Incidence and Risk Factors for Second Malignancies after Transplant in Long Term Survivors of Allogeneic Haematopoietic Stem Cell Transplant: A Single Centre Experience
Authors: Snober Mohammed , Syzdlo Richard , Apperley Jane , Chaidos Aristeidis , Kanfer Edward , Milojkovic Dragana , Olavarria Eduardo , Palanicawandar Renuka , Pavlu Jiri , Todd Jeannie F , Salooja Nina 
Published: October 2019

Abstract
Second malignancies are well recognised complications of haematopoietic stem cell transplantation (HCT). The incidence increases with time after HCT with no evidence of plateau with follow up times of 15-20 years. In this study we have investigated patients over a 37-year period to include all patients transplanted at The Hammersmith hospital since 1979 who survived a minimum of two years after transplant. We aimed to describe the post-transplant malignancies (PTM) that occurred and calculate the cumulative incidence with time.
Methods
Data was gathered through internal databases and supplemented with case notes with all patients giving consent for their data to be used in clinical studies. Additional information on patients who had died at the time of analysis included review of death certificates for evidence of a second malignancy. If a patient had not been seen within 5 years evidence of death was sought on the NHS Spine and if apparently still alive, the date of last follow up was taken as follow up time. Second malignancies included second solid neoplasms (SSN), non-melanoma skin cancer (NMSC) and leukemias/lymphomas. These were recorded and categorised in accordance with the international classification of disease for oncology (ICD-O).
Results
697 patients survived a minimum of two years after HCT between 1979-2018, 60% of whom were male. Follow up was prolonged with 20% of our 2-year survivors followed up for more than 20 years. The majority of patient (80%) were aged between 20-50 at time of HCT. (median age 35.6y, range 4-69) with only 7 patients < 10 y at HCT. The most frequent diagnoses were CML (n=463) or AML (n=103). The majority of patients (n=538, 77%) had received TBI, and the most frequently used conditioning was Cyclo-TBI (479 patients, 69%). At the time of analysis, 222 patients had died and of the remaining 475, 107 were lost to follow up.
We identified 97 PTM in 87 patients a median of 14.2 years post HCT (range 0.8-35.9 years). These included 58 cases of SSN, 28 cases of NMSC and 11 cases of leukemia or lymphoma. The most frequent SSN were breast (n=12), tongue (n=7), colorectal (n=6), melanoma (n=5), bladder (n=4), thyroid (n=3) and oesophagus (n=3). Of 28 patients with NMSC, 19 developed one or more BCC and 9 developed SCC.
The cumulative incidence of PTMs did not plateau with time. Cumulative incidences were as follows with 95% confidence intervals (CI) in parentheses: 4.9% (3.3-7.3) at 10 years, 12.2% (9.1-16.2) at 15 years, 22.5% (17.6-28.9) at 20 years, 39% (30.3-48.4) at 25 years and 53% (41.6-64.1) at 30 years. These data reflected the substantial increases in the CI of SSN and NMSC between these time points. For SSN the cumulative incidence increased from 3% (1.8-5) at 10 years to 37.9% (27.4-49.6) at 30 years; for NMSC the cumulative incidence increased from 1.3% (0.6-2.7) at 10 years 16.6% (9.2-28.2) at 30 years.
In multivariate analyses older age (>50) at time of transplant was associated with significantly increased (p<0.01) risk of PTM with a relative risk (RR) of 4.53 (2.1-9.6). On subgroup analysis this was only relevant to SSN where the RR was 5.17 (2.2-12.1). Patient/donor sex combinations other than male patient/male donor were also at increased risk of PTM, RR 1.797 (1.1-2.9), p=0.033, and again this was only significant for SSN (RR 2.11, 1.13-3.93).
Discussion and conclusions
In this predominantly adult study, the cumulative incidence of SSN and NMSC increased substantially with time after HCT beyond a 10-year follow-up period. The risk was increased in patients who were >50 at time of HCT. Prolonged expert follow-up with a high index of suspicion for second malignancy in these patients is recommended to facilitate early diagnosis.

Disclosures
Apperley: Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.