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INCIDENCE OF COMPLICATIONS AND METHODS FOR CORRECTION OF
GRAFT-VERSUS-HOST DISEASE FOLLOWING ALLOGENEIC
TRANSPLANTATION IN PATIENTS WITH ACUTE LEUKAEMIA
Khudoyor Makhmudovich Shomirzaev
Head of the Blood Transfusion Unit,
Samarkand Regional Multidisciplinary Medical Centre
Dilafruz Abdikhalimovna Amerova
Assistant teachet of the Department of Hematology,
Samarkand State Medical University
Abstract
. Graft-versus-host disease (GVHD) remains one of the most serious and frequent
complications following allogeneic haematopoietic stem cell transplantation (allo-HSCT),
particularly in patients with acute leukaemia. This study aimed to assess the incidence,
clinical features, and outcomes of GVHD, as well as the effectiveness of correction methods
used in a regional transplant centre in Uzbekistan. A total of 54 patients with acute myeloid
or lymphoblastic leukaemia who underwent allo-HSCT between 2020 and 2023 were
included. GVHD developed in 53.7% of cases, with acute GVHD occurring in 38.9% and
chronic GVHD in 14.8%. The skin, gastrointestinal tract, and liver were the most commonly
affected organs. Matched unrelated and haploidentical donors, as well as peripheral blood
stem cell sources, were significantly associated with higher GVHD incidence. First-line
corticosteroid therapy achieved a complete or partial response in 80.9% of acute GVHD
cases, while steroid-refractory patients required advanced treatments such as ruxolitinib or
extracorporeal photopheresis. GVHD-related mortality was 9.3%, with sepsis being the
leading cause of death. These findings emphasise the need for early detection, risk-adapted
prevention strategies, and improved access to second-line therapies to reduce GVHD-related
complications and mortality in resource-limited settings.
Keywords:
Graft-versus-host disease, allogeneic transplantation, acute leukaemia, stem cell
transplant, corticosteroids, ruxolitinib, immunosuppression, Uzbekistan, transplant
complications.
Introduction
Acute leukaemias, including acute myeloid leukaemia (AML) and acute lymphoblastic
leukaemia (ALL), are aggressive haematological malignancies characterised by rapid
proliferation of immature blood cells. Despite recent advances in chemotherapy and targeted
therapies, allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only
potentially curative treatment for many patients with high-risk or relapsed/refractory disease.
The procedure offers the therapeutic benefit of the graft-versus-leukaemia (GVL) effect—
where donor immune cells eliminate residual malignant cells. However, this same
immunological activity underlies one of the most serious post-transplant complications:
graft-versus-host disease (GVHD).
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GVHD is a complex, immunologically mediated condition in which donor T-lymphocytes
recognise host tissues as foreign and initiate an inflammatory attack. This condition is
typically classified as either acute or chronic, based on the timing and clinical presentation.
Acute GVHD (aGVHD) usually occurs within the first 100 days after transplant and
primarily affects the skin, gastrointestinal tract, and liver. Chronic GVHD (cGVHD), which
can develop months or even years after transplantation, resembles autoimmune disorders and
can involve multiple organ systems, causing long-term morbidity and impaired quality of
life. Both forms of GVHD remain major obstacles to the success of allo-HSCT and are
associated with increased treatment-related mortality and reduced long-term survival.
The incidence of GVHD varies depending on several factors, including the degree of HLA
matching, the source of the donor cells (bone marrow vs peripheral blood stem cells), patient
age, the intensity of the conditioning regimen, and the use of prophylactic
immunosuppressive protocols. Even with optimal matching, GVHD develops in 30–70% of
allogeneic transplant recipients. While mild to moderate GVHD may contribute to the
beneficial GVL effect, severe forms of the disease significantly compromise organ function,
increase infection risk, and reduce the likelihood of disease-free survival.
Over the past two decades, numerous strategies have been developed to prevent and treat
GVHD. These include pharmacological prophylaxis with calcineurin inhibitors (e.g.,
cyclosporine, tacrolimus) in combination with methotrexate or mycophenolate mofetil, T-
cell depletion techniques, and post-transplant cyclophosphamide in haploidentical settings.
