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

  


    
Study

    
Study design


      Institution

    
Sample


      size

    
Conditioning


      regimen

    
Median FU


      months


      (range)

    
Number


      of SMs

    
CI of SM


      at 10 years       at 20 years

    
Magnitude


      of risk


      SIR

    
Risk factors

  

  


    
Michelis    (22)


      2007

    
Single    Centre


      Ontario

    
 

      
2415

    
 

      
MAC 2035


        RIC 380

    
 

      
127


        (3-421)

    
 

      
151

    
 

      
6.3%

    
 

      
13.5%

    
 

      
2.07

    
 

      
Older    age at HCT

  

  


    
Martelin    (23)


      2019

    
Single    Centre


      Helsinki

    
 

      
1179

    
 

      
MAC 951


        RIC 228

    
 

      
125


        (28-256)

    
 

      
66

    
 

      
8.7%

    
 

      
13.9%

    
 

      
8.9%^


        10.6%*

    
 

      
cGvHD,    CML

  

  


    
Gallagher    (6)


      2007

    
Single    Centre


      Vancouver

    
 

      
926

    
 

      
MAC 907


        RIC 19

    
 

      
20


        (0-230)

    
 

      
28

    
 

      
3.1%

    
 

      
-

    
 

      
1.85

    
 

      
Age    > 40 years


        Female    donor

  

  


    
Ringden    (9)


      2104

    
Multicentric


      CIBMTR

    
 

      
4269

    
 

      
RIC

    
 

      
72


        (1-188)

    
 

      
-

    
 

      
3.35%

    
 

      
-

    
 

      
0.99

    
 

      
Older    age at HCT

  

  


    
Rizzo    (8)


      2009

    
Multicentric


      CIBMTR

    
 

      
28874

    
 

      
MAC


        RIC

    
 

      
-

    
 

      
189

    
 

      
1.0%

    
 

      
3.3%

    
 

      
2.1

    
 

      
TBI,    LFI, cGvHD

  

  


    
Atsuta    (17)


      2014

    
Multicentric


      JHSHCT

    
 

      
17545

    
 

      
MAC 13195


        RIC 4141

    
 

      
-

    
 

      
269

    
 

      
1.7%

    
 

      
2.9%

    
 

      
1.8

    
 

      
cGvHD

  

  


    
HCT:    Hemopoietic Cell Transplantation; FU: Follow-up; SMs: Secondary Malignancies;    CI: Cumulative Incidence; SIR: Standardized Incidence Ratios    (observed/expected ratios); CIBMTR: Center for International Blood and Marrow    Research; RIC: Reduced Intensity Conditioning; MAC: Myeloablative    Conditioning; cGvHD: Chronic Graft-Versus-Host Disease; CML: Chronic Myeloid    Leukemia; TBI: Total Body Irradiation; LFI: Limited Field Irradiation; JSHCT:    Japan Society for Hematopoietic Cell Transplantation; ^ melanoma; * oropharingeal    cancer 

  

Table 6: Recent large studies of second malignancy after allogeneic HCT.

The cumulative incidence of SM at 10 and 20 years after HCT in our study was similar to that observed in in other reported largest studies using the same statistical method for cumulative incidence, while treating death before SM occurrence as a competing risk. However, our data are important because the median follow-up of our survivors was long at 20 years, and this allowed us to estimate the cumulative incidence of SM at 30 and 35 years since transplantation. What appears relevant in our study is that the cumulative incidence of SM rises considerably over time, going from 5.6% at 20 years after transplantation until reaching a rate of 11.9% at 30 years and even 17% at 35 years without evidence of a plateau. This figure is very close to reality as the vast majority of our patients were updated in the last 3 months before the closure of the study. Moreover, of note in our study, we found that patients developed SM at younger age (median 47 years) if compared to that of the general population (over 60 years) and that of family donors (55 years) and after a median time from HCT to SM of 16.09 years.

In most of the previously published studies, the incidence of SM has been compared with cancer incidence observed in the general population by using standard incidence ratios [6,8-9,17,22-23]. Overall, transplant recipients developed an invasive solid cancer at twice the rate expected based on population incidence rates, as depicted in Table 6. The risk reached 3-fold among patients followed for 15 years or more after transplantation. Since data comparing the incidence of SM between allografted patients and the general population are widely available in most of the many scientific papers published and being able to have follow-up data of our family donors, we chose to compare the cumulative incidence of SM in HCT recipients with the cumulative incidence of malignancy in family donors. This choice allowed us to abrogate the factor related to the familial genetic predisposition which is a well-known risk factor for many cancers. The two groups were matched for age and gender. Even with the limitations of a slightly different median follow-up between transplant recipients and family donors (20 vs 18 years), we found that transplant recipients developed malignancies at triple the rate of malignancies observed in family donors (35-yr cumulative incidence 17.0% vs 5.8%) (P=0.001). Of relevance in our study, transplant recipients develop cancer at a much younger age than family donors (47 years vs 55 years), thus confirming the impact of the transplant and its related factors (chemotherapy and in particular alkylating agents, radiotherapy, GvHD, prolonged immunosuppression) on tumor development.

