predictors of long-term clinical outcome in hurler syndrome patients after successful hematopoietic...

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criteria. Cox proportional hazard and regression models were used. Results: Pharmacokinetic and -dynamic data were available from 196 pediatric HCTs(Table 1); 28 were excluded due to 2 nd /3 rd HCT (13) or antibodies (15). Post-HCT exposures correlates best with the endpoints. 5-year probability of OS and EFS were higher in patients with a low (<20 AU*days/L) post-HCT AUC (p<0.01: OS according to AUC in g 2). Multivariate predictors for lower OS were high (>20 AU*days/L) post-HCT AUC (p¼0.024), mismatch donor (p¼0,01) and malignancy (p¼0,007). In addition, low post- HCT AUC of Thymoglobulin was associated successful T-cell reconstitution (p<0.005) while incidence of aGvHD increased (p¼0.01), although the absolute increase of prob- ability of aGvHD is less relevant (g 3). Conclusion: High (>20 AU*days/L) post-HCT exposure of Thymoglobulin is associated with a lower OS and a lower probability of successful IR. These results may contribute to individualized dosing guidelines of Thymoglobulin in chil- dren, aiming to improved survival. 82 Predictors of Long-Term Clinical Outcome in Hurler Syndrome Patients after Successful Hematopoietic Cell Transplantation: An International Study Mieke Aldenhoven 1 , Paul Orchard 2 , Joanne Kurtzberg 3 , Robert Wynn 4 , Anne OMeara 5 , Paul Veys 6 , Alain Fischer 7 , Vassili Valayannopoulos 7 , Benedicte Neven 7 , Attilio Rovelli 8 , Vinod K. Prasad 3 , Jakub Tolar 2 , Elsa Shapiro 2 , Simon Jones 4 , Rossella Parini 8 , Marleen Renard 9 , Victoria Bordon 10 , Michele Poe 11 , Tom de Koning 12 , Ed Wraith 4 , Maria Escolar 11 , Jaap-Jan Boelens 13 . 1 University Medical Center Utrecht, Utrecht, Netherlands; 2 University of Minnesota, Minneapolis, MN; 3 Pediatric BMT Program, Duke University Medical Center, Durham, NC; 4 Royal Manchester Childrens Hospital, Manchester, United Kingdom; 5 Our Ladys Hospital for Sick Children, Dublin, Ireland; 6 Great Ormond Street Hospital for Children, London, United Kingdom; 7 Hôpital Universitaire Necker-Enfants Malades, Paris, France; 8 San Gerardo University Hospital, Monza, Italy; 9 University Hospital Gasthuisberg, Leuven, Belgium; 10 Ghent University Hospital, Ghent, Belgium; 11 University of Pittsburgh, Pittsburgh, PA; 12 University Medical Center Groningen, Groningen, Netherlands; 13 Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands Objectives: Hurler syndrome (HS), the most severe pheno- type of Mucopolysaccharidosis type I, is caused by a de- ciency of the lysosomal enzyme alpha-L-iduronidase (IDUA). HS is clinically characterized by a progressive and ultimately fatal multi-system deterioration with involvement of the central nervous system (CNS). At present, hematopoietic cell transplantation (HCT) is the only treatment able to prevent disease progression in the CNS and therefore considered the treatment of choice in HS. However, there is a lack of long- term follow-up data on successfully transplanted HS pa- tients as well as the factors inuencing them. Therefore, this international multicenter study was initiated to identify predictors of the long-term outcome of successfully trans- planted HS patients worldwide. Methods: Alive and engrafted HS patients with at least 3 years follow-up after HCT were retrospectively evaluated. The main endpoint included the neurodevelopmental outcome; secondary endpoints included the growth, neurologic, ortho- pedic, cardiac, respiratory, ophthalmologic, audiologic and endocrinologic outcome. The inuence of patient, donor, and transplantation-related variables on these endpoints was analyzed using multivariate Cox proportional hazards, logistic regression, and linear mixed models. Results: 197 HS patients from 10 transplantation centers within Europe and the United States were included. This is estimated to represent about 70% of the HS patients suc- cessfully transplanted worldwide till 2008. Patients had a Figure 3. Height estimated by the obtained leukocyte IDUA enzyme level. Figure 1. Cognitive development estimated by the cognitive status at HCT. Figure 2. Occurrence of surgical intervention for cord compression estimated by the obtained leukocyte IDUA enzyme level. Abstracts / Biol Blood Marrow Transplant 20 (2014) S72eS90 S78

