stata Corporation, Col- treatment. The decision not to administer the GVHD prophy- lege Station, TX), or Gauss (version 3.2.6; Aptech Systems Inc, laxis prescribed by randomization was made by the attending Maple Valley, WA) were used for all other analyses. Results wereanalyzed as of January 1, 1996.
physician. Reasons included mainly concern about steroidadministration to patients who were infected or suboptimal prophylaxis with CSP as the only drug.
Chronic GVHD developed in 12 of the patients receiving CSP at 75 to 305 (median, 127) days posttransplant and in All 104 patients surviving more than 28 days had sus- 25 of the patients receiving CSP plus MP at 75 to 492 tained engraftment; 18 patients who died before day 28 (12 (median, 182) days posttransplant. Thus, the cumulative inci- and 6 patients on CSP and CSP plus MP, respectively) were dences were 21% and 44% for patients receiving CSP and considered unevaluable for engraftment.
CSP plus MP, respectively (Fig 2A). The relative risk ofdeveloping chronic GVHD for patients receiving CSP plus MP was 2.33 (confidence interval [CI], 1.16, 4.71; P Å .02).
The conditional probabilities (conditional on surviving) of Results are summarized in Tables 2 and 3 and Figs 1 and developing chronic GVHD for the two groups were 51% 2. The cumulative incidence of grades I-IV acute GVHD and 94%, respectively (P Å .03; Fig 2B). De novo chronic was 82% and 66% for patients on CSP and CSP plus MP, GVHD developed in 1 of 8 patients at risk on CSP (these respectively (P Å .001, log-rank test). Grades II-IV acute were the only 8 patients who never received any MP) and GVHD, the primary endpoint of the study, developed in 44 in 12 of 19 patients at risk on CSP plus MP, respectively; patients (73%) on the CSP arm at 3 to 67 (median, 10) days the relative risk was 6.28 (CI, 0.81, 48.4; P Å .08). The after transplantation, compared with 37 patients (60%) on pattern was the same in the analysis by actual treatment, the CSP plus MP arm at 4 to 78 (median, 12) days after although the differences did not reach significance.
transplantation. Acute GVHD, grades III-IV, developed in24 patients (40%) receiving CSP and 21 patients (34%) re- ceiving CSP plus MP (Table 2A). Although the incidenceof acute GVHD in patients receiving only CSP was higher The incidence of clinically relevant infections is summa- in all target organs, the difference was most striking in the rized in Table 3. Whereas the numbers of infectious events, skin (Table 2B). In Cox regression analysis (Table 3), the particularly fungal infections, appeared to be slightly higher Table 3. Cox Regression Analysis of Time to Event Data
* Includes gram-negative, fungal, and polymicrobial infections.
in the group of patients receiving CSP plus MP, none of the patients on the CSP arm and 20 patients the CSP plus MP differences was statistically significant. This was true for arm had developed an infection; this difference was not sig- both the number of patients experiencing infections (first nificant (relative risk, 0.99; CI, 0.49, 2.0; P Å .98). Similarly, infection) and the number of episodes (all infections). Be- in the analysis by actual treatment no significant difference cause treatment of GVHD involved the use of MP, it was possible that the therapeutic use of MP in patients originally randomized to receive CSP only would obscure differencesbetween the two prophylactic groups. Therefore, an addi- Among CSP-treated patients, 17 had a recurrence of their tional analysis was performed with censoring of patients at underlying disease compared with 13 receiving CSP plus the time of treatment for acute GVHD. By that time, 14 MP prophylaxis (not significant). Relapse tended to occur Probability of acute GVHD in patients receiving GVHD prophylaxis with CSP alone or CSP plus MP. (A) Acute GVHD grades I-IV (P
! .001); (B) acute GVHD grades II-IV (P ! .01).
