Key Points

  • Nearly 25% of AYAs with AML who were disease-free survivors at 1 year after myeloablative HCT had ≥1 late effects.

  • With the exception of cataracts, high-dose TBI exposure was not an independent predictor for malignant or nonmalignant late effects.

Abstract

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

Introduction

More than 50% of adolescents and young adults (AYAs)1  with high-risk acute myeloid leukemia (AML) will transition to long-term survivorship after allogeneic hematopoietic cell transplantation (allo-HCT), with a rising prevalence of AYA transplant survivors anticipated in the coming years.2  There is a heightened need to understand late effects and survivorship issues in this population because of the unique physiological and/or psychosocial challenges associated with the AYA life stages.3  For example, relative to survivors of childhood and older adult cancer, the incidence of corticosteroid-associated avascular necrosis (AVN) peaks in AYA survivors, as does the likelihood of developing a subsequent neoplasm (SN).4,5  Furthermore, late effects after HCT may have a disproportionately negative effect on the ability of AYA survivors to complete schooling, enter or re-enter the workforce, and/or bear children.6  Survivorship challenges may be underestimated in this transplant population because of the high probability of AYAs terminating follow-up at transplant centers after HCT.7 

The use of HCT is frequently necessary in AYA AML to achieve leukemia cure.8-11  High-dose total body irradiation (TBI) in combination with chemotherapy or high-dose chemotherapy-only regimens have been the two most common myeloablative conditioning (MAC) approaches used in HCT for AYA AML. Studies of childhood HCT survivors demonstrate the potential for certain malignant health conditions related to these transplant exposures, and reports in adults and children suggest that high-dose TBI increases the risk of SNs after HCT.12-15  Less is known about the impact of high-dose TBI or chemotherapy-only MAC regimens on nonmalignant late effects. Furthermore, there is a paucity of literature describing late effects in survivors of MAC HCT for AYA AML.

We therefore conducted a population-based study using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) to identify the cumulative incidence of malignant and nonmalignant late effects, long-term survival, and risk factors for late effects and mortality in AYA AML survivors of HCT. We also sought to evaluate the impact of TBI-based vs chemotherapy-only MAC on the development of late effects and to determine any associations between type of conditioning regimen and survival.

Materials and methods

Data source

The CIBMTR is a research collaboration between the National Marrow Donor Program/Be The Match and the Medical College of Wisconsin. More than 450 transplantation centers worldwide contribute detailed data prospectively on consecutive transplantations to the CIBMTR. Compliance and accuracy of data reported to the CIBMTR are monitored by on‐site audits. All patients are observed longitudinally until death or loss to follow‐up. Patients and/or guardians provide written informed consent for data submission and research participation. The Institutional Review Boards of the Medical College of Wisconsin and the National Marrow Donor Program approved this study.

Patient population

AYA patients (age 15-39 years) with AML who underwent first HCT from an HLA-identical sibling (matched related donor) or matched (8/8) unrelated donor between 2000 and 2014, who remained disease free for at least 12 months after HCT, and who were reported to the CIBMTR were included. Patients received HCT conditioning with myeloablative TBI (≥500 cGy single dose or ≥800 cGy fractionated) or myeloablative doses of chemotherapy-only regimens (busulfan >8 mg/kg orally or the IV equivalent or melphalan >150 mg/m2).16  Exclusion criteria applied to patients who had received previous autologous HCT or allo-HCT, had a diagnosis of therapy-related AML or a cancer predisposition syndrome, or had relapsed and/or died within the first year after HCT. Patients for whom the CIBMTR team follow-up completeness index was less than 80% at 3 years after HCT were also excluded (n = 499).

Late effects and definitions of outcomes

Late effects data are collected through CIBMTR comprehensive report forms that were obtained on a subset of CIBMTR participants selected by weighted randomization for more comprehensive research-level data collection. Transplant centers reported the following late effects using a dichotomized response choice (yes/no) and the date of diagnosis of the late effect if applicable: congestive heart failure (ejection fraction <40%), myocardial infarction, seizure, stroke, cataracts, AVN, diabetes mellitus/hyperglycemia, hypothyroidism, growth hormone deficiency or growth disturbance, gonadal dysfunction or infertility requiring hormone replacement, hemorrhagic cystitis, pancreatitis, thrombotic microangiopathy or hemolytic uremic syndrome, veno-occlusive disease or sinusoidal obstruction syndrome, cirrhosis, renal failure requiring dialysis, bronchiolitis obliterans, cryptogenic organizing pneumonia, diffuse alveolar hemorrhage, noninfectious interstitial pneumonitis or idiopathic pneumonia syndrome, and SNs.

Overall survival (OS) was defined as the time from HCT until death as a result of any cause, and leukemia-free survival (LFS) was defined as the time until disease relapse or death. Patients who were alive without such events were censored at the time of last follow-up. Nonrelapse mortality (NRM) was defined as death in the absence of disease relapse or progression from the time of HCT. The primary cause of death for each patient was reported by the treating center.

