Long Term Complications After Hematopoietic Cell Transplantation

Abstract

The prevalence of autologous and allogeneic hematopoietic cell transplantation (HCT) survivors continues to increase. Among patients whose disease remains in remission for the first 2-5 years after transplantation, it is estimated approximately 80-90% will be alive over the subsequent 10-years. However, their relative mortality rates continue to remain higher than their general population peers with late complications contributing to significant long-term morbidity and mortality. Late effects in HCT survivors include secondary cancers, organ specific complications, late infections, quality of life impairments, psychosocial issues, sexual and fertility concerns, financial toxicity and issues around return to work/school. A patient-centric and multidisciplinary approach to HCT survivorship care with collaborative and coordinated care from transplant centers and community healthcare providers is necessary to ensure their long-term health. Lifelong followup of HCT survivors is recommended, with established guidelines serving as the template for providing screening and preventive care based on patient-specific exposures. This review discussed common late complications, models for care delivery, and gaps and priorities for future research in the field of HCT survivorship.

INTRODUCTION

The long-term survival probability for hematopoietic cell transplantation (HCT) recipients continues to improve with several advances in transplantation techniques and supportive care practices, and it is projected that there will be more than 500,000 HCT survivors in the United States by 2030.^{1, 2} As patients survive longer, there is an increasing recognition that pre-, peri- and post-transplant exposures can contribute to the development of late complications that can cause substantial morbidity, impair quality of life, and can compromise life expectancy in transplant survivors. This review summarizes the contemporary literature on long-term survival after autologous and allogeneic HCT, guidelines for long-term followup of HCT survivors and barriers and opportunities for their followup.^3–5

LONG-TERM SURVIVAL AFTER HCT

Disease relapse is the main cause of treatment failure in the first 2-4 years after transplantation. Patients who do not suffer from disease relapse through this early time period enjoy relatively high rates of subsequent survival. Several contemporary large studies have reported on long-term survival rates in patients who have survived disease-free for 2-5 years after transplantation (Table 1).^6–15 Although studies vary in methodology and patient characteristics, together they indicate high probability of long-term survival in this patient population, although their life-expectancy continues to lag behind that of their age- and gender-matched peers from the general population for at least 15-20 years after HCT. They also indicate disease recurrence, chronic graft-versus-host disease (GVHD; in allogeneic HCT recipients), organ failure and secondary cancers are common causes of late deaths. Collectively, these studies highlight the need for life-long systematic followup for both autologous and allogeneic HCT survivors to screen for disease recurrence and late complications, and for health maintenance following transplantation.

Table 1.

Large contemporary studies evaluating long-term survival after hematopoietic cell transplantation^*

