Blood Res (2024) 59:44
Published online December 24, 2024
https://doi.org/10.1007/s44313-024-00046-2
© The Korean Society of Hematology
Correspondence to : Jong Wook Lee
jwlee@hyumc.com
© 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/.
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
Blood Res 2024; 59():
Published online December 24, 2024 https://doi.org/10.1007/s44313-024-00046-2
Copyright © The Korean Society of Hematology.
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
© 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/.
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
Table 1 . Baseline and transplant-related characteristics of patients.
Characteristics | Total 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 mismatch | 69 (18.4) |
Major mismatch | 119 (31.6) |
HLA (8/8) mismatched (N, %) | 267 (71.0) |
Donor type (N, %) | |
Matched sibling | 184 (48.9) |
Unrelated | 118 (31.4) |
Haploidentical | 74 (19.7) |
Stem cell source (N, %) | |
BM | 157 (41.8) |
PBSC | 204 (54.3) |
BM + PBSC | 15 (4.0) |
Conditioning regimen (N, %) | |
Non-radiation-based | 157 (41.8) |
Radiation-based | 219 (58.2) |
TNI 750 cGy | 23 (6.1) |
Fractionated TBI 400-600 cGy | 97 (25.8) |
Fractionated TBI 800 cGy | 99 (26.3) |
ATG dose (N, %) | |
Not used | 57 (15.2) |
2.5-5 mg/kg | 165 (43.9) |
10 mg/kg | 154 (41.0) |
Transplantation outcomes (%, 95% CI)a | |
Graft failure | |
Primary | 0.9 (0.2–2.3) |
Delayed | 7.5 (5.2–10.9) |
Acute grade II-IV GVHD | 26.2 (21.8–30.7) |
≥ Moderate chronic GVHD | 15.0 (11.5–19.0) |
CMV DNAemia | 40.6 (95.6–45.5) |
CMV disease | 7.2 (4.9–10.1) |
H.cystitis | 7.7 (5.3–10.7) |
OS rates | 91.5 (88.2–94.0) |
GFFS rates | 71.3 (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 (%) | Localized | Regional | Distant |
Hematologic malignancy (N = 10) | ||||
PTLD | 5 (16.1) | 5 | ||
MDS | 2 (6.5) | 2 | ||
DLBCL | 1 (3.2) | 1 | ||
NK/T cell lymphoma | 1 (3.2) | 1 | ||
AML | 1 (3.2) | 1 | ||
Solid malignancy (N = 21) | ||||
Thyroid | 8 (25.8) | 2 | 5 | 1 |
Stomach | 4 (12.9) | 4 | ||
Oral cavity & Pharynx | 3 (9.7) | 1 | 2 | |
Esophagus | 2 (6.5) | 2 | ||
Colon | 1 (3.2) | 1 | ||
Bladder | 1 (3.2) | 1 | ||
Cervical | 1 (3.2) | 1 | ||
Skina | 1 (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.
Univariate | Multivariate | ||||
---|---|---|---|---|---|
Variables | 15-year Incidence | HR (95% CI) | pa | HR (95% CI) | pa |
Recipient age | 0.664 | 0.754 | |||
< 40 years | 12.8% | 1 | 1 | ||
≥ 40 years | 8.1% | 0.84 (0.38–1.86) | 1.15 (0.48–2.73) | ||
Recipient sex | 0.584 | 0.551 | |||
Male | 9.80% | 1 | 1 | ||
Female | 11.70% | 1.24 (0.57–2.71) | 1.27 (0.58–2.82) | ||
Disease severity | 0.607 | ||||
SAA | 13.60% | 1 | |||
VSAA | 5.80% | 0.81 (0.37–1.80) | |||
IST history before HSCT | 0.480 | ||||
No | 6.70% | 1 | |||
Yes | 14.70% | 1.32 (0.61–2.82) | |||
HCT-CI | 0.017 | 0.030 | |||
0–2 | 7.0% | 1 | 1 | ||
≥ 3 | 18.1% | 2.58 (1.18–5.63) | 2.35 (1.09–5.08) | ||
Donor type | 0.359 | ||||
Matched sibling | 7.80% | 1 | |||
Unrelated | 15.50% | 1.76 (0.80–3.85) | |||
Haploidentical | 6.90% | 1.20 (0.38–3.79) | |||
Fludarabine used | 0.414 | ||||
No | 15.50% | 1 | |||
Yes | 8.10% | 0.74 (0.35–1.53) | |||
TBI dose | 0.026 | 0.013 | |||
≤ 600 cGy | 7.00% | 1 | 1 | ||
> 600 cGy | 17.60% | 2.31 (1.11–4.83) | 4.60 (1.37–15.46) | ||
ATG dose | 0.267 | 0.044 | |||
≤ 5 mg/kg | 11.80% | 1 | 1 | ||
> 5 mg/kg | 11.10% | 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 | |||||
---|---|---|---|---|---|
0–1 | 1–5 | 5–10 | 10- | Total | |
Person-years at risk | 376 | 1131 | 697 | 260 | 2464 |
Observed | 8 | 11 | 7 | 3 | 29 |
per 100 person-years | 2.13 | 0.97 | 1.00 | 1.15 | 1.18 |
Expected | 0.95 | 3.35 | 2.60 | 1.28 | 8.18 |
per 100 person-years | 0.25 | 0.30 | 0.37 | 0.49 | 0.33 |
O/E | 8.40 | 3.28 | 2.69 | 2.34 | 3.54 |
EAR, per 100 person-years | 1.87 | 0.68 | 0.63 | 0.66 | 0.85 |
EAR Excess absolute risk, HSCT Hematopoietic stem cell transplantation, O/E Observed-to-expected ratio.
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