Statistical analysis

The primary objectives of this study were to describe the cumulative incidence of late effects among AYA AML survivors of HCT and to compare late effects between patients with MAC TBI vs MAC chemotherapy only. Secondary objectives were to compare the prevalence of individual late effects and survival between the 2 groups and determine predictors of late effects, OS, LFS, relapse, and NRM among the total population.

Categorical variables were summarized by using standard descriptive measures. χ2 test and Wilcoxon rank sum tests were used to compare the distribution of categorical variables and continuous variables, respectively. Late effects were categorized as SNs or as nonmalignant and were then summarized and individually analyzed. A pathology report was used to verify SNs whenever possible. The prevalence of each late effect among 2-, 5-, and 10-year survivors of HCT was computed. The cumulative incidence probability of an individual late effect at 2, 5 and 10 years after HCT was estimated, and death was treated as a competing risk for the whole group and for patients with TBI-based conditioning vs chemotherapy-only conditioning. The cumulative incidence probability of NRM and relapse was estimated at 2, 5, and 10 years after HCT, with relapse and NRM treated as competing risks, respectively. The Kaplan-Meier method was used to estimate the probability of OS and LFS. Gray’s test and log-rank test were used to compare cumulative incidence functions and survival functions, respectively, between the 2 treatment groups.

A Cox proportional hazards regression model was used to assess the impact of myeloablative TBI or chemotherapy only on individual late effects with a sufficient number of events (at least 5 late effects in each of the 2 treatment groups). Conditioning type was the main effect and additional variables were related to the patient (age, sex, race/ethnicity, cytomegalovirus serostatus), disease (disease status at HCT, time from diagnosis to HCT), in vivo T-cell depletion (antithymocyte globulin/alemtuzumab), year of HCT, and having chronic graft-versus-host disease (cGVHD) within 12 months of HCT. Stepwise selection was used to identify covariates to be included in the final models; all covariates associated with outcome at P < .05 were retained in the final models and were considered significant. Proportionality assumptions were checked for all variables considered. Time-dependent covariates were used in case non-proportionality was detected.

A similar Cox regression model was used to predict OS, LFS, NRM, and relapse. cGVHD and late effects were added into the regression model as time-dependent covariates. In addition to the variables used in the late effects analyses, Karnofsky score, donor type, and graft source were included. Patients without an event were censored at the last research-level follow-up date. All statistical analyses were performed using SAS 9.4 software.

The risk of cancer in the study cohort was compared with that of the general population using methods described in previous CIBMTR studies.12,17,18  Briefly, for each transplant recipient, the number of person-years at risk was calculated from the date of transplantation until date of last contact, death, or diagnosis of new cancer, whichever occurred first. Incidence rates for all cancers in the general population were obtained from selected registries.19  Age-, sex-, and region-specific cancer incidence rates were applied to the appropriate person-years at risk to compute the expected numbers of cancers. Observed-to-expected ratios (also called standardized incidence ratios) were calculated and the exact Poisson distribution was used to calculate 95% confidence intervals (CIs).18 

Results

Patient characteristics

In all, 826 AYAs with AML (n = 390 [47%] receiving TBI; n = 436 [53%] receiving chemotherapy-only conditioning) who survived at least 1 year disease-free after MAC HCT were included. Baseline patient demographics and transplant characteristics stratified by TBI vs chemotherapy-only conditioning are described in Table 1. The median follow-up of survivors in the population was 77 months (range, 12-194 months); median follow-up was longer in the TBI group (94 months) relative to the chemotherapy-only group (73 months). The majority (n = 367 [94%]) of those included in the TBI group received TBI doses ≥1200 cGy; the most commonly used myeloablative chemotherapy regimen was busulfan with cyclophosphamide (n = 311 [71%]). Of the patients who were treated with busulfan-based chemotherapy, 156 (30%) received their dose by the oral route and 353 (68%) received their dose IV. Grades 2 to 4 acute GVHD (aGVHD) occurred in 36% of the patients overall, and grades 3 to 4 aGVHD occurred in 9% of patients receiving either TBI or non-TBI–based conditioning (Table 2). cGVHD occurred in 55% of the total study cohort, with extensive cGVHD documented in 45% of those receiving TBI and 44% of those receiving non-TBI–based conditioning. At the time of analysis, 177 deaths (21%) had occurred in the total population, with primary disease representing the most common cause of death in both groups.

Table 1.

Baseline characteristics of patients undergoing first myeloablative HCT for AML at age 15-39 years between 2000-2014 who survived disease free for 12+ months (reported to the CIBMTR)

