Graft-versus-host Disease

Eosinophilia predicts better overall survival after acute graft-versus-host-disease

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Abstract

The prognostic significance of eosinophilia after allogeneic hematopoietic SCT (HSCT) and the relationship between eosinophilia and acute GVHD are not well studied. We retrospectively analyzed 201 adult patients who underwent their first allogeneic HSCT. Seventy-three (36%) patients developed eosinophilia within the first 100 days after HSCT. Eosinophilia was observed more frequently among those patients with acute GVHD than those without it (48 vs 25%, P=0.009). However, it was associated with milder acute GVHD and lower incidence of gut and liver acute GVHD. Among patients with acute GVHD, the 3-year OS for patients with and without eosinophilia was 63.4 and 47.2% (P=0.02), respectively, and 3-year nonrelapse mortality (NRM) was 20.2 and 37.5% (P=0.01), respectively. Multivariate analysis confirmed that eosinophilia was associated with a better OS (P=0.03) and lower NRM (P=0.046) in patients with acute GVHD, whereas it was not associated with a higher relapse rate (P=0.45). In contrast, eosinophilia was not associated with outcomes in those patients without acute GVHD. In conclusion, eosinophilia was associated with milder acute GVHD and better prognosis among patients with acute GVHD. The pathophysiology behind eosinophilia after allogeneic HSCT remains to be investigated.

Introduction

Eosinophils normally constitute only 1–3% of peripheral-blood leukocytes, whereas eosinophilia occurs in a variety of disorders such as allergic diseases, parasitic infections and cancer.1 Eosinophilia after allogeneic hematopoietic SCT (HSCT) has been reported in association with chronic GVHD.2, 3, 4 In addition, there have recently been several reports showing an association between eosinophils and acute GVHD. Basara et al.5 reported that BM eosinophilia after allogeneic HSCT was associated with severe acute GVHD. McNeel et al.6 reported two patients who presented with hypereosinophilia as a presenting sign of acute GVHD. In contrast, eosinophilia after HSCT was not associated with an increased incidence of acute GVHD in another study.7 Therefore, the relationship between eosinophilia after HSCT and acute GVHD is still controversial. Furthermore, as far as we know, there are only two studies investigating the clinical significance of eosinophilia in a large number of patients after allogeneic HSCT.7, 8

Therefore, we retrospectively analyzed a relationship between eosinophilia after allogeneic HSCT and acute GVHD, and the impact of eosinophilia on clinical outcomes (OS, nonrelapse mortality (NRM) and relapse). As eosinophilia after allogeneic HSCT has been reported mainly in association with GVHD, we analyzed separately the impact of eosinophilia on clinical outcomes in the presence of acute GVHD (grades I–IV) and in the absence of acute GVHD.

Materials and methods

Patients

From January 2001 to December 2006, a total of 214 patients with hematological disease received their first allogeneic HSCT consecutively at the Japanese Red Cross Nagoya First Hospital. Patients who died without engraftment (n=9), who used antithymocyte globulin or alemtuzumab in addition to calcineurin inhibitor as a GVHD prophylaxis (n=3), and whose disease continued to progress in spite of conditioning regimen (n=1), were excluded from the analysis. Ultimately, 201 patients were included in the analysis, all of whom received unmanipulated grafts. The median age of the patients was 41 years (range: 16–65 years). Their diagnosis included AML (n=63), ALL (n=27), CML (n=29), myelodysplastic syndrome (n=43), adult T-cell leukemia/lymphoma (n=3), multiple myeloma (n=10), follicular lymphoma (FL) (n=1), diffuse large B-cell lymphoma (n=5), mantle cell lymphoma (n=2), blastic natural killer-cell lymphoma (n=1), T-cell prolymphocytic leukemia (n=1), aplastic anemia (n=13), leukocyte adhesion deficiency type I (n=1) and paroxysmal nocturnal hemoglobinemia (PNH, n=2). None of the patients with adult T-cell leukemia/lymphoma, FL, diffuse large B-cell lymphoma, mantle cell lymphoma, blastic natural killer-cell lymphoma or T-cell prolymphocytic leukemia were in CR at the time of transplantation. Standard risk included AML in first or second CR, ALL without Ph in first CR, CML in first or second chronic phase (CP), myelodysplastic syndrome without leukemic transformation, FL, aplastic anemia, leukocyte adhesion deficiency type I and PNH, whereas others were considered high risk. All patients provided written informed consent.

