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Blood Res (2024) 59:44

Published online December 24, 2024

https://doi.org/10.1007/s44313-024-00046-2

© The Korean Society of Hematology

Incidence and outcomes of subsequent malignancy after allogeneic hematopoietic stem cell transplantation in adult patients with severe aplastic anemia

Daehun Kwag1, Sung‑Soo Park1, Sung‑Eun Lee1, Hee‑Je Kim1 and Jong Wook Lee2*

1 Department of Hematology, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
2 Division of Hematology‑Oncology, Hanyang University Seoul Hospital, Seoul, Republic of Korea

Correspondence to : Jong Wook Lee
jwlee@hyumc.com

Received: November 13, 2024; Accepted: November 15, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Purpose This study investigated the occurrence of subsequent malignancies (SM) in adult patients with severe aplastic anemia (SAA) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to address the lack of largescale, long-term data on this complication.
Methods A retrospective cohort analysis of 376 adult patients with SAA who underwent allo-HSCT between 2002 and 2021 at a single center was conducted. The incidence, risk factors, and survival impact of SM were also examined.
Results During the follow-up period, 31 cases of SM (8.2%) were identified. Approximately one-third (32.3%) of SM cases were hematologic malignancies, including post-transplant lymphoproliferative disorder (16.1%), myelodysplastic neoplasm (6.5%), and acute myeloid leukemia (3.2%). Solid tumors accounted for 67.7% of cases, with thyroid cancer being the most prevalent (25.8%). The 15-year cumulative incidence of SM was 11.2%, and the hazard ratio for overall survival according to the development of SM was 16.25 (p < 0.001). High-dose total body irradiation (TBI), anti-thymocyte globulin (ATG), and moderate-to-severe chronic graft-versus-host disease (GVHD) were identified as significant risk factors for subsequent malignancy. Post-transplant SAA patients exhibited a 3.54-fold higher observed cancer incidence than the expected incidence calculated from the age-, sex-, and calendar year-matched general population.
Conclusion SM is a significant long-term complication in patients with posttransplant SAA and has a substantial survival impact. Patients receiving high-dose TBI or ATG, and those with moderate-to-severe chronic GVHD, require vigilant long-term monitoring.

Keywords Aplastic anemia, Subsequent malignancy, Allogeneic hematopoietic transplantation

Article

RESEARCH

Blood Res 2024; 59():

Published online December 24, 2024 https://doi.org/10.1007/s44313-024-00046-2

Copyright © The Korean Society of Hematology.

Incidence and outcomes of subsequent malignancy after allogeneic hematopoietic stem cell transplantation in adult patients with severe aplastic anemia

Daehun Kwag1, Sung‑Soo Park1, Sung‑Eun Lee1, Hee‑Je Kim1 and Jong Wook Lee2*

1 Department of Hematology, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
2 Division of Hematology‑Oncology, Hanyang University Seoul Hospital, Seoul, Republic of Korea

Correspondence to:Jong Wook Lee
jwlee@hyumc.com

Received: November 13, 2024; Accepted: November 15, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Purpose This study investigated the occurrence of subsequent malignancies (SM) in adult patients with severe aplastic anemia (SAA) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to address the lack of largescale, long-term data on this complication.
Methods A retrospective cohort analysis of 376 adult patients with SAA who underwent allo-HSCT between 2002 and 2021 at a single center was conducted. The incidence, risk factors, and survival impact of SM were also examined.
Results During the follow-up period, 31 cases of SM (8.2%) were identified. Approximately one-third (32.3%) of SM cases were hematologic malignancies, including post-transplant lymphoproliferative disorder (16.1%), myelodysplastic neoplasm (6.5%), and acute myeloid leukemia (3.2%). Solid tumors accounted for 67.7% of cases, with thyroid cancer being the most prevalent (25.8%). The 15-year cumulative incidence of SM was 11.2%, and the hazard ratio for overall survival according to the development of SM was 16.25 (p < 0.001). High-dose total body irradiation (TBI), anti-thymocyte globulin (ATG), and moderate-to-severe chronic graft-versus-host disease (GVHD) were identified as significant risk factors for subsequent malignancy. Post-transplant SAA patients exhibited a 3.54-fold higher observed cancer incidence than the expected incidence calculated from the age-, sex-, and calendar year-matched general population.
Conclusion SM is a significant long-term complication in patients with posttransplant SAA and has a substantial survival impact. Patients receiving high-dose TBI or ATG, and those with moderate-to-severe chronic GVHD, require vigilant long-term monitoring.