Chronic GVHD in patients receiving GVHD prophylaxis with CSP alone or CSP plus MP. (A) Probability (P ! .02); (B) conditional
probability (P ! .03).
later in patients receiving CSP plus MP, but this difference versial.8,9,15,31-33 A recent study suggested that the use of MP was not significant (P Å .10).
concurrently with MTX and CSP increased — rather thandecreased — the incidence of GVHD, leading to the specula- tion that MP interfered with the antimetabolite MTX, therebyreducing or neutralizing its immunosuppressive effect.12 Currently, 36 patients are surviving, 17 who had received However, it is interesting that, in the same study, patients CSP and 19 CSP plus MP prophylaxis, for Kaplan-Meier who had received MP were somewhat less likely to suffer survival estimates at 3 years of 26% and 23%, respectively a posttransplant relapse than patients not receiving MP.12 The (P Å .45). Three-year relapse-free survival estimates for the objective of the present trial was to compare in a prospective, two groups are 18% and 22%, respectively (P Å .07; Fig randomized study single-agent CSP and CSP plus MP in regard to GVHD prevention and incidence of infection. As Causes of death are listed in Table 4. There was no differ- the study population, we chose patients with myeloid or ence in overall mortality between the two groups and there lymphoid malignancies who were considered to be at high was no obvious difference in regard to any particular cause risk of disease recurrence after transplantation. Because these patients would be expected to potentially benefit from a graft-versus-leukemia effect,34-37 not using the standardregimen of CSP plus MTX and accepting a possibly higher MP has been used extensively in patients undergoing mar- incidence of GVHD was felt to be acceptable.
row or solid organ transplantation and is considered standardtherapy for treatment of established acute and chronicGVHD.27-30 Several studies have also incorporated MP for Table 4. Causes of Death
GVHD prophylaxis, but its role for this indication is contro- Leukemia-free survival in patients receiving GVHD prophy-
Abbreviation: MOS, multiorgan system.
laxis with CSP alone or CSP plus MP (P ! .07).
* Disease present at autopsy or within 6 weeks of death.
As suggested by earlier noncontrolled studies,15 the inci- that patients receiving CSP plus MP had a lower incidence dence of acute GVHD of all severity grades in the present of leukemic relapse (P Å .10) and that relapse-free survival study, although high overall, was lower in patients receiving was better in the CSP plus MP group than among patients a combination of CSP plus MP. However, this difference in receiving CSP only (P Å .07). These results are consistent overall grading was significant only for mild to moderate with findings of an earlier trial showing that the addition of but not for severe (grades III-IV) manifestations of GVHD.
MP to CSP plus MTX resulted in fewer relapses.11 In that The difference was most striking in the skin, consistent with study we speculated that MP interfered with the efficacy of earlier observations that skin manifestations are particularly MTX and that the resulting increase in GVHD was associ- responsive to steroids.30 Of note was the rather early onset ated with a more potent graft-versus-leukemia effect. How- of skin exanthemas thought to represent GVHD in some ever, in the present study, the incidence of acute GVHD was patients. Although it is not possible to exclude the possibility actually lower in the CSP plus MP group; the incidence of of nonspecific rashes, the fact that they occurred in both chronic GVHD was nevertheless increased as compared with treatment arms suggests that the omission of MTX, currently patients receiving CSP alone. These data are consistent with used in most standard regimens,5,6 contributed to this phe- either a direct antileukemic effect of MP or a graft-versus- nomenon. This notion is supported by observations in earlier leukemia effect associated with chronic GVHD.36,37 randomized studies comparing MTX and CSP.1,2 In conclusion, this randomized prospective study shows GVHD prophylaxis also influenced the development of that a combination of CSP plus MP is more effective in chronic GVHD, albeit in a direction opposite to that observed preventing acute GVHD than CSP alone. The incidence of with acute GVHD: the incidence of chronic GVHD was chronic GVHD, on the other hand, was higher in the CSP higher in CSP plus MP-treated patients than among patients plus MP group, a finding in support of the notion that MP receiving CSP only. A difference was still present if patients is not an effective agent for the prevention of chronic GVHD.