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Page 1: Predictors of Long-Term Clinical Outcome in Hurler Syndrome Patients after Successful Hematopoietic Cell Transplantation: An International Study

Figure 1. Cognitive development estimated by the cognitive status at HCT.

Abstracts / Biol Blood Marrow Transplant 20 (2014) S72eS90S78

criteria. Cox proportional hazard and regression modelswere used.Results: Pharmacokinetic and -dynamic data were availablefrom 196 pediatric HCT’s (Table 1); 28 were excluded due to2nd/3rd HCT (13) or antibodies (15). Post-HCT exposurescorrelates best with the endpoints. 5-year probability of OSand EFS were higher in patients with a low (<20 AU*days/L)post-HCT AUC (p<0.01: OS according to AUC in fig 2).Multivariate predictors for lower OS were high (>20AU*days/L) post-HCT AUC (p¼0.024), mismatch donor(p¼0,01) and malignancy (p¼0,007). In addition, low post-HCT AUC of Thymoglobulin was associated successful T-cellreconstitution (p<0.005) while incidence of aGvHDincreased (p¼0.01), although the absolute increase of prob-ability of aGvHD is less relevant (fig 3).Conclusion: High (>20 AU*days/L) post-HCT exposure ofThymoglobulin is associated with a lower OS and a lowerprobability of successful IR. These results may contribute toindividualized dosing guidelines of Thymoglobulin in chil-dren, aiming to improved survival.

Figure 3. Height estimated by the obtained leukocyte IDUA enzyme level.

Figure 2. Occurrence of surgical intervention for cord compression estimatedby the obtained leukocyte IDUA enzyme level.

82Predictors of Long-Term Clinical Outcome in HurlerSyndrome Patients after Successful Hematopoietic CellTransplantation: An International StudyMieke Aldenhoven 1, Paul Orchard 2, Joanne Kurtzberg 3,Robert Wynn 4, Anne O’Meara 5, Paul Veys 6, Alain Fischer 7,Vassili Valayannopoulos 7, Benedicte Neven 7, Attilio Rovelli 8,Vinod K. Prasad 3, Jakub Tolar 2, Elsa Shapiro 2, Simon Jones 4,Rossella Parini 8, Marleen Renard 9, Victoria Bordon 10,Michele Poe 11, Tom de Koning 12, Ed Wraith 4, Maria Escolar 11,Jaap-Jan Boelens 13. 1University Medical Center Utrecht,Utrecht, Netherlands; 2University of Minnesota, Minneapolis,MN; 3Pediatric BMT Program, Duke University Medical Center,Durham, NC; 4Royal Manchester Children’s Hospital,Manchester, United Kingdom; 5Our Lady’s Hospital for SickChildren, Dublin, Ireland; 6Great Ormond Street Hospital forChildren, London, United Kingdom; 7Hôpital UniversitaireNecker-Enfants Malades, Paris, France; 8San Gerardo UniversityHospital, Monza, Italy; 9University Hospital Gasthuisberg,Leuven, Belgium; 10Ghent University Hospital, Ghent, Belgium;11University of Pittsburgh, Pittsburgh, PA; 12University MedicalCenter Groningen, Groningen, Netherlands; 13Blood andMarrow Transplantation Program, University Medical CenterUtrecht, Utrecht, Netherlands

