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Every Tuesday, NEJM Medical Frontiers [Tumor In-Depth Observation] column combs through recent papers in top journals such as the New England Journal of Medicine on hot issues in clinical oncology, reviews cutting-edge progress, and provides insight into future directions
.
Hematopoietic stem cell transplantation (HSCT) offers the possibility
of curing more than 70 benign and malignant hematological diseases and immune diseases.
With improved transplant strategies and supportive care, early post-transplant mortality rates have dropped significantly, the number of HSCT survivors has continued to grow, and the focus of transplant medicine has shifted to the management
of "long-term" survivors.
Patients with allogeneic HSCT have difficulty returning to pre-transplant status, have a unique disease risk spectrum, and must be monitored for long-term transplant complications, including chronic graft-versus-host disease (GVHD), multi-organ complications, and secondary malignancies
.
We synthesize papers published in the New England Journal of Medicine (NEJM), J Clin Oncol, JAMA Oncol, Bone Marrow Transplant and other journals in recent years, especially last year and this year, to sort out the long-term complications and management strategies
of patients with hematological malignancies after receiving HSCT.
Long-term survival
Over the past four decades, allogeneic HSCT has undergone profound changes, including transplantation in elderly patients, peripheral blood stem cell transplantation, and low-intensity/non-myeloablative pretreatment
.
These innovations have enabled more patients to receive HSCT, better supportive care, effective antiviral and antifungal drugs to reduce infectious complications, and advances in the management of acute GVHD are all contributing to the increasing
number of long-term HSCT survivors.
Disease recurrence is the main reason for
treatment failure in the first 2~4 years after HSCT.
Patients who do not relapse during this period have a relatively high long-term survival
.
A number of large studies have reported that the long-term survival rate of this patient group is high, but at least 15~20 years after HCT, its life expectancy is still lower than that of age and sex matchers
in the general population.
HSCT survivors have a nearly 55% incidence of serious or life-threatening illness, compared with 30%
for siblings.
The most common conditions include secondary tumors, diabetes, cataracts, venous thromboembolism, and joint replacement
.
HSCT survivors are more likely to report poor general health, limited mobility, and functional impairment
.
Chronic GVHD is associated with an increased
risk of lung disease, cataracts, and venous thromboembolism.
Tumor recurrence-related mortality is stable at 30%, while non-recurrence-related mortality increases to 50% after 30 years
.
All studies highlighted the need for lifelong follow-up of autologous and allogeneic HSCT survivors and screening for
disease recurrence and late complications.
Long-term complications
Chronic GVHD
In patients receiving allogeneic HSCT (non-modified grafts) and receiving standard calcineurin inhibitors and antimetabolite prophylaxis, chronic GVHD
developed in 30%~70% of patients.
Compared with those without chronic GVHD, people with chronic GVHD have a reduced quality of life and an increased
risk of long-term morbidity and mortality.
Chronic GVHD can affect not only the epithelial tissue (gastrointestinal, liver, skin, and lungs) typically affected by acute GVHD, but also any other organ system, including the mouth, esophagus, musculoskeletal, joints, fascia, eyes, and lymphatic hematopoietic system, hair and nails, and genitals
.
The clinical and histological features of chronic GVHD are shown in Figure 1
.
Figure A shows cutaneous hardening chronic GVHD with diffuse increased radiance and a tightening-like appearance due to thickening of the dermis (fibrosis), resulting in elbow and knee contractures
.
Figure B shows localized cutaneous chronic GVHD
.
The arrow points to hardened skin
.
Figure C shows chronic GVHD, gum recession and hardening
in the oral cavity.
The arrow points to a receding
gum.
Patients with chronic GVHD of the oral mucosa often present with thickening and hardening of the soft tissues in the oral cavity, resulting in mouth opening difficulties and pain
.
Figure D shows sclerotic changes
in the esophageal wall in a patient with chronic GVHD.
The arrow points to the hardened mucosa
.
Patients with esophageal involvement often report dysphagia
.
Figure E shows the nail chronic GVHD with the 3rd and 4th fingernails missing (arrows).
Figure F shows chronic GVHD in the eye with characteristic hypervascularism
.
Figure G shows computed tomography showing significant fibrotic changes (arrows)
in the lungs of a patient with chronic GVHD.
Typical symptoms of obliterative bronchitis include centripetal narrowing of the bronchial lumen, air retention, thickening of the bronchial wall, and central lobular nodules
.
Figure H (hematoxylin and eosin staining) shows skin sections
from patients with cutaneous sclerotic chronic GVHD.
The arrow points to collagen deposits (red fibers).
Figure I (hematoxylin and eosin staining) shows inflammatory cell infiltration (arrowhead)
in skin sections of patients with inflammatory chronic GVHD of the skin.
Figure J (hematoxylin and eosin staining) shows inflammatory cell infiltration (arrowhead)
in lung sections of patients with chronic GVHD.
Figure K (hematoxylin and eosin staining) shows peribile duct inflammatory cell infiltration (arrowhead)
seen in liver sections of patients with chronic hepatic GVHD.