Transplantation procedure

A myeloablative conditioning regimen was used in 123 patients, whereas a reduced-intensity conditioning regimen was used in 78 patients. The myeloablative conditioning regimen included a CY/TBI-based regimen (n=51), BU/CY-based regimen (n=34) and melphalan/TBI-based regimen (n=31). Of the 78 patients who underwent the reduced-intensity conditioning regimen, 67 patients received fludarabine plus melphalan. GVHD prophylaxis consisted of a combination of tacrolimus or CYA and short-term MTX, except in three patients who received CYA alone. G-CSF was administered in all but two patients.

Acute and chronic GVHD were evaluated by established criteria.9, 10 Patients surviving without relapse for more than 100 days after transplantation were considered as assessable for chronic GVHD. Acute GVHD of grade II or greater was generally treated with prednisolone or methylprednisolone (0.5–2 mg/kg/day), although acute GVHD of grade II with only skin involvement was observed without therapy if it did not progress rapidly and started to improve within the first 5 days. The corticosteroid dose was left to the physician's discretion.

Peripheral complete blood cell counts with microscopic examination of blood smear were performed two or three times a week. Eosinophilia was defined as an absolute eosinophilia count of >500/μl on at least two consecutive days within the first 100 days after HSCT or before patients experienced relapse or death, whichever occurred first.2, 4, 7

Statistical considerations

Chi-square, Fisher's exact test and Mann–Whitney tests were used to compare clinical and patient characteristics. Time-to-event curves were estimated by the Kaplan–Meier method, and the differences between groups were compared using the log-rank statistic. The Cox proportional hazards regression model was used to test the statistical significance of several potential prognostic factors for OS, NRM and relapse. NRM was defined as death in the absence of persistent or recurrent disease. For those who developed acute GVHD, time to event was defined as the interval between the onset of acute GVHD and the date when the event occurred or when the patient was censored. For those who did not develop acute GVHD, time to event was defined as the interval between the time of transplantation and the date when the event occurred or when the patient was censored.

Potential prognostic factors considered in the analysis were recipient age, recipient sex, disease risk, hematopoietic cell transplantation-specific comorbidity index,11 stem cell source, HLA disparity in the GVH direction in HLA-A, -B, -DR alleles, donor type (related or unrelated), recipient–donor sex-match, conditioning regimen, GVHD prophylaxis and eosinophilia. In the Japanese population, a single allele mismatch at HLA-DRB1 has no effect on survival.12, 13 Therefore, we considered cases with a single allele mismatch at HLA-DRB1 as HLA-matched cases. The presence or absence of eosinophilia was analyzed in a time-dependent manner. Patients were included in the eosinophilia-negative group until the onset of eosinophilia, at which time they were switched to the eosinophilia-positive group. Factors found to be significant (P<0.05) in the univariate analysis were included in the multivariate analysis. A level of P<0.05 was defined as statistically significant. The data were analyzed as of May 2008.

Results

Patient characteristics

Among all patients analyzed, 101 developed acute GVHD (grades I–IV) (acute GVHD group), whereas 100 did not (non-acute GVHD group). The patient characteristics of the acute GVHD group and the non-acute GVHD group are shown in Tables 1 and 2, respectively. There were no significant differences in patient characteristics, including age, sex, disease risk, hematopoietic cell transplantation-specific comorbidity index, stem cell source, donor type (related or unrelated), HLA disparity, conditioning regimen, GVHD prophylaxis and recipient–donor sex-match between those who had eosinophilia (Eo group) and those who did not (non-Eo group) in both the acute GVHD group and the non-acute GVHD group. However, there was a trend toward an increased proportion of high-risk disease in the non-Eo group among patients who developed acute GVHD. Median follow-up of surviving patients was 39.9 months (range, 5.8–86.2 months).

