Allogeneic hematopoietic stem cell transplant (HSCT)

Utilizes stem cells from bone marrow, peripheral blood or umbilical cord blood of a healthy related or unrelated donor whose human leukocytes antigen matches the patient’s.

Allogeneric peripheral blood progenitor cells are associated with an increased risk of graft versus host disease compared with bone marrow transplants.

Provides normal stem cells and immune cells and is used to treat diseases of these cells including aplastic anemia, immunodeficiency syndromes, leukemias, or lymphomas, myeloma, and hemoglobinopathies.

The therapeutic mechanism behind allogeneic transplant in the management of the hematologic malignancies relies on an immunologic graft versus malignancy effect, meaning donor leukocytes form an immune response against the recipients malignancy which can hopefully lead to durable remissions.

Often associated with significant mortality risk, short and long-term morbiditirs such as graft versus host disease, serious infections, organ toxicity, hemorrhage, secondary malignancies, and prolonged immunosuppression.

The non-relapse mortality rate is 10-20% in the first two years.

This mechanism is also the pathophysiology behind graft versus host disease.

GVHD is a condition in which donor T cells attack host tissue, affecting multiple organs, particularly the skin, liver, and gastrointestinal tract.
The pathogenesis of GVHD is influenced by the release of molecular patterns and tissue damage caused by neutrophil granulocytes.
GVHD develops in approximately 50% of recipients of allogeneic  stem cell transplantation.
GVHD is a substantial cause of death in patients undergoing allogeneic stem cell transplantation.

More than 15, 000 performed annually in the U.S.

In 2019 AHSCT was performed in Europe and North America at almost 30,000 cases.

Mean hospital stay 25 days.

The patient receives large doses of chemotherapy and sometimes radiation to ablate their bone marrow and immune system.

Requires suppression of ablation of the host immune system to facilitate engraftment of donor cells and donor T cells must be removed, reduced, or suppressed to prevent graft versus host disease.

Following the above stem cells are obtained from related or unrelated donors by simple surgical procedure of extraction of cells from the posterior iliac crest or, today more frequently, from the blood collected by leukapheresis procedures.

Stem cells are transplanted by simple intravenous infusion and home to the bone marrow.

Changes in bone marrow transplant have occurred by the use of alternative stem cells forces, such as peripheral blood stem cells and cord blood, and the use of non-myeloablative or reduced intensity conditioning.

Choice of allogeneic stem cell donor is dependent on donor availability, donor compatibility and health, recipient disease and recipient condition.

The number of matched sibling donor transplants has been relatively stable over the last 10 years.

For individuals who do not have a matched sibling donor alternatives include volunteer or matched unrelated donors, one-antigen mismatched unrelated donors, umbilical cord blood, and haploidentical donors.

To determine the degree of human leukocyte antigen (HLA) match for a donor-recipient pair, a blood sample or buckle swab must be obtained from the donor and recipient for comparison.

Human leukocyte antigen loci are located on chromosomes 6 and inherited as haplotypes, 1/2 from the mother and 1/2 from the father.

The newly derive blood cells appear in the bloodstream within approximately 2 weeks and within a few months in normal hematopoietic and immune is established..

Only curative modality for chronic myeloproliferative disorders and myelodysplastic syndromes.

Treatment of choice for some patients with acute myelogenous leukemia.

Acute myelogenous leukemia is the most common indication for allogeneic HSCT.

Allogeneic hematopoietic stem cell transplants cure at least 90% of patients with immune deficiency syndromes.

Potentially curative for acute and chronic leukemia is, Hodgkin disease, non-Hodgkin disease, and myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplants cure at least 90% of patients with hemoglobinopathies.

Allogeneic hematopoietic stem cell transplants cure at least 80% of patients with aplastic anemia, and 25-75% patients with leukemias or lymphomas depending upon the stage of their disease.

Efficacy due in part from donor T cell recognizing and killing residual leukemic cells, the graft-versus-leukemia (GVL) effect.

