Treatment options for steroid-refractory GVHD (SR-GVHD) are unsatisfactory and prognosis is poor. Inflammatory cytokines IL-2 and TNF-α are important mediators of GVHD and may be critical targets for therapy. We retrospectively reviewed our experience using combination anti-cytokine therapy of daclizumab and infliximab. Seventeen evaluable patients had a median age of 47 years (range 35–63). The conditioning regimen was myeloablative in 13 and non-myeloablative in 4 cases. GVHD occurred at a median of 49 days after transplant in 12 patients (range 21–231 days) and at a median of 46 days (range 25–119 days) after donor lymphocyte infusion in 5 patients. All patients had persistent or progressive GVHD despite 1–2 mg/kg/day of corticosteroids for a median of 7 days (range 2–26 days). They received a combination of daclizumab and infliximab for acute GVHD IBMTR severity index B (3), C (10) or D (4). Of the 17 patients analyzed, 47% responded to treatment, 24% had complete resolution of symptoms and 24% had partial responses. Survival was limited and all the patients died a median of 6.7 months (range 1.6–26) from transplant and 35 days from initiation of daclizumab/infliximab. This retrospective analysis suggests that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in SR-GVHD, but outcomes remain poor. New methods to prevent and treat GVHD are urgently needed.
Acute GVHD (aGVHD) results in significant mortality and remains a major limitation to successful allogeneic hematopoietic SCT (HSCT). Corticosteroids are typical first-line therapy for aGVHD, but only 25–35% of patients achieve a complete response (CR) with another 15–20% achieving partial responses.1, 2, 3, 4 Antithymocyte globulin has been the most common therapy for steroid-refractory GVHD (SR-GVHD) and leads to overall clinical improvement in 31–40% of patients. Unfortunately, this results in a median survival of only 2–4 months from initiation of treatment.5, 6 Regardless of the treatment for SR-GVHD, only 5–30% of patients who fail initial therapy survive long term, compared with 50–60% of those with stable response or better.7, 8 Given the dismal prognosis for patients with SR-GVHD, there is an immediate need for more effective treatment approaches.
There is compelling rationale for incorporating anti-cytokine therapy into GVHD management. aGVHD pathogenesis is a multistep process, initiated in part by cytokine release from tissue damaged during cytotoxic preparative regimens, resulting in donor T-cell activation and subsequent release of IL-2, TNF-α and IFN-γ. These molecules cause expansion and activation of cytotoxic T cells and other inflammatory cells, creating the characteristic tissue damage of the liver, gut and skin seen in aGVHD.9 Daclizumab and infliximab can block T-cell activation mediated by IL-2 and TNF-α, respectively; daclizumab binds CD25 (IL-2 receptor α chain) and infliximab can bind the soluble subunit and the membrane-bound precursor of TNF-α. These Abs have shown modest success independently in achieving durable responses against SR-GVHD.10, 11, 12, 13, 14 Concurrent use of these agents was evaluated in a small number of patients receiving non-myeloablative hematopoietic cell transplantation and resulted in superior survival of patients compared with those on an antithymocyte globulin-based regimen.14, 15 In an attempt to enhance response and improve prognosis, we have used a combination anti-cytokine therapy and reported our experience in treating 17 patients with SR-GVHD using a combination of daclizumab and infliximab.
All patients treated with a combination of daclizumab and infliximab for SR-GVHD after allogeneic HSCT at the Hospital of the University of Pennsylvania were identified through query of the hospital pharmacy database and then confirmed through retrospective chart review. We identified 22 patients from a total of 354 recipients of an allogeneic HSCT between June 2001 and May 2008. This report is limited to the 17 patients whose records contained sufficient information regarding presentation, treatment and response to GVHD therapy for analysis. This retrospective study was approved by and conducted in accordance with the requirements of the institutional review board of the Hospital of the University of Pennsylvania.
aGVHD was defined as both classic aGVHD and late GVHD occurring beyond 100 days post transplant but without features characteristic of chronic GVHD. Initial steroid doses of 1–2 mg/kg/day were used to treat aGVHD. GVHD was refractory to steroids in all cases and initiation of daclizumab and infliximab was at the discretion of the treating physician. Daclizumab was intended to be given at 1.5 mg/kg on day 1 and 1 mg/kg on days 4, 8, 15 and 22. Infliximab was intended to be given at 10 mg/kg on days 1, 8, 15 and 22.
