Volume 15, Issue 9 , Pages 1116-1121, September 2009
Infliximab for Managing Steroid-Refractory Acute Graft-versus-Host Disease
Article Outline
Infliximab has demonstrated activity in the treatment of steroid-refractory acute graft-versus-host disease (aGVHD). We aimed to confirm the effectiveness of infliximab as a salvage therapy for steroid-refractory aGVHD. In a series of 52 patients, 71% of whom had grade III-IV aGVHD, only 15% achieved complete remission (CR) with the use of infliximab alone as salvage therapy. CR of aGVHD differed according to overall aGVHD grade at salvage (grade II, 5/15; grade III, 2/17; grade IV, 1/20; P
=.03). Median overall survival (OS) was only 1.7 months (95% confidence interval [CI]=0.99 to 2.3 months). CR of aGVHD was significantly associated with OS, with a hazard ratio of 8.4 for death in those without CR (95% CI=3.6 to 19.6; P < .0001). This series demonstrates the limited activity of infliximab in patients with high-grade aGVHD. Further work is needed to identify effective therapy for aGVHD.
Key Words: Infliximab, Steroid-refractory, Acute graft-versus-host disease
Introduction
Acute graft-versus-host disease (aGVHD), an important source of treatment-related morbidity and treatment-related mortality (TRM), occurs in up to 50% of recipients of matched related donor allogeneic hematopoietic cell transplantation (HCT), with an even higher rate in unrelated and mismatched HCT, despite prophylaxis. Unfortunately, only 30% to 40% of patients treated with glucocorticoids will demonstrate complete resolution of aGVHD. Steroid-refractory disease portends a poor prognosis, with published estimates of survival of only 5% to 30% 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Various immunosuppressive agents have demonstrated modest activity in this setting 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. Interest in infliximab for treating GVHD has been driven by an understanding of the underlying etiologic role of tumor necrosis factor alpha (TNF-α) in the pathogenesis of aGVHD 32, 33, 34, 35, 36.
Infliximab, a murine-human chimeric monoclonal antibody (mAb) that binds the soluble subunit and the membrane-bound precursor of TNF-α, has been examined in the treatment of steroid-refractory aGVHD by several investigators. Several small case series have suggested clinical activity of infliximab in this setting 37, 38, 39, 40. Larger series also have demonstrated infliximab's clinical activity, while drawing attention to important infectious complications of its use in this setting 41, 42, 43. In the present study, we examined the effectiveness of infliximab in the treatment of 52 patients with steroid-refractory aGVHD.
Methods
A nonconsecutive series of 52 patients treated at the Moffitt Cancer Center between 2001 and 2008 with steroid-refractory aGVHD after allogeneic HCT (as defined by grade progression within 3 days or failure to achieve grade improvement within 5 days after the initiation of glucocorticoid therapy) was identified from a total of 521 patients who underwent allogeneic HCT during that period by retrospective chart review. The study design was approved by the University of South Florida's Institutional Review Board. Starting doses of systemic prednisone or methylprednisolone ranged from 1 to 2mg/kg. Data on aGVHD were collected on the day of onset and weekly thereafter; organ-specific grade and overall grade were assigned according to the Glucksberg modified consensus criteria [44]. Both classic aGVHD occurring within 100 days after HCT and persistent or late aGVHD occurring after 100 days, in the absence of features consistent with cGVHD, were included in the sample. Data collected also included the initial dose of glucocorticoids, duration of steroid exposure and overall duration of immunosuppression, incidence and severity of chronic GVHD (cGVHD) [45], cytomegalovirus (CMV) reactivation, primary disease relapse, and death. Any additional immunosuppressive therapies given after infliximab for ongoing refractory aGVHD also were recorded.
Response rates for aGVHD resolution were calculated. Complete response (CR) was defined as complete resolution of aGVHD after initiation of infliximab that was sustained for at least 1 month. Partial response (PR) was defined as overall grade improvement of 1 grade or more. Those who achieved a CR of aGVHD after requiring additional salvage agents beyond infliximab for persistent aGVHD were designated nonresponders to infliximab. Any recurrent aGVHD until date of death or last follow-up was noted. Univariate logistic regression analysis was performed to evaluate baseline characteristics as predictors for CR with infliximab. The cumulative incidences of primary disease relapse, cGVHD, and CMV reactivation were calculated. The Kaplan-Meier method was used to estimate overall survival (OS) and relapse-free survival (RFS). Survival endpoints were calculated using the starting date of infliximab therapy as the baseline. The Cox proportional hazard model was used to examine baseline characteristics as predictors of OS. The Kaplan-Meier method also was used to calculate the time to<20mg prednisone, time to liberation from prednisone, and time to complete liberation from immune suppression. Finally, any infectious complications of infliximab treatment were noted.
