Mortality and Morbidity in 15-Year Survivors of Stem Cell Transplants for Haematological Malignancy

Introduction: Haemopoietic stem cell transplantation (SCT) is a potentially curative treatment for haematological disease. Relapse, second malignancies, cardiovascular events, infection and GVHD-related disease are all established causes of death in the first 10 years post-SCT. Significant morbidity has also been described including cardiac risk factors, cardiovascular disease, malignancy, endocrinopathies and infertility. Although many of these complications are well documented in the first 5-15 years of follow-up, few studies have addressed mortality and morbidity in patients surviving longer than 15 years.

Methods: In this single centre study, the causes of death and cumulative burden of morbidity were investigated for patients who survived a minimum of 15 years after allogeneic SCT. Survival status was verified by a) confirming recent attendance in clinic b) review of National Health Service data which records mortality statistics for patients registered with a family doctor (GP) in the UK. Causes of death were sought from hospital records, GP records or death certificates. Data on second malignancies (excluding non-melanoma skin cancer) and cardiac disease were documented from patient notes. Use of medication at 15, 20, 25 and 30 years was collected as a surrogate indicator of the cumulative burden and nature of morbidity.

Results: 178 patients were identified who were known to be alive and in the UK 15 years post-SCT. The median follow up from this point was 7.4 years (range 0-20). The majority (170/178) received TBI conditioning with a median dose of 12Gy (range 10-14.4). The median age 15 years post-SCT was 48 years (range 20-74). Original disease was CML in 152 (85.4%) and acute leukaemia in 18 (10.1%). Probabilities of survival at 20, 25 and 30 years post-SCT were 90.0% (CI 85.4-94.6), 79.5% (72.2-86.7) and 73.5% (63.9-83.1). 32/178 (20%) of the 15-year survivors died, at a median of 19.1 years (range 15.1-30.6) post-SCT. Causes of death were available for 26/32 (81%) patients: eleven were due to infection, ten attributed to second malignancy, 2 cardiac, 2 respiratory and 1 was due to acute pancreatitis.  Of infective deaths, 9 were from pneumonia and 8/9 of these were associated with underlying lung disease, organ failure or immune suppression. No patient died from primary disease relapse.

Second malignancies affected 35/178 (20%) patients with 9 developing them prior to 15 years. The probabilites of having a second malignancy at 15, 20, 25 and 30 years post-SCT were 5.6% (95% CI 2.2-9.0), 17.6% (11.0-23.2), 29.1% (18.9-39.3) and 42.7% (26.1-59.3). Seven patients developed multiple second malignancies. From a total of 43 malignancies the most common tumour sites were breast (n=8) and oral cavity (n=5). Development of second malignancy was associated with significantly reduced survival compared to patients who did not have a second malignancy (p=0.001). Cardiovascular disease affected 14.7% of patients with cumulative incidences of 5.7% (1.7-9.7), 8.2% (3.2-13.2) and 22.3% (12.1-32.5) by 15, 20 and 25 years post-SCT respectively.

Fifteen years post SCT, the use of anti-hypertensive. lipid lowering medication and (in women) anti-platelet agents were higher than the use in the gender matched normal  population (Table 1). Use of these drugs increased significantly further (p<0.05) between 15 and 30 years to 38.5%, 48.7% and 15.4% respectively.  

Conclusion: Our data indicate that deaths after 15 years in this group of patient are most frequently due to second malignancy or else pneumonia in a setting of post-transplant complications. There were no deaths due to relapse. The burden of morbidity increased substantially between 15 and 30 years and this warrants lifelong specialist follow up.

	15years  post SCT	Age matched population data*	25 years post SCT	Age matched population data*
	MALE PATIENTS
Median age (range)	47.4 years (29-74)n=100		51.1 years (39-65)  n=25
Lipid lowering drugs	15%	11%	52.6%	11%
Anti-hypertensive agents	30%	12%	36.8%	12%
Anti-platelet agents	5%	4%	15.8%	4%
	FEMALE PATIENTS
Median age (range	48.2  years (20-73)  n=78		56.2 years (31-75)  n=33
Lipid lowering drugs	23.3%	6%	42.9%	17%
Anti-hypertensive agents	35%	10%	42.9%	22%
Anti-platelet agents	5%	2%	14.3%	6%
Table 1: comparison of medication use between study group and age matched population statistics from *HSCIC (UK Health and Social Care Information Centre, Use of prescribed Medicines 2013)