VariableAll PatientsTBIChemotherapy only
No.%MedianRangeNo.%MedianRangeNo.%MedianRange
No. of patients 826    390    436    
No. of centers 147    92    113    
Follow-up of survivors, mo   77 12-194   94 13-194   73 12-182 
Year of transplant             
 2000-2004 257 31   133 34   124 28   
 2005-2009 359 43   180 46   179 41   
 2010-2014 210 25   77 20   133 31   
Patient age at transplant, y   29 15-40   30 15-40   28 15-40 
 15-19 127 15   52 13   75 17   
 20-29 325 39   151 39   174 40   
 30-39 374 45   187 48   187 43   
Patient age at last contact/death, y   35 17-55   36 17-55   34 17-53 
 15-19 24   12   12   
 20-29 221 27   85 22   136 31   
 30-39 350 42   173 44   177 41   
 40+ 231 28   120 31   111 25   
Sex             
 Male 449 54   213 55   236 54   
 Female 377 46   177 45   200 46   
Race/ethnicity             
 White 654 79   296 76   358 82   
 Black/African American 18     11   
 Hispanic 63   27   36   
 Other* 81 10   56 14   25   
Performance score             
 90-100 624 76   290 74   334 77   
 <90 182 22   87 22   95 22   
Disease status before transplant             
 CR1 576 70   267 68   309 71   
 CR2+ 250 30   123 32   127 29   
Cytogenetics             
 Favorable 124 15   58 15   66 15   
 Intermediate 502 61   231 59   271 62   
 Unfavorable 148 18   76 19   72 17   
Donor             
 HLA-identical sibling 362 44   158 41   204 47   
 Matched (8/8) unrelated donor 464 56   232 59   232 53   
Graft type             
 Bone marrow 294 36   140 36   154 35   
 Peripheral blood 532 64   250 64   282 65   
Conditioning regimen             
 TBI + cyclophosphamide 355 43   355 91   NA    
 TBI + cyclophosphamide + etoposide 17   17   NA    
 TBI + etoposide 18   18   NA    
 Busulfan + cyclophosphamide 311 38   NA    311 71   
 Busulfan + fludarabine 125 15   NA    125 29   
Total TBI dose (cGy)   1200 550-1440   1200 550-1440 NA    
 550-799     NA    
 800-1199 14   14   NA    
 ≥1200 367 44   367 94   NA    
Busulfan route             
 Oral 156 30   NA    156 30   
 IV 353 68   NA    353 68   
Corticosteroids as part of GVHD prophylaxis             
 No 760 92   353 91   407 93   
 Yes 64   35   29   
Antithymocyte globulin/alemtuzumab before transplant             
 No 688 83   356 91   332 76   
 Yes 138 17   34   104 24   
VariableAll PatientsTBIChemotherapy only
No.%MedianRangeNo.%MedianRangeNo.%MedianRange
No. of patients 826    390    436    
No. of centers 147    92    113    
Follow-up of survivors, mo   77 12-194   94 13-194   73 12-182 
Year of transplant             
 2000-2004 257 31   133 34   124 28   
 2005-2009 359 43   180 46   179 41   
 2010-2014 210 25   77 20   133 31   
Patient age at transplant, y   29 15-40   30 15-40   28 15-40 
 15-19 127 15   52 13   75 17   
 20-29 325 39   151 39   174 40   
 30-39 374 45   187 48   187 43   
Patient age at last contact/death, y   35 17-55   36 17-55   34 17-53 
 15-19 24   12   12   
 20-29 221 27   85 22   136 31   
 30-39 350 42   173 44   177 41   
 40+ 231 28   120 31   111 25   
Sex             
 Male 449 54   213 55   236 54   
 Female 377 46   177 45   200 46   
Race/ethnicity             
 White 654 79   296 76   358 82   
 Black/African American 18     11   
 Hispanic 63   27   36   
 Other* 81 10   56 14   25   
Performance score             
 90-100 624 76   290 74   334 77   
 <90 182 22   87 22   95 22   
Disease status before transplant             
 CR1 576 70   267 68   309 71   
 CR2+ 250 30   123 32   127 29   
Cytogenetics             
 Favorable 124 15   58 15   66 15   
 Intermediate 502 61   231 59   271 62   
 Unfavorable 148 18   76 19   72 17   
Donor             
 HLA-identical sibling 362 44   158 41   204 47   
 Matched (8/8) unrelated donor 464 56   232 59   232 53   
Graft type             
 Bone marrow 294 36   140 36   154 35   
 Peripheral blood 532 64   250 64   282 65   
Conditioning regimen             
 TBI + cyclophosphamide 355 43   355 91   NA    
 TBI + cyclophosphamide + etoposide 17   17   NA    
 TBI + etoposide 18   18   NA    
 Busulfan + cyclophosphamide 311 38   NA    311 71   
 Busulfan + fludarabine 125 15   NA    125 29   
Total TBI dose (cGy)   1200 550-1440   1200 550-1440 NA    
 550-799     NA    
 800-1199 14   14   NA    
 ≥1200 367 44   367 94   NA    
Busulfan route             
 Oral 156 30   NA    156 30   
 IV 353 68   NA    353 68   
Corticosteroids as part of GVHD prophylaxis             
 No 760 92   353 91   407 93   
 Yes 64   35   29   
Antithymocyte globulin/alemtuzumab before transplant             
 No 688 83   356 91   332 76   
 Yes 138 17   34   104 24   
*

Multiple races (n = 11), Asian (n = 61), American Indian or Alaska Native (n = 4), Native Hawaiian or Pacific Islander (n = 3), other unspecified (n = 2).

Table 2.