Results
This series of 52 patients with refractory aGVHD (median time to onset of aGVHD from date of HCT, 84 days; range, 8 to 1658 days) was treated with infliximab as salvage therapy after an initial 1 to 2mg/kg dose of glucocorticoids (median time from steroid initiation to infliximab initiation, 13 days; range, 1 to 100 days). No other salvage therapies were used before infliximab. As shown in Table 1, the overall grade at the time of aGVHD onset was generally advanced, with grade III-IV constituting 71% of the total sample. In addition, although a range of organ involvement is represented in the sample, the preponderance (96%) had gastrointestinal (GI) involvement at onset. Infliximab was dosed uniformly at 10mg/kg; however, only 20 of 52 patients received all of the 4 planned doses (12 patients received 1 dose, 9 received 2 doses, and 11 received 3 doses). Reasons for giving fewer than 4 total doses included death from refractory aGVHD, death from sepsis, or substitution of an alternative salvage agent at the discretion of the treating physician.
Table 1. Baseline characteristics
| Frequency | Percent | |
|---|---|---|
| Median age, years (range) | 47.5 (18 to 69) | |
| Disease category | ||
| SAA | 1 | 2% |
| Acute lymphocytic leukemia | 4 | 8% |
| Acute myelogenous leukemia/myelodysplastic syndrome | 22 | 42% |
| Chronic lymphocytic leukemia | 4 | 8% |
| Chronic myelogenous leukemia | 7 | 13% |
| Hodgkin disease | 1 | 2% |
| Multiple myeloma | 2 | 4% |
| Myeloproliferative disorder | 3 | 6% |
| Non-Hodgkin lymphoma | 8 | 15% |
| Remission status at time of HCT | ||
| Remission | 20 | 38% |
| Not | 32 | 62% |
| Stem cell source | ||
| Peripheral blood stem cells | 50 | 96% |
| Bone marrow | 2 | 4% |
| Donor relation | ||
| Related | 21 | 40% |
| Unrelated | 31 | 60% |
| HLA matching | ||
| 10/10 | 36 | 69% |
| 9/10 | 9 | 17% |
| 8/10 | 1 | 2% |
| 6/6 | 5 | 10% |
| 5/6 | 1 | 2% |
| Recipient/donor sex | ||
| Female/female | 7 | 13% |
| Female/male | 14 | 27% |
| Male/female | 16 | 31% |
| Male/male | 15 | 29% |
| GVHD prophylaxis | ||
| CSA/MMF | 1 | 2% |
| CSA/MTX | 3 | 6% |
| TAC/MMF | 12 | 23% |
| TAC/MTX | 32 | 62% |
| TAC/MTX/visilizumab | 2 | 4% |
| TAC/RAPA | 2 | 4% |
| Donor/recipient CMV | ||
| Negative/negative | 13 | 27% |
| Negative/positive | 12 | 24% |
| Positive/negative | 5 | 10% |
| Positive/positive | 19 | 39% |
| Overall aGVHD grade at salvage | ||
| I | 0 | 0% |
| II | 15 | 29% |
| III | 17 | 33% |
| IV | 20 | 38% |
| aGVHD organ involvement at salvage | ||
| Skin (total) | 12 total | 23% total |
| 1 | 5 | 42% |
| 2 | 4 | 33% |
| 3 | 3 | 25% |
| 4 | 0 | 0% |
| GI (total) | 50 total | 96% total |
| 1 | 14 | 8% |
| 2 | 9 | 18% |
| 3 | 7 | 14% |
| 4 | 20 | 40% |
| Liver (total) | 6 total | 12% total |
| 1 | 2 | 33% |
| 2 | 0 | 0% |
| 3 | 3 | 50% |
| 4 | 1 | 17% |
In total, 15% of the patients in our sample achieved a CR of aGVHD after treatment with infliximab alone for steroid-refractory aGHVD at a median of 6 days (range, 2 to 26 days) after initiation of infliximab. Allowing for both those patients who had CR to infliximab alone and those who ultimately achieved CR after infliximab and additional salvage agents, the composite CR rate was 35%. As shown in Figure 1, we found a progressive increase in the number of living patients who achieved a CR of aGVHD over 8 weeks after the initiation of infliximab. On univariate analysis, the only baseline characteristic significantly associated with the achievement of a CR with infliximab was overall aGVHD grade at salvage (grade II, 5/15; grade III, 2/17; grade IV, 1/20), with an odds ratio of 5.7 for CR of aGVHD for grade I/II versus III/IV (95% CI=1.1 to 27.9; P=.03). No significant association was found between time of infliximab administration and CR of aGVHD. One patient experienced recurrent aGVHD of the liver after an initial CR with infliximab, which developed after discontinuation of tacrolimus in the setting of thrombotic microangiopathy.
