Treatment of steroid-resistant acute graft-versus-host disease with rabbit antithymocyte globulin.Acute graft-versus-host disease A-GVHD is a life-threatening complication of allogeneic steroid resistant gvhd cell transplantation SCT steroid resistant gvhd, and steoid therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institution's experience treating steroid-resistant GVHD in 36 adult patients median age 39 years, range with a rabbit antithymocyte globulin product thymoglobulin. Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily steroid nedir yan etkileri to the high risk of developing either steroid resistant gvhd opportunistic infection or a PTLD.
How I Treat: How I treat refractory acute GVHD
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We sought to identify a subgroup of patients less likely to benefit from initial therapy with corticosteroids as well as the impact of response on day 14 on outcome. Anderson Cancer Center from through Patients who fail to respond to steroids by day 14 should be considered for clinical trials. Severity of aGVHD, hyperacute GVHD, and sex mismatch could be integrated into prognostic scoring systems which may allow for pretreatment identification of patients unlikely to benefit from standard therapy with corticosteroids.
Acute graft-versus-host disease aGVHD remains one of the major limiting factors in successful allogeneic hematopoietic stem cell transplantation HSCT [ 1 , 2 ]. Standard treatment for aGVHD consists of corticosteroids, although there is a lack of consensus over optimal dosing and schedule [ 3 ]. Response to first-line therapy as a predictor of outcome has been systematically assessed in multiple recent studies [ 5 — 7 ] which concurred that both day 14 and day 28 responses were highly correlated with outcome and each other.
However, day 28 response was the strongest predictor statistically. These findings are in line with a consensus statement endorsing day 28 response as the optimal endpoint in aGVHD treatment trials [ 3 ]. There are currently no established prognostic models or biomarkers to assist in the identification of patients at high risk of failing first-line therapy. We have previously described the hyperacute presentation, defined as that occurring within 14 days after transplantation irrespective of engraftment, as associated with inferior response rate and survival outcomes [ 8 ].
In the current study, we systematically evaluate patient, transplant, and aGVHD characteristics as predictors for failure to respond to initial therapy with corticosteroids in a large patient population treated with standard first-line therapy. We specifically evaluated the effect of these risk factors on response to initial therapy with corticosteroids on day 14 and the impact of response on nonrelapse mortality NRM. We studied all consecutive patients who underwent an allogeneic HSCT as part of prospective clinical trials at the University of Texas M.
Anderson Cancer Center between January and September Patients who received umbilical cord blood transplantation or T-cell depleted graft were excluded from this study. If a patient received more than one allogeneic transplant during the study period, only the initial transplant was utilized for the statistical analysis, and further data was censored at the time of subsequent transplantation.
Patients who had primary graft failure were not eligible for inclusion in the study. All patients were treated on Institutional Review Board approved research protocols at the M.
Patients signed informed consent in accordance with the Declaration of Helsinki. Demographic and clinical data were retrieved from the Department of Stem Cell Transplantation and Cellular Therapy electronic database, which is prospectively updated according to standardized data entry criteria and from the electronic medical records. A retrospective chart review protocol was approved by the institutional IRB for the current analysis. Conditioning regimens are listed in Table 1.
Myeloablative regimens were expected to result in profound pancytopenia for greater than 28 days, and hematopoietic recovery was completely donor-derived. Reduced-intensity regimens were defined as those in which recipient hematopoietic recovery was expected to occur within 28 days without transplantation and, after transplantation, chimerism could be documented in most patients [ 9 , 10 ]. Failure to engraft by day 30 was considered primary graft failure. Diagnosis of aGVHD involved clinical features, positive biopsy results from at least one involved organ, and exclusion of other causes of rash, diarrhea, and liver function abnormalities.
Patients without biopsy-proven GVHD were excluded from the analysis. The staging and grading of aGVHD were performed using the modified Glucksberg consensus criteria and occurred at the time of initiation of treatment [ 11 ]. Each organ system was prospectively and retrospectively assessed for response to therapy. Complete responses CR and partial responses PR were assessed 14 days after the initiation of therapy [ 2 ]. A PR was a decrease in organ stage by 1.
Progressive disease PD was defined as an increase in organ stage by 1 and was evaluated 48 hours gastrointestinal GI and liver or 72 hours skin after the initiation of corticosteroids. Overall response integrated the responses at all sites skin, GI, and liver. Overall PR was any improvement in at least one evaluable organ without deterioration of others. Overall PD was deterioration in at least one evaluable organ without improvement of the others.
Thus, steroid refractory patients were those in the NR and PD categories. Analysis was performed on the basis of outcomes documented by July Patients who experienced secondary graft failure after neutrophil engraftment were censored at the time of the secondary graft failure.
Predictors of response to first line therapy in patients diagnosed with grade I—IV aGVHD were assessed on univariate and multivariate analysis using logistic regression analysis. The cumulative incidence of NRM and chronic GVHD were estimated by the cumulative incidence method [ 13 ] considering death due to persistence or recurrence of underlying malignancy and death before the development of chronic GVHD as competing risks, respectively.
Actuarial survival was estimated by the Kaplan-Meier method. All outcomes were estimated since the initiation of first-line therapy. Factors significant at the 0. Two-sided values less than. A total of patients received allogeneic HSCT transplantation during the study period including who met the inclusion criteria for the current analysis. Patient characteristics are listed in Table 1. Time to development of aGVHD was assessed by quartiles, and day 14 corresponded to the 25th percentile of the distribution our study population.
