Nanoparticle that cuts middlemen could improve stem cell therapy  Futurity: Research News

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Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy  Science

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How the bone marrow microbiome responds to immunotherapy  Chemical & Engineering News

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GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome  Nature.com

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My Experience With Stem Cell Therapy: Snake Oil or Silver Bullet?  GearJunkie

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Continuing Education Activity

Hematopoietic stem cell transplant (HPSCT), sometimes referred to as bone marrow transplant, involves administering healthy hematopoietic stem cells to patients with dysfunctional or depleted bone marrow. There are several types of HPSCT in clinical use, and transplanted cells may be obtained from several sources. This procedure has several benefits and may be used to treat malignant and non-malignant conditions. It helps to augment bone marrow function. In addition, depending on the disease being treated, it may allow for the destruction of malignant tumor cells. It can also generate functional cells that replace dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases. Survival rates after HPSCT are increasing, but morbidity due to complications of the procedure continues. This activity reviews the indications for HPSCT, the different options by which to obtain donor cells, including the advantages and disadvantages of each, and the acute and chronic complications of the procedure. Additionally, it highlights the role of the interprofessional team in managing patients who undergo HPSCT to improve patient outcomes and decrease procedure-associated morbidities.

Objectives:

Describe the malignant and non-malignant indications for hematopoietic stem cell transplants.

Contrast the advantages and disadvantages of different types of hematopoietic stem cells.

Outline the potential complications of hematopoietic stem cell transplants and apply strategies to ameliorate these risks.

Describe the need for a well-integrated, interprofessional team approach to improve care for patients undergoing hematopoietic stem cell transplants.

Hematopoietic stem cell transplant (HPSCT), sometimes referred to as bone marrow transplant, involves administering healthy hematopoietic stem cells to patients with dysfunctional or depleted bone marrow. This procedure has several benefits. It helps to augment bone marrow function. In addition, depending on the disease being treated, it may allow for the destruction of malignant tumor cells. It can also generate functional cells that replace dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases.

History and Evolution

Hematopoietic stem cell transplantation (HPSCT) was first explored for use in humans in the 1950s. It was based on observational studies in mice models, which showed that infusion of healthy bone marrow components into a myelosuppressed bone marrow could induce recovery of its function in the recipient.[1]These animal-based studies soon found their clinical application in humans when the first successful bone marrow transplant was performedbetween monozygotic twins in New York in 1957 to treatacute leukemia.[2]The performing physician, E. Donnell Thomas, continued his research on the development of bone marrow transplantationand later received the Nobel Prize for Physiology and Medicine for his work. The first successfulallogeneicbone marrow transplant was reported in Minnesota in 1968 for a pediatric patient with severe combined immunodeficiency syndrome.[3]

Since then, allogeneic and autologous stem cell transplants have increased in the United States (US) and worldwide. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogeneic transplants performed in the US in 2016, with an evengreaternumber of autologous transplants; autologous transplants have steadily outpaced allogeneic transplants over time.[4][5]

Definitions

Major Histocompatibility Complex (MHC)

The human MHC genes on the short arm of chromosome 6 (6p) encode for human leukocyte antigens (HLA) and are highly polymorphic. These polymorphisms lead to significant differences in the resultant expressed human cell-surface proteins. They are divided into MHC class I and MHC class II.

Human Leukocyte Antigens (HLA)

The HLA proteins are expressed on the cellular surface and play an essential role in alloimmunity. HLA class I molecules, encoded by MHC class I, can be divided into HLA-A, HLA-B, and HLA-C. These proteins are expressed on all cell types and present peptides derived from the cytoplasm and recognized by CD8+ T cells. HLA class II molecules are classified as HLA- DP, HLA-DQ, and HLA-DR, are encoded by MHC class II, can be found on antigen-presenting cells (APCs), andare recognized by CD4+ T cells.

Syngeneic Bone Marrow Transplantation

The donor and the recipient are identical twins. The advantages of this type of transplant include no risk of graft versus host disease (GVHD) or graft failure. Unfortunately, however, only a very fewtransplant patients will have an identical twin available for transplantation.

