Survival and Late Effects After Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less Than Three Years of Age

Biol Blood Marrow Transplant 23 (2017) 1327–1334

Biology of Blood and Marrow Transplantation

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Survival and Late Effects after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less than Three Years of Age

Lynda M. Vrooman 1,*, Heather R. Millard 2, Ruta Brazauskas 2,3, Navneet S. Majhail 4, Minoo Battiwalla 5, Mary E. Flowers 6, Bipin N. Savani 7, Görgün Akpek 8, Mahmoud Aljurf 9, Rajinder Bajwa 10, K. Scott Baker 6, Amer Beitinjaneh 11, Menachem Bitan 12, David Buchbinder 13, Eric Chow 6, Christopher Dandoy 14, Andrew C. Dietz 15, Lisa Diller 1, Robert Peter Gale 16, Shahrukh K. Hashmi 17, Robert J. Hayashi 18, Peiman Hematti 19, Rammurti T. Kamble 20, Kimberly A. Kasow 21, Morris Kletzel 22, Hillard M. Lazarus 23, Adriana K. Malone 24, David I. Marks 25, Tracey A. O’Brien 26, Richard F. Olsson 27,28, Olle Ringden 27, Sachiko Seo 29, Amir Steinberg 24, Lolie C. Yu 30, Anne Warwick 31, Bronwen Shaw 2, Christine Duncan 1

1 Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts 2 Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 3 Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin 4 Blood and Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 5 Hematology Branch, National Heart, Lung and Blood Insititute, Bethesda, Maryland 6 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 7 Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 8 Stem Cell Transplantation and Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois 9 Department of Oncology, King Faisal Specialist Hospital Center and Research, Riyadh, Saudi Arabia 10 Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, Ohio 11 Division of Hematology and Oncology, University of Miami, Miami, Florida 12 Department of Pediatric Hematology/Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 13 Division of Hematology, Children’s Hospital of Orange County, Orange, California 14 Division of Bone Marrow Transplant and Immune Deﬁciency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 15 Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, California 16 Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom 17 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 18 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, Missouri 19 Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin 20 Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 21 Division of Hematology-Oncology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 22 Division of Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois 23 Division of Hematology and Oncology, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio 24 Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 25 Adult Bone Marrow Transplant, University Hospitals Bristol NHS Trust, Bristol, United Kingdom 26 Blood and Marrow Transplant Program, Kids Cancer Centre, Sydney Children’s Hospital, Sydney, Australia 27 Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 28 Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden 29 National Cancer Research Center, East Hospital, Kashiwa, Chiba, Japan 30 Division of Hematology/Oncology, The Center for Cancer and Blood Disorders, Children’s Hospital/Louisiana State University Medical Center, New Orleans, Louisiana 31 Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Financial disclosure: See Acknowledgments on page 1333. * Correspondence and reprint requests: Lynda M. Vrooman, MD, Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, 450 Brookline Avenue, Boston, MA 02215-5450. E-mail address: [email protected] (L.M. Vrooman).

Article history: ABSTRACT Received 12 December 2016 Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable pop- Accepted 16 April 2017 ulation. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for ≥1 year after allogeneic myeloablative HCT for hematologic malignancy at <3 years of age, between 1987 and 2012. The Key Words: median follow-up was 8.3 years (range, 1.0 to 26.4 years); median age at follow-up was 9 years (range, 2 to Hematopoietic cell 29 years). Ten-year overall and relapse-free survival were 87% (95% confidence interval [CI], 85% to 90%) and transplantation (HCT) 84% (95% CI, 81% to 87%). Ten-year cumulative incidence of relapse was 11% (95% CI, 9% to 13%). Of 84 deaths, Survival relapse was the leading cause (43%). Chronic graft-versus-host-disease 1 year after HCT was associated with Infants increased risk of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; P = .0018). Thirty percent of patients ex- Pediatric ≥ > Late effects perienced 1 organ toxicity/late effect 1 year after HCT. The most frequent late effects included growth hormone Hematologic malignancy deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% Relapse CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone Total body irradiation replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was Graft-versus-host disease reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P < .001), growth deficiency (HR, 3.5; 95% CI, 2.2 to 5.5; P < .001), and hypothyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; P < .001). In summary, those who survived relapse free ≥1 year after HCT for hematologic malignancy at <3 years of age had favorable overall survival. Chronic graft-versus- host-disease and TBI were associated with adverse outcomes. Future efforts should focus on reducing the risk of relapse and late effects after HCT at early age. © 2017 American Society for Blood and Marrow Transplantation.

