Secondary Malignancies in Patients after Allogeneic Hematopoietic Cell Transplantation at Triple the Incidence of Malignancies in Their Family Donors

Research Article

Ann Hematol Onco. 2023; 10(5): 1438.

Secondary Malignancies in Patients after Allogeneic Hematopoietic Cell Transplantation at Triple the Incidence of Malignancies in Their Family Donors

Santarone S1*; Angelini S2; Natale A1; Olioso P1; Vaddinelli D1; Spadano R1; Di Bartolomeo P1

¹Department of Oncology Hematology, Ospedale Civile, Pescara, Italy

²UOC Ematologia e Terapia Cellulare, Ospedale Mazzoni, Ascoli Piceno, Italy

*Corresponding author: Santarone S Department of Oncology Hematology, Ospedale Civile, Via Fonte Romana 8, Pescara 65125, Italy Tel +39 0854252689; Fax: +39 0854242583 Email: [email protected]

Received: August 17, 2023 Accepted: September 11, 2023 Published: September 18, 2023



The primary end point of this retrospective study was to determine the incidence, risk factors and clinical outcome of secondary malignancies in 951 patients who were given an allogeneic Hemopoietic Cell Transplantation (HCT) and to compare them with the incidence of malignancy observed in the cohort of 761 stem cell family donors. With a median follow-up of 20 years, 74 HCT recipients (40 males) developed SM at a median of 16.09 years since transplant and at a median age of 47 years. The 35-yr cumulative incidence of SM was 17.0% (95% confidence interval, 12.8-21.6%). In univariate analysis, factors associated with increased incidence of SM were cumulative (limited and extensive) chronic graft-versus-host disease (cGvHD) and duration of cumulative cGvHD >24 months. By multivariate analysis, cumulative cGvHD was the only independent risk factor for SM. Patients with cGvHD had 2.85x higher risk as compared to patients without cGvHD (P<0.001). With a median follow-up of 18 years, 13 family donors (7 males) out of 761 developed malignancy at a median of 15.04 years since stem cell donation and at a median age of 55 years. As compared to the cumulative incidence of SM observed in the cohort of transplant recipients, the cumulative incidence of malignancy in family donors at 35 years since stem cell donation was statistically lower [5.8% vs 17.0% (P=0.001)]. This study demonstrates that HCT recipients have a significantly higher incidence of developing post-transplant malignancy as compared to family donors and that cGvHD is a strong risk factor for SM development.

Keywords: Malignancy; HCT; cGvHD; Stem cell donors


Allogeneic Hematopoietic Cell Transplant (HCT) represents a potential curative procedure for a variety of malignant and nonmalignant hematologic disorders. Improvement in survival rate following HCT has resulted in a need to assess issues related to long-term complications, including the development of Secondary Malignancy (SM), which represent an important cause of late morbidity and mortality. Malignancies occurring after HCT fall into three general categories: hematologic malignant diseases, lymphoproliferative disorders, and solid tumors [1]. Several studies have reported that the magnitude of the increased risk of SM has ranged from 2.1- to 2.7-fold when compared to an age- and sex-matched general population and the risk among long-term survivors ranges from 3% to 15% at 15 years after transplantation [2-9]. We conducted a single center retrospective cohort study to determine the incidence, risk factors and clinical outcome of SM in patients who survived after allogeneic HCT and took into account the incidence of malignancies among their stem cell family donors.


Study Cohort

Our study included 989 consecutive patients who received an allogeneic HCT between March 1977 and December 2018 at the Bone Marrow Transplant Center of Pescara, Italy. Patients with Fanconi anemia (n=12), acquired immunodeficiency syndrome (n=2), and Down syndrome (n=2) were excluded because of their inherent susceptibility to cancer. Patients with a history of solid cancer before HCT (n=22) were also excluded. The study was approved by the local institutional review board. Informed consent for HCT and for follow-up studies was obtained from all patients and donors or their legal guardians in accordance with the Declaration of Helsinki.


