RESEARCH ARTICLE
A JH
Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults Aazim K. Omer,1,2 Haesook T. Kim,3 Bhargavi Yalamarti,4,5 Steven L. McAfee,6,7 Bimalangshu R. Dey,6,7 Karen K. Ballen,6,7 Eyal Attar,6,7 Yi-Bin Chen,6,7 and Thomas R. Spitzer6,7* We performed a retrospective study of the engraftment syndrome (ES) as defined by the Spitzer Criteria in adult patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematological malignancies at a single institution, over a decade, and analyzed its relationship to acute GVHD; 217 patients underwent either myeloablative (38.7%) or reduced intensity (61.3%) HCT; 22.1% met the criteria for ES. Acute GVHD prophylaxis (P 5 0.006) and transplants prior to 2006 (P < 0.0001) were significantly associated with a risk of ES in univariable analysis. Early aGVHD within 4 weeks of engraftment was significantly more common in the ES compared to the non ES cohort (21 vs. 8.3% respectively, P 5 0.02). ES did not predict for future GVHD, as at day 1180, the cumulative incidences of grades II–IV aGVHD (31 vs. 23%, P 5 0.19) and of chronic GVHD at 2 years of engraftment (42 vs. 36%, P 5 0.28) were not significantly different between the ES and non ES groups, respectively. No significant differences in NRM, overall survival and progression-free survival were observed between the two groups. Although predictive of early aGVHD, ES occurred independently of GVHD in 79% of the patients. Survival outcomes should be evaluated in a larger randomized study to investigate if there is a correlation with ES. C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 89:698–705, 2014. V
䊏 Introduction Engraftment Syndrome (ES) is a constellation of features occurring in the periengraftment period after hematopoietic cell transplantation (HCT), which has been described following autologous, allogeneic, and syngeneic transplantation [1–15]. The incidence of ES has been reported to range from 5 to 72%, mainly because various authors have proposed different criteria to define ES [2–16]. In an earlier article, we proposed a uniform definition, the Spitzer criteria, to diagnose ES in recipients of allogeneic transplantation [1]. Of note, these initial criteria were based on clinical observations in a small cohort of patients who underwent nonmyeloablative HCT with the intentional induction of mixed lymphohematopoietic chimerism, and as discussed, the manifestations of ES were indistinguishable between patients who developed sustained donor chimerism and those who rejected their graft [17]. The three major criteria include, (1) noninfectious fever of 38.3 C, (2) erythrodermatous rash involving more than 25% of body surface area, not attributable to a medication or acute graft versus host disease (aGVHD), and (3) noncardiogenic pulmonary edema with hypoxia. The four minor criteria include, (1) hepatic dysfunction with either total bilirubin >2 mg/dl or transaminase levels > two times normal, (2) renal insufficiency with serum creatinine > two times baseline, (3) weight gain >2.5% of baseline body weight, and (4) transient encephalopathy unexplainable by other causes. ES is diagnosed if either all three major criteria or at least two major and one or more minor criteria are present within 96 hr of engraftment. We proposed that after allogeneic HCT, additional clinical and pathologic symptoms and signs of GVHD should not be present, at least during the early peri-engraftment course. The pathophysiology of ES is not well understood but proinflammatory cytokines such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-a), and interferon gamma (IFN-g), and subsequent cellular and cytokine interactions including complement activation are believed to play an important role in its development [18–23]. After allogeneic HCT, the signs and symptoms of ES have often been attributed to early GVHD [1]. Few data are available about ES after allogeneic HCT for hematological malignancies in adults [5,8]. Because, we initially based the Spitzer criteria on clinical observations in a small number of patients undergoing nonmyeloablative allogeneic HCT, we included in this study a larger cohort of adult patients who received either myeloablative or reduced intensity allogeneic HCT, from a variety of donor sources, for various hematological malignancies and analyzed the relationship of ES to acute GVHD (aGVHD).