Evaluation of response
Responses were assessed weekly until death or date of last follow-up. Data were collected regarding dose and duration of steroids, time of steroid failure, additional immunosuppressant agents given following therapy with daclizumab and infliximab as well as the ability to reduce the steroid dose. aGVHD was graded using either modified Glucksberg criteria16 or International Bone Marrow Transplant Registry (IBMTR) severity index.17 For consistency, for all patients included in this analysis, we determined the stage of GVHD for each organ group and overall clinical grade was assigned using the IBMTR severity index. CR was defined as resolution of GVHD in all organ systems. PR signified improvement in at least one organ system by at least one grade without deterioration in another. A mixed response was used to describe improvement in one organ system with worsening of another and progression of disease describes worsening of at least one organ system without improvement in others. Patients without improvement or deterioration during treatment with daclizumab and infliximab were described as no change. Patients were considered refractory to corticosteroids if they did not have a CR or PR. Cause of death was assessed in all patients on the basis of chart review. Infectious complications during treatment with daclizumab and infliximab were noted.
The Kaplan–Meier method18 was used to estimate OS from the time of transplant, donor lymphocyte infusion or onset of GVHD. Fisher's exact test19 was used to determine the impact on response and survival of several outcomes including GVHD severity and the number of doses of therapy. The threshold for significance was a P-value of 0.05.
Between June 2001 and May 2008, 354 patients underwent allogeneic HSCT. During this time period, 55% of patients developed aGVHD. Grade I/II aGVHD developed in 29% of patients and grade III/IV aGVHD developed in 26% of patients. Among this group, we identified 22 patients who received a combination of daclizumab and infliximab for SR-aGVHD; sufficient data were available for 17 of these patients for a detailed review of outcomes. GVHD grade in these patients was reassigned using the IBMTR severity index. Patient characteristics are summarized in Table 1. All patients underwent allogeneic HSCT for hematologic malignancies with BM (n=7), PBSC (n=9) or cord blood grafts (n=1) from matched siblings (n=5), unrelated donors (n=11) or umbilical cord blood (n=1). Except for one patient who received CYA and prednisone, all received primary GVHD prophylaxis with calcineurin inhibitors and MTX. The majority of patients developed aGVHD after initial transplantation (n=12, 71%) at a median of 49 days after transplant (range 21–231 days). Five additional patients developed aGVHD at a median of 46 days after donor lymphocyte infusions (range 25–119 days).
GVHD and treatment
Patients were treated with corticosteroids at an initial dose 1–2 mg/kg/day for a median of 7 days (range 2–26 days) before initiation of daclizumab and infliximab. Two patients were escalated to 3 mg/kg/day of corticosteroids upon initiation of daclizumab and infliximab. All other patients’ steroids were tapered as their clinical response allowed. One patient was treated with daclizumab and infliximab 2 days after initiation of high-dose steroids for progression to stage IV gastrointestinal GVHD with a life-threatening gastrointestinal bleed. All other patients had received at least 4 days of high-dose steroids. The aGVHD severity and organ involvement on initiation of daclizumab and infliximab is detailed in Table 2. Most patients had severity index C/D disease (n=14, 82%). Skin was involved in 9 patients, liver in 9 and gastrointestinal tract in 15. Multiple organs were involved in 11 patients. All five planned doses of daclizumab were given to 53% of patients (median five doses, range 2–5) and all four planned doses of infliximab were given to 53% of patients (median four doses, range 1–4). Reasons for failure to deliver the full treatment course included death, sepsis or lack of response. Seven patients were given additional therapies for aGVHD, including alemtuzumab, mycophenolate mofetil, rituximab and pentostatin at a median of 27 days after starting daclizumab and infliximab (range 6–43 days).
Response and survival
Of the 17 patients analyzed, 8 (47%) responded to treatment with daclizumab and infliximab (Table 2). Complete response (CR) occurred at a median of 11 days after treatment in four patients. Three of these four patients had severity index B disease. One patient with a CR went on to develop recurrent aGVHD 2 weeks after completing therapy with daclizumab and infliximab, and died as a result of GVHD. The other three patients who achieved a CR died of infections either during or 3–6 weeks following the initiation of daclizumab and infliximab therapy. The four patients who achieved a PR died 22–35 days after initiation of therapy for SR-GVHD due to infection or GVHD. The majority of infections were bacterial, although viral reactivation was common (Table 3); we did not observe any documented mycobacterial infections.