Table 1 Patient characteristics in acute GVHD group
Table 2 Patient characteristics in non-acute GVHD group

Of 59 patients who developed grades II–IV acute GVHD, 41 received corticosteroid therapy (defined as systemic corticosteroid administration equivalent to 0.5 mg/kg/day or more of prednisolone), but the remaining 18 patients did not receive it because of the skin-only grade II acute GVHD, which did not progress rapidly and improved promptly. Six patients with grade I acute GVHD received corticosteroid therapy within the first 100 days after HSCT for lung complications such as interstitial pneumonia (n=4) and others (n=2). In total, of the 101 patients in the acute GVHD group, 47 received corticosteroid therapy within the first 100 days after HSCT. On the other hand, of the 100 patients in the non-acute GVHD group, 29 received corticosteroid therapy. The reasons for starting corticosteroid therapy were engraftment syndrome (n=11), reduction or withdrawal of calcineurin inhibitor because of its adverse effects (n=7), lung complications such as interstitial pneumonia (n=5) and others (n=6). Fewer patients with eosinophilia had corticosteroid therapy in both the acute GVHD group (33 vs 58%, P=0.01) and the non-acute GVHD group (12 vs 35%, P=0.03).

Eosinophilia after allogeneic HSCT

The acute GVHD group had a higher incidence of eosinophilia compared with the non-acute GVHD group (48 vs 25%, P=0.009). The median time to the onset of eosinophilia was 38.5 days (range, 22–98 days) and 43 days (range, 25–99 days) after HSCT in the acute GVHD group and non-acute GVHD group, respectively.

Of the 48 patients with acute GVHD and eosinophilia after HSCT, acute GVHD preceded eosinophilia by a median of 17 days (range: 1–87 days) in 37 patients, and eosinophilia preceded acute GVHD by a median of 6 days (range: 1–40 days) in 9 patients. In the remaining two patients, eosinophilia and acute GVHD developed concurrently.

Eosinophilia and acute GVHD

The median time to the onset of acute GVHD was 29 days (range, 11–83 days) in the Eo group and 22 days (range, 7–71 days) in the non-Eo group (P=0.21). The relationship between eosinophilia and the severity of acute GVHD is summarized in Table 3. In the acute GVHD group, the Eo group had a lower proportion of patients who suffered from severe acute GVHD (grades III–IV) (8 vs 30%, P=0.006). As glucocorticoids reduce circulating eosinophils1, 14 and grades II–IV acute GVHD is treated with them, we analyzed separately the relationship between eosinophilia and the severity of acute GVHD among those patients who had corticosteroid therapy and those who did not. Among those 47 patients who had corticosteroid therapy, the proportion of patients who suffered from more severe acute GVHD (grades III–IV) was prone to be lower in the patients with eosinophilia (25 vs 52%, P=0.08). Similarly, among those 54 patients who did not have corticosteroid therapy, the proportion of patients who suffered from more severe acute GVHD (grade II) was lower in the patients with eosinophilia (22 vs 50%, P=0.03).

Table 3 Relationship between eosinophilia and severity of acute GVHD

In terms of affected organs, the incidence of skin GVHD was similar between the Eo group and the non-Eo group (97.9% in the Eo group vs 96.2% in the non-Eo group, P=0.62); however, that of gut and liver GVHD was significantly lower in the Eo group (10.4 vs 26.4%, P=0.04 for gut GVHD; 6.3 vs 20.8%, P=0.04 for liver GVHD).

Eosinophilia and chronic GVHD

Of the 164 patients who were evaluable for chronic GVHD, 84 developed chronic GVHD. Eosinophilia was not associated with an increased risk of chronic GVHD (P=0.48, hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.55–1.32).

OS, NRM and relapse in the acute GVHD group

Overall survival and NRM are shown in Figure 1a and b, respectively. OS was significantly higher in the Eo group than in the non-Eo group (3-year OS 63.4 vs 47.2%, P=0.02). NRM was significantly lower in the Eo-group than in the non-Eo group (3-year NRM 20.2 vs 37.5%, P=0.01). On the other hand, in the patients with hematologic malignancies, the relapse rate did not differ significantly between the Eo group and the non-Eo group (3-year relapse rate 25.9 vs 35.2%, P=0.45).

Figure 1
figure1

Overall survival (a) and nonrelapse mortality (b) by the absence (solid line) or presence (broken line) of eosinophilia in the acute GVHD group.

Multivariate Cox regression analysis showed that the prognostic factor for higher OS was eosinophilia (P=0.03, HR 0.48, 95% CI 0.25–0.91), whereas patients with high-risk disease had a poorer OS (P=0.03, HR 2.12, 95% CI 1.06–4.26) (Table 4). In addition, eosinophilia was associated with lower NRM (P=0.046, HR 0.41, 95% CI 0.17–0.98), whereas high-risk disease was associated with higher NRM (P=0.02, HR 2.51 95% CI 1.12–5.60) in multivariate analysis (Table 4). On the other hand, eosinophilia was not a risk factor for relapse in univariate analysis (P=0.45, HR 0.73, 95% CI 0.32–1.66).