Reference	Data source and patients	Overall survival from HCT	Important risk factors for late mortality	Life expectancy
Autologous HCT
Bhatia et al (2005)7	BMT SS, N=854 (≥ 2-yr survivors); auto HCT for ALL, AML, lymphoma	69% @ 10 yrs	Older age at HCT, disease with high relapse risk, diagnosis of ALL or lymphoma	Mortality rates approached that of general population by >10 yrs after HCT for patients with AML and standard risk disease
Majhail et al (2009)9	CIBMTR, N=1,367 (≥ 2-yr survivors); auto HCT for lymphoma	52-85% @ 10 yrs (varied by lymphoma type)	Older age at HCT	Mortality rates approached that of general population by 4 yrs after HCT
Majhail et al (2011)14	CIBMTR, N=315 (≥ 2-yr survivors); auto HCT for AML	94% @ 10 yrs	Older age at HCT, poor cytogenetic risk disease	Mortality rates higher than general population through 10 yrs after HCT
Vanderwalde et al (2013)13	Single center, N=2,388 (1,577 ≥2 yr survivors); auto HCT for lymphoma, myeloma, AML	5-year survival 75% for 2-yr survivors, 81% for 5-yr survivors, 88% for 10-yr survivors	Older age at HCT, disease at high risk for relapse	Mortality rates approached general population for 10-yr survivors, with exception of female Hodgkin lymphoma patients transplanted before 1995 at age ≤ 40 yrs
Allogeneic HCT
Bhatia et al (2007)6	BMT SS, N=1,479, (≥ 2-yr survivors); MAC allo HCT for ALL, AML, CML, lymphoma, metabolic disorders, SAA	80% @15 yrs	Chronic GVHD, older age at HCT, disease with high relapse risk	Mortality rates higher than general population through 15 yrs after HCT
Goldman et al (2010)8	CIBMTR; N=2,444 (≥ 5-yr survivors); MAC allo HCT for CML	87-88% @ 15 yrs (varied by donor type)	Chronic GVHD	Mortality rates approached that of general population by 14 yrs after HCT
Wingard et al (2011)11	CIBMTR; N=10,632 (≥ 2-yr survivors); MAC allo HCT for ALL, AML, lymphoma, MDS, SAA	80-92% @ 10 yrs (varied by disease)	Chronic GVHD, older age at HCT, disease	Mortality rates higher than general population for most diseases through 15 yrs after HCT
Atsuta et al (2016)15	Japan Society for HCT, N=11,047 (≥ 2-yr survivors); MAC/RIC allo HCT for any diagnosis	83% @ 15 yrs	Chronic GVHD, older age at HCT, disease risk	Mortality rates higher than general population at 20 yrs after HCT
Combined
Nivison-Smith et al (2009)12	ABMTRR, N=1,461 (≥ 5-yr survivors); auto or allo HCT for multiple diagnoses	67-93% @ 10 yrs (varied by disease)	Older age at HCT	Mortality rates approached that of general population by 10 yrs after HCT
Martin et al (2010)10	FHCRC, N=2,574 (≥ 5-yr survivors); auto or allo HCT for multiple diagnoses	80% @ 20 yrs	Chronic GVHD, HCT for malignant diseases other than CML in chronic phase	Mortality rates higher than general population through 30 yrs after HCT

Abbreviations: ABMTRR – Australasian Bone Marrow Transplant Recipient Registry; ALL – acute lymphoblastic leukemia; AML – acute myeloid leukemia; BMT SS – Bone Marrow Transplant Survivor Study; CIBMTR – Center for International Blood and Marrow Transplant Research; CML – chronic myeloid leukemia; FHCRC – Fred Hutchinson Cancer Research Center; GVHD – graft-versus-host disease; HCT – hematopoietic cell transplantation; MAC – myeloablative conditioning; MDS – myelodysplastic syndrome; RIC – reduced intensity conditioning; SAA – severe aplastic anemia

^*Adapted with permission from: NS Majhail, JD Rizzo. Surviving the cure: Long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplantation, 2013, 48(9):1145-51.

LATE COMPLICATIONS AFTER HCT

Late complications are medical issues that occur months to years after transplantation and can be broadly categorized as secondary cancers, organ specific complications, late infections, quality of life (QOL) impairments, psychosocial issues, sexual and fertility concerns, financial toxicity and integration back to society. Some complications (e.g., cardiovascular complications, end stage renal disease, bronchiolitis obliterans) contribute to late non-relapse mortality among transplant survivors. Other complications (e.g., dry eyes, xerostomia, avascular necrosis) may not directly impact mortality but can impair quality of life. The genesis of these complications can be partly or completely attributed to transplant related exposures. In addition, pre-transplant treatment exposures (e.g., disease specific chemotherapy or radiation) as well as modifiable and non-modifiable life-style factors (e.g., smoking, hereditary cancer risk factors) can contribute to the risk. Conditioning regimen related chemotherapy and total body irradiation (TBI) exposures are commonly associated with risks for late complications in all HCT recipients. Among allogeneic HCT recipients, chronic GVHD and its treatment are also major contributors to late complication risks. Table 2 summarizes common late complications of transplantation and the recommendations for their screening and prevention.

Table 2.