INTRODUCTION dysfunction/infertility requiring hormone replacement, growth hormone Hematopoietic cell transplantation (HCT) is an impor- deficiency/growth disturbance, hemorrhagic cystitis, hypothyroidism, myocardial infarction, pancreatitis, thrombotic thrombocytopenic purpura/ tant treatment modality in infants and young children with hemolytic uremic syndrome, renal failure severe enough to warrant dialysis, very-high-risk and relapsed or refractory leukemias [1-3]. stroke/seizures, bronchiolitis obliterans, pulmonary hemorrhage, crypto- Infants and very young children may be at particular risk for genic organizing pneumonia, interstitial pneumonitis/idiopathic pneumonia morbidities after HCT, including those from transplantation- syndrome, noninfectious liver toxicity, and new malignancy. This report related exposures, such as total body irradiation (TBI) [4,5]. focuses on organ impairment and disorders following 1 year after HCT. There are, however, few reports focusing on survival and mor- Study Population bidities after HCT for hematologic malignancy in the first years The study population consisted of patients who underwent allogeneic of life [4-8]. A comprehensive characterization of outcomes myeloablative HCT for hematologic malignancy at less than 3 years of age following HCT for hematologic malignancy at a very young between January 1, 1987 and December 31, 2012 (Figure 1). Patients in- age would help to inform the care of this potentially vulner- cluded in this analysis survived, relapse free, at least 1 year after HCT. able population. Underlying diagnoses included acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myelomonocytic In a retrospective, international, multicenter cohort of leukemia, and juvenile myelomonocytic leukemia. Twin donor and multi- patients reported to the Center for International Blood and ple donor cases were excluded. Stem cell sources included bone marrow, Marrow Transplant Research (CIBMTR) between 1987 and peripheral blood, or umbilical cord blood; patients who received multiple 2012, we sought to characterize the survival and late effects stem cell sources were excluded. Myeloablative conditioning regimens were defined as previously described [9]. Patients for whom baseline or day 100 of patients who underwent allogeneic myeloablative HCT for forms were unavailable were excluded. Also excluded were those for whom hematologic malignancy before the age of 3 years and who the CIBMTR completion team index (demonstrating the ratio of observed were alive and relapse free for at least 1 year after HCT. We versus expected follow-up) was less than 80% at 5 years after HCT. aimed to report overall and disease-free survival, causes of death, risk factors for mortality, and the frequency and cu- Statistical Analysis mulative incidence of organ toxicities and late effects. Descriptive statistics for categorical variables are presented as frequencies and percentages. Median and range were used to summarize continuous variables. The primary endpoint was overall survival. Second- MATERIALS AND METHODS ary endpoints included relapse-free survival (survival without relapse), Data Collection relapse, transplantation-related mortality, and occurrence of organ toxicities/ We obtained data from the CIBMTR, a voluntary working group of more late effects. Overall and relapse-free survival were estimated using Kaplan- than 450 international transplantation centers. Centers contribute de- Meier methodology. The cumulative incidence of relapse, transplantation- tailed pre- and post-HCT data to the Statistical Center at the Medical College related mortality, organ toxicities, and late-effects were estimated using the of Wisconsin in Milwaukee, Wisconsin and the National Marrow Donor cumulative incidence function to account for competing risks. Analyses of Program in Minneapolis, Minnesota. Computerized checks for discrepan- organ toxicities and late effects were limited to those experienced at least cies, physicians’ review of submitted data, and on-site audits of participating 1 year after HCT. Summaries of aggregated organ toxicities/late effects include centers ensure data quality. Observational studies conducted by the CIBMTR items specified on CIBMTR reporting form fields, as noted above. Propor- are performed under guidance of the institutional review board of the Na- tional hazard models were developed to explore potential risk factors for tional Marrow Donor Program and are in compliance with all applicable overall mortality (in the full cohort) and for the most frequently occurring federal regulations pertaining to the protection of human research late effects (limited to those undergoing HCT after the year 1994) includ- participants. ing assessment by age at HCT, sex, underlying diagnosis, interval from The CIBMTR data repository includes information about patient diagnosis to HCT, disease status at HCT, donor type, graft type, exposure to demographics, disease type, survival, relapse, graft type, the presence of TBI, exposure to corticosteroid for GVHD prophylaxis, history of chronic GVHD graft-versus-host disease (GVHD), and cause of death. A subset of CIBMTR at 1 year after HCT, and year of HCT. Analyses were performed using SAS, participants is selected for more comprehensive research level data collec- version 9.3 (SAS Institute, Cary, NC) [10]. tion by weighted randomization. Late effects data were collected from this group of patients. Transplantation centers report the occurrence of clini- RESULTS cally significant organ impairment or disorders at 6 months and 1 year Patient and Transplantation Characteristics following transplantation and annually thereafter, or until death. Centers report the presence of the following specific organ toxicities and late effects: Patient selection and exclusions are summarized in avascular necrosis, cataracts, congestive heart failure, diabetes, gonadal Figure 1. Of 1737 patients potentially eligible based on age L.M. Vrooman et al. / Biol Blood Marrow Transplant 23 (2017) 1327–1334 1329