Posttransplant characteristics of patients undergoing first myeloablative HCT for AML at age 15-39 years between 2000-2014 who survived disease free for 12+ months (reported to the CIBMTR)

VariableAll patientsTBIChemotherapy only
No.%No.%No.%
No. of patients 826  390  436  
aGVHD grade       
 0 354 43 138 35 216 50 
 1 163 20 82 21 81 19 
 2 223 27 127 33 96 22 
 3 68 33 35 
 4 10 
Maximum grade of cGVHD       
 None 371 45 178 46 193 44 
 Limited 87 11 35 52 12 
 Extensive 367 44 177 45 190 44 
Reported cause of death       
 Total deaths 177 21 92 24 85 19 
 Primary disease 68 33 35 
 GVHD 28 18 10 
 Infection 22 12 10 
 IPn/ARDS <1 <1 <1 
 Organ failure 19 11 
 SN <1  <1 
 Other cause 21 10 11 
VariableAll patientsTBIChemotherapy only
No.%No.%No.%
No. of patients 826  390  436  
aGVHD grade       
 0 354 43 138 35 216 50 
 1 163 20 82 21 81 19 
 2 223 27 127 33 96 22 
 3 68 33 35 
 4 10 
Maximum grade of cGVHD       
 None 371 45 178 46 193 44 
 Limited 87 11 35 52 12 
 Extensive 367 44 177 45 190 44 
Reported cause of death       
 Total deaths 177 21 92 24 85 19 
 Primary disease 68 33 35 
 GVHD 28 18 10 
 Infection 22 12 10 
 IPn/ARDS <1 <1 <1 
 Organ failure 19 11 
 SN <1  <1 
 Other cause 21 10 11 

ARDS, acute respiratory distress syndrome; IPn, interstitial pneumonitis.

SNs

An SN was reported in 2% (n = 16) of evaluable AYA AML survivors (supplemental Table 1). Solid cancers accounted for 15 of the 16 SNs; skin cancer was the most prevalent (1 melanoma and 7 non-melanoma skin cancers). The estimated 2-, 5-, and 10-year cumulative incidence of SNs was 0% (95% CI, 0%-1%), 1% (95% CI, 0%-2%), and 4% (95% CI, 2%-6%), respectively (Table 3). There was no difference in the estimated 10-year cumulative incidence of SNs after stratifying for age (15-19 years, 20-29 years, and 30-39 years) (supplemental Table 2). Overall, the estimated 10-year cumulative incidence of SNs did not significantly differ based upon conditioning therapy type (3% for TBI-based vs 4% for chemotherapy-only conditioning; P = .73). Multivariable analysis demonstrated that the type of conditioning regimen was not associated with SNs; however, achieving a second or greater complete remission (CR2+) at the time of transplant was a risk factor for an SN compared with undergoing HCT in the first CR (CR1) (hazard ratio [HR], 2.70; 95% CI, 1.00-7.27; P = .049) (Table 4). Seven patients (44%) with SNs died; death as a result of the SN occurred in 1 patient (supplemental Table 3).

Table 3.

Estimated cumulative incidence of select late effects for AYA patients with AML after ablative HCT

Late effectAll patients (N = 826)TBI (n = 390)Chemotherapy only (n = 436)P*
No.95% CINo.95% CINo.95% CI
SNs       .73 
 2-y 0-1 0-1 0-1  
 5-y 0-2 0-2 0-2  
 10-y 2-6 1-7 1-8  
AVN       .2 
 2-y 1-4 2-5 1-3  
 5-y 4-7 4-9 3-7  
 10-y 5-10 6-13 4-9  
Cataracts       <.001 
 2-y 0-1 0-3 0-1  
 5-y 3-7 6-12 0-2  
 10-y 10 7-13 15 11-19 2-10  
Diabetes mellitus       .21 
 2-y 1-2 1-5 0-1  
 5-y 2-4 2-6 1-4  
 10-y 3-7 3-9 1-8  
Hypothyroidism       .38 
 2-y 0-1 0-2 0-1  
 5-y 1-3 1-4 1-3  
 10-y 2-5 2-7 1-5  
Gonadal dysfunction       .98 
 2-y 2-5 2-6 2-5  
 5-y 5-9 5-10 4-9  
 10-y 10 8-13 10 6-13 11 7-16  
Late effectAll patients (N = 826)TBI (n = 390)Chemotherapy only (n = 436)P*
No.95% CINo.95% CINo.95% CI
SNs       .73 
 2-y 0-1 0-1 0-1  
 5-y 0-2 0-2 0-2  
 10-y 2-6 1-7 1-8  
AVN       .2 
 2-y 1-4 2-5 1-3  
 5-y 4-7 4-9 3-7  
 10-y 5-10 6-13 4-9  
Cataracts       <.001 
 2-y 0-1 0-3 0-1  
 5-y 3-7 6-12 0-2  
 10-y 10 7-13 15 11-19 2-10  
Diabetes mellitus       .21 
 2-y 1-2 1-5 0-1  
 5-y 2-4 2-6 1-4  
 10-y 3-7 3-9 1-8  
Hypothyroidism       .38 
 2-y 0-1 0-2 0-1  
 5-y 1-3 1-4 1-3  
 10-y 2-5 2-7 1-5  
Gonadal dysfunction       .98 
 2-y 2-5 2-6 2-5  
 5-y 5-9 5-10 4-9  
 10-y 10 8-13 10 6-13 11 7-16  
*

P value for comparison of TBI and chemotherapy-only MAC regimen.