Carries significant risks for treatment related mortality, arising primarily from infections, condition regimen related toxicities and graft versus host disease.

Major causes of poor outcomes after AHCST infection and graph-versus-host disease, and the gut microbiome  may affect susceptibility to both.

Graft recipients are susceptible to viral infections after transplant and more than 40% are at risk recipients, meaning those Seropositive or whose doner was seropositive experience infection within the first 100 days after transplant.

Most deaths occur within the first two years as a result of relapse, acute or chronic graft versus host disease, infection, or other toxicities from transplant.

Its safety is dependent on the intensity of the conditioning regimen, the genetic disparity between the donor and the recipient.

Death beyond two years after allogeneic HSCT uncommon.

More than 70% of patients who survive the first 2 years after HCT are expected to be long-term survivors.

Approximately 30-70% of individuals undergoing allogeneic hematopoetic  stem cell transplant for hematologic malignancy may experience chronic graft versus host disease, which is the leading cause of non-relapse mortality in HSCT  survivors.

The selection of genetically similar donors limits alloreactivity between the immune systems of the donor and recipient, and reduces the incidence of graft versus host disease and graft rejection.

Increased mortality with increasing age.

Pretransplantation transfusions in immunocmpetent patients should be avoided because state are associated with increased graft failure rates: Immunocompetent individuals are capable of mounting an immune response to transfusions, leading to alloimmunization against platelets, HLAs present on the surface of white blood cells and platelets.

The most important factor in preventing immune complications is the matching of major histocompatibility antigens, the human leukocyte antigens (HLAs), which is determined into molecular based testing.

Matching for human leucocyte antigen HLA-A, HLA-B, HLA-C HLA-DRB1, and HLA-DQB1 alleles between an unrelated donor and patient is undertaken to lower risks of acute graft versus host disease and mortality after hematopoietic stem cell transplant.

Allele mismatch at HLA-DPB1 increases risk of acute graft vs. host disease.

High-resolution matching at HLA-A,–B,-C and DRB1 has a strong impact on mortality and morbidity following unrelated donor hematopoietic stem cell transplantation.

Regardless of the degree of HLA match overall survival of transplanted patients is better in those transplanted earlier in their disease than in patients with advanced disease.

Minor histocompatibility antigen mismatches are of secondary importance and can lead to alloreactivity with resultant GVHD and graft rejection, although to a lesser degree than major HLA antigens.

HLA antigens are inherited on the short arm of chromosome six and separated into two clinically relevant classes: numeral I-HLA A,B,and C. and II HLA DRB1, DQB1, and DPB1.

Each HLA antigen is inherited as 2 haplotypes: one from the mother and one from the father.

There is a 25% chance for a pair of siblings to inherit the same haplotypes from both parents, and overall only 30% of patients requiring an allogeneic hematopoietic cell transplant have a HLA matched related donor.

Chemotherapy regimens used for HSCT may be fully myeloablative or of reduced intensity conditioning to partially ablate the bone marrow.

Reduced intensity myeloablative therapy for allogeneic SCT has made the technique more attractive.

Reduced intensity myeloablative theray reduces transplant-related mortality.

Chemotherapy regimens cause the patient to be dependent on RBC and platelet transfusions until engraftment.

HSCT does not typically interfere with production of coagulation factors.

Post-transplantation support recommends a restrictive transfusion strategy of a hemoglobin of 7-8 g/dL instabilized patients unless the patient is symptomatically anemic.

Post-transplantation patients receiving transfusions should receive irradiated RBC units alone, because of the high risk for transfusion associated graft-versus-host disease is high in patients receiving HSCT.

The risk of organ toxicities has limited the use of high-dose regimens to younger patients in good medical condition, with age cutoff 55-60 years.

High-dose busulfan and cyclophosphamide (BuCy) widely used as a myelo ablative conditioning regimen.