Figure 1. Summary of patient selection and exclusions.

at HCT, diagnosis, and year of HCT, 19 patients were ex- Chronic GVHD was reported in 186 patients (26%) at 1 year cluded based on donor or graft source, 22 based upon use after transplantation and was ultimately reported in a total of a nonmyeloablative condition regimen, and 215 based upon of 226 patients (32%). Of those with chronic GVHD, 107 pa- missing forms or team completeness index. Of the 1481 tients (47%) had extensive and 116 patients (51%) limited patients potentially eligible after the exclusions above, 738 GVHD. GVHD severity was unknown in 3 patients. patients were excluded based on events within the first year after HCT (148 relapses, 586 deaths, and 4 lost to follow- Survival, Transplantation-Related Mortality, and Relapse up). Of the 586 patients who died within the first year after Overall and relapse-free survival in patients who sur- HCT, the majority of deaths were due to relapse (322 pa- vived, relapse free, at least 1 year after HCT are presented in tients, 55%), followed by organ failure (18%), infection (12%), Figure 2. The 3, 5, and 10-year overall survival estimates were and GVHD (6%). Less than 1% of deaths within 1 year after 92% (95% confidence interval [CI], 90% to 94%), 90% (95% CI, HCT were due to new malignancy (4 cases) or graft rejec- 88% to 92%), and 87% (95% CI, 85% to 90%). The 3, 5, and 10- tion (3 cases); 7% of deaths were due to other or unknown year relapse-free survival estimates were 89% (95% CI, 87% cause. Twenty-six additional patients were excluded having to 91%), 86% (95% CI 84, to 89%), and 84% (95% CI, 81% to 87%). undergone a second HCT within 1 year of initial HCT. A total The cumulative incidence of transplantation-related mortal- of 717 patients from 117 centers were included in the analysis. ity (with relapse as a competing risk) was estimated at 3, 5, The median follow-up was 8.3 years (range, 1 to 26.4 and 10 years at 3% (95% CI, 2% to 4%), 4% (95% CI, 2% to 5%), years). Median age at follow-up (at last contact or death) was and 5% (95% CI, 4% to 7%). 9 years (range, 2 to 29 years). The CIBMTR completeness index Of the 717 patients in this analysis, there were 84 deaths of follow-up was 96% at 5 years, 90% at 10 years, and 82% at (12%). Relapse was the leading cause of death (43% of deaths), 15 years. followed by infection (18%), organ failure (11%), subse- Patient and transplantation characteristics are summa- quent malignancy (8%), and GVHD (7%). The cause of death rized in Table 1. The median age at time of HCT was 19 was not reported in 13% of deaths. The occurrence of chronic months (range, 3 to 35 months), with 24% of patients less than GVHD at 1 year after HCT was predictive of an increased risk 1 year of age at HCT, 40% 12 to 23.99 months of age, and 36% of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; 24 to 35.99 months of age. The most frequent underlying di- P = .0018). In regression analysis, there were no other signif- agnoses were AML (45%) and ALL (33%). Four patients had icant predictors of overall mortality identified. The 3, 5, and an underlying diagnosis of Down syndrome. For those with 10-year estimates of cumulative incidence of relapse were acute leukemia, 65% of patients were in a first complete re- 8% (95% CI, 6% to 10%), 10% (95% CI, 8% to 12%), and 11% (95% mission at the time of HCT. The majority of patients (66%) CI, 9% to 13%). Thirty patients (4%) underwent a second HCT underwent unrelated donor transplantation. Two hundred at least 1 year after initial HCT. ninety-five (41%) patients received TBI; 7% of patients received a dose of less than 1200cGy (3% having had a single Organ Toxicities and Late Effects dose, 4% receiving fractionated dosing), 51% of patients re- The frequencies of organ toxicities and late effects are pre- ceived a total dose of 1200 cGy in fractionated doses, 21% of sented in Table 2. The most frequently reported organ patients received 1300 Gy to 1375 cGy in fractionated doses, toxicities were growth hormone deficiency/growth distur- and 21% of patients received greater than or equal to 1400 cGy bance (17%), cataracts (13%), hypothyroidism (11%), gonadal in fractionated doses. TBI dose was unknown in 1 patient. Cor- dysfunction/infertility requiring hormone replacement (4%), ticosteroids were included in the GVHD prophylaxis regimen and stroke/seizure (3%). Cumulative incidences for these organ in 31% of transplantations. toxicities are presented in Table 3. The 10-year cumulative 1330 L.M. Vrooman et al. / Biol Blood Marrow Transplant 23 (2017) 1327–1334