Data were extracted from the Allogeneic Transplant Program Database of the Center and included patient and donor demographic information (age, gender), diagnosis of hematologic disease, stem cell source, donor relationship and HLA compatibility, intensity of the conditioning regimen defined as Myeloablative (MAC) or Reduced-Intensity (RIC), drugs used in the preparative therapy, and drugs used as Graft-Versus-Host disease (GvHD) prophylaxis. Other information regarding the post-transplant clinical outcome including engraftment, acute GvHD (aGvHD) and chronic GvHD (cGvHD) occurrence, relapse of the original disease, survival and most important and common transplant-related complications (veno-occlusive disease of the liver, hemorrhagic cystitis, infections, neurological and cardiac involvement) were also obtained from the Database. History of duration and quantity of smoking, alcohol consumption and drug abuse before and after HCT were collected only for patients diagnosed with SM and for donors who developed a malignancy.

Transplant Procedure

Each recipient was given Unique Patient Number (UPN). The day of transplant was designated as day 0. The intensity of conditioning regimen, MAC vs RIC, was defined following the criteria published by the Center for International Blood and Marrow Transplantation Research [10]. RIC regimens were generally administered to patients over age 60 years or recipients with comorbidities that precluded the use of MAC. aGVHD was diagnosed according to Glucksberg’s criteria [11], and cGvHD according to the modified Seattle criteria (for categorization of cGVHD as clinical limited or clinical extensive) [12].

Post-Transplant Cancer Screening

In the first 5 years after transplantation, all patients were followed at least annually at the transplant Center and every 2 to 3 years later or when a new clinical event appeared. In any occasion patients were asked to give information on the clinical health status of their stem cell donors. Patients were informed about the importance of an accurate screening for common cancers using brochures illustrating the increased risk of SMs after allografts. Information on SM, including date of diagnosis, site of involvement, morphologic features, therapy (surgery alone, chemotherapy, radiotherapy, immunotherapy, palliation), and outcome with Eastern Cooperative Oncology Group (ECOG) performance score at last follow-up were collected by a review of medical records provided either by the patients or by the physician who had made the diagnosis and had taken care of them. The same procedure was followed for the donors who manifested the occurrence of any malignancy. Cancer type was classified according to International Classification of Diseases, 10th revision. Pathology and physician reports of each case of SM were reviewed centrally at the transplant center by a committee including the transplant expert, the pathologist, the surgeon expert in each type of tumor, and the oncologist.

Statistical Analysis

A descriptive analysis of all variables was performed including mean, median, standard deviation, range, minimum and maximum value for continuous variables, absolute and relative frequencies for categorical variables. Using parametric and nonparametric statistical procedures, the possible interdependence between 2 or more variables was evaluated and a P value of .05 was considered significant.

Taking into consideration death without occurrence of malignancy as competing risk, the probability of both SM in transplant recipients and malignancies in stem cell donors has been studied by fitting cumulative incidence function [13]. Univariate analysis of possible factors predicting for SM in transplant recipients included: age at transplant, gender, underlying hematologic disease, type of underlying hematologic disease, ferritin level at HCT, radiotherapy performed before transplantation, number and type of transplants, drugs used in conditioning therapy, intensity of conditioning regimen, use of anti-thymocyte globulin, GvHD prophylaxis, donor relationship and compatibility, stem cell source, occurrence and duration of cGvHD. The curves of various subgroups were compared using the Gray’s test whereas the duration of cGvHD was compared using the Mann-Whitney test [14]. The duration of cGvHD was transformed into categorical variable and the 24 months cut-off value was identified as follows: i) with graphic investigations using Martingale residual plots [15]; ii) with maximization of the Gray test; and iii) on the basis of medical expertise and consensus. The joint effect of variables on cumulative incidence function of SM was evaluated using the multivariate model of Fine and Gray were the occurrence of aGvHD and cGvHD was treated as a time-dependent covariate [15]. Covariates were selected in the multivariate analysis using a stepwise procedure adapted to multiple imputation methodology. The probability of Overall Survival (OS) and Disease-Free Survival (DFS) was calculated with the method of Kaplan-Meyer [16].

Statistical analyses were performed with the use of R Statistical Software (version 3.3.3; R Foundation for Statistical Computing, Vienna, Austria).


The final study population included 951 patients (532 males, 56%). Ninety-eight patients underwent a second allogeneic HCT for either primary or secondary graft failure (n=26) or leukemia relapse (n=72). Moreover, 104 patients had received an autologous HCT before allogeneic transplant as part of the therapeutic program. Baseline patient and donor clinical characteristics are shown in Table 1.