The majority of patients who failed first-line corticosteroids were subsequently treated on protocols with various investigational agents. There was also a trend for higher response in patients who had active disease at transplant, and those who received a grafted from a matched donor. Factors that were significant or marginally significant on univariate analysis were assessed in multivariate analysis including the severity of aGVHD at the initiation of therapy grade I-II versus grade III-IV , time of onset of aGVHD hyperacute versus other , donor type, and disease status at the time of transplantation.
Sex mismatch in the severe aGVHD group was not considered in multivariate analysis because the estimate was based on a very small number of patients. Among these factors, only severity and time of onset of aGVHD remained significant on multivariate analysis.
To quantify the independent effects of severity and time of onset of aGVHD, the multivariate model was constructed based on four mutually exclusive groups of patients depending on the severity and the time of onset of aGVHD Table 3. This grouping of patients will be used for further evaluation of the independent effect of severity and time of onset of aGVHD on survival. The median followup among survivors was 42 months range 16— Causes of death according to response to first line therapy are presented in Table 4.
The rate of GVHD mortality including both acute and chronic was significantly lower in the responding group ,. On univariate analysis, failure to respond was the most significant predictor of NRM at two years after initiation of first-line therapy ,.
This effect was consistent in patients with mild-to-moderate , and those with severe , aGVHD. Covariates considered in multivariate analysis included response to first-line therapy, time of onset, and severity of aGVHD severe hyperacute aGVHD, and severe aGVHD diagnosed after day 14 , the use of TBI in the conditioning regimen, the use of a matched-related donor, and sex mismatch. Although the dose of steroid was significant on univariate analysis, it was not considered in multivariate analysis because only one of the 24 patients who received lower doses had severe aGVHD, which precludes adjusting for confounding variables.
Results of the multivariate analysis were consistent with those of the univariate analysis and confirmed the independent prognostic value of the response to first-line therapy.
We performed additional subanalyses to further demonstrate the independent effect of response on NRM by grouping patients based on the severity, timing of onset, and response of aGVHD Table 6.
Our data showed that response to therapy was associated with more favorable outcome in patients with mild-moderate aGVHD irrespective of time of onset. We could not evaluate the impact of response in patients with severe hyperacute GVHD because of sample size limitations. These findings indicate that response is an independent factor that adds prognostic value beyond the severity and timing of onset of aGVHD. In this study, we evaluated patient, transplant, and aGVHD factors as predictors of response to standard first-line therapy.
The purpose of this evaluation was to identify a subset of patients unlikely to receive significant benefit from corticosteroids and who may benefit from alternative therapeutic strategies. None of the patient demographic or transplant characteristics independently predicted response to corticosteroids.
This highlights the need for the development of biomarker panels in the evaluation of aGVHD using a newer available technology [ 14 ]. Acute GVHD characteristics were the only factors significantly associated with response to first-line therapy, including the time of onset of aGVHD and its severity at the initiation of therapy.
Hyperacute GVHD may be related to damage induced by the conditioning regimen and its resulting inflammatory cytokine production. This pretransplantation physical damage may be less responsive to corticosteroids than typical GVHD, prompting a more durable cytokine production and thus a worse outcome.
Severe aGVHD was also significantly associated with a worse response to therapy, consistent with previous studies [ 2 , 15 , 16 ]. Sex mismatch female donor to male recipient was associated with a decreased response to first-line therapy in severe aGVHD. Sex mismatch may contribute to an increased rate of aGVHD due to exposure of a parous female donor to non-self-antigens during pregnancy, thus priming the future donor immune system to recognize and attack host antigens.
It is unclear why the mismatch would increase the risk for refractory aGVHD. Our data showed that day response to first-line therapy provides additional independent prognostic value beyond severity and timing of aGVHD. We could not evaluate its impact in severe hyperacute GVHD because of sample size limitations.
Recent publications have evaluated the validity of using response to therapy as primary endpoint in upfront aGVHD treatment trials [ 5 — 7 , 14 ].
Although these reports found response at day 28 to be statistically a stronger predictor, both days 14 and 28 were associated with long-term outcomes and in good agreement. Our data compliment findings of these studies indicating that patients who do not respond to therapy by day 14 are likely to achieve inferior outcomes.
In the current study, we could not compare response on day 14 with response assessed on days 28 or 56 due to the unavailability of consistent data on response to therapy at these time points. While response on day 28 is a valid endpoint that facilitates comparison of outcomes across clinical trials in aGVHD, it does not necessarily dictate the best clinical practice to improve outcomes in nonresponding patients. Early identification of these patients may allow for aggressive intervention and perhaps improve outcomes.
Independent of the definition of steroid refractory aGVHD and the timing for second-line therapy used by each transplant center, rethinking the management of these patients prior to day 28 may be warranted. Inclusion of severity, time of onset, and day 14 response to first-line therapy in scoring criteria may aid in the early identification of patients who are unlikely to receive significant benefit from corticosteroids.
These patients would, therefore, be eligible for investigational approaches, including customization of therapy and inclusion in clinical studies which consider more aggressive or innovative strategies earlier in the disease course [ 17 ].
Sex mismatch, the use of an unrelated donor, and the use of TBI in the conditioning regimen independently contribute to the mortality rate associated with aGVHD. Development of a scoring system that integrates these factors along with timing and severity of aGVHD, as well as early response is warranted in a larger study population. In conclusion, our results indicate that patients with severe hyperacute GVHD have inferior response to initial therapy and higher NRM rates.
This patient subgroup is potentially eligible for innovative strategies that ideally could be implemented upfront, and not after steroid failure has occurred. Our results also suggest that a change in therapy is warranted by 2 weeks of corticosteroids in patients who have not developed at least a partial response. Westin reviewed and collected data, interpreted data, and wrote the paper; R.
Saliba designed and performed data analysis and helped in writing the paper, M. Alousi, helped in writing the paper; I.