In patients who develop steroid-refractory GVHD, treatment options have expanded to
include biologics and targeted therapies such as ruxolitinib, extracorporeal photopheresis,
and anti-IL-2 receptor antibodies. However, the efficacy of these treatments varies widely,
and their availability is often limited in low- and middle-income countries, including
Uzbekistan.
In clinical practice, managing GVHD requires timely recognition of early symptoms,
accurate staging, risk stratification, and prompt initiation of appropriate therapy. Moreover,
balancing immunosuppression to control GVHD while preserving the GVL effect and
minimising infection risk is a delicate and often complex process. This is particularly
important in patients with acute leukaemia, who are already highly immunocompromised
due to prior chemotherapy and disease-related marrow suppression.
In Uzbekistan, allo-HSCT has become increasingly accessible in recent years, and more
patients with acute leukaemia are undergoing transplantation at regional centres such as the
Samarkand Regional Multidisciplinary Medical Centre. However, structured data on the
incidence, severity, and management outcomes of GVHD in this population remain limited.
There is a critical need to assess the frequency and nature of GVHD-related complications
and to evaluate the effectiveness of locally implemented correction methods, including both
first-line and salvage therapies.
This study aims to analyse the frequency of GVHD and associated complications in patients
with acute leukaemia undergoing allogeneic stem cell transplantation. It also examines the
treatment approaches employed at our centre, their clinical efficacy, and the challenges
encountered in GVHD management. The findings are intended to guide improvements in
clinical protocols and enhance transplant outcomes through better prevention, early
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detection, and tailored therapeutic strategies for GVHD in resource-constrained healthcare
environments.
Methodology
This retrospective clinical study was conducted at the Blood Transfusion Unit and
Haematology Department of the Samarkand Regional Multidisciplinary Medical Centre
between January 2020 and December 2023. The purpose of the study was to assess the
frequency, severity, and treatment outcomes of graft-versus-host disease (GVHD) in patients
with acute leukaemia who underwent allogeneic haematopoietic stem cell transplantation
(allo-HSCT), and to evaluate the clinical efficacy of various correction methods used in
managing GVHD.
A total of 54 patients with acute leukaemia were included in the study, all of whom received
allo-HSCT during the specified period. Among them, 35 were diagnosed with acute myeloid
leukaemia (AML), and 19 with acute lymphoblastic leukaemia (ALL). Inclusion criteria
required patients to be aged 18 or older, have a confirmed diagnosis of acute leukaemia, and
have undergone allo-HSCT with complete clinical follow-up data available for at least 180
days post-transplant. Patients who received autologous transplants or had incomplete
medical records were excluded from the analysis.
All patients received conditioning regimens based on their disease type and transplant risk
profile. Most regimens included a combination of fludarabine, busulfan, and anti-thymocyte
globulin (ATG), with adjustments based on age, comorbidities, and donor type. Donors
included matched related donors (MRD), matched unrelated donors (MUD), and
haploidentical donors. Peripheral blood stem cells were used in 63% of cases, and bone
marrow stem cells in 37%.
GVHD prophylaxis consisted of cyclosporine or tacrolimus in combination with
methotrexate or mycophenolate mofetil, initiated prior to stem cell infusion and continued
post-transplant according to institutional protocols. In haploidentical transplants, post-
transplant cyclophosphamide was also used as an adjunct for T-cell modulation.
Data were collected from patient medical records and included demographics (age, sex),
type of leukaemia, donor type and source, conditioning regimen, GVHD prophylaxis used,
time to GVHD onset, and clinical features. GVHD diagnosis was made clinically and
confirmed histologically where indicated. Acute GVHD was graded based on the modified
Glucksberg criteria, and chronic GVHD was assessed using the NIH 2014 consensus
classification. Severity grading was based on organ involvement and functional impairment.