Cyclophosphamide combined with ablative doses of total body irradiation or the oral alkylating agent busulfan have been the main conditioning regimens for allogeneic hematopoetic stem cell transplantation for patients with acute myelogenous leukemia.

Intravenous busulfan has increasingly replaced oral busulfan in conditioning regiments for allogeneic hematopoietic stem cell transplant.

In myeloid malignancies a comparative study of survival of busulfan intravenous versus ablative total body radiation resulted in superior survival of busulfan with no increased risk for relapse or treatment related mortality (Bredeson C et al).

The above regimen is generally well-tolerated but cyclophosphamide may be toxic to hepatic sinusoidal endothelial cells causing hepatotoxicity.

In an analysis of 6691 survivors of allogeneic HCT for a variety of malignancies who worldwide and free of recurrent disease at two years, survival at five years was 89% (Socie G et al).

80-92% of two-year survivors , survive at 10 years after allogeneic HCT.

Risk of transplantation related mortality is influenced by patients age, a donor type conditioning regimen and intensity among other factors.

Risk of transplantation related mortality ranges from less than 10% in children younger than age 10 receiving an HLA matched related donor transplant to 30% or higher in adolescents and adults receiving unrelated donor transplantation.

In a comparison of 1418 patients transplanted in 1993-1997 compared to 1148 patients transplanted from 2003-2007: there was a significant decrease in mortality not preceded by relapse-60% at day 200 and overall by 52%, the rate relapse or progression of the malignant condition by 21%, and overall mortality by 41% (Gooley TA et al).

In the above study significant decreases in the risk of GVHD, infections by viruses, bacteria and fungi, and damage to liver kidneys and lungs were noted in the more contemporary studies.

Among patients 60-75 years treated with non-myeloablative allogeneic HCT for advanced hematopoietic malignancies, 5 year overall and progression free survivals were 35% and 32%, respectively (Sorror ML et al).

Acute GVHD due to T cell coinfused with stem cell graft and involves interaction between cellular and cytokine components of the immune system.

Acute GVHD in SCT involves mainly the skin, gastrointestinal system and the liver.

Acute GVHD in SCT the GI involvement generally parallels the skin and liver involvement, although severe involvement can occur without gross skin and liver changes.

Acute graft-versus-host-disease (GVHD), grade II or higher develops in 20-65% of patients.

Acute and chronic graft vs. host disease have significant morbidity, escalate and prolonged immunosuppressive therapy, promote organ dysfunctions, impairs quality of life and increases risk for mortality.

Chronic GVHD occurs in 40-80% of long term survivors of allogeneic SCT (Fung HC).

Chronic GVHD resembles an autoimmune disorder with involvement of the skin and mucous membranes.

Chronic graft versus host disease associated with pigment and atrophy (poikiloderma), findings of lichen planus like mucosal changes, sclerosis, vaginal scarring, joint contractures, esophageal webbing and strictures.

Chronic graft versus host disease associated with skin depigmentation, nail loss, xerostomia, alopecia, and myositis.

Death due to acute GVHD accounts for approximately 50% of deaths not due to relapse of the cancer.

Involves a conditioning regimen that is myeloablative and immunosuppressive.

A nonmyeloablative procedure with lymphoablation preparation can be used to treat nonmalignant disease processes such associated SLE.

Conditioning with total lymphoid irradiation plus antithymocyte globulin associated with a markedly reduced incidence of graft-versus-host disease compared to nonmyeloablative conditioning with total body irradiation, chemotherapy or both.

The probability of treatment related and acute graft-versus-host disease related mortality is approximately 25-40%.

Conventionally limited to patients younger than 50-55 years of age and without major organ dysfunction.

Engraftment can be achieved with reduced intensity nonmyeloablative conditioning regimens which are sufficiently immunosuppressive to prevent graft rejection but can lead to the presence of mixed chimerism, i.e. the presence of both donor and recipient cells in the bone marrow.