Table 1 A Patient and Transplantation Characteristics

Variable Value No. of patients 717 No. of centers 117 Male/female 405 (56)/312 (44) Race Caucasian/White 552 (77) Asian/Hawaiian/Pacific Islander 47 (7) Black 36 (5) Hispanic 35 (5) Other 34 (5) Unknown 13 (<2) AgeatHCT Median (range) Mo 19 (3-35) <12 Mo 174 (24) 12-23.99 Mo 286 (40) B 24-35.99 Mo 257 (36) Lansky score ≥90% before HCT 457 (84) (patients age ≥1yr,n= 543) Underlying diagnosis AML/other acute leukemia 325 (45) ALL 239 (33) JMML 117 (16) MDS 27 (4) CMML 9 (1) Interval from diagnosis to HCT, median 6(<1-30) (range), Mo Disease status before HCT (acute leukemia, n = 564) CR1 365 (65) CR2 144 (26) >CR2 8 (1) Relapse 28 (5) Primary induction failure 15 (3) Figure 2. Overall (A) and relapse-free (B) survival among patients who sur- Unknown 4 (<1%) vived, relapse free at least 1 year after HCT for hematologic malignancy Donor type (performed at less than 3 years of age.). HLA-identical sibling 203 (28) Other related 42 (6) Unrelated 472 (66) Stem cell source Bone marrow 417 (58) incidence of individual toxicities and late effects were as Peripheral blood 49 (7) follows: growth hormone deficiency/growth disturbance Umbilical cord blood 251 (35) 23% (95% CI, 19% to 28%), cataracts 18% (95% CI, 15% to 22%), Conditioning regimen hypothyroidism 13% (95% CI, 10% to 16%), gonadal dysfunction/ TBI + cyclophosphamide ± others 246 (34) infertility requiring hormone replacement 3% (95% CI, 2% TBI + others 49 (7) Busulfan + cyclophosphamide ± others 325 (46) to 5%) and stroke/seizure 3% (95% CI, 2% to 5%). At least 1 organ Busulfan + melphalan ± others 80 (11) toxicity was reported in 30% of patients, with 16% of patients Others 17 (2) reporting 1 toxicity, 8% reporting 2 toxicities, and 6% reporting Corticosteroid included in GVHD prophylaxis 223 (31) 3 or more toxicities. Year of HCT 1987-1989 27 (4) In multivariable analysis, TBI exposure was an indepen- 1990-1994 87 (12) dent predictor of increased risk for cataracts (HR, 17.2; 95% 1995-1999 175 (24) CI, 7.4 to 39.8; P < .001), growth hormone deficiency/growth 2000-2004 164 (23) disturbance (HR, 3.5; 95% CI, 2.2 to 5.5; P < .001), and hypo- 2005-2009 206 (29) thyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; P < .001) (Table 4). 2010-2012 58 (8) Development of acute GVHD after HCT Donor type and stem cell source were independent predic- Any grade 434 (60) tors of growth hormone deficiency/growth disturbance, with Grade 1-2 325 (45) unrelated bone marrow or stem cell donor and unrelated Grade 3-4 109 (15) cord blood donor HCT associated with greater risk (HR, 2.9; Geographical location of HCT = = United States 481 (67) 95% CI, 1.5 to 5.6; P .0014; HR, 2.2; 95% CI, 1.1 to 4.5; P .023, Europe 82 (11) respectively). Age 2 to 3 years at HCT was associated with Australia/New Zealand 59 (8) higher risk of cataracts than younger age at HCT (HR, 2.0; 95% Canada 32 (4) CI, 1.0 to 3.7; P = .044). Females were more likely than males Mideast/Africa 26 (4) to be reported with gonadal dysfunction (HR, 7.0; 95% CI, 2.0 Asia 23 (3) = Central/South America 14 (2) to 24.0; P .0019). Neither chronic GVHD at 1 year after HCT nor exposure to corticosteroid for GVHD prophylaxis were Data presented are n (%) unless otherwise indicated. JMML indicates juvenile myelomonocytic leukemia; MDS, myelodysplastic identified as risk factors for these reported outcomes. syndrome; CMML, chronic myelomonocytic lymphoma; CR, complete A subsequent malignant neoplasm was reported in 26 pa- remission. tients (3.6%). One subsequent malignancy was diagnosed less than 1 year after HCT (spindle cell tumor of the kidney) and 3 subsequent malignancies occurred after relapse or a second HCT (including diagnoses of AML, myelodysplastic syndrome, L.M. Vrooman et al. / Biol Blood Marrow Transplant 23 (2017) 1327–1334 1331