Objectives: Hurler syndrome (HS), the most severe pheno-type of Mucopolysaccharidosis type I, is caused by a defi-ciency of the lysosomal enzyme alpha-L-iduronidase (IDUA).HS is clinically characterized by a progressive and ultimatelyfatal multi-system deterioration with involvement of thecentral nervous system (CNS). At present, hematopoietic celltransplantation (HCT) is the only treatment able to preventdisease progression in the CNS and therefore considered thetreatment of choice in HS. However, there is a lack of long-term follow-up data on successfully transplanted HS pa-tients as well as the factors influencing them. Therefore, thisinternational multicenter study was initiated to identifypredictors of the long-term outcome of successfully trans-planted HS patients worldwide.Methods: Alive and engrafted HS patients with at least 3years follow-up after HCT were retrospectively evaluated. Themain endpoint included the neurodevelopmental outcome;secondary endpoints included the growth, neurologic, ortho-pedic, cardiac, respiratory, ophthalmologic, audiologic and

endocrinologic outcome. The influence of patient, donor, andtransplantation-related variables on these endpoints wasanalyzed using multivariate Cox proportional hazards, logisticregression, and linear mixed models.Results: 197 HS patients from 10 transplantation centerswithin Europe and the United States were included. This isestimated to represent about 70% of the HS patients suc-cessfully transplanted worldwide till 2008. Patients had a

Page 2: Predictors of Long-Term Clinical Outcome in Hurler Syndrome Patients after Successful Hematopoietic Cell Transplantation: An International Study

Abstracts / Biol Blood Marrow Transplant 20 (2014) S72eS90 S79

median age of 16 (2-80) months at transplantation with amedian follow-up of 8.9 (3-22.6) years after last HCT. Post-transplant leukocyte IDUA enzyme levels below the lowerreference were seen in 25% of patients due to mixed-chimerism or the use of a carrier donor. Following successfulHCT, the clinical course of HS patients is strikingly improved,evident in all organ systems. Residual disease burden ispresent in the majority of the patients with high variabilitybetween patients. A better cognitive status at HCT was amajor predictor for superior cognitive development afterHCT (figure 1). Significant predictors for superior long-termoutcome in all organ systems were the presence of “normalIDUA enzyme levels obtained after HCT” and a “youngerage at transplantation”. See the association between theleukocyte IDUA enzyme level obtained after HCTand surgicalintervention for cord compression and growth, in figure 2and 3 respectively.Conclusion: Although HCT significantly improved theclinical course in HS patients, residual disease burden wasobserved in the majority of transplanted HS patients.Using exclusively non-carrier donors and accepting onlyfull donor-chimerism will improve the prognosis ofHS patients. Reducing the age at HCT through newbornscreening could further improve the outcomes of HS pa-tients after HCT.

83Allogeneic Stem Cell Transplantation for Children withSickle Cell Disease Achieves Quality of Life Similar toNormal Children and Is Cost EffectiveStaci Arnold 1, Zhezhen Jin 2, Alan Weinberg 3,4,Jacquelyn Bishop 5, Stephen Sands 1, Maureen Licursi 1,Monica Bhatia 6, Andrew Kung 6, Prakash Satwani 6. 1ColumbiaUniversity Medical Center, New York, NY; 2Biostatistics,Columbia University, New York, NY; 3Health Evidence andPolicy, Mount Sinai Hospital, New York, NY; 4Health Policy andManagement, Columbia University Medical Center, New York,NY; 5Pediatrics, New York Presbyterian Hospital, NewYork, NY;6Pediatrics, Columbia University, New York, NY

Allogeneic stem cell transplantation (alloSCT) remains theonly curative option for sickle cell disease (SCD). However, nosystematic analysis exists comparing cost and quality of life(QOL) among this population. We investigated the QOLoutcomes and health care utilization associated with alloSCTin children with SCD.Internal financial data from 2002-2011 was analyzed retro-spectively across two groups e post-alloSCT patients(>day+365) and patients with SCD referred for alloSCT and/or HLA typed. Surviving alloSCT recipients (A) and SCDcontrols (B) were surveyed with age appropriate PediatricQuality of Life Inventory (PedsQLa) and EuroQOL (EQ-5Da)

Post-AlloSCT(>D+365, group A)