Graft failure is a rare event leading to extreme vulnerability to infection.

Overall transplant success influenced by the burden of malignant cells present at the time of transplant, with a higher recurrence rate if tumor is active or advanced.

High rates of bone marrow transplantation graft rejection seen in sickle cell patients, thalassemia and aplastic anemia patients that have received chronic transfusions before transplant.

Chronic transfusions immunizes the recipient to multiple antigens which contributes to the likelihood of bone marrow graft rejection.

Residual recipient hematopoiesis may be eradicated by alloreactive T cells of donor origin by withdrawing immunosuppressive drugs or administering more T cells by donor leukocyte infusions: these processes may eradicate residual disease by graft vs. leukemia effect by increasing GVHD.

CMV post transplant infection strongly associated with pretransplantation CMV antibody status of the recipient.

Most patients who undergo hematopoietic stem cell transplant have evidence of prior infection with CMV and at are at risk for CMD reactivation after transplant.

Patients with CMV infection have an increased incidence of secondary graft failure possibly due to antiviral therapy induced myelosuppression.

CMV infections are a significant cause of post transplantation morbidity and mortality.

CMV reactivation occurs in approximately 50-70% of seropositive patients undergoing allogeneic transplant.

When a donor is seropositive and the recipient is negative the incidence of CMV is 20-25%.

CMV infection occurs in approximately 1% of patients, even if both the donor and the recipient are seronegative and CMV safe blood is used.

The threshold for treating CMV infection remains controversial, and monitoring with a PCR assay once or twice weekly to identify virus during the high risk period and using and antiviral agent is the test becomes positive at a certain level.

Treatment is administered for CMV for several weeks until the PCR assay becomes negative.

The first 3 months after allogeneic transplantation is considered the high risk period for CMV, and some patients require treatment for up to one year.

The overwheling majority of patients with blood reactivation for CMV are asymptomatic.

CMV infection after allogeniec transplant may be associated with gastrointestinal symptoms including nausea, epigastric pain, diarrhea and cramps.

CMV infection may involve the lungs leading to pneumonia.

In CMV infection the eyes and CNS can be infected leading to changes in vision or signs of encephalitis.

CMV infection impairs immune reconstitution of the stem cell transplant recipient and increases the risk of other infection, especially fungal infections.

Antiviral agents employed include letermovir and brincidofovir.

Letermovir is now used for CMV prophylaxis in HSCT CMV seropositive recipients.

A Canadian study of 926 patients who underwent allogeneic hematopoietic stem cells transplantation have an 85% increased risk of developing a second malignancy later in life.

Median time to the development of a second malignancy after a allogeneic hematopoietic stem cell transplant is 6.8 years.

Following such a transplant the 10-year cumulative incidence of a second malignancy is 3.1%, but if skin cancers and cervical in-situ cancers are excluded, it was 2.3%.

The relative risk of a second malignancy after allogeneic hematopoietic stem cell transplantation is quite high in patients over the age of 40 years at the time of transplantation.

Second malignancies after the procedure are most commonly basal and squamous cell carcinomas of the skin, followed by lung, oral cavity colon and bladder cancers.

Second malignancies after such a procedure were increased in those individuals that received stem cells from female donors.

Minor histocompatibility antigens are the molecular targets of all immunity causing antitumor and graft versus host disease affects.

Recognition of HLA bound polymorphic peptides or minor histocompatibility antigens by donor T cells responsible for graft versus disease and graft versus tumor reactions.

Allogeneic stem cell transplant for AML in first remission may improve survival only in patients with poor risk AML (Yanata).

Has significant relapse free survival and overall survival benefit for intermediate and poor risk AML but not for good risk AML in first complete remission (Koreth).

Less toxic conditioning regimens are being utilized because data shows that higher dose regimens result in more organ damage without reduced risk of recurrent malignant conditions.

Presently, lower dose myeloablative regimens with lower dose of total body radiation, fludarabine substitution for cyclophosphamide have decreased fatal hepatic sinusoidal obstruction syndrome and multi-organ failure.

