Hematopoietic stem cell transplantation

Bone marrow is supplemented as a stem cell source by peripheral or cord blood.

HSCT Involves the infusion of hematopoietic progenitor cells in the patient with malignant or non-malignant hematologic disorders with the goal of reestablishing normal hematopoietic and immune function.

HSCT involves the infusion of autologous or allogeneic hematopoietic cells after preparation with cytotoxic conditioning regimens to eradicate disease and establish adequate hematopoietic and immune function.

HSCT utilized to treat a variety of hematologic and congenital diseases.

HSCT is potentially curative for patients with certain types of hematologic malignancies and is also used to support patients undergoing high-dose chemotherapy for the treatment of certain solid tumors.

An autologous HSCT uses the patient’s own cells, whereas an allogeneic HSCT uses hematopoietic cells from a human leukocyte antigen (HLA) compatible related or unrelated donor.

Prior to HSCT most patients receive chemotherapy, immunotherapy, and/or radiation therapy for pre-transplant conditioning.

In allogeneic, HSCT, conditioning regimens are administered to eradiccate malignant cells in the bone marrow and to immunosuppress the recipient so that engraftment of healthy donor cells can occur.

In autologous HSCT, high dose, myeloablative condition regimens are used to treat the malignancy, followed by rescue infusion of the patients own cells, which are collected and stored before high dose therapy, to restore hematopoiesis and reconstitute the immune system.

In 2020 it was estimated that greater than 8300 allogeneic  transplants, and greater than 11,500 autologous transplants were performed in the US.

Outcomes of HCT varies with the type and stage of the disease being treated, the overall health of the patient, the degree of HLA-mismatch between donor and recipient for allogeneic HCT and the source of hematopoietic cells.
AML, ALL, and myelodysplastic syndromes are the most common malignancies treated with allogeneic HSCT.
Autologous HSCT is most often used in multiple myeloma, non-Hodgkin’s lymphoma, and Hodgkin disease.

Hematopoetic cells can be obtained from the peripheral blood, bone marrow, or umbilical cord.

Peripheral blood mobilization of blood progenitor cells by colony stimulating factors has largely replaced bone marrow grafts  in particular for autologous HCT due to the ease of collection, avoidance of generalized anesthesia, more rapid engraftment, reduced risk of graft failure, and lower transplant related mortality.

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

HLA-matched sibling is the preferred donor, but only 30% of patients who may benefit from HSCT have such a donor available.

Ideal HSCT donor is an HLA-identical sibling, but this condition applies to less than 25% of recipients.

Even in HLA-identical sibling minor histocompatibility antigens encoded by non-HLA polymorphic genes at loci not on chromosome 6 are present.

HLA matching is an important predictor of success with HSCT.

An autologous HSCT uses the patient’s own cells while in allogeneic HSCT uses hematopoietic cells from a human leukocyte antigen compatible donor.
Prior to HSCT most patients receive receive chemotherapy, serotherapy, and/or radiation for pre-transplant conditioning.
In allogeneic HSCT preparative regimens are administered to eradicate  malignant cells in the bone marrow and induce immunosuppression so that engraftment of healthy donor cells occur.
In autologous HSCT, high dose myeloablative regimens are used to treat the malignancy and this is followed by rescue infusion of the patient’s own cells, which are harvested before high-dose therapy, to restore hematopoesis and reconstitute the immune system.
The number of hemopoietic cell transplantations has increased in recent years with an estimated 9028 allogeneic transplants and 14,700 autologous transplants performed in the US in 2018.
AML, ALL  and myelodysplastic syndromes  are the most common malignancies treated with allogeneic stem cell transplant, while autologous stem cell transplants are so used most frequently in multiple myeloma, non-Hodgkin’s lymphoma, and Hodgkin lymphoma.

Most often administered to individuals under age of 60 years because of toxicity of chemotherapy and conditioning regimens, and because of unacceptable morbidity in older patients.

A determinant of successful process includes the ability of transplanted cells to mobilize, migrate, home and engraft with functional cells.

Transplantation of either autologous or allogeneic stem cells requires the acquisition of sufficient numbers of hamatopoietic stem cells to ensure engraftment, and minimize the period of pancytopenia following transplantation.

Hematopoietic progenitor cells for allogeneic transplantation, and from apheresis-derived, mobilized from peripheral blood progenitor cells, bone marrow cells and umbilical cord.

Apheresis-derived mobilized peripheral blood progenitor cells are commonly used for autologous transplantation.

Pediatric patients receive more umbilical cord progenitor cells, where his adults receive more apheresis derived, mobilized peripheral blood progenitor cells.

Umbilical cord progenitor cells are being utilized increasingly in children and adults.

To optimize peripheralization of hematopoietic stem cells the use of cytokines, such as granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF), or cytokines plus chemotherapy to induce egress of such cells from the bone marrow into the peripheral blood, where it can be collected by aphoresis.

Standard procedure to administer G-CSF and collect CD133+CD34+ cells transferred from the bone marrow into the circulation and to use such cells for transplantation.