Figure 1
Overall aGVHD grade in patients on weekly evaluation after initiation of infliximab therapy.
The OS realized in this series of patients with steroid-refractory aGVHD was in keeping with the poor outcomes reported with alternative salvage therapies used in high-grade steroid-refractory aGVHD (Figure 2), with a median OS from initiation of infliximab treatment of 1.68 months (95% CI=0.99 to 2.3 months). The OS was 5.0 months (95% CI=2.3 to 17.6 months) in patients who achieved a CR with infliximab alone, versus 1.3 months (95% CI=0.9 to 2.1 months) in those who did not (P=.046; log-rank test) (Figure 3). Causes of death included refractory aGVHD with or without sepsis (n=25), sepsis (n=4), pneumonia/respiratory failure (n=13), relapse (n=3), and hepatic veno occlusive disease (n=1). Examining baseline characteristics, a CR of aGVHD with infliximab alone demonstrated borderline significance, with a hazard ratio (HR) for death of 0.44 (95% CI=0.2 to 1.0; P=.05); however, overall achievement of CR of aGVHD (including both a CR with infliximab and a CR with infliximab and additional salvage agents) was significantly associated with OS. The HR for death in those without a CR of aGVHD was 8.4 (95% CI=3.6 to 19.6; P < .0001). No other baseline characteristic was significantly associated with OS in this analysis.
Figure 2
Overall survival.
Figure 3
Overall survival, those achieving a CR of aGVHD with infliximab versus those not achieving a CR.
Steroid-refractory aGVHD was associated with a substantial burden of glucocorticoid exposure in this sample. Of the 4 patients who received prednisone of<20mg, the median time to this event was 17.28 months. Only 2 patients were successfully weaned off prednisone, at a median time of 17.35 months. Finally, no patient achieved complete liberation from all immunosuppressant medications by time of death or last follow-up.
CMV reactivation was monitored by weekly serum CMV polymerase chain reaction (PCR) studies in all patients; if CMV reactivation was detected, preemptive therapy was initiated. The cumulative incidence of CMV reactivation in this series was 54%. cGVHD was seen in 15% of the patients; in this group, the maximum score was 1 (mild) in 12%, 2 (moderate) in 63%, and 3 (severe) in 25%. The cumulative incidence of primary disease relapse was 23%.
Although concurrently administered with corticosteroids and often additional immunosuppressive agents, treatment of refractory aGVHD with infliximab resulted in a large burden of bacterial, viral (invasive viral infections other than CMV reactivation), and invasive fungal infectious complications (Table 2).
Table 2. Cumulative incidence of patients experiencing infectious complications after treatment with infliximab
| Frequency | Percent | |
|---|---|---|
| Bacterial | 37 | 71% |
| Viral | 19 | 37% |
| Fungal | 25 | 48% |
Discussion
Steroid-refractory aGVHD remains a significant contributor to treatment-related morbidity and TRM. Based on an understanding of the etiologic role of TNF-α in the pathogenesis and maintenance of aGVHD, infliximab has been developed as a salvage therapy for refractory aGVHD. Although several reports, case series, and larger series have documented infliximab's efficacy, treatment of advanced-grade refractory aGVHD remains a challenge. In the present study, we examined the outcomes of a series with predominantly advanced-grade steroid-refractory aGVHD of the GI tract to further elucidate the benefit of infliximab therapy in this setting.