Originally thought to occur at least 100 days after transplantation, chronic GVHD is now considered a unique systemic disease with many autoimmune disease-like properties that can occur
at any time after transplantation.
The National Institutes of Health has established diagnostic criteria and grading systems
for chronic GVHD.
This grading system scores the severity of 8 organs (skin, mouth, eyes, gastrointestinal tract, liver, lungs, reproductive tract, and fascia or joints) separately and adds up the scores to calculate the overall severity of chronic GVHD, thereby classifying chronic GVHD as mild, moderate, or severe, helping to predict survival
.
Risk factors for chronic GVHD include history of acute GVHD, peripheral blood stem cell transplantation, female donor transplantation in men, different HLAs from recipients, older recipients or donors, and patients with
chronic myeloid leukemia.
Whole-body irradiation is a risk factor for
disabling, sclerotic chronic GVHD.
Because chronic GVHD donor anti-host immune response can target normal host cells and leukemia cells shared allogeneic antigens, chronic GVHD is associated with an overall decrease in leukemia recurrence rate.
However, the benefit of reduced leukaemia recurrence is offset
by increased mortality in the absence of recurrence due to chronic GVHD.
Standard first-line regimens for chronic GVHD include systemic glucocorticoids, but approximately 50% of patients progress to glucocorticoid-refractory or glucocorticoid-dependent GVHD
.
In 2021, NEJM published an international, multicenter, phase 3 clinical trial (click to read: REACH3), which showed that the selective JAK1/2 tyrosine kinase inhibitor luxotinib has better
efficacy in patients with hormone-refractory or dependent chronic GVHD.
Drugs with multiple mechanisms of action are in clinical
trials.
Common secondary malignancies can be broadly divided into post-transplant lymphoproliferative disorders (PTLD), hematologic malignancies, and solid tumors
.
PTLD is almost exclusively seen in allogeneic HSCT recipients
.
This is a heterogeneous group of lymphoproliferative diseases that mainly involve B lymphocytes and occur
as a result of Epstein-Barr virus infection.
The disease usually develops early after transplantation, and more than 80% of cases are diagnosed
within the first year.
Increasing the intensity of immunosuppression increases its risk, such as in vivo or in vitro T cell depletion, presence of severe GVHD, and transplantation with HLA mismatch
.
Patients with these risk factors should be actively monitored for EBV reactivation and initiated prophylactic therapy
.
After an incubation period of 2~5 years, 5%~15% of patients receiving autologous HSCT developed secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Patients with secondary MDS/AML often present with characteristic cytogenetic abnormalities (including balanced translocations to 11q23, 5q, and 7q haploidies) and multiple chromosomal aberrations
.
Older age at transplantation and use of alkylated drugs before and during HSCT are associated with
an increased risk of morbidity.
In general, the incubation period of secondary solid tumors after HSCT is 2~5 years, and the incidence rate continues to increase with time, and no plateau period
has been observed.
It has been reported that the cumulative incidence of HSCT is 1%~2% at 5 years, 2%~6% at 10 years, and 4%~15%
at 15 years.
Basal cell carcinoma of the skin and squamous cell carcinoma of the skin or head and neck are the most common cancers
after HSCT.
Advanced age is one of
these risk factors for cancer.
Experience has shown that such tumors
can also occur in young patients with HSCT.
There is a clear correlation
between GVHD and non-melanoma skin cancer and head and neck cancer.
Organ-specific complications
Any organ can be affected, and major transplant-related exposure factors for advanced organ-specific complications include pretreatment with total body irradiation, GVHD, and long-term use of corticosteroids or calcineurin inhibitors
.
The risk of most organ-specific late complications continues to increase over time, and all HSCT survivors should be actively monitored
.
Table 1 summarizes common complications and their screening and preventive measures
.
Table 1 Common organ-specific complications and their screening and preventive measures
Cataracts, nonvascular osteonecrosis, or osteoporosis are common late complications
after transplantation.
The burden of cardiac and thrombotic events is particularly pronounced
in long-term survivors.
The World Health Organization's European database shows that the post-HSCT cardiac event rate in Europe is 2500 per 100,000* years
.
Using this as a baseline, patients with HSCT have a much
higher rate of cardiac complications.
Similarly, the incidence of venous thromboembolism within 10 years after HSCT is as high as nearly 12%, which is much higher than the estimate of 0.
1%~1% in the general population
.
All transplant survivors need to be rigorously monitored and managed for treatable risk factors for cardiovascular disease, such as diabetes, hypertension, and dyslipidemia
.
Malignant and non-malignant complications and major risk factors are summarized in
Figure 2.
Figure 2 Major late complications and risk factors
Before, during, and after transplant exposures need to be considered when developing a survivor management plan, with a focus on recommending prevention and screening measures
based on patient exposure and risk factors.
For example, a young child with autologous HSCT who receives no total body radiation for neuroblastoma has developed chronic GVHD in an older patient who has developed chronic GVHD in an older patient who has undergone allogeneic HSCT pretreated with total body irradiation for MDS.