Once given intravenously the transplanted cells home to the bone marrow where they engraft in stromal or vascular niches.

CD133+ cells home by chemoattraction to the bone marrow and then extravasate across bone marrow sinusoidal endothelium and transmigrate through the basal lamina to hematopoietic stem cell niches.

Homing of transplanted cells involves interaction of stem cells with bon marrow sinusoidal endothelial cells and transmigration through the endothelium.

Optimum time to start hematopoietic progenitor/stem cell collection utilizes surface expression of CD34 to predict success of collection and to enumerate such cells in the collected material.

Variables that affect successful mobilization include patient’s age, diagnosis, precollection platelet count, type and quantity of previous chemotherapy exposure and the general health of the patient.

Mobilzation failure associated with: older age, female sex, exposure to toxic chemotherapy, CD34 and platelet counts prior to mobilization and genetic vriants in Chemoligand 12.

Donor’s peripheral blood may be monitored by daily flow cytometry or an automated cell counter which evaluates cells based on the surface expression of CD34.

High resolution mismatches at HLA-A and –DRB1 associated with increased death.

HLA-A mismatching associated with higher risk for grade III/IV GVHD and a trend for acute GVHD for HLA-B, HLA-C and HLA-DR mismatching.

Outcomes of both related an unrelated donor HSCT Impacted by the extent of HLA matching between transplant recipient and donor.

Matched unrelated donors are hard to find for all HLA loci.

Cord mismatched donors, with the introduction of haploidentical donors, that share with the recipient half of the genetic background and half of the alleles at the HLA loci, the number of potential donors had dramatically increased, now to include siblings, relatives and parents in particular, making HSCT available to a higher percentage of patients.

With haploidentical donors there is a 50% HLA incompatibility, making the risk of rejection and severe graft vs host disease extremely high.

The greater degree of HLA match between donor and recipient improves overall survival, and reduces the incidence and severity of both acute and chronic graft-versus-host disease, and improves rates of engraftment.

For most HSCT, a minimum of 4 HLA loci (HLA-A, HLA-B, HLA-C, HLA DRB1) and, more often, 5 (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1) are generally match between recipient and donor pairs.

Ethnic and racial groups affect the likelihood of finding a high resolution HLA-A, HLA-B, HLA-C, HLA-DRB1 match.

Whites of European descent have the highest probability,PROBABLY will be here by THANKS of 75%, and Blacks of the South or Central America descent have the lowest, 16%, likelihood of matching.

Some centers start collection when there are 5-20 CD34+ cell/µL.

Usual goal of collection to provide a graft for transplant is 2-4 x 10 to the 6th CD34+ cells/kg. in a single apheresis.

In a single center study of 704 patients transplanted with unrelated donors for acute or chronic leukemias or myelodysplastic syndromes compared with outcomes of 1,211 patients who have received matched sibling grafts, there was no difference in seven year overall survival between related and unrelated donor transplant recipients (Woolfrey).

Patients having undergone HSCT are dependent on red blood cell, and platelet transfusions until engraftment occurs.

Platelets are considered engrafted when the blood count is at least 20,000/microliters after 3 consecutive days without platelet transfusions.

RBC engraftment is defined by the appearance of 1% reticulocytes in the peripheral blood or, on the day of the last RBC transfusion, with no transfusion given the following 30 days.

Neutrophil engraftment as defined by an absolute neutrophil count of more than 500/microliters across 3 consecutive days.

Engraftment is influenced by many factors including donor-recipient relationship, stem cell source, and dose of CD34 cells in the transplant.

Engraftment time is shortest with mobilize peripheral progenitor blood stem cells, and the greatest when umbilical cord stem cells is used, With considerable patient to patient variation.

Prolonged engraftment time is associated with higher transfusion rates for red blood cells and platelets.

HSCT can often cross ABO barriers making transfusion ABO compatibility complex: switching blood type may be necessary for transfusions.

Post transplant the patient is a chimera of donor and nadir blood types, so that ABO incompatibility issues may arise with transfusions.

Washed platelet units become outdated in 4 hours.

Patients who develop metabolic syndrome after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies.

HSCT recipients had a higher prevalence of metabolic syndrome than the general population, and the incidence of metabolic syndrome increased with age.

Rates of metabolic syndrome after HSCT ranging from 31% to 49%.

The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.

The prevalence of metabolic syndrome in this population was 30.4%.

There was no significant difference in metabolic syndrome prevalence between allogeneic and autologous HSCT recipients―29% and 35.6%, respectively.

There is a significant difference in metabolic syndrome prevalence with increasing age.

Among allogeneic HSCT recipients, no relationship exists between metabolic syndrome prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with metabolic syndrome than in patients without the syndrome―22.6% and 10.7%, respectively.

Increasing age influenced the prevalence of metabolic syndrome and CV events for patients older than 50, compared to patients in the 18-29 age group.

And CV events are associated with second malignancy.

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