Autologous Bone Marrow Transplantation

The bone marrow products are collected from the patient and are reinfused after purification methods. The advantage of this type of transplantis no risk of GVHD. The disadvantage is that the reinfused bone marrow products may contain abnormal cells that can cause relapse in the case of malignancy; hence, theoretically, this method cannot be used in all cases of abnormal bone marrow diseases.

Allogeneic Transplantation

The donor is an HLA-matched family member, an unrelated HLA-matched donor, or a mismatched family donor (haploidentical).

Engraftment

The process by which infused transplanted hematopoietic stem cells produce mature progeny in the peripheral circulation.

Preparative Regimen

This regimen comprises high-dose chemotherapy or total body irradiation (TBI) or both, which are administered to the recipient before stem cell infusion to eliminate the largest number of malignant cells and induce immunosuppression in the recipient so that engraftment can occur.

Malignant Disease

Multiple Myeloma

Studies have shown increased overall survival and progression-free survival in patients younger than 65 years when consolidation therapy with melphalan is initiated, followed by autologous stem cell transplantation and lenalidomide maintenance therapy.[6]The study showed a favorable outcome of high-dose melphalan plusHPSCT compared to consolidation therapy with melphalan, prednisone, and lenalidomide. It also showed better outcomes in patients who received maintenance therapy with lenalidomide.

Hodgkin and Non-Hodgkin Lymphoma

Studies have shown that in cases of recurrent Hodgkin and Non-Hodgkin lymphomas that do not respond to initial conventional chemotherapy, chemotherapy followed by autologous stem cell transplantation leads to better outcomes. A randomized controlled trial by Schmitz showed a better outcome at three years of high-dose chemotherapy with autologous stem cell transplant compared to aggressive conventional chemotherapy in relapsed chemosensitive Hodgkin lymphoma. However, the overall survival was not significantlydifferent between the two groups.[7]CIBMTR reports that his group of malignancies accounts for the second highest number of HPSCTs in the US, after multiple myeloma.

Acute Myeloid Leukemia (AML)

Allogeneic stem cell transplant has been shown to improve outcomes. It may prolong overall survival in patients with AML who fail primary induction therapy and do not achieve a complete response.[8]The study recommended that early HLA typing for patients with AML is beneficial if they fail induction therapy and are considered for HPSCT.

Acute Lymphocytic Leukemia (ALL)

Allogeneic stem cell transplant is indicated in refractory and resistant cases of ALL when induction therapy fails for a second time to induce remission. Some studies suggest an increased benefit of allogeneicHPSCT in patients with high-risk ALL, including patients with the Philadelphia chromosome and those with t(4;11).[9]

Myelodysplastic Syndrome (MDS)

Allogeneic stem cell transplant is considered curative in cases of disease progression and is only indicated in intermediate- or high-risk patients with MDS.

Chronic Myeloid Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL)

Patients with CML and CLL received the fewest number of allogeneic transplants in 2020.HPSCT has high cure rates for CML, but because tyrosine kinase inhibitors pair high success rates with a low adverse risk profile, HPSCTis reserved for patients with refractory disease.

Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera

Allogeneic stem cell transplant has been shown to improve outcomes in patients with myelofibrosis and those diagnosed with myelofibrosis preceded by essential thrombocytosis or polycythemia vera.[10]

Solid Tumors

Autologous stem cell transplant is consideredthestandard of care in patients with testicular germ cell tumors that are refractory to chemotherapy; in this case, refractory is defined as the third recurrence with chemotherapy.[11]HPSCT has also been studied in medulloblastoma, metastatic breast cancer, and other solid tumors.

Non-Malignant Diseases

Aplastic Anemia

Systematic and retrospective studies have suggested an improved outcome with HPSCT in acquired aplastic anemia compared to conventional immunosuppressive therapy.[12]In a study of 1886 patients with acquired aplastic anemia, transplanted cells collected from the bone marrow produced superior outcomes compared to those collected from the peripheral blood.[13]Patients with aplastic anemia need a preparative regimen, as they still can develop immune rejection to the graft.