Table 2 Table 3 Frequency of Nonmalignant Organ Toxicities and Late Effects Cumulative Incidence of Organ Toxicities and Late Effects

Organ Toxicities and Late Effects Value Organ Toxicities and Late Effects Cumulative Incidence, % (95% CI)* No. of nonmalignant late effects Growth hormone 3 Yr 6 (4-7) 0 403 (56) deficiency/growth disturbance 5 Yr 11 (9-14) 1 114 (16) 10 Yr 23 (19-28) 2 60 (8) Cataracts 3 Yr 3 (2-5) ≥3 41 (6) 5 Yr 10 (7-12) Missing 99 (14) 10 Yr 18 (15-22) Cataracts Hypothyroidism 3 Yr 5 (3-7) Yes 105 (15) 5 Yr 8 (6-10) No 567 (79) 10 Yr 13 (10-16) Missing 45 (6) Gonadal dysfunction/infertility 3 and 5 Yr 0 (0-1) Congestive heart failure requiring hormone replacement 10 Yr 3 (2-5) < Yes 1 ( 1) Stroke/seizure 3 Yr 3 (1-4) No 505 (70) 5 Yr 3 (2-4) Missing 211 (29) 8Yr† 3 (2-5) Diabetes mellitus New malignancy 3 Yr 0 Yes 8 (1) 5 Yr 1 (0-1) No 499 (70) 10 Yr 3 (1-5) Missing 210 (29) Gonadal dysfunction/infertility requiring hormone replacement Includes events occurring at least 1 year after HCT and reported in ≥3% Yes 27 (4) of patients. No 643 (90) * Death as competing risk. Patients censored at relapse or second HCT. Missing 47 (7) † No events reported after 8 years. Growth hormone deficiency/growth disturbance Yes 122 (17) No 539 (75) After relapse or second HCT 8 (1) After 1 year, but relapse status unknown 1 (<1) and brain tumor). The 22 subsequent malignant neoplasms Missing 47 (7) occurring after 1 year after HCT and before relapse or a second Hemorrhage cystitis HCT included the following diagnoses: thyroid cancer Yes 1 (<1) (8 cases), nonmeningioma brain tumor (6), sarcoma (4), breast No 665 (93) Missing 51 (7) cancer (1), other non–central nervous system solid tumor (2), Hypothyroidism and 1 unspecified subsequent malignancy. The 10-year cu- Yes 76 (11) mulative incidence of subsequent malignant neoplasm was No 589 (82) 3% (95% CI, 1% to 5%). After relapse or second transplantation 5 (<1) Missing 47 (7) Pancreatitis DISCUSSION Yes 4 (<1) No 503 (70) HCT is an important treatment modality in infants and Missing 210 (29) young children with very-high-risk and relapsed or refrac- TTP/HUS tory leukemias. However, there is little reported that considers Yes 3 (<1) No 637 (89) a range of important outcomes after HCT in the first years Missing 77 (11) of life, including survival, risk factors for mortality, cumula- Renal failure severe enough to warrant dialysis tive incidence of relapse, second malignant neoplasms, and Yes 2 (<1) organ toxicities [4,6-8]. As the numbers of survivors of pe- No 672 (94) Missing 43 (6) diatric HCT expand over time, understanding the issues faced Stroke/seizures by survivors of HCT at early age is increasingly important [11]. Yes 20 (3) In a large, multicenter, multinational cohort, we sought to No 620 (86) characterize the outcomes of patients who underwent allo- Missing 77 (11) Bronchiolitis obliterans geneic myeloablative HCT for hematologic malignancy early Yes 6 (<1) in childhood, here assessed as undergoing HCT at less than No 542 (76) 3 years of age. < After relapse or second transplantation 1 ( 1) We report that those who survived relapse free for at least Missing 168 (23) Interstitial pneumonitis/idiopathic pneumonia syndrome 1 year after HCT had favorable overall survival and low sub- Yes 8 (1) sequent transplantation-related mortality. These are important No 700 (98) findings for those caring for very young children undergo- < After relapse or second transplantation 2 ( 1) ing HCT for hematologic malignancy. The favorable overall Missing 7 (<1) Noninfectious liver toxicity survival outcomes support the use of HCT as a successful treat- Yes 1 (<1) ment modality in the youngest of patients. Nonetheless, No 701 (98) relapse of hematologic malignancy was found to be the < After relapse or second transplantation 4 ( 1) leading cause of death after 1 year of relapse-free survival Missing 11 (2) (as well as within the first year after HCT). Prior reports in Includes those occurring at least 1 year after HCT, before relapse or second HCT, high-risk AML, infant ALL, and juvenile myelomonocytic leu- unless otherwise specified. Data presented are n (%) unless otherwise indicated. There were no events at least 1 year after transplantation and before relapse or kemia have also shown that relapse is a leading cause of second HCT for the following organ toxicities/late effects: avascular necrosis, adverse outcomes after pediatric HCT [1-3]. Our results, in myocardial infarction, pulmonary hemorrhage, and cryptogenic organizing the context of a relatively large cohort of patients undergo- pneumonia. TTP indicates thrombotic thrombocytopenic purpura; HUS, hemolytic uremic ing HCT in early childhood, reinforce the importance of syndrome. investigations aimed at reducing the risk of relapse in this population. 1332 L.M. Vrooman et al. / Biol Blood Marrow Transplant 23 (2017) 1327–1334