Additional Supporting Information may be found in the online version of this article. 1 Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota; 2Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; 4Hematology/Oncology Division, University of Massachusetts, Worcester, Massachusetts; 5Department of Medicine, University of Massachusetts, Worcester, Massachusetts; 6Hematology/Oncology Division, Massachusetts General Hospital, Boston, Massachusetts; 7Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
Conflicts of Interest: Nothing to report. *Correspondence to: Thomas R Spitzer, MD, Hematology/Oncology Division, Massachusetts General Hospital, 55 Fruit Street, Zero Emerson Place, Suite 118, Boston, MA 02114. E-mail: [email protected] Received for publication: 8 October 2013; Revised: 19 March 2014; Accepted: 20 March 2014 Am. J. Hematol. 89:698–705, 2014. Published online: 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23716 C 2014 Wiley Periodicals, Inc. V
698
American Journal of Hematology, Vol. 89, No. 7, July 2014
doi:10.1002/ajh.23716
RESEARCH ARTICLE
䊏 Methods Adult patients (18 yrs) who underwent allogeneic HCT for hematological malignancies in the Bone Marrow Transplant Unit at the Massachusetts General Hospital between 2000 and 2010 were analyzed in this retrospective study. Exclusion criteria were as follows: (1) primary graft failure; (2) lack of a neutrophil nadir of 2.5% 3 baseline No Yes Transient encephalopathy No Yes
doi:10.1002/ajh.23716
%
1 2.1 47 97.9 102.3 (99.3, 104.3) 9 39
18.8 81.3
23 25
47.9 52.1
38 10
79.2 20.8
38 10
79.2 20.8
35 13
72.9 27.1
13 35
27.1 72.9
43 5
89.6 10.4
els and ES, although the sample size is small for this analysis as only 6 patients who received TAC developed ES.
Treatment of ES Thirty-four patients (71%) with ES received corticosteroids for ES, while 14 patients (29%) received only supportive care. Thirty-two patients (67%) achieved complete resolution of ES, while 15 (31%) had partial resolution of their symptoms. One patient did not respond and died of complications related to severe ES. Eleven patients had complete resolution with supportive measures only.
ES and GVHD Biopsies of the affected target tissues (skin, gut, and/or liver) to rule out aGVHD or other alternate diagnosis were performed more frequently in the ES subgroup than in patients without ES (42 vs. 13%, respectively, P < 0.0001). Median time to develop grades II–IV aGVHD from engraftment was 36 (1–179) days. The development of early aGVHD within 4 weeks of engraftment was significantly more common in the ES cohort (21 vs. 8.3%, P 5 0.02; Table V). However, at day 1180, the cumulative incidence of grades II–IV aGVHD (31% for ES vs. 23% for non ES, P 5 0.19) was not significantly different between the two groups (Table V). The same holds true for the cumulative incidence of chronic GVHD between the two groups at 2 years (42 for ES vs. 36% for non ES, P 5 0.28; Table V).
Relapse, NRM, and survival At 100 days, the relapse rate was 31.3% in ES and 19.5% in no ES (P 5 0.11); the NRM rate was 9.5% in ES and 6.3% in no ES (P 5 0.77; Table V). At 2 years, the cumulative incidence of relapse was 49% in the ES and 46% in the no ES group (P 5 0.46); the cumulative incidence of NRM was 21% in the ES and 17% in the no ES group (P 5 0.63). Similarly, OS and PFS were also lower in the ES group but the difference was not statistically significant. At 2 years, the OS was 50% in the ES group and 60% in the no ES group (P 5 0.43); the PFS was 30% in the ES group and 38% in the no ES group (P 5 0.15; Table V). These results are consistent when other prognostic factors are adjusted for in multivariable cox regression analysis (HR 1.22, 95%CI 0.73–2.04, P 5 0.45 for OS and HR 1.29, 95%CI 0.86–1.95, P 5 0.22 for PFS) (Supporting Information Table S2). Factors that are significantly associated with OS in the multivariable analysis include year of transplant (HR 0.55 for 2006 vs.