Table 4.

Multivariate Cox models for individual late effects in AYA patients with AML after ablative HCT

Late effect/variablenHR95% CIP
SN     
 Conditioning regimen    .696 
  Non-TBI MAC 435   
  TBI MAC 383 0.82 0.31-2.20  
 Disease status at HCT    .049 
  CR1 571   
  CR2+ 247 2.70 1.00-7.27  
 cGVHD     
  No 368   
  Yes 450 1.28 0.46-3.55 .637 
AVN     
 Conditioning regimen    .178 
  Non-TBI MAC 422   
  TBI MAC 367 1.48 0.84-2.64  
 cGVHD    .006 
  No 354   
  Yes 435 2.49 1.29-4.76  
Cataracts     
 Conditioning regimen     
  Non-TBI MAC 432   
  TBI MAC 379 4.98 2.42-10.24 <.0001 
  TBI MAC 550-1200 cGy 23 2.08 0.26-16.45 .486 
  TBI MAC ≥1200 cGy 356 5.16 2.51-10.63 <.0001 
 Disease status at HCT    .049 
  CR1 567   
  CR2+ 244 1.74 1.00-3.03  
 cGVHD    .0006 
  No 363   
  Yes 448 3.22 1.65-6.29  
Diabetes mellitus     
 Conditioning regimen    .202 
  Non-TBI MAC 340   
  TBI MAC 314 1.82 0.72-4.58  
 cGVHD    .030 
  No 300   
  Yes 354 3.36 1.12-10.04  
Gonadal dysfunction     
 Conditioning regimen    .980 
  Non-TBI MAC 419   
  TBI MAC 365 0.99 0.60-1.64  
 Sex of recipient    .019 
  Male 437   
  Female 347 1.83 1.10-3.04  
 Disease status before HCT    .006 
  CR1 544   
  CR2+ 240 2.02 1.22-3.35  
Hypothyroidism     
 Conditioning regimen    .367 
  Non-TBI MAC 426   
  TBI MAC 372 1.55 0.60-4.00  
Late effect/variablenHR95% CIP
SN     
 Conditioning regimen    .696 
  Non-TBI MAC 435   
  TBI MAC 383 0.82 0.31-2.20  
 Disease status at HCT    .049 
  CR1 571   
  CR2+ 247 2.70 1.00-7.27  
 cGVHD     
  No 368   
  Yes 450 1.28 0.46-3.55 .637 
AVN     
 Conditioning regimen    .178 
  Non-TBI MAC 422   
  TBI MAC 367 1.48 0.84-2.64  
 cGVHD    .006 
  No 354   
  Yes 435 2.49 1.29-4.76  
Cataracts     
 Conditioning regimen     
  Non-TBI MAC 432   
  TBI MAC 379 4.98 2.42-10.24 <.0001 
  TBI MAC 550-1200 cGy 23 2.08 0.26-16.45 .486 
  TBI MAC ≥1200 cGy 356 5.16 2.51-10.63 <.0001 
 Disease status at HCT    .049 
  CR1 567   
  CR2+ 244 1.74 1.00-3.03  
 cGVHD    .0006 
  No 363   
  Yes 448 3.22 1.65-6.29  
Diabetes mellitus     
 Conditioning regimen    .202 
  Non-TBI MAC 340   
  TBI MAC 314 1.82 0.72-4.58  
 cGVHD    .030 
  No 300   
  Yes 354 3.36 1.12-10.04  
Gonadal dysfunction     
 Conditioning regimen    .980 
  Non-TBI MAC 419   
  TBI MAC 365 0.99 0.60-1.64  
 Sex of recipient    .019 
  Male 437   
  Female 347 1.83 1.10-3.04  
 Disease status before HCT    .006 
  CR1 544   
  CR2+ 240 2.02 1.22-3.35  
Hypothyroidism     
 Conditioning regimen    .367 
  Non-TBI MAC 426   
  TBI MAC 372 1.55 0.60-4.00  