Among transplant recipients, squamous cell carcinoma of the oral cavity was the most common type of SM, whereas in the cohort of family donors carcinoma of the breast was predominant as in the general population. In a recent study, we have demonstrated that a diagnosis of hematological nonmalignant disease and duration of oral cGvHD for more than 15 months were factors significantly associated with higher incidence of squamous cell carcinoma of the oral cavity [18]. A particular mention must be reserved to the finding of an ever-increasing incidence of secondary malignancies in patients affected by thalassemia major. The data found in the present study (17 cases in 137 patients for a cumulative incidence of 21.7%), confirms and extends what we have previously reported in two other studies [19,20]. The incidence of malignancies in the cohort of family donors (13 cases in 761 donors, 1.7%) was apparently similar to that described by Pulsipher et al (26 cases in 2408 PB donors, 1.1%) [21].

Several risk factors have been identified that may contribute to the development of SM after HCT. Younger age at transplantation, male gender, use of total body irradiation in conditioning regimen, cGVHD, and immunodeficiency from incomplete recovery after transplant have been implicated as risk factors in some studies, while a strong association between these factors and second cancers has not been observed in others [22-25]. In our study the univariate analysis based on different and multiple risk factors estimated that cGvHD and its duration for more than 24 months were associated to a higher incidence of SM. However, the multivariate analysis showed that only cGvHD was an independent risk factor for development of SM with a hazard ratio of 2.85. The independent risk of cGvHD, as shown in many other series, highlights a stringent need to prevent this complication or treat it with novel therapies that don’t result, if possible, in prolonged immunosuppression. In any case, tumor screening every 6 months may be considered for patients at high risk for developing SM, such as patients with prolonged previous cGVHD.

Standard therapeutic strategies to treat SM after HCT are lacking because there are no large studies in this regard. With respect to outcome, some series indicate that the 5-year OS rates after diagnosis of SM varied by cancer site, with 88%-100% for thyroid, testis and melanoma, approximately 50% for breast, mouth, soft tissue and female reproductive organs, and 20% or less for bone, lung, lower gastrointestinal tract, and central nervous system [26,27]. These rates were similar to those of de novo cancers, except that rates were lower for female reproductive organs, bone, colorectum, and central nervous system. Our study shows similar results considering that, the 35-yr Kaplan-Meyer OS and DFS for the entire cohort of patients with SM were 49.4% and 39.1% after a median time of survival of 31 years and 26.5 years, respectively. A comprehensive study of a large number of patients with SM will help to determine the nature of these tumors and their outcomes compared with de novo tumors. Until then, patients with SM developing after HCT should be treated with the best available therapy for that tumor, unless there is compelling evidence that they will not be able to tolerate that therapy. Considering that the prognosis for patients with SM still remains poor despite therapeutic advances in the oncologic setting, early diagnosis and treatment remains to be the key to improving survival of patients [28-31]. For this purpose, an international working group was established through the Center for International Blood and Marrow Transplant Research Late Effects and Quality of Life Working Committee and the European Group for Blood and Marrow Transplantation Complications and Quality of Life Working Party with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. As a clinical output of this working group’s effort, consensus-based recommendations applicable for screening and prevention of individual secondary solid cancers among HCT recipients were published in 2015 [30].

Important strengths of our study include its large size from a single center, the long median duration (20 years) and completeness (99% at 35 years) of follow-up for transplant recipients and a statistical analysis that included many risk factors potentially involved in the development of SM. Similar follow-up is difficult, if not impossible, to achieve through large multicenter allogeneic transplant registries. The present study is not conclusive, but extends our understanding of SM risk after HCT. However, the study has several limitations, mainly because of its retrospective design. A further weakness of the study is the lack of detailed information on family history of cancer and on the exposure of all recipients and all donors to well-known risk factors for malignancies such as smoking, alcohol consumption, drug abuse, use of chemicals and health-related lifestyle. The follow-up completeness index for the entire cohort of living recipients is different in transplant recipients (99%) than in family donors (75%). Moreover, other information is lacking on the specific treatments (chemotherapy, immunotherapy, radiotherapy) adopted for each patient affected by MS.

In conclusion, HCT offers curative therapy for many patients with otherwise incurable disease. The incidence of post-transplant SM appears high, although reliable estimates of the overall risk will require longer follow-up. Despite the lack of randomized studies, the benefit of HCT, as compared with conventional therapy alone, in certain clinical situations outweighs the risk of late SM. It is imperative to follow HCT recipients closely and screen them for the development of SMs to decrease the morbidity and mortality associated with this complication.

Author Statements

Acknowledgements

The authors acknowledge the contribution of the outstanding team of the medical, nursing, technician staff at the UOSD Terapia Intensiva Ematologica and the UOSD Istituto dei Tessuti e Biobanche. Special thanks also are reserved to all the patients with their families.

Author’s Contribution

S.S., P.D.B. contributed patients, designed the study, analyzed the data, and wrote the manuscript; A.N., P.O., D.V., R.S. contributed to data acquisition and analysis; S.A. performed statistical study and contributed to the interpretation of the results.

Conflict of Interest Disclosure

All authors declare no competing financial interest.

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