A JH
Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults Aazim K. Omer,1,2 Haesook T. Kim,3 Bhargavi Yalamarti,4,5 Steven L. McAfee,6,7 Bimalangshu R. Dey,6,7 Karen K. Ballen,6,7 Eyal Attar,6,7 Yi-Bin Chen,6,7 and Thomas R. Spitzer6,7* We performed a retrospective study of the engraftment syndrome (ES) as defined by the Spitzer Criteria in adult patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematological malignancies at a single institution, over a decade, and analyzed its relationship to acute GVHD; 217 patients underwent either myeloablative (38.7%) or reduced intensity (61.3%) HCT; 22.1% met the criteria for ES. Acute GVHD prophylaxis (P 5 0.006) and transplants prior to 2006 (P < 0.0001) were significantly associated with a risk of ES in univariable analysis. Early aGVHD within 4 weeks of engraftment was significantly more common in the ES compared to the non ES cohort (21 vs. 8.3% respectively, P 5 0.02). ES did not predict for future GVHD, as at day 1180, the cumulative incidences of grades II–IV aGVHD (31 vs. 23%, P 5 0.19) and of chronic GVHD at 2 years of engraftment (42 vs. 36%, P 5 0.28) were not significantly different between the ES and non ES groups, respectively. No significant differences in NRM, overall survival and progression-free survival were observed between the two groups. Although predictive of early aGVHD, ES occurred independently of GVHD in 79% of the patients. Survival outcomes should be evaluated in a larger randomized study to investigate if there is a correlation with ES. C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 89:698–705, 2014. V
䊏 Introduction Engraftment Syndrome (ES) is a constellation of features occurring in the periengraftment period after hematopoietic cell transplantation (HCT), which has been described following autologous, allogeneic, and syngeneic transplantation [1–15]. The incidence of ES has been reported to range from 5 to 72%, mainly because various authors have proposed different criteria to define ES [2–16]. In an earlier article, we proposed a uniform definition, the Spitzer criteria, to diagnose ES in recipients of allogeneic transplantation [1]. Of note, these initial criteria were based on clinical observations in a small cohort of patients who underwent nonmyeloablative HCT with the intentional induction of mixed lymphohematopoietic chimerism, and as discussed, the manifestations of ES were indistinguishable between patients who developed sustained donor chimerism and those who rejected their graft [17]. The three major criteria include, (1) noninfectious fever of 38.3 C, (2) erythrodermatous rash involving more than 25% of body surface area, not attributable to a medication or acute graft versus host disease (aGVHD), and (3) noncardiogenic pulmonary edema with hypoxia. The four minor criteria include, (1) hepatic dysfunction with either total bilirubin >2 mg/dl or transaminase levels > two times normal, (2) renal insufficiency with serum creatinine > two times baseline, (3) weight gain >2.5% of baseline body weight, and (4) transient encephalopathy unexplainable by other causes. ES is diagnosed if either all three major criteria or at least two major and one or more minor criteria are present within 96 hr of engraftment. We proposed that after allogeneic HCT, additional clinical and pathologic symptoms and signs of GVHD should not be present, at least during the early peri-engraftment course. The pathophysiology of ES is not well understood but proinflammatory cytokines such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-a), and interferon gamma (IFN-g), and subsequent cellular and cytokine interactions including complement activation are believed to play an important role in its development [18–23]. After allogeneic HCT, the signs and symptoms of ES have often been attributed to early GVHD [1]. Few data are available about ES after allogeneic HCT for hematological malignancies in adults [5,8]. Because, we initially based the Spitzer criteria on clinical observations in a small number of patients undergoing nonmyeloablative allogeneic HCT, we included in this study a larger cohort of adult patients who received either myeloablative or reduced intensity allogeneic HCT, from a variety of donor sources, for various hematological malignancies and analyzed the relationship of ES to acute GVHD (aGVHD).