Nonmalignant late effects

Among the total population, 22% of AYA survivors reported at least 1 nonmalignant late effect (supplemental Table 4) with a higher frequency of 1 late effect (22% vs 12%) and ≥2 late effects (7% vs 3%) reported in patients exposed to TBI relative to chemotherapy-only MAC. The estimated cumulative incidence of nonmalignant late effects increased over 10 years (Table 3), particularly for cataracts, gonadal dysfunction, and AVN in which the estimated cumulative incidence was ≤4% at 2 years and approached 10% at 10 years. There was no difference in the estimated 10-year cumulative incidence of any nonmalignant late effect between younger and older AYAs (supplemental Table 2). Multivariable analyses of individual late effects demonstrated that TBI-based conditioning was significantly associated only with the development of cataracts (HR, 4.98; 95% CI, 2.42-10.24; P < .001) (Table 4). cGVHD at 1 year after HCT was independently associated with a greater risk of AVN (HR, 2.49; 95% CI, 1.29-4.76; P = .006), cataracts (HR, 3.22; 95% CI, 1.65-6.29; P = .0006), and diabetes mellitus (HR, 3.36; 95% CI, 1.12-10.04; P = .030). Female patients were more likely to have gonadal dysfunction compared with males (HR, 1.83; 95% CI, 1.10-3.04; P = .019). Disease status (CR2+ vs CR1) was significantly associated with a higher risk of cataracts (HR, 1.74; 95% CI, 1.00-3.03; P = .049) and gonadal dysfunction (HR, 2.02; 95% CI, 1.22-3.35; P = .006).

Survival outcomes

Unadjusted survival outcomes are described in Table 5. NRM at 10 years among the total population was 14% (95% CI, 11%-17%) and did not significantly differ based upon conditioning type. The cumulative incidence of relapse at 10 years was significantly lower in patients receiving TBI vs chemotherapy (13% vs 19%; P = .01); however, this did not translate into differences in LFS or OS between the conditioning groups. Multivariable analyses (Table 6) revealed that the presence of cGVHD at 1 year after HCT (HR, 1.62; 95% CI, 1.19-2.21; P < .002) and development of SNs (HR, 7.97; 95% CI, 3.62-17.53; P < .0001) were associated with increased mortality.

Table 5.

Unadjusted survival estimates of AYAs with AML who survived at least 1 year disease free after ablative HCT

OutcomesAll patients (N = 826)TBI (n = 390)Chemotherapy only (n = 436)P*
Probability95% CIProbability95% CIProbability95% CI
OS       .47 
 2-y 93 92-95 92 90-95 94 92-96  
 5-y 81 78-84 80 76-84 83 79-86  
 10-y 73 69-76 72 66-77 73 67-79  
Relapse       .01 
 2-y 6-10 4-8 10 8-13  
 5-y 15 13-18 12 9-16 18 15-22  
 10-y 17 14-19 13 10-17 19 16-23  
NRM       .09 
 2-y 2-5 3-7 1-4  
 5-y 7-12 11 8-15 5-10  
 10-y 14 11-17 16 12-21 11 7-15  
LFS       .40 
 2-y 88 86-91 90 86-92 87 84-90  
 5-y 75 72-78 77 72-81 74 70-78  
 10-y 70 66-74 70 65-76 70 65-75  
OutcomesAll patients (N = 826)TBI (n = 390)Chemotherapy only (n = 436)P*
Probability95% CIProbability95% CIProbability95% CI
OS       .47 
 2-y 93 92-95 92 90-95 94 92-96  
 5-y 81 78-84 80 76-84 83 79-86  
 10-y 73 69-76 72 66-77 73 67-79  
Relapse       .01 
 2-y 6-10 4-8 10 8-13  
 5-y 15 13-18 12 9-16 18 15-22  
 10-y 17 14-19 13 10-17 19 16-23  
NRM       .09 
 2-y 2-5 3-7 1-4  
 5-y 7-12 11 8-15 5-10  
 10-y 14 11-17 16 12-21 11 7-15  
LFS       .40 
 2-y 88 86-91 90 86-92 87 84-90  
 5-y 75 72-78 77 72-81 74 70-78  
 10-y 70 66-74 70 65-76 70 65-75  
*

P value for comparison of TBI vs chemotherapy-only MAC regimen.

Table 6.

Multivariable analyses of survival outcomes of AYAs with AML who survived at least 1 year disease free after HCT

Outcome/variablenHR95% CIP
OS     
 Conditioning regimen    .541 
  Non-TBI MAC 436   
  TBI MAC 390 1.10 0.82-1.48  
 cGVHD    .002 
  No 371   
  Yes 455 1.62 1.19-2.21  
 SN    <.0001 
  No 810   
  Yes 16 7.97 3.62-17.53  
Relapse     
 Conditioning regimen    .02 
  Non-TBI MAC 436   
  TBI MAC 390 0.65 0.45-0.94  
NRM     
 Conditioning regimen    .238 
  Non-TBI MAC 436   
  TBI MAC 390 1.29 0.85-1.97  
 cGVHD    <.0001 
  No 371   
  Yes 455 3.39 2.01-5.72  
 Donor    .001 
  HLA-identical sibling 362   
  8/8 MUD 464 2.16 1.35-3.45  
 SN    <.0001 
  No 810   
  Yes 16 14.57 5.78-36.75  
LFS     
 Conditioning regimen    .347 
  Non-TBI MAC 436   
  TBI MAC 390 0.88 0.67-1.15  
 cGVHD    .006 
  No 371   
  Yes 455 1.47 1.11-1.95  
 SN    <.0001 
  No 810   
  Yes 16 9.09 4.12-20.02  
Outcome/variablenHR95% CIP
OS     
 Conditioning regimen    .541 
  Non-TBI MAC 436   
  TBI MAC 390 1.10 0.82-1.48  
 cGVHD    .002 
  No 371   
  Yes 455 1.62 1.19-2.21  
 SN    <.0001 
  No 810   
  Yes 16 7.97 3.62-17.53  
Relapse     
 Conditioning regimen    .02 
  Non-TBI MAC 436   
  TBI MAC 390 0.65 0.45-0.94  
NRM     
 Conditioning regimen    .238 
  Non-TBI MAC 436   
  TBI MAC 390 1.29 0.85-1.97  
 cGVHD    <.0001 
  No 371   
  Yes 455 3.39 2.01-5.72  
 Donor    .001 
  HLA-identical sibling 362   
  8/8 MUD 464 2.16 1.35-3.45  
 SN    <.0001 
  No 810   
  Yes 16 14.57 5.78-36.75  
LFS     
 Conditioning regimen    .347 
  Non-TBI MAC 436   
  TBI MAC 390 0.88 0.67-1.15  
 cGVHD    .006 
  No 371   
  Yes 455 1.47 1.11-1.95  
 SN    <.0001 
  No 810   
  Yes 16 9.09 4.12-20.02  