The median survival was 44 days (range 14–77 days) after the development of aGVHD and 35 days (range 9–72 days) after the initiation of daclizumab and infliximab. Median survival was 39 days (range 33–74 days) after onset of aGVHD in responding patients and 45 days (range 14–77 days) after aGVHD onset in patients without a response (P=NS).
Cause of death is outlined in Table 2 and included infection in eight patients, progressive GVHD in five patients, disease relapse in two patients, hypoxic respiratory failure in one patient and marrow failure and bleeding in one patient. Infections occurring after start of therapy are listed in Table 3.
Patients with severity index B SR-GVHD were more likely to achieve a CR (3/3) compared to patients with severity index C/D (1/14; P=0.006). There was no significant association with all responses (PR plus CR) and severity index B (3/3) vs C/D (5/14; P=0.08). There was no association of OS with achieving a CR (P=0.34) or any response (PR plus CR; P=0.68) though the number of patients analyzed is quite small and survival was limited in all cases.
GVHD remains a major cause of morbidity and mortality after allogeneic HSCT. The prognosis for patients who fail to respond to corticosteroids is historically poor, and there is no standard or consistently effective therapy for SR-GVHD.20 Given the importance of inflammatory cytokines to the pathogenesis of GVHD,9 agents that interfere with cytokines such as IL-2 and TNF-α have been studied to treat SR-GVHD with variable results.10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27 CRs have been reported in 15–100% of patients and seem to depend on severity of GVHD, specific organ involvement, timing of therapy, previous and concurrent therapy and other patient-specific factors that cannot be controlled in small phase II or retrospective studies.23 Despite reasonable response rates that show clear activity from this approach, most of these studies confirm a poor overall prognosis particularly for patients with the most severe GVHD.
We have analyzed outcomes of 17 patients treated with a combination of daclizumab and infliximab to block both IL-2 and TNF-α activity as therapy for SR-GVHD. We show a significant response rate of 47% with four patients achieving CR. This is similar to response rates noted in other reports using daclizumab and/or infliximab.11, 12, 25
We found that severity index B aGVHD was associated with increased probability of CR to daclizumab and infliximab compared with severity index C/D (P=0.008) in keeping with other reports using infliximab alone in SR-GVHD.10, 12 Some reports have identified younger age,13, 23 specific organ involvement and time from HSCT to initiation of therapy as predictors of GVHD response.23 Although only approximately one half of our patients received all planned doses of therapy, treatment was stopped in most cases because of infection or death. There was no correlation of the number of doses with response or survival. Other studies using infliximab to treat SR-GVHD also report that many patients do not receive all planned doses of therapy typically because of infection or death.10, 12, 23 Given the small number of patients in our cohort, and most with advanced disease (14 with severity index C/D), it was not possible to identify other predictors of response.
Despite these significant response rates, OS was poor in our series. In a similar study of 18 adult patients with SR-GVHD, Srinivasan et al.,14 reported on 12 patients treated with daclizumab ± antithymocyte globulin and/or infliximab. These patients had a 100% CR rate, a 73% day 200 survival and a median survival of 453 days. However, only 34% of their patients had grade III/IV aGVHD and patients were treated for GVHD after predominantly non-myeloablative allogeneic HSCT. Of the five surviving patients, two had received antithymocyte globulin in addition to daclizumab. Furthermore, of the five recipients of combination daclizumab/infliximab, only two were alive at publication (at 82 and 170 days). Rao et al.28 reported a very high response rate with this combination (19 of 22 patients) in pediatric patients and 68% OS, with a median follow-up of 31 months. All patients had grade III/IV aGVHD. The median age was 5.6 and only four patients received a myeloablative-conditioning regimen and most patients had nonmalignant disorders. In our series, the median age was 49 years (range 35–63), 76% of patients were treated with myeloablative-conditioning regimens, and all but three patients had IBMTR severity index C/D GVHD, three factors that may account for the observed differences in outcomes. Unlike some reports,12, 23 but consistent with others,10 we did not find a survival advantage for patients who achieved a CR. Taken together, our results are consistent with other reports of SR-GVHD,11, 12, 25 and different outcomes compared with other studies of cytokine-specific therapy may be related to the heterogeneity of patients studied, particularly with respect to important GVHD prognostic factors of age, conditioning regimen and severity of disease.