Management of GVHD was documented, including first-line and second-line treatment
strategies. First-line therapy for acute GVHD involved systemic corticosteroids
(methylprednisolone 2 mg/kg/day). In steroid-refractory cases, salvage therapies such as
ruxolitinib, extracorporeal photopheresis, or combination immunosuppressants were
administered depending on drug availability and patient response. Chronic GVHD was
treated with prolonged immunosuppressive therapy and symptomatic management,
including topical agents, ocular care, and nutritional support.
Outcomes assessed included incidence and severity of acute and chronic GVHD, response to
treatment (complete, partial, or refractory), duration of immunosuppressive therapy,
infection complications, overall survival, and GVHD-related mortality. The effectiveness of
each therapeutic intervention was evaluated based on symptom resolution, reduction in
immunosuppressive requirement, and patient quality of life during follow-up.
Statistical analysis was performed using SPSS version 26.0. Descriptive statistics
summarised the baseline characteristics and GVHD incidence. Continuous variables were
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presented as means and standard deviations, and categorical variables as percentages. Group
comparisons (e.g. MRD vs MUD, peripheral vs bone marrow source) were analysed using
chi-square and t-tests. Kaplan–Meier survival curves were generated to estimate overall
survival and GVHD-free survival, and a p-value < 0.05 was considered statistically
significant.
Ethical approval for the study was obtained from the Institutional Review Board of
Samarkand State Medical University. All data were anonymised, and patient confidentiality
was strictly maintained. Informed consent was obtained prior to transplantation, and patients
were informed that their data might be used anonymously for research purposes.
Results
This study included 54 patients with acute leukaemia who underwent allogeneic
haematopoietic stem cell transplantation (allo-HSCT) between 2020 and 2023. Of the total
cohort, 35 patients (64.8%) had acute myeloid leukaemia (AML) and 19 (35.2%) had acute
lymphoblastic leukaemia (ALL). The median age was 39 years (range: 18–61), with a male-
to-female ratio of 1.5:1. Donor types included matched related donors in 28 patients (51.9%),
matched unrelated donors in 14 (25.9%), and haploidentical donors in 12 patients (22.2%).
Peripheral blood stem cells were used in 34 cases (63%), and bone marrow in 20 cases
(37%).
Graft-versus-host disease (GVHD) developed in 29 patients (53.7%) during the post-
transplant follow-up period. Acute GVHD (aGVHD) occurred in 21 patients (38.9%), with
organ involvement most commonly seen in the skin (76.2%), gastrointestinal tract (52.4%),
and liver (33.3%). Among aGVHD cases, 9 (42.8%) were classified as grade I–II, and 12
(57.2%) as severe (grade III–IV). The median time to onset of aGVHD was 21 days post-
transplant. Chronic GVHD (cGVHD) developed in 8 patients (14.8%), predominantly
affecting the skin, oral mucosa, and eyes. Chronic GVHD typically presented after day 100,
with a median onset at day 142. Limited cGVHD was observed in 5 patients, and extensive
cGVHD in 3.
All patients who developed aGVHD received first-line therapy with systemic corticosteroids.
A complete clinical response was achieved in 12 out of 21 patients (57.1%), partial response
in 5 (23.8%), and 4 patients (19.0%) were classified as steroid-refractory. These refractory
cases were treated with second-line interventions: ruxolitinib was used in 2 patients with
good response; extracorporeal photopheresis was initiated in 1 patient; and combination
immunosuppression (cyclosporine + mycophenolate mofetil) was used in another. Among
cGVHD patients, immunosuppressive therapy achieved stable control in 6 patients, while 2
required prolonged treatment due to ongoing symptoms.
The overall survival (OS) at one year post-transplant was 81.5%, and GVHD-related
mortality occurred in 5 patients (9.3%), all of whom had severe aGVHD with multi-organ
involvement and infectious complications. A statistically significant association was
observed between unrelated or haploidentical donors and higher GVHD incidence (p =
0.031), as well as between peripheral blood stem cell grafts and increased risk of cGVHD (p
= 0.044). The median duration of immunosuppressive therapy in patients with GVHD was
5.8 months (range: 2–14 months).