URD, unrelated donor.

Discussion

This population-based report is among the first to describe the burden of late effects and SNs in survivors of AYA AML. By using data reported to the CIBMTR on AYA AML patients who underwent HCT between 2000 and 2014, we were able to report the estimated cumulative incidence over time of developing a host of chronic health conditions. We also report that 4% of AYA survivors are estimated to develop an SN at 10 years. These data are important because data on late effects for AYA patients are lacking, thus hampering the development of evidence-based AYA-focused survivorship guidelines and SN monitoring.

For AYA AML patients undergoing HCT, a MAC regimen consisting of high-dose TBI or high-dose chemotherapy alone followed by HCT is considered standard of care.11  Although there has not been a modern prospective randomized study comparing the 2 regimens in AYA AML, retrospective and observational reports demonstrate at least equivalent outcomes, if not superiority of non-TBI–based approaches for AML.20-22  This equipoise provides a strong rationale for studying the late effects in young adults receiving these regimens and may provide additional support in favor of one conditioning type over another. However, in this study cohort of AYAs who had survived disease-free for at least 1 year after HCT, we did not find many significant differences in late effects based upon the type of conditioning regimen. Specifically, we found that although the prevalence of 1 or more late effects was greater in AYAs who received TBI, the estimated cumulative incidences of late effects and SNs were not significantly associated with type of conditioning regimen, with the exception of the development of cataracts, which were more likely to develop after TBI (HR, 4.98; P < .001).

Among the AYA HCT survivors included in our cohort, the estimated 10-year cumulative incidence of SNs was 4% (95% CI, 2%-6%), representing a threefold increase in the rate of malignancy compared with that in the healthy AYA population.19  There was no significant difference in incidence of SNs by exposure to myeloablative TBI vs high-dose chemotherapy-based regimens. Although it is generally believed that the development of SNs is higher in patients conditioned with high-dose TBI, the literature is inconclusive because some studies that included AYA patients have demonstrated similar rates of SN development regardless of the conditioning regimen backbone, whereas others have shown that high-dose TBI leads to greater SN development.12,14,17,23-29  In an evaluation of children and adults with AML in CR1 who were undergoing non-TBI–based MAC HCT, Majhail et al30  reported a 10-year cumulative incidence of solid SNs of 1.2%, although only half the patients in the study population were AYAs. In a recent large analysis of SNs after HCT performed at a single institution, Baker et al14  showed that the 20-year cumulative incidence of SNs in the AYA age range was 13.5% (95% CI, 11.8%-15%) and that use of a TBI dose of >450 cGy as part of conditioning was independently associated with SNs.

This study had more extensive follow-up than most other studies reported in the transplant literature, and the findings are particularly concerning because the estimated incidence of SNs continued to rise substantially in every decade after HCT. Although we did not find a difference in SNs based upon type of conditioning, our median follow-up time was shorter (∼8 years for the TBI-exposed cohort), and the latency period for radiogenic cancers can be much longer.31,32  Our study also showed an increased risk of SNs among patients achieving CR2+ at the time of transplant. This finding suggests that patients who receive additional therapies to obtain disease remission before transplant may need more vigorous surveillance for SNs. Our findings, in combination with those from other reports, suggest that the incidence of SNs for AYAs after HCT are not trivial, and life-long monitoring for SNs (including skin cancer) is necessary for this group of patients who are otherwise cured of their original disease and have many potential years of personal and societal productivity.

