Growth hormone therapy was associated with greater improvement in final adult height among patients who developed short stature following hematopoietic cell transplantation in childhood, although responses varied substantially.
The investigators conducted a nationwide, multicenter retrospective cohort study using medical records from 55 institutions participating in the Japan Children’s Cancer Group. Eligible patients had a hematologic malignancy or solid tumor diagnosed at a participating institution between January 1990 and December 2018, underwent autologous or allogeneic hematopoietic cell transplantation (HCT) at age 15 years or younger, were aged 15 to 39 years at study registration, and survived for at least 2 years after HCT with short stature, defined as a height standard deviation score (SDS) of −2.0 or lower. Patients with preexisting short stature or underlying conditions associated with short stature were excluded. The final study population included 213 patients.
Final adult height data were available for 171 patients, including 58 who received growth hormone (GH) therapy and 113 who did not. Median follow-up was 18.2 years. Among the 58 patients who received GH and had final height data, treatment was initiated at a median age of 11.4 years, approximately 6 years following transplantation, and continued for a median of 5.3 years. GH deficiency was confirmed in 40 patients.
Investigators assessed final adult height SDS and change in height SDS (ΔSDS) from the diagnosis of short stature to final height. Patients who received GH had greater improvement in both measures compared with those who did not receive GH. In multivariable analysis, GH therapy was associated with a 0.94-SDS greater improvement in ΔSDS. Undergoing HCT at age 5 years or older was associated with a 0.75-SDS greater improvement.
In contrast, total body irradiation (TBI) was associated with a 0.76-SDS lower ΔSDS, and chronic graft-vs-host disease (GVHD) was associated with a 0.60-SDS lower ΔSDS. The researchers identified TBI as one of the strongest negative predictors of height outcomes and GH responsiveness, noting that GH therapy may not fully overcome radiation-related limitations on growth.
Among the 58 patients who received GH and had final height data, absence of TBI, initiation of GH therapy at age 10 years or older, and female sex were associated with more favorable responses in the overall multivariable analysis. Associations differed by transplant type. Among patients who underwent allogeneic HCT, TBI was associated with a 1.99-SDS lower ΔSDS, and male sex was associated with a 0.93-SDS lower ΔSDS. Among patients who underwent autologous HCT, starting GH at age 10 years or older was associated with a 1.08-SDS greater ΔSDS.
The authors cautioned that the association between GH initiation at age 10 years or older and better response should be interpreted in light of several potential sources of bias. Patients who initiated GH at age 10 years or older tended to have a higher prevalence of severe GH deficiency, although the difference was not statistically significant, and age at HCT was positively correlated with age at GH initiation. Survivor and indication bias could also have influenced the finding because the analysis included patients who survived following transplantation and subsequently received GH, and treatment was initiated according to clinical judgment rather than randomly assigned.
Longitudinal analyses showed that height improvement continued beyond the first year of GH therapy, with greater gains at 5 years than at 1 year and further improvement by final height.
Responses, however, were heterogeneous. Among 57 evaluable patients receiving GH, 31 had a 5-year ΔSDS below 1. Eleven achieved a 5-year ΔSDS of at least 1 but had a final ΔSDS below 0.5, which the researchers classified as a transient response. Fifteen achieved a 5-year ΔSDS of at least 1 and maintained a final ΔSDS of at least 0.5. Absence of TBI was associated with a favorable 5-year height response.
This delayed response pattern differed from that reported in the general population with GH deficiency. The authors suggested that assessing treatment efficacy early after GH initiation may underestimate longer-term benefit and that prolonged follow-up is important when evaluating response following childhood HCT.
Complications in the full cohort of 213 patients were also examined, including 72 who received GH and 141 who did not. GH therapy was not associated with an increased risk of slipped capital femoral epiphysis, secondary malignancies, or relapse of the primary disease. TBI exposure, however, was associated with secondary malignancies. The authors characterized these safety findings as exploratory because of the limited number of events and cautioned that the observational design and observation period precluded definitive conclusions about long-term safety.
The study had several limitations. Its retrospective design introduced the possibility of residual confounding, and criteria for initiating GH therapy, dosing, and treatment duration were not standardized across institutions. Some patients received GH without confirmed GH deficiency. Selection bias was also unavoidable because only patients referred for GH evaluation and treatment were included. Information on parental height and genetic growth potential was unavailable, and the limited sample size and variability in growth response constrained interpretation of some analyses.
GH therapy was associated with improved final height among patients who developed short stature following childhood HCT, but responses varied and were strongly influenced by transplant-related factors. The observational design does not establish a causal effect of GH therapy, and the longitudinal findings indicated that early response may not capture the full extent of subsequent growth.
“These findings underscore the need for individualized, long-term management strategies and careful counseling when considering GH therapy in this complex population,” wrote lead study author Maiko Shimomura, of the Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan, and colleagues.
Disclosures: The researchers reported no commercial or financial conflicts. Satoshi Okada was a Frontiers editorial board member at submission.The study was supported by the Hiroshima University Hospital Research Support Grant.
Source: Frontiers in Endocrinology