Table 4 Multivariable Analysis of Risk for Organ Toxicities and Late Effects

Parameter Category n HR (95% CI) P Value Cataracts AgeatHCT,yr <1 146 1.00 .027* 1-1.99 218 1.06 (.52-2.14) .88 2-2.99 204 1.95 (1.02-3.74) .044 TBI No 324 1.00 <.0001* Yes 244 17.20 (7.44-39.75) <.0001 Gonadal dysfunction/infertility AgeatHCT,yr <1 147 1.00 .041* 1-1.99 220 .60 (.15-2.41) .47 2-2.99 204 2.36 (.76-7.33) .14 Sex Male 326 1.00 .0019 Female 245 7.03 (2.06-24.01) .0019 GH deﬁciency/growth disturbance Donor/stem cell source HLA-identical sibling 125 1.00 .0025* Other related 29 .31 (.04-2.41) .2627 Unrelated donor (BM or PB) 174 2.91 (1.51-5.62) .0014 UCB (BM or PB) 231 2.23 (1.11-4.49) .024 TBI No 339 1.00 <.0001* Yes 220 3.51 (2.22-5.54) <.0001 Hypothyroidism TBI No 340 1.00 <.0001* Yes 223 5.28 (2.97-9.40) <.0001

Includes events occurring at least 1 year after HCT and reported in ≥3% of patients. Significant predictors are presented. There were no significant predictors of stroke/seizure identified. GH indicates growth hormone; UCB, umbilical cord blood; BM, bone marrow; PB, peripheral blood. * Overall P value.