The increased use of peripheral blood donor cells results in significantly faster neutrophil recovery and engraftment, and earlier recovery of immunity to bacterial and fungal infections.

Improved antibacterial prophylaxis, antifungal prophylaxis and preemptive antiviral therapy has improved contemporary management of allogeneic hematopoietic stem cell transplant.

Less intense conditioning regimens associated with lesser degrees of jaundice, less frequent bacterial sepsis and less frequent GVHD.

Ursodiol prophylaxis improves liver function tests in patients with GVHD, decreases jaundice and increases survival.

Ideal suitable stem cell donors include HLA-identical sibling with the likelihood of 2 siblings being HLA matched is 25%.

Other sources for stem cell transplant include HLA-matched unrelated donors, umbilical cord blood stem cells, stem cells from HLA-mismatched individuals who are matched and only half rather than all of the HLA genes (haploidentical).

HCT survivors are at increased risk for treatment related chronic health conditions including: malignant tumors, cardiovascular diseases, adverse psychological outcomes, limited activities, and functional impairment.

HCT survivors have a higher risk of frailty and subsequent mortality than the general population.

At a median of seven years post transplant in childhood HSCT survivors 93% had at least one late effect, while 24% had a high burden of multiple late affects (Bresters D).

HSCT survivors are at higher risk of severe late cardiovascular, metabolic, and renal toxic effects.

The cumulative incidence of secondary malignant disease approaches 10-20% by 20 years post


Escape from immunosurveillance by the loss of mismatched HLA alleles may be a crucial mechanism of relapse after HLA-haploidentical HSCT.

There is a high cumulative incidence of severe life-threatening fatal chronic diseases, reaching as high is 41% by 15 years post transplant of HSCT survivors.

Patients undergoing allogeneic hematopoietic stem cell transplantion have microbiota disruption with expansion of potentially pathogenic bacteria and loss of alpha diversity.
These changes reflected number of unique bacterial taxa present and the relative frequencies.
The diversity of the intestinal microbiota is linked with inflammatory bowel disease and response to cancer immunotherapy.
Enterococcus faecalis an E faecium are opportunistic pathogens that frequently cause life-threatening bloodstream infection in patients who have undergone allogeneic HSCT.
The use of more intense conditioning regimen is associated with a negative association with overall survival and a higher non-relapse mortality in non-Hodgkin’s lymphoma.
Compared with the general population, hematopoietic stem cell transplant recipients have an 8.8 fold higher risk for all cause mortality and experience a relative 8.7 year life reduction.
The relative mortality rate is high after transplant as expected in the first 2–5 years, but persisted beyond
30 years.
Factors estimating mortality include age, high risk disease, chronic graft versus host disease, and the use of peripheral blood stem cell grafts.
The 30 year survival rate is 57.8% of patients.
The risk of recurrence related mortality plateaus at about 10 years, but the risk of non-recurrence related mortality continues to increase with time.
Nonrecurrence related mortality is related to: infections, secondary neoplasms, cardiovascular disease and pulmonary disease being the most common causes for late deaths.
An estimated 30% of patients with HSCT have pulmonary complications in the year after transplantation.
Autopsies of patients with HSCT identified pulmonary complications in 80 to 89% of decedents and are implicated in 52 to 74% of deaths.
Infections account for approximately half of such complications.
Findings suggest peripheral blood stem cells as a stem cell source is associated with increase rates of chronic graft versus host disease with result resultant morbidity and sometimes mortality.
Non-recurrent mortality risk is continually increased in late survivors and contributes to a 20% cumulative incidence of death by the year 30.
Long-term studies have found that late mortality has declined but this decline is limited to transplants performed in children or with bone marrow as a stem source, without meaningful declines for older patients or for those who receive peripheral blood stem cell transplant.

Leave a Reply

Your email address will not be published. Required fields are marked *