Severe Combined Immune Deficiency Syndrome (SCID)

Large retrospective studies have shown increased overall survival in infants with SCID when they received the transplant early after birth before the onset of infections.[14]

Thalassemia

Allogeneic stem cell transplant from a matched sibling donor is an option to treat certain types of thalassemia and has shown 15-year survival rates reaching near 80%. However, recent retrospective data showed similar overall survival compared to conventional treatments withmultiple blood transfusions.[15]

Sickle CellDisease

An allogeneic stem cell transplant is recommended to treat sickle cell disease.[16]

Other Non-malignant Diseases

HPSCT has been used to treat chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan-Diamond anemia, and enzymatic disorders.Moreover, the role ofHPSCT is expanding in non-malignant autoimmune diseases, including systemic sclerosis and systemic lupus erythematosus, and has already shown promising results in cases like neuromyelitis optica.[17][18][19][20][21][22][23][24][25] It is also considered best practice for relapsing-remitting multiple sclerosis.[26][27]

There are no absolute contraindications for hematopoietic stem cell transplant.

Special equipment exists for collecting, preserving, and administering stem cell products.

An interprofessional team approach is amainstay of ensuring the high-quality collection and infusion of stem cell products.

Preparation includes:

Preparativeregimen:high-dose chemotherapy ortotal body irradiation (TBI) or both

Collection of hematopoietic stem cells

Instant infusion or cryopreservation followed by infusion

Mechanism of Action

The mechanism of action of HPSCT in leukemia is based on the effect of the graft and donor immunity against malignant cells in recipients. These findings were demonstrated in a study that involved over 2000 patients with different leukemias treated with HPSCT. The study showed the lowest relapse rates were in patients who received non-T-cell-depleted bone marrow cells and those who developed GVHD compared to patients who received T-cell-depleted stem cells, those who did not develop GVHD, and patients who received syngeneic grafts. These findings support the notion that donor cellular immunity is central to engraftment efficacy against tumor cells.[28]

The mechanism of action of HPSCT in autoimmune diseases is believed to be secondary to the increase in T-cell regulatory function, which promotes immune tolerance. However, more studies are needed to determine the exact physiology.

In hemoglobinopathies, the transplanted stem cells produce functional cells after engraftment that replace the diseased cells.

Administration

HLA Typing

HLA typing is essential to determine the most suitable donor for stem cell collection. In theory, matched, related donors are the best candidates, followed by matched unrelated donors, cord blood, and haploidentical donors. HLA typing is analyzed at either an intermediate-resolution level, which entails detecting a small number of matched alleles between the donor serum and the recipient, or at a high-resolution level to determine the specific number of polymorphic alleles at a higher level. Polymerase chain reaction and next-generation sequencing are used for HLA typing, and the results are reported as a score correlating with a match of two alleles for a specific HLA type. Different institutions use a different number of HLA subtypes for the eligibility of donors. However, studies that showed high-resolution matching for HLA-A, HLA-B, HLA-C, and HLA-DRB1 were associated with improved survival and outcomes.[29]The Blood and Marrow Transplant Clinical Trials Network (BM CTN) has proposed donor HLA assessment and matching recommendations.[30]

The process may vary depending on the source of the stem cell site collection, whether it is bone marrow, peripheral blood, or cord blood. Moreover, there is a slight difference based on whether it is autologous, allogeneic, or syngeneic HPSCT. For example, the procedure consists of the initial mobilization of stem cells, in which peripheral blood stem cells are collected, given the low number and the need for high levels of progeny cells. This is thenfollowed by a preparative regimen and, finally, infusion.