Summary of 2012 international consensus guidelines for screening and prevention of late complications in autologous and allogeneic HCT recipients (detailed guidelines are available through references^3–5)

Tissues/organs	Followup considerations in all HCT recipients	Additional considerations in special populations
Immune system	-PCP prophylaxis -Post-transplant immunizations -Endocarditis prophylaxis	Patients with cGVHD -Prophylaxis against PCP and encapsulated organisms -Screening for CMV reactivation
Ocular	-Clinical evaluation for ocular complications -Ophthalmologic exam	Patients with cGVHD -May require more frequent assessments
Oral	-Education about preventive oral health practices -Clinical oral assessment for oral complications -Dental exam	Patients with cGVHD -May require more frequent assessments Pediatric recipients -Evaluation of teeth development
Respiratory	-Smoking cessation (if applicable) -Clinical evaluation for pulmonary complications	Patients with cGVHD -May require more frequent clinical evaluation
Cardiac and vascular	-Education on “heart“ healthy lifestyle -Assessment and early treatment of cardiovascular risk factors (e.g., diabetes) -Endocarditis prophylaxis
Liver	-Liver function tests periodically -Viral load monitoring and liver biopsy in patients with known hepatitis B or C -Serum ferritin at 1 yr with additional workup if needed (e.g., MRI, liver biopsy)
Renal and genitourinary	-Aggressive treatment of hypertension -Evaluation of renal function
Muscle and connective tissue	-Encourage physical activity	Patients with cGVHD or prolonged steroid exposure -Clinical assessment for myopathy -Physical therapy consultation
Skeletal	-Encourage physical activity and vit D and calcium supplementation -Dual photon densitometry at 1 yr for adult women, all allogeneic transplant recipients and patients at high risk for bone loss	Patients with cGVHD or prolonged steroid exposure -Consider dual photon densitometry at an earlier date
Nervous system	-Clinical evaluation for neurological complications	Pediatric recipients -Assessment for cognitive development
Endocrine	-Thyroid function testing -Clinical and endocrinologic gonadal assessment for post-pubertal women -Gonadal function assessment in men	Patients with cGVHD or prolonged steroid exposure -Slow terminal tapering of steroids -Stress doses of steroids during acute illness Pediatric recipients -Clinical and endocrinologic gonadal assessment -Growth velocity monitoring
Mucocutaneous	-Education on skin self exam and minimizing sunlight exposure -Gynecologic exam for detecting early involvement by cGVHD	Patients with cGVHD and TBI recipients -May require more frequent gynecologic exam
Second cancers	-Counsel patients about second cancer risks and to avoid high risk behaviors (e.g., smoking) -Follow general population recommendations for cancer screening	Patients with cGVHD -Evaluation for oral and pharyngeal cancer TBI and chest irradiation recipients -Screening mammography in women at an earlier age than general population recommendations
Psychosocial and sexual	-Clinical evaluation and if needed referral to mental health professional -Assess caregiver/spouse for psychological adjustment and family functioning -Sexual dysfunction
Fertility	-Referral to appropriate specialists -Birth control

Abbreviations: cGVHD, chronic graft-versus-host disease; CMV, cytomegalovirus; PCP, Pneumocystis pneumonia; TBI, total body irradiation; MRI; magnetic resonance imaging; PTLD, post-transplant lymphoproliferative disorder

^*Reproduced with permission from: NS Majhail, JD Rizzo. Surviving the cure: Long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplantation, 2013, 48(9):1145-51.