In this analysis, a CR rate of 15% was achieved with infliximab alone in steroid-refractory aGVHD. All baseline characteristics were examined as predictors of CR of aGVHD with infliximab, and only the overall aGVHD grade at salvage was found to reach statistical significance. This effect of overall aGVHD grade on the likelihood of a CR of aGVHD is in keeping with trends reported in the literature. Couriel et al. [41] reported a CR rate of 62% in a series of 21 patients who received infliximab 10mg/kg in several weekly doses as the sole salvage therapy in refractory aGVHD; however, only 4 of the 21 patients in this series had grade III-IV aGVHD. Conversely, Patriarca et al. [42] reported a CR rate of 19% in a series of 32 patients with more advanced aGVHD (grade II, 12%; grade III, 25%; grade IV, 63%). In terms of predictors of aGVHD response, Patriarca et al. found age<35 years, GI involvement, and time from HCT to infliximab initiation to be significant predictors of response to infliximab. Our analysis did not support these variables as significant predictors of response, but our conclusions are necessarily limited here because of the overrepresentation of GI involvement in our series. Finally, the number of infliximab doses received was not a significant predictor of aGVHD response or OS in our analysis. Only 38% of our patients received 4 doses (median, 3; range, 1 to 4), whereas in the study of Couriel et al. [41], 71% of the patients received 4 doses (median, 4; range, 2 to 9), and in the study of Patriarca et al. [42], a median of 3 doses (range, 2 to 8) was delivered.
The long-term outcome of patients with steroid-refractory aGVHD in our series was poor, with a median OS from time of infliximab treatment of 1.68 months (95% CI=1.0 to 2.3), but nonetheless consistent with reported OS in advanced-grade, steroid-refractory aGVHD using other salvage therapies. Major mortality factors here included refractory aGVHD, sepsis, pneumonia/respiratory failure, and primary disease relapse. Importantly, a CR of aGVHD was a significant predictor of OS. The impact of a CR of aGVHD on OS also was suggested by the study of Patriarca et al. [42], where the OS at a median of 449 days after infliximab treatment was 68% in those with responsive disease, whereas all of the unresponsive patients died of refractory aGVHD by a median of 43 days after onset. Conversely, Couriel et al. [41] reported an OS of 38% at a median follow-up of 21 months, along with a median survival after HCT of 8.7 months. Long-term survival in steroid-refractory aGVHD remains elusive for most patients.
In the present study, infliximab administered along with high-dose glucocorticoids and often additional immunosuppressive agents led to a number of infectious complications despite the administration of standard infectious prophylaxis in all patients. These results are comparable to those reported by Couriel et al. [41] (bacterial infection, 81%; viral infection [including CMV reactivation], 67%; fungal infection, 48%). Marty et al. [43] also have reported that infliximab is a significant risk factor for noncandidal invasive fungal infections in severe aGVHD, with an HR of 13.6 (95% CI=2.29 to 80.2; P=.004). Treatment of steroid-refractory aGVHD mandates cautious surveillance for and prophylaxis against infectious complications.
Overall, our results demonstrate the limited complete remission of advanced-grade steroid-refractory aGVHD induced by infliximab. Given that preclinical data demonstrates a mechanistic role of TNF-α in aGVHD development and maintenance, and that elevated levels of TNF-α have been found in those patients with aGVHD, there is a clear rationale for pursuing anti-TNF therapy for aGVHD treatment 32, 33, 34, 35, 36. Although the reasons for infliximab's limited utility in this series of advanced-grade steroid-refractory aGVHD are not known, possible explanations could include the role of other inflammatory cytokines or other effector mechanisms involved in aGVHD because of the advanced stage of the syndrome, or irreversible tissue injury that was no longer salvageable. Further work remains to be done to identify effective prophylaxis against and primary therapy for aGVHD.
Acknowledgments
Financial disclosure: Supported by National Cancer Center Grants 3 P30-CA7692 and 5 K12-CA087989 and National Center for Research Resources Grant K30-RR022270.
Author contributions: J.P. collected data, performed analysis, and wrote the manuscript. J.K. performed statistical analysis. T.F. contributed to the data analysis and critical review of the manuscript. A.M. contributed to data collection. M.K.D., J.P., H.F., L.P., and E.A. contributed to the critical review of the manuscript. C.A. contributed to data analysis and the critical review of the manuscript.
The authors report no significant conflicts of interest.
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Financial disclosure: See Acknowledgments on page 1120.
PII: S1083-8791(09)00253-5
doi:10.1016/j.bbmt.2009.05.019
© 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 15, Issue 9 , Pages 1116-1121, September 2009