Table 4 Multivariate analysis of risk factors for mortality and NRM in acute GVHD group

In the acute GVHD group, fewer patients with eosinophilia received corticosteroid therapy compared with those without eosinophilia (33 vs 58%, P=0.01), and patients who need corticosteroid therapy after transplantation generally have poor outcomes. Therefore, we analyzed the impact of eosinophilia on OS and NRM separately in the presence of corticosteroid therapy and in its absence. Among the 47 patients who had corticosteroid therapy, eosinophilia was associated with better OS (3-year OS 51.1 vs 36.9%, P=0.04) and lower NRM (3-year NRM 35.1 vs 47.5%, P=0.049). On the other hand, among 54 patients who did not have corticosteroid therapy, eosinophilia was not associated either with better OS (3-year OS 70.4% in the Eo group vs 60.2% in the non-Eo group, P=0.59) or with lower NRM (3-year NRM 10.6% in the Eo group vs 24.4% in the non-Eo group, P=0.39).

OS, NRM and relapse in the non-acute GVHD group

In univariate analysis, eosinophilia was not a risk factor for poorer OS, higher NRM and higher relapse rate (P=0.49, HR 1.25, 95% CI 0.66–2.39 for OS; P=0.71, HR 0.83, 95% CI 0.31–2.22 for NRM; P=0.35, HR 1.46, 95% CI 0.66–3.22 for relapse).

Multivariate Cox regression analysis showed that the risk factor for poorer OS was high-risk disease (P=0.0009, HR 2.86, 95% CI 1.54–5.33), whereas those for higher NRM were high-risk disease (P=0.02, HR 2.72, 95% CI 1.18–6.27) and male patients with female donors (P=0.04, HR 2.30, 95% CI 1.03–5.17). Similarly, a risk factor for relapse was high-risk disease (P=0.005, HR 3.02, 95% CI 1.39–6.59).

Discussion

In this study, we investigated the relationship between eosinophilia after allogeneic HSCT and acute GVHD, and the prognostic significance of eosinophilia. First, eosinophilia was observed more frequently among those patients who developed acute GVHD than among those who did not develop it. This was in accordance with a previous study.6 In addition, there were two studies that compared the incidence of grades II–IV acute GVHD among patients with eosinophilia with that among patients without it. One of these studies observed no statistical difference in the incidence of grades II–IV acute GVHD between patients with and without eosinophilia,7 which was also in accordance with our study (data not shown). In contrast, the other study revealed that eosinophilia was associated with a lower incidence of grades II–IV acute GVHD.8 However, they defined eosinophilia as a relative eosinophil count >4% within the first 100 days after HSCT, which was different from our definition. This may explain the discrepancy between our results and theirs. In terms of the relationship between eosinophilia and chronic GVHD, eosinophilia within the first 100 days after HSCT was not associated with an increased risk of chronic GVHD in this study. Although previous studies have reported that eosinophilia was associated with chronic GVHD, we cannot compare the results of our study with those of other studies because the timing of evaluating eosinophilia was different.

Second, eosinophilia after HSCT was associated with milder acute GVHD. It has been shown that a variety of cytokines are associated with acute GVHD.15, 16, 17, 18, 19, 20, 21 There are several studies suggesting that type 2 helper T (Th2) cytokines suppress GVHD in a murine model.22, 23 In humans, it has been shown that a higher number of IL-4 and IL-10 producing cells are associated with the reduced severity or absence of acute GVHD.24, 25 These observations provide an explanation for the possible protective role of Th2 cytokines in acute GVHD. IL-5 is another Th2 cytokine that has a crucial role in the proliferation, differentiation, survival and activation of eosinophils,1, 14, 26 and the CD4+ Th2 cells are known to produce large amounts of IL-5. Therefore, as speculated in the previous study,8 we speculate that eosinophilia after allogeneic HSCT may reflect activation of Th2 cells, resulting in higher production of Th2 cytokines, less severe GVHD and better outcomes. Further studies are warranted to clarify the potential role of Th2 cytokines, including IL-5, in acute GVHD. Several studies in animals and human volunteers have shown that G-CSF promotes Th2 immune deviation.22, 27 Thus, administration of G-CSF might have increased the incidence of eosinophilia and attenuated the risk of acute GVHD in this study. As all but two patients received G-CSF in this study, we could not evaluate this point. However, considering that post transplantation G-CSF was not associated with a decreased risk of acute GVHD in several large studies,28, 29, 30 it is unlikely that the administration of G-CSF affected the incidence of eosinophilia or that of acute GVHD in this study.