Mobilization and Collection

Mobilization and collection procedures involve using medication to increase the number of stem cells in the peripheral blood, given that there are insufficient stem cells in the peripheral blood. Medications include granulocyte colony-stimulating factors (G-CSF) or chemokine receptor 4 (CXCR4) blockers like plerixafor. G-CSF is believed to enhance neutrophils to release serine proteases, which break vascular adhesion molecules and promote the release of hematopoietic stem cells from the bone marrow. Plerixafor blocks the binding of stromal cell-derived factor-1-alpha (SDF-1) to CXCR, leading to stem cell mobilization to the peripheral blood.[31]CD34+ is considered the marker for progenitor hematopoietic stem cells in the peripheral blood, and usually, a dose of 2 to 10 x 10/kg CD34+ cells/kg is needed for proper engraftment. Chemotherapy can sometimes be used to mobilize hematopoietic stem cells; this process is termed chemoembolization.

The usual site of bone marrow collection is the anterior or posterior iliac crest. The aspiration procedure can be performed under local or general anesthesia. Common complications include pain and fever; serious iatrogenic complications occur in less than 1% of cases. Each aspiration contains 15 mL, and multiple aspirations are done. The goal is to collect 1 to 1.5 L of bone marrow product from the aspirations. The dose of nucleated cells from bone marrow should range between 2 to 4 x 10 cells/kg; overall survival and long-term engraftment are strongly influenced by cell dose in allogeneic HPSCT.[32]

Preparative Regimen

The preparative regimen consists of the administration of chemotherapy with or without total body irradiation for the eradication of malignant cells and induction of immune tolerance for the transfused cells to engraft properly. This process is not limited to patients with malignancies. It extends to cases like aplastic anemia and hemoglobinopathies, given that these patients have intact immune systems that could cause graft failure if there is no conditioning.

The administration of the preparative regimen should immediately precede the HPSCT. As a general rule, the effect of the regimen should produce bone marrow suppression within 1 to 3 weeks of administration. The preparative regimen is divided into myeloablative conditioning and reduced-intensity conditioning. Different combination regimens are used in the preparative period, depending on the disease being treated, existing comorbidities, previous radiation exposure, and the source of the harvested hematopoietic stem cells.

Reduced-intensity conditioning is preferred in patients who are older, have had prior radiotherapy, have comorbidities, and have a history of extensive chemotherapy before HPSCT.[33]The advantages of using reduced-intensity conditioning include less need for transfusion due to transient post-transplant pancytopenia, less chemotherapy-induced liver damage, and less radiation-induced lung damage.[34]However, the relapse rates after reduced-intensity conditioning are higher. Nevertheless, these regimens are better tolerated and have a better safety profile in specific patient populations.

Most chemotherapies used in preparative regimens consist of potent immunosuppressive agents like high doses of cyclophosphamide, alkylating agents like busulfan, nucleoside analogs like fludarabine, and many other agents like melphalan, anti-thymocyte globulin, rituximab, and gemcitabine. Totalbodyirradiation is performed using fractionated doses; there is less pulmonary toxicity than with a one-dose regimen.[35]

Reinfusion of either fresh or cryopreserved stem cells can occur in an ambulatory setting and takes up to two hours. Before the infusion begins, quality measures are performed to ensure the number of CD34+ cells is sufficient.

In the particular case of SCID, there is no need for a preparative regimen in patients receiving cells from HLA-matched siblings. This is because no abnormal cells need to be eliminated, and the immunosuppression caused by SCID can prevent graft rejection.

Advantages and Disadvantages of Different Hematopoietic Stem Cells

One advantage of peripheral blood stem cell transplant (PBSCT) is a more rapid engraftment rate than the bone marrow-derived stem cells; recovery in the former is two weeks and is delayed for five days more in the latter. Using a post-transplant immunosuppressive regimen to prevent GVHD can prolong the increase in bone marrow products.[36] Moreover, the rate of acute GVHD between PBSCT and bone marrow transplantation appears to be similar in HLA-identical matched related donors.[36]However, chronic GVHD is a more common occurrence after PBSCT, which could lead to more complications. Two-year overall survival rates seem to be similar regardless of stem cell origin.[37]Other studies comparing bone marrow-derived transplant andPSCT concluded that the psychological burden due to chronic GVHD and the 5-year ability to restore normal activities, including returning to work, was better in the bone marrow-derived transplant group.[38]