Keywords: Aplastic anemia, Subsequent malignancy, Allogeneic hematopoietic transplantation

Fig 1.

Figure 1.Patient configuration and allo-HSCT procedure. Allo-HSCT = Allogeneic hematopoietic stem cell transplantation; ATG = Anti-thymocyte globulin; Cy = Cyclophosphamide; Flu = Fludarabine; MSD = Matched sibling donor; SAA = Severe aplastic anemia; TBI = Total body irradiation; TNI = Total nodal irradiation; URD = Unrelated donor

Fig 2.

Figure 2.Cumulative incidence of (a) all types of subsequent malignancies, (b) hematologic malignancies, and (c) solid malignancies after hematopoietic stem cell transplantation. CI = confidence interval

Fig 3.

Figure 3.a Kaplan–Meier curve for overall survival in all patients. The other panels are Simon-Makuch plots for overall survival according to the occurrence of b whole SM, c hematologic SM, d solid SM, e limited SM, f ≥ regional SM. Red lines mean the SM development groups. P values are calculated using the Mantel-Byar test. CI = confidence interval; SM = subsequent malignancy

Table 1 . Baseline and transplant-related characteristics of patients.

CharacteristicsTotal N = 376
Age, years (median, IQR)34 (27–45)
> 40 years (N, %)141 (37.5)
Male (N, %)170 (45.2)
VSAA (N. %)129 (34.3)
PNH clone positive (N, %)329 (87.5)
IST history preceding HSCT (N, %)195 (51.9)
≥ 20U Transfusion before HSCT (N, %)316 (84.0)
> 6 months from diagnosis to HSCT (N, %)272 (72.3)
HCT-CI (median, IQR)2 (0–3)
≥ 3 (N, %)132 (35.1)
Female to male sex mismatch (N, %)145 (38.6)
ABO mismatched (N, %)
Minor mismatch69 (18.4)
Major mismatch119 (31.6)
HLA (8/8) mismatched (N, %)267 (71.0)
Donor type (N, %)
Matched sibling184 (48.9)
Unrelated118 (31.4)
Haploidentical74 (19.7)
Stem cell source (N, %)
BM157 (41.8)
PBSC204 (54.3)
BM + PBSC15 (4.0)
Conditioning regimen (N, %)
Non-radiation-based157 (41.8)
Radiation-based219 (58.2)
TNI 750 cGy23 (6.1)
Fractionated TBI 400-600 cGy97 (25.8)
Fractionated TBI 800 cGy99 (26.3)
ATG dose (N, %)
Not used57 (15.2)
2.5-5 mg/kg165 (43.9)
10 mg/kg154 (41.0)
Transplantation outcomes (%, 95% CI)a
Graft failure
Primary0.9 (0.2–2.3)
Delayed7.5 (5.2–10.9)
Acute grade II-IV GVHD26.2 (21.8–30.7)
≥ Moderate chronic GVHD15.0 (11.5–19.0)
CMV DNAemia40.6 (95.6–45.5)
CMV disease7.2 (4.9–10.1)
H.cystitis7.7 (5.3–10.7)
OS rates91.5 (88.2–94.0)
GFFS rates71.3 (66.4–75.7)

ATG Anti-thymocyte globulin, BM Bone marrow, CI Confidence interval, CMV Cytomegalovirus, GFFS Graft-versus-host disease-free, failure-free survival, GVHD Graft-versus-host disease, HCT-CI Hematopoietic Cell Transplantation-specific Comorbidity Index, H. cystitis Hemorrhagic cystitis, HSCT Hematopoietic stem cell transplantation, HLA Human leukocyte antigen, IST Immunosuppressive therapy, OS Overall survival, PBSC Peripheral blood stem cell, PNH Paroxysmal nocturnal hemoglobinuria, SAA Severe aplastic anemia, TBI Total body irradiation, TNI Total nodal irradiation, VSAA Very severe aplastic anemia.

a The incidence of primary graft failure and acute GVHD was estimated at 28 and 100 days, respectively. The incidence of other outcomes was estimated at five years.