The cumulative incidence of nonmalignant late effects increased over time in this AYA AML survivor cohort. In particular, the estimated 10-year cumulative incidence of cataracts (10%) and AVN (8%) are alarming in this population of young adult survivors. Similar rates of AVN may be seen after use of steroid therapy in AYA acute lymphocytic leukemia; however, non-HCT–based treatments for AML rarely incorporate steroids or other agents known to predispose for AVN. Similarly, the substantial risk of developing cataracts in this young cohort suggests that early screening may be appropriate for survivors of AYA HCT. Unsurprisingly, the presence of cGVHD was linked to these late effects and to diabetes mellitus, likely because of the higher use of long-term corticosteroids by these patients. These findings underscore the importance of developing curative HCT platforms that do not result in cGVHD and also highlight the need for ongoing comprehensive long-term follow-up in AYA survivors with a history of cGVHD. Because patients in this age group are often late to report symptoms and may be less adherent to long-term follow-up care after HCT,7,33  these are areas that would benefit from further AYA-focused interventional research.34  Finally, the prevalence of gonadal dysfunction requiring hormone replacement was 7%, which is much lower compared with that in other studies of patients from childhood to adulthood.35,36  Gonadal dysfunction, an important issue for AYA survivors because of its impact on reproductive potential, may be difficult to capture via the current reporting method; this will likely be improved by the routine use of population-based quality-of-life and patient-centered surveys and measures after HCT as proposed by the CIBMTR.37 

Ten-year estimated OS was 73% and estimated LFS was 70% for AYA AML patients who survived disease-free for at least 1 year after HCT. Similar to other observational studies performed across a range of patient ages,20-22  long-term survival estimates in our study did not differ based upon whether patients received TBI or a chemotherapy-only conditioning regimen. However, the estimated 10-year cumulative incidence of NRM of 14% again suggests that AYAs require ongoing medical care beyond 1 year after HCT. Furthermore, late relapse remains an issue as evidenced by a 15% cumulative incidence of relapse at 5 years. Fortunately, very late relapses (beyond 5 years) seem to be rare events. Consistent with other studies of HCT survivors,38,39  AML relapse was identified as the leading cause of death in our cohort, underscoring the importance of relapse prevention strategies after HCT.

Although all retrospective studies have inherent limitations, studying late effects after HCT raises important challenges. First, the prevalence of late effects reported in our cohort was lower than expected. For example, we found a 10-year cumulative incidence of cataracts of 15% (95% CI, 11%-19%) for patients exposed to TBI, whereas other studies in children and adults have reported rates of 30% to 70% for cataract development at 10 years after transplant for patients exposed to fractionated TBI.40-42  However, it is possible that technological advances in radiotherapy techniques beginning in the year 2000 may have contributed to less ocular toxicity in recent years. Similarly, as mentioned earlier, the low rate of gonadal dysfunction reported in this cohort was quite low. Our findings, therefore, likely reflect an underestimation of the true burden of late complications after HCT for AYA AML. It is unclear whether potential underreporting may be a result of inconsistent follow-up at the HCT center level or a result of the evolving late effects collection methods used by the CIBMTR over time. Future efforts aimed at improving the ascertainment of late effects and SNs are currently ongoing through the recommendations provided by the American Society of Transplantation and Cellular Therapy Late Effects Task Force. Our study was also hampered by the relatively short median follow-up time of survivors after HCT. It is well known that certain late complications, including late cardiac events43  and SNs appear years, and even decades, after HCT.17,23  Our cohort included patients who received transplants as recently as 2014, which potentially affected our ability to capture late effects commonly occurring many years after HCT; however, we believe that evaluation of late effects that occur early in the disease process, potentially occurring as soon as 1 year after HCT, was important for understanding the full range of late effects and their time to development.

Finally, our study did not include survivors who developed disease relapse in the first year after HCT. Although some late effects may occur very early after HCT (eg, cataracts, infertility, hypothyroidism) and precede disease relapse, our rationale for excluding these patients was based upon the understanding that these patients have poor survival after early relapse and/or they received additional intensive therapies that may influence the development of late effects and confound the primary exposure-outcome relationship.

We acknowledge the difficulties related to studying late effects in this population, and we believe that our study provides meaningful data to the nascent literature regarding late effects in AYA AML. The development of cataracts seems to be associated with TBI-based conditioning; however, other late effects, including SNs, cannot be clearly linked to TBI in our AYA cohort. Systematic ascertainment of late effects in AYAs is critically necessary for developing AYA-focused survivorship guidelines and care plans, as has been done for survivors of childhood cancers. The HCT community is poised to conduct the studies that will further the understanding of late complications in AYAs and improve the care of this important population of cancer survivors.

Authorship

Contribution: C.J.L., L.S.M., and B.E.S. designed, directed, and performed research, analyzed data, and wrote the manuscript; H.R.T., R.P., and S.B.-S. provided data sets for analysis; H.R.T., S.B.-S., S.K., and R.B. performed statistical analysis; B.E.S., D.B., and B.K.H. reviewed data and the manuscript; and M.B., N.S.M., H.M.L., P.J.S., D.I.M., M.R.L., S.C., Y.I., Z.D., G.C.H., R.F.O., K.A.K., J.L.L., S.J.R., S.M.B., N.S.B., J.A.Y., K.M.P., M.L.A., M.K., N.F., S.S., P.H., C.O.F., A.R., S.G., S.N., and L.B. critically reviewed the data and approved the final manuscript before it was submitted.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Catherine J. Lee, Utah Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 2152, Salt Lake City, UT 84112; e-mail: catherine.lee@hci.utah.edu.

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Author notes

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