Additional Supporting Information may be found in the online version of this article. 1 Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota; 2Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; 4Hematology/Oncology Division, University of Massachusetts, Worcester, Massachusetts; 5Department of Medicine, University of Massachusetts, Worcester, Massachusetts; 6Hematology/Oncology Division, Massachusetts General Hospital, Boston, Massachusetts; 7Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
Conflicts of Interest: Nothing to report. *Correspondence to: Thomas R Spitzer, MD, Hematology/Oncology Division, Massachusetts General Hospital, 55 Fruit Street, Zero Emerson Place, Suite 118, Boston, MA 02114. E-mail: [email protected] Received for publication: 8 October 2013; Revised: 19 March 2014; Accepted: 20 March 2014 Am. J. Hematol. 89:698–705, 2014. Published online: 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23716 C 2014 Wiley Periodicals, Inc. V
698
American Journal of Hematology, Vol. 89, No. 7, July 2014
doi:10.1002/ajh.23716
RESEARCH ARTICLE
䊏 Methods Adult patients (18 yrs) who underwent allogeneic HCT for hematological malignancies in the Bone Marrow Transplant Unit at the Massachusetts General Hospital between 2000 and 2010 were analyzed in this retrospective study. Exclusion criteria were as follows: (1) primary graft failure; (2) lack of a neutrophil nadir of 2.5% 3 baseline No Yes Transient encephalopathy No Yes
doi:10.1002/ajh.23716
%
1 2.1 47 97.9 102.3 (99.3, 104.3) 9 39
18.8 81.3
23 25
47.9 52.1
38 10
79.2 20.8
38 10
79.2 20.8
35 13
72.9 27.1
13 35
27.1 72.9
43 5
89.6 10.4
els and ES, although the sample size is small for this analysis as only 6 patients who received TAC developed ES.
Treatment of ES Thirty-four patients (71%) with ES received corticosteroids for ES, while 14 patients (29%) received only supportive care. Thirty-two patients (67%) achieved complete resolution of ES, while 15 (31%) had partial resolution of their symptoms. One patient did not respond and died of complications related to severe ES. Eleven patients had complete resolution with supportive measures only.
ES and GVHD Biopsies of the affected target tissues (skin, gut, and/or liver) to rule out aGVHD or other alternate diagnosis were performed more frequently in the ES subgroup than in patients without ES (42 vs. 13%, respectively, P < 0.0001). Median time to develop grades II–IV aGVHD from engraftment was 36 (1–179) days. The development of early aGVHD within 4 weeks of engraftment was significantly more common in the ES cohort (21 vs. 8.3%, P 5 0.02; Table V). However, at day 1180, the cumulative incidence of grades II–IV aGVHD (31% for ES vs. 23% for non ES, P 5 0.19) was not significantly different between the two groups (Table V). The same holds true for the cumulative incidence of chronic GVHD between the two groups at 2 years (42 for ES vs. 36% for non ES, P 5 0.28; Table V).
Relapse, NRM, and survival At 100 days, the relapse rate was 31.3% in ES and 19.5% in no ES (P 5 0.11); the NRM rate was 9.5% in ES and 6.3% in no ES (P 5 0.77; Table V). At 2 years, the cumulative incidence of relapse was 49% in the ES and 46% in the no ES group (P 5 0.46); the cumulative incidence of NRM was 21% in the ES and 17% in the no ES group (P 5 0.63). Similarly, OS and PFS were also lower in the ES group but the difference was not statistically significant. At 2 years, the OS was 50% in the ES group and 60% in the no ES group (P 5 0.43); the PFS was 30% in the ES group and 38% in the no ES group (P 5 0.15; Table V). These results are consistent when other prognostic factors are adjusted for in multivariable cox regression analysis (HR 1.22, 95%CI 0.73–2.04, P 5 0.45 for OS and HR 1.29, 95%CI 0.86–1.95, P 5 0.22 for PFS) (Supporting Information Table S2). Factors that are significantly associated with OS in the multivariable analysis include year of transplant (HR 0.55 for 2006 vs.
