engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes

Accepted Manuscript Engraftment Syndrome following allogeneic hematopoietic cell transplantation predicts poor outcomes Lawrence Chang , M.D., M.P.H David Frame , Pharm.D Thomas Braun , Ph.D Erin Gatza , Ph.D David A Hanauer , M.D., M.S Shuang Zhao , M.S John M Magenau , M.D Kathryn Schultz , Ph.D Hemasri Tokala , M.D James L.M Ferrara , M.D John E Levine , M.D., M.S Pavan Reddy , M.D Sophie Paczesny , M.D., Ph.D Sung Won Choi , M.D., M.S PII: S1083-8791(14)00320-6 DOI: 10.1016/j.bbmt.2014.05.022 Reference: YBBMT 53476 To appear in: Biology of Blood and Marrow Transplantation Received Date: May 2014 Accepted Date: 22 May 2014 Please cite this article as: Chang L, Frame D, Braun T, Gatza E, Hanauer DA, Zhao S, Magenau JM, Schultz K, Tokala H, Ferrara JLM, Levine JE, Reddy P, Paczesny S, Choi SW, Engraftment Syndrome following allogeneic hematopoietic cell transplantation predicts poor outcomes, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.05.022 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Engraftment syndrome following allogeneic HCT CHANG et al Engraftment Syndrome following allogeneic hematopoietic cell transplantation predicts poor outcomes Lawrence Chang, M.D., M.P.H.,1,2* David Frame, Pharm.D.,3* Thomas Braun, Ph.D.,4 RI PT Erin Gatza, Ph.D.,1,2 David A Hanauer, M.D., M.S.,2,5 Shuang Zhao, M.S.,2,6 John M Magenau, M.D.,1,7 Kathryn Schultz, Ph.D.,8 Hemasri Tokala, M.D.,2,9 James L.M Ferrara, M.D.,1,2 John E Levine, M.D., M.S.,1,2 Pavan Reddy, M.D.,1,7 Sophie Paczesny, SC M.D., Ph.D.,10 and Sung Won Choi, M.D., M.S.1,2 Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, United States; Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States; College of Pharmacy, M AN U University of Michigan, Ann Arbor, MI; Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States; Informatics Core of the Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States; 6Uiversity of Michigan Medical School, University of Michigan, Ann Arbor, MI, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Department of Pharmacy, Rush University Medical Center, Chicago, IL, United States; Department of Internal Medicine, Michigan State University, East Lansing, MI, United States; 10 Pediatric Hematology TE D Oncology, Indiana University, Indianapolis, IN, United States Submitted May 9, 2014 (version 1) Re-submitted May 21, 2014 (version 2) Word Count: EP *L.C and D.F contributed equally to this study Abstract: 200 Text: 4207 AC C Number of Tables: Number of Figures: Supplementary Data: Tables S1–S7 Key Words: Engraftment syndrome, hematopoietic cell transplantation, cytokine storm Running Title: Engraftment syndrome following allogeneic HCT Corresponding Author: Sung Won Choi, M.D., M.S Blood and Marrow Transplantation Program, University of Michigan 1500 E Medical Center Drive, 5304 Cancer Center Ann Arbor, MI, 48109-5942, United States Phone: 734-615-5707 Fax: 734-936-8688 E-mail: sungchoi@umich.edu ACCEPTED MANUSCRIPT Engraftment syndrome following allogeneic HCT CHANG et al Abstract Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight RI PT gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery following hematopoietic cell transplantation (HCT) In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT Among 927 patients, 119 (13%) SC developed ES at a median of 10 days (interquartile range 9–12) post-HCT ES patients experienced significantly higher cumulative incidence of grade 2–4 acute GVHD at day M AN U 100 (75% vs 34%, p10% of baseline (pre-engraftment immune reaction as or more days before engraftment, peri-ES within days of engraftment, post-ES greater than days post-engraftment were regarded as acute GVHD) Within 96 hours of the start of neutrophil recovery develop two or more of the following symptoms: 1) noninfectious fever; 2) weight gain ≥ CB 45 [unspecified] 149 ACCEPTED MANUSCRIPT CHANG et al ENGRAFTMENT SYNDROME FOLLOWING ALLOGENEIC HCT 2.5% over baseline; 3) non-medication rash; 4) hypoxia or pulmonary infiltrates (not related to cardiogenic, infectious, thromboembolic, pulmonary hemorrhage, nor fluid overload) Modified Glucksberg consensus criteria Grade II–IV GVHD by day 14 of HCT* ES patients Saliba et al6 2007 Adult Allogeneic BM, PB 809 Narimatsu et al7 2007 Adult Allogeneic CB 77 Same as Kishi et al PIR 38%; ES 12% Schmid etal8 2008 Pediatric myeloablative conditioning Allogeneic BM, PB 61† 47.5% Nishio et al9 2009 Pediatric First-time Allogeneic BM, PB, CB 100 Within days before neutrophil engraftment, develop ≥2 of 1) fever, 2) rash, 3) weight gain and albumin drop, 4) dyspnea, hypoxia, pulmonary infiltrates Spitzer criteria but with symptom occurrence within 96 hours after engraftment Patel et al10 2009 Adult Allogeneic DCB 52 Frangoul et al11 2009 Pediatric Allogeneic Unrelated Lee J-H et al12 2011 AML or ALL Allogeneic • MUD • MMRD • myeloablative conditioning regimen • > lines of chemotherapy prior to transplant AC C EP TE D M AN U SC RI PT 9.02%* 20% Unexplained fever >38.3°C and or unexplained skin rash resembling acute GVHD, either occurring prior to or at neutrophil recovery 30.7% CB 326 