The advantages of cord blood transplant include the rapid collection and administration times, which facilitate treating urgent conditions, less frequent infections, lower rates of GVHD with the same rate of GVT, and less need for a stringent identical HLA. The disadvantages include delayed engraftment, a higher possibility of graft rejection, and higher rates of disease relapses. The cord blood transplant is most commonly used in patients without matched-related or unrelated donors. One major study demonstrated the utility of cord blood transplants in patients with thalassemia-major and sickle cell disease,indicating similar 6-year overall survival rates compared to the bone marrow-derived transplants.[39]

The most important factors affecting the success of cord blood transplant are the total nucleated cell dose and HLA matching; the recommended minimum dose of total nucleated cells for successful engraftment is 2 x 10^7 cells/kg. Theoretically, strict HLA matching is not required in the case of cord blood transplant as cord blood is devoid of mature T cells, but studies have shown better outcomes when matching recipients at HLA-A, HLA-B, HLA-C, and HLA-DRB1.[40]Given that a single cord blood unit might not contain the required amount of nucleated cells, a double cord transplant is used. However, only one cord blood transplant product will dominate within three months of infusion. Further, randomized controlled trials failed to show a significant difference in outcome, benefits, or risks between double cord blood and a single cord blood transplant.[41][42]

Haploidentical stem cell transplantation involves administering bone marrow products from a first-degree related haplotype-mismatched donor.[43]This helps underserved patients without broad access to resources as they have fewer chances of having a matched unrelated donor.[44]The advantages of this method include lower cost and rapid availability of hematopoietic cell products. However, the disadvantages include hyperacute GVHD, which increases mortality and graft rejection.[45]This has been overcome by the depletion of T cells responsible for the reaction mentioned above, but this also leads to delayed immune recovery and decreased graft versus tumor effect. Recently strategies including selective depletion of subsets of T cells, including alpha-beta, have shown improved outcomes compared to conventional ex vivo depletion of large T-cell populations.[46]

Complications after bone marrow transplant may be acute or chronic. Many factors can affect these adverse events, including age, baseline performance status, the source of stem cell transplant, and the type and intensity of the preparative regimen. Acute complications occur in the first 90 days, including myelosuppression with neutropenia, anemia, or thrombocytopenia; sinusoidal obstruction syndrome; mucositis; acute graft versus host disease; bacterial infections with gram-positive and gram-negative organisms; Herpesviridaeinfections; and fungal infection withCandidaand Aspergillus. Chronic complications include chronic GVHD, infection with encapsulated bacteria, and reactivation of the varicella-zoster virus.

Antimicrobial Prophylaxis

Levofloxacin is usually given orally or intravenously and initiated on the first day post-transplant. It is continued until the absolute neutrophil count is more than 1000 cells/microL or until the discontinuation of prednisonein cases of GVHD.[47]

Prophylaxis against Pneumocystis jirovecii (PCP)is warranted, given the immunosuppression following a hematopoietic stem cell transplant.[48]Trimethoprim-sulfamethoxazole (TMP-SMX) is usually used, and several dosing regimens have been proposed. TMP-SMX may be given twice weekly until the patient is off immunosuppression.[49]Antifungal infection prophylaxis with fluconazole is recommended for one month following the transplant as it has been shown to decrease the incidence of fungal infections. No difference was seen when fluconazole was compared to voriconazole.[50][51]However, voriconazole is used in patients with an elevated risk of developing severe antifungal infections.Anti-viral prophylaxis is achieved with acyclovir, continued for one month to prevent herpes-simplex virus and one year to prevent varicella-zoster virus.[52]Prophylaxis against cytomegalovirus is only recommended in patients who test positive by PCR, and the treatment of choice is ganciclovir.