who developed acute GVHD and, therefore, received thera- However, only very few patients were able to avoid the use peutic MP even if originally randomized to receive CSP only of MP completely. There was a suggestion that the prophy- were censored. The occurrence of de novo chronic GVHD lactic use of MP resulted in a slight improvement of relapse- was marginally more likely in patients on CSP plus MP prophylaxis (P Å .08). The reason for such an effect of MPis not clear. Conceivably, MP, although suppressing an acute GVHD reaction, interfered with signals required for T-cell We thank all of the nurses and physicians on the Transplant selection and the establishment of tolerance.38 As a result, Wards, the Outpatient Department, and the Long-term Follow-up host-reactive T cells would initiate GVHD once immunosup- Office for their contributions and Bonnie Larson and Harriet Childs pression was tapered or discontinued. Although it is known for typing the manuscript. Special thanks to Russ Schwartz and the that acute GVHD represents a major risk factor for the subse- staff of the Microbiology Laboratory for compiling the bacterial and quent development of chronic GVHD,39,40 the present results suggest that the prophylactic use of MP, even though effec-tive in reducing the incidence of acute GVHD, does not provide prophylaxis for chronic GVHD.
1. Deeg HJ, Storb R, Thomas ED, Flournoy N, Kennedy MS, A previous prospective trial in patients receiving MTX Banaji M, Appelbaum FR, Bensinger WI, Buckner CD, Clift RA, plus CSP and randomized to receive or not to receive MP Doney K, Fefer A, McGuffin R, Sanders JE, Singer J, Stewart P, as GVHD prophylaxis had shown a significantly higher prob- Sullivan KM, Witherspoon RP: Cyclosporine as prophylaxis for ability of infection in patients on MP.10 In the present study, graft-versus-host disease: A randomized study in patients undergoing the probabilities of fungal and bacterial infections were simi- marrow transplantation for acute nonlymphoblastic leukemia. Blood65:1325, 1985 lar in the two groups. There may be several reasons for the 2. Storb R, Deeg HJ, Thomas ED, Appelbaum FR, Buckner CD, discrepancy between previous and present results. For one, Cheever MA, Clift RA, Doney KC, Flournoy N, Kennedy MS, Loug- the MP dose in the present study was lower (0.5 mg/kg/d v hran TP, McGuffin RW, Sale GE, Sanders JE, Singer JW, Stewart 1 mg/kg/d) in the early posttransplant period. Secondly, the PS, Sullivan KM, Witherspoon RP: Marrow transplantation for use of MTX in the previous (but not in the current) study chronic myelocytic leukemia: A controlled trial of cyclosporine ver- might impair mucosal integrity, thereby facilitating the de- sus methotrexate for prophylaxis of graft-versus-host disease. Blood velopment of invasive infections, an effect that may have been amplified by the addition of MP. The lack of a signifi- 3. Deeg HJ: Chemoprevention of graft-vs-host disease: Effects cant difference between CSP and CSP plus MP-treated pa- on donor marrow and host environment, in Gale RP, Champlin RE(eds): Bone Marrow Transplantation: Current Controversies. New tients in the present study was not explained by the therapeu- tic use of MP: results were indistinguishable (P Å .98) when 4. Deeg HJ, Storb R, Weiden PL, Raff RF, Sale GE, Atkinson patients receiving therapeutic MP were censored.
K, Graham TC, Thomas ED: Cyclosporin A and methotrexate in The probability of relapse of the underlying disease is canine marrow transplantation: Engraftment, graft-versus-host dis- influenced not only by disease stage, but also by other fac- ease, and induction of tolerance. Transplantation 34:30, 1982 tors, including the type and intensity of the GVHD prophy- 5. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Ben- lactic regimen and the development of acute or chronic singer W, Buckner CD, Clift R, Doney K, Farewell V, Hansen J, GVHD.34-36 There was a suggestion in the present analysis Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P, Sullivan K, Witherspoon R, Yee G, Thomas ED: Methotrexate and 19. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty cyclosporine compared with cyclosporine alone for prophylaxis of P, Hows J, Thomas ED: 1994 Consensus conference on acute GVHD acute graft versus host disease after marrow transplantation for leu- grading. Bone Marrow Transplant 15:825, 1995 20. Sullivan KM, Shulman HM, Storb R, Weiden PL, With- 6. Ringden O, Klaesson S, Sundberg B, Ljungman P, Lonnqvist erspoon RP, McDonald GB, Schubert MM, Atkinson K, Thomas B, Persson U: Decreased incidence of graft-versus-host disease and ED: Chronic graft-versus-host disease in 52 patients: Adverse natural improved survival with methotrexate combined with cyclosporin course and successful treatment with combination immunosuppres- compared with monotherapy in recipients of bone marrow from donors other than HLA identical siblings. Bone Marrow Transplant 21. Loughran TP Jr, Sullivan K, Morton T, Beckham C, Schubert M, Witherspoon R, Sale G, Sanders J, Fisher L, Shulman H, Thomas 7. Butturini A, Bortin MM, Gale RP: Graft-versus-leukemia fol- ED, Storb R: Value of day 100 screening studies for predicting the lowing bone marrow transplantation. Bone Marrow Transplant development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76:228, 1990 8. Forman SJ, Blume KG, Krance RA, Miner PJ, Metter GE, Hill 22. Bowden RA, Cays M, Gooley T, Mamelok R, van Burik J: LR, O’Donnell MR, Nademanee AP, Snyder DS: A prospective Phase I study of amphotericin B colloidal dispersion (ABCD) for randomized study of acute graft-v-host disease in 107 patients with the treatment of invasive fungal infections after marrow transplant.