The majority of deaths in our patients were related to GVHD and infection. It has been our standard during the time period of this study to use prophylactic antifungal therapy for all transplant recipients and for all patients treated with corticosteroids for GVHD. Agents used for antifungal prophylaxis in this time period have varied based on evolving clinical practices and clinical trials open at our institution but have included fluconazole, voriconazole and caspofungin. For patients initially on empiric fluconazole, we have a low threshold to broaden this empiric coverage in the event of persistent fever or radiographic suggestion of invasive fungal infection. All transplant recipients and patients on high-dose steroids receive prophylaxis for pneumocystis pneumonia with either trimethoprim/sulfamethoxazole or dapsone. It has not been our practice to use prophylactic antibacterial antibiotics but when indicated for fevers or suspected or documented clinical infection, broad-spectrum empiric and targeted antibiotics (a third- or fourth-generation cephalosporin, a carbapenem or a fluoroquinolone with an aminoglycoside) would be started. As this is a retrospective analysis, we reviewed antibiotic use in our recipients of daclizumab and infliximab and found that these guidelines were followed in this cohort of patients. The high rate of deaths related to bacterial infections raises the controversial issue of the need for prophylactic antibacterial therapy.
During the same time period, our center performed 354 allo-SCTs and 26% of patients developed grade III/IV aGVHD. Patients with grade III/IV aGVHD who did not receive daclizumab and infliximab had a 2-year OS of 25%. This was not statistically different from OS of recipients of daclizumab/infliximab (P=0.42) though it may be clinically relevant. A detailed retrospective review of response outcomes for these patients was not performed for the current analysis. However, as our institutional practice during this timeframe was to use daclizumab and infliximab for SR-GVHD, we assume that most of these patients had at least an initial response to steroids.
A major limitation to these observations is the retrospective nature of this report. Combination treatment with daclizumab/infliximab was likely selected for patients with the most severe cases of GVHD, and it is not possible to compare outcomes of this approach with other therapies. In addition, seven patients received other immunosuppressive therapy during or after administration of daclizumab/infliximab, complicating the ability to assess response to these drugs alone though additional therapy was added because of lack of response. Finally, five additional patients received daclizumab/infliximab for SR-GVHD during the time period of this report, but there were insufficient data for complete evaluation of presentation or response and these subjects were excluded from the analysis. Although response data are limited for these patients, all five patients died, and it seems unlikely that inclusion of these patients would alter the conclusions of this study. Regardless of these issues, our report confirms the poor prognosis associated with SR-GVHD treated with combination anti-cytokine therapy despite high response rates. This was because of both progression of GHVD and infection despite the use of standard prophylactic and empiric antibiotics, similar to other reports.10, 12, 29
Targeting IL-2 and TNF with daclizumab and infliximab may continue to have an important role in GVHD management, though it is likely to be most effective earlier in the course of the disease. The utility of anti-cytokine therapy as prevention or initial therapy of GVHD30, 31 remains to be determined. Because the addition of agents to further inhibit T cells and the use of anti-cytokine therapy reported in this study result in poor outcomes for SR-GVHD, future efforts should include earlier and more intensive treatment of advanced GVHD before it turns steroid refractory. Given the conflicting outcomes reported by different trials using anti-cytokine therapy for SR-GVHD, further studies will need to determine the impact of age, underlying disease and conditioning regimen intensity on management and prognosis of GVHD. The identification of biomarkers or other clinical characteristics that predict poor response to steroids will be particularly important to allow trials of earlier intervention in the highest risk patients. In addition, using aggressive antifungal prophylaxis resulted in no deaths in this cohort from fungal infection and the majority of infection-related deaths were from bacterial infection. This raises the controversial issue of using prophylactic antibacterial agents for patients with SR-GVHD. Prospective studies would be needed to determine if this would affect the outcome or just lead to acquired antibiotic resistance without improvement in survival. Given our current findings, we do not recommend combination daclizumab and infliximab for advanced SR-GVHD.
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This work was supported in part by a grant from the NIH (K24 CA11787901; to DLP).
The authors declare no conflict of interest.
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Rager, A., Frey, N., Goldstein, S. et al. Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD. Bone Marrow Transplant 46, 430–435 (2011). https://doi.org/10.1038/bmt.2010.117
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