Secondary Cancers

Secondary cancers account for 5-10% of deaths among HCT recipients who survive two years or longer, and can be broadly categorized as post-transplant lymphoproliferative disorders (PTLD), hematologic malignancies and solid cancers.^{2, 11, 16, 17} PTLD is almost exclusively seen in allogeneic HCT recipients and comprises of a heterogeneous group of lymphoid proliferations, primarily involving B-lymphocytes, which arise as a result of Epstein-Barr virus (EBV) infection.^{16, 18} It typically manifests early post-transplantation with >80% cases diagnosed within the first year. Increase in intensity of immunosuppression increases its risks, such as in vivo or ex vivo T-cell depletion, presence of severe GVHD and use of HLA mismatched grafts, and active surveillance for EBV reactivation in these high-risk settings with initiation of preemptive therapy is generally recommended. Secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) can be seen in 5-15% of autologous HCT recipients after a latency period of 2-5 years.¹⁷ Characteristic cytogenetic abnormalities (e.g., balanced translocations to 11q23, monosomy of 5q and 7q) and multiple chromosomal aberrations are frequent in secondary MDS/AML and older age at transplant, use of alkylating agents prior to and during HCT, and use of TBI increase its risks. Generally, there is a latency period of 3-5 years before secondary solid cancers occur after HCT, but subsequently, their incidence continues to rise with time and a plateau in their incidence has not been observed. The reported cumulative incidence ranges from 1-2% at 5-years, 2-6% at 10-years and 4-15% at 15 years after HCT.^{17, 19–21} Lifelong cancer screening for all HCT survivors according to established guidelines is recommended.^{4, 5, 22}

Organ Specific Complications

In general, any organ can be affected and major transplant related exposures for delayed organ specific complications include the use of TBI in conditioning, GVHD and protracted use of corticosteroids or calcineurin inhibitors. The risk for most organ specific late complications continues to increase with time and continued active surveillance for these problems is indicated in all HCT survivors. Table 2 highlights common complications and evaluations for their screening and prevention. For an individual patient, pre-, peri- and post-transplant exposures need to be considered in establishing a survivorship care plan that focuses on preventive and screening practices that would be recommended based on that patients exposures and risk factors. For example, the profile of late complications, their risk factors, and recommended long-term followup evaluations would be different for a young child who has received an autologous HCT without TBI for neuroblastoma compared to an older patient who has received an allogeneic HCT using TBI based conditioning for MDS and has developed chronic GVHD. Hence, the emphasis should be on exposures and risk-factors, such that the long-term followup care can be optimized and individualized to specific patient needs.

Late Infections

Adequate reconstitution of the cellular and humoral immune systems occurs within 6-12 months after autologous HCT and can take 2 years or more in allogeneic HCT recipients, and can be further delayed in patients who develop GVHD. Hence, late infections are an important cause of late morbidity and mortality in both autologous and allogeneic HCT recipients. Patients needing long term immunosuppression for ongoing chronic GVHD are particularly at risk and are susceptible to infections by encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitides and Hemophilus influenzae), fungi (Aspergillus spp., Candida spp. and Pneumocystis jiroveci) and viruses (cytomegalovirus and varicella zoster virus), and need appropriate anti-microbial prophylaxis. Vaccinations should begin at 6-12 months after transplantation, and should follow consensus recommendations for infection prevention in HCT recipients.^{23, 24}

Other Late Complications

QOL impairments are common in HCT survivors and its recovery after HCT is a 2- to 5-year process that is influenced by transplant type (autologous vs. allogeneic), phase (early vs. late post-transplant) and complications (e.g., GVHD).^25–27 QOL decline nadirs earlier and overall recovers sooner in autologous HCT recipients compared to patients undergoing allogeneic HCT. While continued long-term impairments may persist in all domains of QOL for allogeneic HCT survivors, they are most evident in physical functioning, role functioning and overall QOL in autologous HCT survivors.²⁶ In addition to medical complications, autologous and allogeneic HCT survivors are prone to sexual dysfunction, occupational disability, economic burden, negative body image and difficulties with social reintegration.^{28, 29}