Noninfectious fever and rash prior to neutrophil engraftment 20% BM, PB 380 Pre-engraftment GVHD defined by 1994 Consensus Conference on Acute 5.8% Not specifiable as PIR, ES, and acute GVHD were grouped as a single outcome “immune reactions” in the statistical analysis • Post-transplant G-CSF • amphotericin • high MNC • associated with HLA disparity, younger age • no significant difference in disease risk, gender, blood type compatibility, engraftment day, infused cell concentration, amphotericin B, conditioning regimen, GVHD prophylaxis, stem cell source No significant differences in demographic (age, gender, weight, diagnosis) or transplant (conditioning, cells infused, matching) • higher TNC count • nonmalignant disease More capillary leak, renal involvement No significant difference in survival, NRM, chronic GVHD between hyperacute GVHD and other acute GVHD • Higher cumulative incidence of mortality among MMRD or MUD transplant patients with hyperacute GVHD than with other acute GVHD • lower response rate to first line GVHD therapy by hyperacute GVHD than by other acute GVHD patients [NA] • no significant difference in overall survival nor TRM • no association between ES and development of acute GVHD or chronic GVHD • more frequent chronic GVHD among ES patients • no significant difference in overall survival, event free survival, or transplant-related mortality No significant difference in acute GVHD, OS, or TRM • increased risk of acute GVHD (grade 2–4 and 3–4) • increase risk of chronic GVHD • no significant difference in overall survival • Pre-engraftment GVHD had lower incidence of relapse, ACCEPTED MANUSCRIPT CHANG et al ENGRAFTMENT SYNDROME FOLLOWING ALLOGENEIC HCT RI PT GVHD Grading13 and occurring before neutrophil engraftment Wang et al14 2011 Adult, Pediatric Allogeneic Unrelated CB, DCB 81 Unexplained fever > 38.3°C and/or unexplained skin rash before neutrophil engraftment Brownback et al15 2013 Adult Allogeneic Unrelated CB, DCB 44 Noninfectious fever ≥ 38.3°C and rash before neutrophil engraftment 50% Kanda et al16 2013 Allogeneic Unrelated DCB 57 Noninfectious fever or rash on or before neutrophil engraftment 77.2% Hong et al17 2013 ≥12 years old, TBI-based myeloablative conditioning Pediatric Allogeneic BMT, PB, CB, DCB 176 Spitzer without time criterion 17.0% overall 50% in DCB Khandelwal et al18 2013 Pediatric Allogeneic BM 52 [not listed] Park et al19 2013 Pediatric, Adult Allogeneic SC M AN U TE D EP AC C CB 381 62.9% Pre-engraftment syndrome: noninfectious fever > 38.3°C and or unexplained skin rash before neutrophil recovery 7.7% ES without GVHD (23.1% GVHD without ES, 61.5% neither ES nor GVHD) 26.8% • myeloablative conditioning, younger age • no association with cell infusion concentration, gender, disease risk, HLA matching, conditioning regimen, blood type compatibility •higher incidence in myeloablative conditioning • GVHD prophylaxis regiment Cyclosporine A + MMF had higher risk of GVHD than Tacrolimus + MMF • DCB transplant was most significant risk factor • early-complete chimerism more than late complete chimerism • TBI increased trended (not significant) •Significantly elevated plasma MCP-1 and MIP1b in first weeks post-transplant in isolated ES compared to patient who develop acute GVHD or neither ES nor GVHD •low-risk disease, myeloablative conditioning, GVHD prophylaxis with MTX or corticosteroids, higher TNC infused higher incidence of NRM, lower overall survival than non-GVHD patients • similar incidence of relapse, NRM, OS as post-engraftment GVHD • more severe GVHD than post-engraftment GV HD patients • increased risk of acute GVHD 2–4 • no difference in overall survival or TRM • ES more likely to have hypoxemia in the preengraftment period • no difference in time of engraftment, acute GVHD, relapse, overall survival no statistical difference in time to grade 2–3 or grade 3–4 acute GVHD, overall survival, relapse • no difference in overall survival • no difference in event free survival and NRM [not an analysis described in this study] • increased risk of primary graft failure • increased risk of acute GVHD 2–4 *Proportion of all patients who developed “hyperacute GVHD” which is different from the paper’s report of cumulative incidence † study used counts based on number of transplants: Schmid et al study had 61 transplants in 60 patients; Cornell et al study had 591 transplants in 547 patients For most studies, pediatric was defined as age 5% BSA >15 Severe abdominal pain with or without ileus, or grossly bloody stool (regardless of stool volume) RI PT Stage M AN U SC • For GI staging: the “adult” stool output values should be used for patients ≥ 50 kg in weight • 3-day averages for GI staging based on stool output If stool and urine are mixed, stool output is estimated to be 50% of total stool/urine mix • For stage GI: the term “severe abdominal pain” will be defined as: (a) Pain control requiring institution of opioid use, or an increase in on-going opioid use PLUS (b) Pain that significantly impacts performance status, as determined by the treating physician • If colon or rectal biopsy is positive, but stool output is < 500 mL/day (