Table 2 . Incidence, types, and stage of subsequent malignancies.

SEER summary stage
Type (Total N = 31)N (%)LocalizedRegionalDistant
Hematologic malignancy (N = 10)
PTLD5 (16.1)5
MDS2 (6.5)2
DLBCL1 (3.2)1
NK/T cell lymphoma1 (3.2)1
AML1 (3.2)1
Solid malignancy (N = 21)
Thyroid8 (25.8)251
Stomach4 (12.9)4
Oral cavity & Pharynx3 (9.7)12
Esophagus2 (6.5)2
Colon1 (3.2)1
Bladder1 (3.2)1
Cervical1 (3.2)1
Skina1 (3.2)1

AML Acute myeloid leukemia, DLBCL Diffuse large B-cell lymphoma, MDS Myelodysplastic neoplasm, PTLD Post-transplant lymphoproliferative disorder, SEER Surveillance, Epidemiology, and End Results.

a Squamous cell carcinoma.


Table 3 . Univariate and multivariate Fine-Gray models for risk factors affecting the incidence of SMs following allogeneic HSCT.

UnivariateMultivariate
Variables15-year IncidenceHR (95% CI)paHR (95% CI)pa
Recipient age0.6640.754
< 40 years12.8%11
≥ 40 years8.1%0.84 (0.38–1.86)1.15 (0.48–2.73)
Recipient sex0.5840.551
Male9.80%11
Female11.70%1.24 (0.57–2.71)1.27 (0.58–2.82)
Disease severity0.607
SAA13.60%1
VSAA5.80%0.81 (0.37–1.80)
IST history before HSCT0.480
No6.70%1
Yes14.70%1.32 (0.61–2.82)
HCT-CI0.0170.030
0–27.0%11
≥ 318.1%2.58 (1.18–5.63)2.35 (1.09–5.08)
Donor type0.359
Matched sibling7.80%1
Unrelated15.50%1.76 (0.80–3.85)
Haploidentical6.90%1.20 (0.38–3.79)
Fludarabine used0.414
No15.50%1
Yes8.10%0.74 (0.35–1.53)
TBI dose0.0260.013
≤ 600 cGy7.00%11
> 600 cGy17.60%2.31 (1.11–4.83)4.60 (1.37–15.46)
ATG dose0.2670.044
≤ 5 mg/kg11.80%11
> 5 mg/kg11.10%1.51 (0.73–3.15)3.45 (1.04–11.53)

ATG Antithymocyte globulin, CI Confidence interval, HCT-CI Hematopoietic cell transplantation-specific comorbidity index, HR Hazard ratio, HSCT Hematopoietic stem cell transplantation, IST Immunosuppressive therapy, SAA Severe aplastic anemia, SM Subsequent malignancies, TBI Total body irradiation, VSAA Very severe aplastic anemia.

a P values were calculated using the likelihood-ratio test.


Table 4 . Observed and expected cases of subsequent malignancies, calculated from population data, from the time of HSCT.

Years from HSCT
0–11–55–1010-Total
Person-years at risk37611316972602464
Observed8117329
per 100 person-years2.130.971.001.151.18
Expected0.953.352.601.288.18
per 100 person-years0.250.300.370.490.33
O/E8.403.282.692.343.54
EAR, per 100 person-years1.870.680.630.660.85

EAR Excess absolute risk, HSCT Hematopoietic stem cell transplantation, O/E Observed-to-expected ratio.


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