leukemia: Methotrexate/prednisone v cyclosporine A/prednisone.
23. Pepe MS, Anderson GL: Two-stage experimental designs: 9. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner Early stopping with a negative result. Appl Stat 41:181, 1992 WE, Bias WB, Braine HG, Burns WH, Farmer ER, Hess AD, Kaizer 24. Andersen PK, Gill RD: Cox’s regression model for counting H, Mellits D, Sensenbrenner LL, Stuart R, Yeager AM: Cyclosporine processes: A large sample study. Ann Stat 10:1100, 1982 plus methylprednisolone versus cyclophosphamide plus methylpred- 25. Pepe MS, Longton G, Pettinger M, Mori M, Fisher LD, Storb nisolone as prophylaxis for graft-versus-host disease: A randomized R: Summarizing data on survival, relapse, and chronic graft-versus- double-blind study in patients undergoing allogeneic marrow trans- host disease after bone marrow transplantation: Motivation for and description of new methods. Br J Haematol 83:602, 1993 10. Sayer HG, Longton G, Bowden R, Pepe M, Storb R: Increased 26. Pepe MS, Mori M: Kaplan-Meier, marginal or conditional risk of infection in marrow transplant patients receiving methylpred- probability curves in summarizing competing risks failure time data? nisolone for graft-versus-host disease prevention. Blood 84:1328, 27. Hings IM, Filipovich AH, Miller WJ, Blazar BL, McGlave 11. Verfaillie C, Weisdorf D, Haake R, Hostetter M, Ramsay PB, Ramsay NK, Kersey JH, Weisdorf DJ: Prednisone therapy for NKC, McGlave P: Candida infections in bone marrow transplant acute graft-versus-host disease: Short-versus long-term treatment. A recipients. Bone Marrow Transplant 8:177, 1991 prospective randomized trial. Transplantation 56:577, 1993 12. Storb R, Pepe M, Anasetti C, Appelbaum FR, Beatty P, Doney 28. Bacigalupo A, Van Lint MT, Frassoni F, Podesta M, Venezi- K, Martin P, Stewart P, Sullivan KM, Witherspoon R, Bensinger ano G, Avanzi G, Vitale V, Marmont AM: High dose bolus methyl- W, Buckner CD, Clift R, Hansen J, Longton G, Loughran T, Petersen prednisolone for the treatment of acute graft versus host disease.
FB, Singer J, Sanders J, Thomas ED: What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing 29. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum FR, Doney KC, Weiden P, Anasetti C, 13. Ringde´n O, Persson U, Gunnar S, Johansson O, Gahrton G, Loughran TP, Hill R, Shields A, Yee G, Shulman H, Nims J, Strom Groth C-G, Lundgren G, Lo¨nnqvist B: Early diagnosis and treatment S, Thomas ED: Alternating-day cyclosporine and prednisone for of acute human graft-versus-host disease. Transplant Proc 15:1490, treatment of high-risk chronic graft-versus-host disease. Blood 14. Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Ana- 30. Kennedy MS, Deeg HJ, Storb R, Doney K, Sullivan KM, setti C, Appelbaum FR, Bowden RA, Deeg HJ, Doney K, Martin Witherspoon RP, Appelbaum FR, Stewart P, Sanders J, Buckner PJ, Sullivan KM, Sanders J, Witherspoon RP: Acute graft-versus- CD, Martin P, Weiden P, Thomas ED: Treatment of acute graft- host disease: Analysis of risk factors after allogeneic marrow trans- versus-host disease after allogeneic marrow transplantation: Ran- plantation and prophylaxis with cyclosporine and methotrexate.