Our results also demonstrate that late effects are common In addition, our findings reinforce the risks of TBI at very in this population. Hypothyroidism, growth hormone young age. TBI exposure was associated with an increased deficiency/growth disturbance, and cataracts appeared to risk of endocrine toxicities, including hypothyroidism and increase in cumulative incidence over time, whereas the oc- growth hormone deficiency/growth disturbance, in keeping currence of stroke/seizure appeared to plateau. Endocrine with prior reports [8,17]. Survivors of pediatric HCT, partic- toxicities were among the most frequently reported. Indeed, ularly those exposed to TBI, are considered at greater risk endocrine late effects have been previously reported with high of developing insulin resistance [14,15,18]. In our cohort, only prevalence after HCT in childhood, including in those under- 1% of patients were reported with diabetes mellitus and going HCT at very young age [8,12-14]. Bresters and colleagues glucose intolerance was not systematically captured. Con- described a prevalence of thyroid dysfunction after HCT at tinued monitoring will be needed to assess late endocrine young age of 30% [8]. In our cohort, the cumulative incidence effects with increasing age, such as manifestations of gonadal of hypothyroidism increased over time, suggesting an ongoing dysfunction, infertility, thyroid dysfunction, and glucose in- risk of developing this late effect. Survivors of HCT in child- tolerance. TBI exposure was also an independent predictor hood are considered at risk for gonadal dysfunction and of increased risk of cataracts. Radiation exposure, including infertility [12,13,15]. Here, among those undergoing HCT at TBI and cranial radiation, is a known risk factor for cataract age less than 3 years, females were more likely than males development [19,20]. The extent of visual impairment or need to be reported with gonadal dysfunction/infertility requir- for surgical intervention associated with cataracts in this ing hormone replacement, highlighting the importance of cohort is not known. Despite these risks, TBI currently remains attention to pubertal development and reproductive func- an important modality for members of this population. Our tion in female survivors of HCT. The reporting of gonadal findings highlight the risks of TBI at very young age and re- dysfunction and infertility is anticipated to increase with inforce the importance of ongoing clinical follow-up with further aging of the cohort, as many in this cohort were still attention to these risks. too young to have gonadal dysfunction fully evaluated or di- Our results also underscore the impact of chronic GVHD agnosed, supporting careful ongoing monitoring of both male in those undergoing HCT at very young age. Chronic GVHD and female survivors. Some prior reports have suggested has been associated with an increased risk of adverse out- higher frequencies of short stature and growth hormone de- comes after HCT in pediatric and adult HCT [12,21-23]. Here, ficiency after HCT at young age than reported here, which may chronic GVHD at 1 year after HCT was predictive of an in- reflect differences in age at follow-up, means of assessment creased risk of mortality. It is of note, however, that we did of chronic conditions, or rates and doses of TBI and other ex- not demonstrate an increased risk for individual organ tox- posures [6,16]. We note that the mechanism underlying the icities based on the occurrence of chronic GVHD at 1 year after relationship seen between donor type and stem cell source HCT. It is possible that our exploration of the potential impact and growth hormone deficiency/growth disturbance is unclear, of GVHD on individual late effects may have been limited by but may be related to other treatment-associated factors. patient numbers. Armenian and colleagues, reporting on sur- Overall, we recommend long-term monitoring of those un- vivors of childhood HCT from the Bone Marrow Transplant dergoing HCT at very young age, as the potential for the Survivor Study, demonstrated that active chronic GVHD was development of morbidities with advancing age remains a associated with high risk of adverse health status [12].We concern. note that our analysis did not account for the ongoing status L.M. Vrooman et al. / Biol Blood Marrow Transplant 23 (2017) 1327–1334 1333