Infectious complications occurred in 19 GVHD patients (65.5%), most commonly bacterial
sepsis and viral reactivations (CMV and HSV). These complications contributed to
prolonged hospitalisation and increased immunosuppression burden. Among patients who
responded well to GVHD correction strategies, quality of life measures improved
significantly during follow-up, with reduction in immunosuppressive doses and recovery of
performance status.
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These results underscore that GVHD remains a frequent and clinically significant
complication following allo-HSCT in acute leukaemia patients. While most cases of
aGVHD responded to corticosteroids, a notable subset required advanced or prolonged
interventions. Donor type and stem cell source were critical factors influencing GVHD risk
and severity, and early identification combined with aggressive management improved
clinical outcomes and survival rates.
Discussion
The findings of this study highlight the high frequency and clinical burden of graft-versus-
host disease (GVHD) among patients with acute leukaemia undergoing allogeneic
haematopoietic stem cell transplantation (allo-HSCT). With over half of the study
population developing some form of GVHD, it is evident that this complication remains one
of the primary barriers to achieving long-term transplant success and disease-free survival.
The incidence of acute GVHD (38.9%) and chronic GVHD (14.8%) observed in this study is
consistent with global reports, although the severity and outcomes are influenced by donor
type, graft source, and available treatment modalities.
A key observation from this cohort is the strong association between the use of peripheral
blood stem cells (PBSC) and an increased risk of both acute and chronic GVHD. This aligns
with previous studies demonstrating that PBSC grafts contain a higher T-cell load compared
to bone marrow, leading to more robust immune activation. Similarly, patients who received
grafts from matched unrelated or haploidentical donors showed significantly higher GVHD
rates compared to those with matched related donors, reinforcing the importance of HLA
compatibility in mitigating post-transplant immune complications.
The response to first-line corticosteroid therapy in acute GVHD was satisfactory in more
than half of the patients, reflecting current standards where steroids remain the cornerstone
of treatment. However, nearly 20% of patients were steroid-refractory, necessitating second-
line therapies such as ruxolitinib, extracorporeal photopheresis, or intensified
immunosuppression. While these approaches provided symptomatic relief, they also
increased the risk of infectious complications and extended the duration of hospitalisation.
This underscores the clinical dilemma of managing GVHD aggressively while preserving
immune competence and minimising secondary risks.
Chronic GVHD, although less frequent, contributed significantly to long-term morbidity.
Patients with extensive cGVHD required prolonged immunosuppressive therapy and
frequent outpatient visits, and often experienced reduced quality of life due to
mucocutaneous involvement, fatigue, and ocular discomfort. The need for multidisciplinary
care—including dermatology, ophthalmology, and psychological support—became apparent
in these cases, especially when managing symptoms resistant to systemic therapy.
The GVHD-related mortality rate in this study (9.3%) reflects the severity of the disease in
patients with multi-organ involvement and concurrent infections. This mortality was most
pronounced in patients with severe aGVHD who did not respond to initial therapy. Sepsis,
reactivation of latent viruses (notably CMV and HSV), and prolonged neutropenia
contributed to the fatal outcomes. These findings highlight the importance of early diagnosis,
timely initiation of therapy, and aggressive infection prophylaxis in improving survival.
Furthermore, the study illustrates the challenges faced in regional transplant centres in low-
and middle-income settings. Limited access to advanced biologic therapies, donor diversity,
and diagnostics hampers the early detection and optimal treatment of GVHD. However, the
favourable outcomes in patients who received standard prophylaxis and responded to initial
therapy indicate that a well-coordinated transplant and post-transplant care protocol can
significantly reduce complications and improve quality of life.
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In conclusion, GVHD remains a common and serious complication of allo-HSCT in patients
with acute leukaemia, with its incidence and outcomes closely tied to donor characteristics
and stem cell source. While corticosteroids remain effective in many cases, steroid-
refractory GVHD requires more advanced therapeutic approaches that may not always be
accessible. Enhancing early diagnostic capacity, improving donor selection, and expanding
access to modern immunosuppressive agents are essential steps to improving GVHD
management in Uzbekistan. These findings provide a valuable foundation for updating
national treatment protocols and guiding future research aimed at reducing the impact of
GVHD in haematological transplant patients.
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