Therefore, the focus should be on exposure and risk factors so that long-term follow-up management can be optimized and individualized
to the specific needs of the patient.
Late infection
6~12 months after autologous HSCT, the cellular and humoral immune system can be completely rebuilt; However, patients with allogeneic HSCT may take 2 years or more, and patients with GVHD may experience further delays
.
Thus, late-stage infection is an important cause of
late-stage morbidity and mortality in autologous and allogeneic HSCT survivors.
Patients requiring long-term immunosuppression due to persistent chronic GVHD are particularly at risk and are susceptible to infection by capsular bacteria (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae), fungi (Aspergillus, Candida, and Pneumocystis), and viruses (cytomegalovirus and varicella zoster virus), who require appropriate antimicrobial prophylaxis
.
Vaccination should be started 6~12 months after transplantation and should follow the consensus recommendations
for infection prevention in HSCT survivors.
Psychosocial and quality of life
The transition from transplant patient to transplant survivor can be fraught with hardships
.
Survivors may continue to experience distress with underlying disease recurrence, financial stress related to treatment, pressures in the doctor-patient relationship, severe illness and limitations in physical functioning associated with chronic GVHD, and concerns about
secondary malignancies.
Returning to normal work, study and normal family life can be more difficult
than expected due to severe physical and psychological impairments.
In most cases, the patient's career goals, spiritual world, and outlook on life may have been changed
by their transplant experience.
Autologous and allogeneic HSCT survivors are prone to sexual dysfunction, career development disorders, financial burden, poor body image, and difficulties
in social reintegration.
Patients with these problems require prompt referral to a psychiatrist
.
The prevalence of depression in the general cancer population is 10%~25%, and the prevalence of allogeneic HSCT may be higher
.
Some studies have shown that the incidence of depression in the first year after transplantation is as high as 25%~35%.
In addition, studies have shown a link
between depressive symptoms and reduced survival in allogeneic HSCT survivors.
This may mean that stronger induction regimens, greater financial pressure, and more serious complications can cause higher levels of distress
than other groups of oncology patients.
Among transplant survivors, the incidence of post-traumatic stress disorder (PTSD) can be as high as 5%.
In addition, a European study showed that the suicide mortality rate per 100,000 transplants is twice the
expected rate in the general population.
Mental health screening and evaluation should be done regularly, at least once a
year after transplantation.
Support groups and individual therapy can help patients deal with a variety of emotions, including anxiety, depression, and survivor guilt
.
Support groups can also provide forum functions to help patients respond positively to post-traumatic emergencies
.
For clinically symptomatic patients, pharmacotherapy or referral to a psychiatric disorder treatment facility
should be considered.
Quality of life (QOL) decline is common in HSCT survivors, and QOL recovery takes 2~5 years after HSCT; Factors such as transplant type (autologous vs.
allogeneic), stage (early versus late transplantation), and complications (e.
g.
, GVHD) can all influence QOL
.
Compared with patients with allogeneic HSCT, autologous HSCT survivors have an earlier decline in QOL, but overall recovery is faster
.
While all aspects of QOL in allogeneic HSCT survivors may be sustained and long-term, autologous HSCT survivors have the most pronounced
physical function, role function, and overall QOL.
Future research areas
Several areas, such as late complications and survival in HSCT survivors, require further study
.
Most of the literature on the late effects of HSCT was retrospective or cross-sectional, and the lack of adequate control groups led to a low level of evidence
.
We know very little about the pathophysiology of some late-stage complications, and the effectiveness of prevention strategies is unclear
.
In addition, the methodology itself is challenging, such as some HSCT late-stage effects that take up to 10 years to appear, making it difficult to conduct high-quality studies
with sufficient statistical power.
To address these challenges and identify key and priority areas of mid- and late-stage impact in HSCT survivors, the National Institutes of Health launched the HSCT Late Impact Initiative and identified six focus areas: healthcare delivery, research methodology and study design, secondary oncology, QOL and psychosocial outcomes, immune dysregulation, and cardiac, vascular, and metabolic complications
.
References
1.
Zeiser R, Blazar BR.
Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets.
N Engl J Med 2017; 377:2565-79.
2.
Socie G.
Long-term outcomes after transplantation for acute myelogenous leukemia.
J Clin Oncol 2022; 40:3235-38.
3.
Bhatia S, Dai C, Landier W, et al: Trends in late mortality and life expectancy after allogeneic blood or marrow transplantation over 4 decades: A Blood or Marrow Transplant Survivor Study Report .
JAMA Oncol 2021; 7:1626-34.
4.
Armenian SH, Chen Y, Hageman L, et al.
Burden of long-term morbidity borne by survivors of acute myeloid leukemia treated with blood or marrow transplantation: The results of the BMT survivor study.
J Clin Oncol 2022; 40:3278-88.
5.
Del Galy AS, Rousseau A, Capes A, et al.
Life expectancy and burden of late complications after reduced intensity conditioning allogeneic transplantation.
Bone Marrow Transplant 2022; 57:1365-72.
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.
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