CARE DELIVERY FOR HCT SURVIVORS

Lifelong systematic followup is recommended for all HCT survivors. However, several challenges to providing this care exist at the patient, provider and healthcare system level. Patients may not be aware of their exposures, risks and risk-factors for late complications, and increasing duration or survival after HCT may lead them to under-appreciate the importance and need for continued surveillance for late effects. Patient socio-demographic factors such as accessibility to a transplant center and specialists and healthcare disparity factors may serve as a barrier to obtaining appropriate followup care. Transplant centers may lack the resources, infrastructure and expertise to provide care to long-term transplant survivors and community health care providers (e.g., primary care physicians and hematologists-oncologists) may not be aware of HCT related exposures, their late consequences, and may lack expertise in managing patients complex health care needs. Overall, a multidisciplinary approach that incorporates the expertise and resources of transplant centers, referring hematologists-oncologists, primary care physicians, and other health care providers is recommended, that focuses on the following components: surveillance for disease recurrence, surveillance and prevention of late complications, screening for new second cancers, routine health maintenance, health promotion and education, psychosocial support, rehabilitation, and financial counseling and reintegration into society. Some of this care may be provided through the transplant centers, whereas community providers and other specialists may be responsible for providing other aspects of survivorship care, with an overall patient-centric coordinate care approach that ensures communication and collaboration among all providers. A treatment summary and survivorship care plan, a tool that provides a comprehensive summary of patient’s diagnosis, pre-transplant therapies, transplant course, and post-transplant complications, can facilitate care coordination by detailing patient specific exposures and evaluations recommended for late effects monitoring and the provider responsible for conducting them.

AREAS FOR FUTURE RESEARCH

Several areas around late complications and survivorship in HCT recipients warrant further investigation.³⁰ The majority of HCT late effects literature is limited to retrospective or cross-sectional studies without adequate control groups resulting in a low-level of evidence. The pathobiology of individual late effects is poorly understood and the effectiveness of preventive strategies has not been well defined. Methodologic challenges such as difficulty in conducting adequately powered studies of late effects which may occur decades after HCT further compound the ability to perform high-quality research to understand the prevalence, mechanisms and management of late effects in this population. In order to address these challenges and identify gaps in understanding and prioritize areas of key late effects among HCT survivors, the National Institutes of Health has recently sponsored the HCT Late Effects Initiative with the objectives of defining the critical issues or barriers in the field, set research priorities, and to create a framework for studying late effects. Six broad areas of emphasis included health care delivery, research methodology and study design, subsequent neoplasms, QOL and psychosocial outcomes, immune dysregulation, and cardiac, vascular and metabolic complications.^31–37 Table 3 provides an overview of the recommendations and priority areas for research identified by this initiative.

Table 3.

Overview of research priorities identified by the NIH HCT Late Effects Consensus Conference (comprehensive recommendations are available at each Working Group white papers)^31–37