domized study comparing corticosteroids and cyclosporine. Am J 15. Tutschka PJ, Copelan EA, Klein JP: Bone marrow trans- 31. Ramsay NKC, Kersey JH, Robison LL, McGlave PB, Woods plantation for leukemia following a new busulfan and cyclophospha- WG, Krivit W, Kim TH, Goldman AI, Nesbit ME Jr: A randomized study of the prevention of acute graft-versus-host disease. N Engl J 16. Deeg HJ, Cottler-Fox M: Clinical spectrum and pathophysiol- ogy of acute graft-vs.-host disease, in Burakoff SJ, Deeg HJ, Ferrara 32. Yau JC, LeMaistre CF, Zagars GK, Williams LA, Meneghetti J, Atkinson K (eds): Graft-vs.-Host Disease: Immunology, Patho- CM, Luke DR, Dunphy FR, Spinolo JA, Jagannath S, Spitzer G, physiology, and Treatment. New York, NY, Marcel Dekker, 1990, Zander AR, Dicke KA: Methylprednisone, cyclosporine and metho- trexate for prophylaxis of acute graft-versus-host disease. Bone Mar- 17. Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD: Bone-marrow trans- 33. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nadamanee AP, Negrin RS, O’Donnell MR, Parker PM, 18. Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appel- Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman baum FR, Beatty PG, Doney K, McDonald GB, Sanders JE, Sullivan SJ: Cyclosporine, methotrexate, and prednisone compared with KM, Storb R, Thomas ED, Witherspoon RP, Lomen P, Hannigan cyclosporine and prednisone for prophylaxis of acute graft-versus- J, Hansen JA: A retrospective analysis of therapy for acute graft- host disease. N Engl J Med 329:1225, 1993 versus-host disease: Initial treatment. Blood 76:1464, 1990 34. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, and the Seattle Marrow Transplant Team: Antileukemic effect of J, Kolb H, Rimm AA, Ringden O, Rozman C, Speck B, Truitt RL, chronic graft-versus-host disease. Contribution to improved survival Zwaan FE, Bortin MM: Graft-versus-leukemia reactions after bone after allogeneic marrow transplantation. N Engl J Med 304:1529, 1981 marrow transplantation. Blood 75:555, 1990 35. Sullivan KM, Storb R, Buckner CD, Fefer A, Fisher L, 38. Sprent J, Kosaka H, Gao EK: T cell tolerance after bone Weiden PL, Witherspoon RP, Appelbaum FR, Banaji M, Hansen J, marrow transplantation in mice. Bone Marrow Transplant 10:5, 1992 Martin P, Sanders JE, Singer J, Thomas ED: Graft-versus-host dis- ease as adoptive immunotherapy in patients with advanced hemato- 39. Ochs LA, Miller WJ, Filipovich AH, Haake RJ, McGlave logic neoplasms. N Engl J Med 320:828, 1989 PB, Blazar BR, Ramsay NK, Kersey JH, Weisdorf DJ: Predictive 36. Weisdorf DJ, Woods WG, Nesbit ME Jr, Uckun F, Dusenbery factors for chronic graft-versus-host disease after histocompatible K, Kim T, Haake R, Thomas W, Kersey JH, Ramsay NK: Allogeneic sibling donor bone marrow transplantation. Bone Marrow Transplant bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcome. Br J Haematol 86:62, 1994 40. Vogelsang GB: Acute and chronic graft-versus-host disease.
37. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey

Source: http://dlin.web.unc.edu/files/2013/04/DeegEA97.pdf