of chronic GVHD in relation to the risk for organ toxicities monitoring for organ dysfunctions and toxicities is therefore and late effects, which could be of interest in future inves- a critical element in the health care of survivors. Exposure to tigations. Nonetheless, our findings highlight the importance TBI emerged as an independent predictor of multiple fre- of improving strategies for preventing and eliminating GVHD quently reported toxicities. Transplantation survivors treated in those undergoing HCT early in childhood. with TBI at age less than 3 years likely warrant heightened The development of a subsequent malignant neoplasm is late effects surveillance. Future efforts should more precise- a particularly concerning outcome after HCT. Here, the 10- ly assess the impact of HCT at very young age on long-term year cumulative incidence of subsequent malignant neoplasm neurocognitive development and function, growth, endo- was 3% (95% CI, 1% to 5%), in keeping with prior reports crine function, and emerging toxicities with advancing age, after pediatric allogeneic HCT [24]. Risk factors for the de- and also focus on interventions aimed at mitigating these velopment of subsequent malignant neoplasms or specific toxicities. diagnoses were not explored, given the overall low number of events. Survivors of HCT at very young age should be moni- ACKNOWLEDGMENTS tored with attention to an ongoing risk for second malignant CIBMTR Support List neoplasms, as the number of subsequent neoplasms is an- The CIBMTR is supported primarily by Public Health ticipated to increase with age [24-26]. There were several Service grant/cooperative agreement 5U24-CA076518 from cases of thyroid cancer in this cohort. Although this reflects the National Cancer Institute (NCI), the National Heart, Lung a small percentage of patients, it is of note that the overall and Blood Institute (NHLBI) and the National Institute of annual incidence of thyroid cancer in children less than 15 Allergy and Infectious Diseases (NIAID); a grant/cooperative years of age has been estimated at 2.0 cases per million people agreement 5U10HL069294 from NHLBI and NCI; a contract per year [27]. Radiation exposure, including TBI, is a known HHSH250201200016C with Health Resources and Services risk factor for the development of thyroid cancer, and Administration (HRSA/DHHS); 2 grants N00014-15-1-0848 younger age has been associated with increased radiation and N00014-16-1-2020 from the Office of Naval Research; risk [28-30]. Providers caring for survivors exposed to TBI at and grants from *Actinium Pharmaceuticals, Inc.; Alexion; young age should have increased awareness of the risk of *Amgen, Inc.; anonymous donation to the Medical College thyroid cancer, an understanding of evolving screening rec- of Wisconsin; Astellas Pharma US; AstraZeneca; Atara ommendations, and should counsel survivors about this risk. Biotherapeutics, Inc.; Be The Match Foundation; *Bluebird Bio, Current late effects surveillance recommendations support Inc.; *Bristol-Myers Squibb Oncology; *Celgene Corpora- annual palpation of the thyroid for nodules by an experi- tion; Cellular Dynamics International, Inc.; Cerus Corporation; enced examiner [15,31]. Optimal screening schedules and *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; modalities for secondary thyroid cancers in those with TBI Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; exposure at very young age are an important area for further Gilead Sciences, Inc.; Health Research, Inc. Roswell Park investigation. Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; There are several limitations to this study. First, CIBMTR Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; data forms capture a discrete listing of late complications, with Jeff Gordon Children’s Foundation; The Leukemia & Lym- other potential late effects of interest, such as hypertension, phoma Society; Medac, GmbH; MedImmune; The Medical dyslipidemia, dental abnormalities, skeletal toxicities and College of Wisconsin; *Merck & Co., Inc.; *Mesoblast; neurocognitive impairments, not systematically captured. MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Therefore, our finding that approximately one third of pa- Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis tients experienced at least 1 of the CIBMTR-designated organ Pharmaceuticals Corporation; Onyx Pharmaceuticals; toxicity or late effect may underestimate the full burden of Optum Healthcare Solutions, Inc.; Otsuka America Pharma- post-HCT morbidities. In considering the frequency of late ceutical, Inc.; Otsuka Pharmaceutical Co., Ltd. – Japan; PCORI; effects, the extent of missing values could result in over or Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; underestimation of late effects. Other limitations include that *Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; additional details regarding reported toxicities are not avail- *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, able and that the study was not powered to assess potential Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; Universi- risk factors for less frequently occurring toxicities. In addi- ty of Minnesota; and *Wellpoint, Inc. The views expressed tion, these results do not assess the impact of pre-HCT in this article do not reflect the official policy or position of treatment exposures. Finally, data from early years may the National Institute of Health, the Department of the Navy, have more limited applicability to current practice. These the Department of Defense, Health Resources and Services results should be considered in the context of important Administration (HRSA) or any other agency of the U.S. general changes in the care of pediatric HCT patients over Government. the 25 years evaluated, including trends of increased use of *Corporate Members. unrelated donor and umbilical cord blood sources, as well as Financial disclosure: There is nothing to disclose. improvements in supportive care and a greater emphasis Conflict of interest statement: There are no conflicts of in- on monitoring for late effects. Acknowledging these limita- terest to report. tions, we believe this study provides a comprehensive characterization of outcomes after HCT for hematologic malignancy in the first years of life. REFERENCES In conclusion, those who survived relapse free for at least 1. Locatelli F, Masetti R, Rondelli R, et al. 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