Controls(group B)

p-value

Mean outpatient visits 0.93 1.81 <0.0001Mean outpatient cost ($) 831.10 739.2 0.840Mean outpatient cost

per QOL ($/QALM)723.67 442.16 0.3506

Mean inpatient visits 0.02 0.52 <0.0001Length of stay 0.06 1.05 <0.0001Mean inpatient cost ($) 293.80 2050.20 0.115Mean inpatient cost

per QOL ($/QALM)345.69 769.08 0.0023

questionnaires. Group A siblings without SCD (C) were alsosurveyed as unaffected controls. Mean QOL scores werecalculated for each group with a max score of 100. Utilityscores were determined based on EQ-5D responses. Thesescores and costs for groups A and B were used to calculatecost per quality adjusted life month (QALM) for the cohort ofpatients surveyed. Wilcoxon test was used to determinestatistical significance.Group A, B, and C had 16 (mean age - 14yrs), 19 (mean age -12yrs), and 14 children (mean age - 14yrs), respectively. SCDtherapy included hydroxyurea (group A n¼8, group B n¼10)and chronic transfusions (group A n¼7, group B n¼2). MeanPedsQL scaled scores were 83, 81, and 88, respectively. MeanEQ-5D visual analogue scale scores were 92, 87, 96, respec-tively. Mean utility scores were 0.87, 0.91, and 0.89, respec-tively. All QOL scores were not statistically significant (p ¼0.2638). Healthcare utilization among groups A and B waspreviously reported (see details in table below). The medianinpatient cost per QALM for group A was $0 and $514 forgroup B (p ¼ 0.0023). Outpatient cost per QALM for group Awas $353 and $236 for group B (p ¼ 0.3506).SCD patients’ post-alloSCT QOL scores are similar to unaf-fected siblings, indicating that QOL has normalized. Controlswith SCD also had scores similar to unaffected controls.However, a statistically significant difference exists in theinpatient cost per QALM post-alloSCT compared to controlswith SCD. Outpatient was not significant which may reflectthe limitations of the study period as post-alloSCT QOL andcost can change over time (Felder-Puig 2006; Majhail 2010).Ultimately, this study provides the first combined analysis ofQOL as an outcome and the economic impact of alloSCT forpediatric SCD patients. Further analysis is ongoing to affirmthat alloSCT is a beneficial and cost effective managementoption for patients.

84Low Day 100 Transplant-Related Mortality and RelapseRate Following Clofarabine in Combination withCytarabine, Total Body Irradiation and Allogenic StemCell Transplantaiton in Children, Adolescents and YoungAdults with Poor-Risk Acute LeukemiaNan Chen 1, Kavita Radhakrishnan 2, Jennifer Krajewski 3,Angela Ricci 4, Mark Geyer 5, Lauren Harrison 1,M Fevzi Ozkaynak 1, Alexandra Cheerva 6, Julie-An Talano 7,Theodore B. Moore 8, Alfred P. Gillio 9, Mark Walters 10,Lee Ann Baxter-Lowe 11, Mitchell S. Cairo 1,12,13,14,15. 1Pediatrics,New York Medical College, Valhalla, NY; 2Internal Medicine,University of San Francisco, San Francisco, NY; 3Pediatrics,Hackensack University Medical Center, Hackensack, NJ;4Pediatrics, Boston Children’s Hospital, Boston, MA; 5Medicine,Massachusetts General Hospital, Harvard Medical School,Boston, MA; 6Pediatric Hem/Onc, University of Louisville,Louisville, KY; 7Pediatric Hematology/Oncology and BMT,Children’s Hospital of Wisconsin, Milwaukee, WI; 8Pediatrics,David Geffen School of Medicine at UCLA, Los Angeles, CA; 9Ped.Heme Onc, HUMC, Hackensack, NJ; 10Hematology/Oncology,Children’s Hospital & Research Center, Oakland, Oakland, CA;11Immunogentics and Transplantation Lab, UCSF, SanFrancsico, CA; 12Microbiology and Immunology, New YorkMedical College, Valhalla, NY; 13Pathology, New York MedicalCollege, Valhalla, NY; 14Cell Biology and Anatomy, New YorkMedical College, Valhalla, NY; 15Medicine, New York MedicalCollege, Valhalla, NY

Background: Children, adolescents, and young adults(CAYA) with Acute Leukemia in third complete remission