Working Group	HCT Survivorship: Research Gaps and Priorities
Cardiac, Vascular and Metabolic	Arterial Disease -Determine incidence, risk factors (including allo-effect), at risk populations, and pathobiology -Establish HCT-specific risk prediction models -Evaluate novel imaging and blood biomarkers for screening -Test interventions in high-risk survivors Cardiac Dysfunction -Determine contribution of pre-HCT exposures and comorbidities -Examine mechanisms of enhanced cardiotoxicity -Characterize asymptomatic cardiac dysfunction -Novel imaging and blood biomarkers for screening -Test preventive interventions in high risk survivors Cardiovascular Risk Factors -Hypertension: Optimize timing of interventions based on markers of vascular and endothelial dysfunction; assess magnitude of under-treatment and barriers to treatment -Hyperglycemia: Assess effects of pre-HCT metabolic status and exposures; evaluate optimal timing and methods for screening; investigate pharmacologic and non-pharmacologic interventions in prediabetic states -Dyslipidemia: Define high-risk survivors; evaluate association of dyslipidemia with inflammation after HCT and immunomodulatory aspects of statins; assess effect of lifestyle and lipid-lowering therapy -Sarcopenic obesity: Evaluate longitudinal changes in body composition in association with outcomes, Assess risk factors, exposures, and effect of exercise or dietary modification on fat/muscle mass
Subsequent Neoplasms	-Establish multicenter mechanisms to conduct prospective large-scale long-term studies of HCT survivors that capture detailed data on pre-, peri- and post-transplant exposures -Define magnitude of risks for specific SN -Evaluate interaction between traditional risk factors (e.g. smoking) with HCT-related risk factors -Bank cryopreserved donor and recipient blood and marrow cells along with SN tissue for laboratory investigations -Assess genetic risk factors -Investigate validity, cost-effectiveness, magnitude of risk-reduction, optimal techniques and timing of screening for specific SN -Validate cancer prevention interventions (e.g., HPV vaccination)
Immune Dysregulation	Late infections -Establish a long-term multicenter registry to identify serious infections, types of pathogens, and risk factors -Evaluate immunologic correlates using banked samples -Evaluate early and late microbiota changes with late infections and immune reconstitution -Examine effectiveness of consensus infection control guidelines in the prospective registry Immune reconstitution -Identify the molecular mechanisms of late dysfunctional adaptive immunity -Investigate adaptive immune system neogenesis, maturation and exhaustion -Examine the influence of persistent alloreactivity, inflammation and viral infections -Asses late functional pathogen-specific T- and B-cell responses Prevention of infections -Correlate immune reconstitution markers with vaccine responses to standardize thresholds for initiating vaccination -Conduct vaccination specific prospective multicenter trials -Assess role of other therapies such as IVIG
Quality of Life and Psychosocial Outcomes	-Establish registry for prospective collection of patient reported outcomes that includes underrepresented groups -Design and test risk-targeted interventions that address resource utilization and costs, process measures including feasibility, treatment fidelity, sustainability and dissemination potential. Priority domains are sexual dysfunction, fatigue/sleep disruption, non-adherence, health behaviors such as physical inactivity, and psychological dysfunction -Design a consensus-based methodological framework including standardized time points and longitudinal prospective designs -Evaluate and compare existing practices for integrating patient-centered outcome screening across HCT survivorship programs to identify best practices and barriers; address opportunities to incorporate patient centered outcome data into electronic medical records
Research Methodology and Study Design	-Establish new cohorts or expand existing cohorts to study late effects using comprehensive and complete capture of pre-, peri- and post-HCT exposures and follow-up of HCT recipients; include detailed information on chronic GVHD, socio-demographic data, patient reported outcomes and healthcare costs -High priority areas for data collection are late effects that have high incidence of morbidity, impairment, disability and/or premature mortality, have excess risk compared to general population and have potentially modifiable risk factors -Develop or supplement existing biospecimen repositories to facilitate investigation; priority specimens include germline DNA, total leukocyte of cell-specific RNA, plasma/serum, and fresh-frozen tissue of SN
Healthcare Delivery	Healthcare delivery models -Identification, development, implementation and efficacy of patient-centered care delivery models. Emphasis on novel models, integration of information technology and care by non-physician providers -Evaluate patient self-management and information technology tools for enhancing patient involvement -Evaluate healthcare disparities and issues in special populations including caregivers -Assess models for implementation and utilization of treatment summary and survivorship care plans -Evaluate development and implementation of evidence-based screening and prevention guidelines -Evaluate role of supportive therapies Coverage and value -Establish infrastructure and databases to conduct studies on costs and value of HCT; link existing databases to electronic health records -Identify patient-centered coverage models for preventive care and late complications -Investigate resource utilization, costs, and cost-effectiveness of healthcare delivery models; emphasize innovative models for coverage through the care continuum and coverage of other services required to provide survivorship care -Assess impact of health policy (e.g., Affordable Care Act, Medicare payment reform) -Evaluate prevalence, risk factors, and interventions for short- and long-term financial toxicity to patients and caregivers -Evaluate patient reported outcomes to inform value and coverage models

^*Reproduced with permission from: M Battiwalla, A Tichelli, NS Majhail. Long-term survivorship after hematopoietic cell transplantation: Roadmap for research and care. Biology of Blood and Marrow Transplantation, 2017 (in press).

CONCLUSIONS

In the contemporary era, patients who are able to successfully endure the early post-transplant period can enjoy relatively excellent long-term survival. However, HCT survivors remain at risk for late complications and pre-mature mortality. The field of HCT survivorship is rapidly evolving as our understanding of risk factors, mechanisms and prevention of late effects increases with ongoing research. However, there are several research gaps that need to be addressed. In the meantime, HCT survivors need individualized and patient-centric followup care provided through a multidisciplinary collaborative care model that considers their preferences and needs.