Third, eosinophilia was associated with lower NRM and better OS in the acute GVHD group. As the maximum grade of acute GVHD in individual patients shows a good correlation with their eventual outcome,31, 32 the favorable outcomes associated with eosinophilia may be explained by the milder acute GVHD that patients with eosinophilia developed. As eosinophilia is associated with chronic GVHD, it may be argued that the better prognosis associated with eosinophilia was due to the inclusion of patients who lived long enough to develop chronic GVHD accompanied by eosinophilia in the Eo group. However, none of the patients with eosinophilia in the acute GVHD group had chronic GVHD at the time of onset of eosinophilia. Furthermore, only one patient in the acute GVHD group developed eosinophilia after day +70. Therefore, it is unlikely that the positive impact of eosinophilia was due to the association between eosinophilia and chronic GVHD. There are two studies investigating the relationship between post transplant eosinophilia and outcomes after allogeneic HSCT.7, 8 One reported a higher OS among patients with eosinophilia.7 Another study found that patients with eosinophilia possessed a higher OS and lower NRM compared with those without eosinophilia.8 However, eosinophilia after transplantation was treated as a time-fixed covariate (a variable known at the time of transplantation) in these studies, raising the concern that favorable outcomes associated with eosinophilia are due to the fact that patients need to live longer after transplantation to develop eosinophilia.33 Treating eosinophilia after transplantation as a time-dependent covariate, we clarified that eosinophilia after HSCT was indeed associated with better outcomes among those who developed acute GVHD.

Fourth, corticosteroid therapy decreases the incidence of eosinophilia and is used for the treatment of grades II–IV acute GVHD.34, 35 Furthermore, patients who need corticosteroids after transplantation generally have a poor prognosis.36, 37, 38 Accordingly, milder acute GVHD and better outcomes associated with eosinophilia may be due to the lower proportion of patients with eosinophilia who needed corticosteroids after transplantation compared with those without eosinophilia. To clarify this point, we analyzed separately the results among those patients who had corticosteroid therapy and those who did not. The association between eosinophilia and milder acute GVHD was likely to be independent of the presence or absence of corticosteroid therapy. In addition, eosinophilia in the acute GVHD group was associated with better OS and lower NRM even after we restricted the patients included in the analysis to those who had corticosteroid administration. These results suggest that milder acute GVHD and better outcomes associated with eosinophilia are not simply due to the lower proportion of the patients who had corticosteroids in the Eo group.

This study has several limitations. First, this was a retrospective study involving patients with heterogeneous backgrounds. Unrecognized bias might have influenced the results. Second, although the results of subgroup analyses suggest that the favorable results associated with eosinophilia are likely to be independent of the presence or absence of corticosteroid therapy, the number of patients included in these subgroup analyses is relatively small to draw firm conclusions. Third, as most patients developed eosinophilia after the onset of acute GVHD, the prognostic significance of eosinophilia after HSCT is limited. Fourth, the acute GVHD group and non-acute GVHD group are not exactly comparable as time to events was calculated differently.

In conclusion, we have clearly shown that patients with eosinophilia after allogeneic HSCT have milder acute GVHD, lower incidence of gut and liver acute GVHD, lower NRM and higher OS than patients without it among those who developed acute GVHD. In contrast, eosinophilia was not associated with clinical outcomes in the non-acute GVHD group. The pathophysiology behind eosinophilia after allogeneic HSCT needs to be confirmed by cytokine profiling.

Conflict of interest

The authors declare no conflict of interest.

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Imahashi, N., Miyamura, K., Seto, A. et al. Eosinophilia predicts better overall survival after acute graft-versus-host-disease. Bone Marrow Transplant 45, 371–377 (2010) doi:10.1038/bmt.2009.135

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Keywords

  • eosinophilia
  • GVHD
  • allogeneic hematopoietic stem cell transplantation
  • corticosteroids

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