One unique syndrome encountered with cord stem cell transplant is cord colitis which involves diarrhea in recipients of cord blood and is believed to be secondary to Bradyrhizobium enterica,which usually responds to a course of metronidazole or levofloxacin.[53]

Sinusoidal Obstruction Syndrome (SOS)

Sinusoidal obstruction syndrome (SOS), or veno-occlusive disease (VOD), results from chemotherapy during a preparative regimen and occurs within six weeks of HPSCT. This syndrome consists of tender hepatomegaly, jaundice due to hyperbilirubinemia, ascites, and weight gain due to fluid retention. The incidence is reported to be 13.6% in an analysis study assessing the existing literature on the incidence of the disease.[54]The pathophysiology consists of endothelial damage to the hepatic sinusoids leading to obstruction and necrosis of the centrilobular liver.[55]The destruction of the sinusoids leads to hepatic failure and hepatorenal syndrome, which areresponsible for the related mortality. The agents most commonly implicated in causing this syndrome are oral busulfan and cyclophosphamide. Using intravenous busulfan has been shown to decrease the occurrence of SOS.[56]

The diagnosis of SOS is clinical and is based on hyperbilirubinemia greater than 2 mg/dL in the presence of the aforementioned clinical findings. Treatment consists of ursodeoxycholic acid, which has been shown to significantly decrease the occurrence of SOS when given pre- and post-transplant.[57]Another medication, defibrotide, has shown efficacy in treating SOS when it occurs.[58][59]

Idiopathic Pneumonia Syndrome (IPS)

Idiopathic pneumonia syndrome usually occurs in the first 90 days post-transplant. The incidence is low and is related to the direct chemotoxicity of the preparative regimen. Treatment with steroids is standard, although no randomized controlled clinical trials have been done to support their efficacy. Recently, etanercept has been studied; adding soluble TNF-inhibitors to steroids has not shown added efficacy.[60]

Graft Rejection or Failure

A loss of bone marrow function after reconstitution following infusion of hematopoietic stem cells or no gain of function after infusion is termed graft rejection or failure. The incidence of failure is highest when there is a high HLA disparity; this disparity is highestin cases of cord blood and haploidentical donors and lowest with autologous and matched donor siblings. Factors responsible for graft failure include but are not limited to functional residual host immune response to the donor cells, a low number of infused cells, in vitro damage during collection and cryopreservation, inadequate preparative regimen, and infections.

Chimerism refers to the presence ofa cell population from a person in the blood of a different person. Evaluating for chimerism is an important step in ensuring engraftment and success of the transplantation. This evaluation is done by checking the expression of CD33, which indicates the presence ofgranulocytes, and CD3, which indicates the presence ofT cells, and confirming that most of thecells present are from the donor. The importance of effective chimerism has beendemonstrated in many studies that showed decreased relapse rates and increased survival in allogeneic transplantation.[61]

Graft Versus Host Disease (GVHD)

Graft versus host disease (GVHD) is a reaction between T cells from the donor in an allogeneic transplant and the recipient's HLA polymorphic epitopes, leading to a constellation of symptoms and manifestations. GVHD may be acute or chronic; each is sub-categorized into classic and late-onset, classic, and chronic overlap.[62]

Acute GVHD usually develops within three months. However, it can develop after three months and is then termed delayed acute GVHD. Prophylaxis is generally achieved with calcineurin inhibitors, methotrexate, and anti-thymocyte globulins. The severity of GVHD is estimatedusingthe Glucksberg scale, which classifies acute GVHD from grade I to VI. Treatment with either high-dose prednisone or methylprednisolone isindicated in higher-grade disease.[63]

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Doctors retrieve stem cells from 20-month-old to treat thalassaemic sister  The Times of India

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YolTech Therapeutics to Initiate a Clinical Trial for YOLT-204, a First-in-Class Bone Marrow-Targeted In Vivo Gene Editing Therapy for -Thalassemia  The Manila Times

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School of Medicine professor receives grant to study improved cancer treatments  Mercer University

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1st stem cell therapy, new HIV drug approved  ecns

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Suppression of thrombospondin-1mediated inflammaging prolongs hematopoietic health span  Science

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Stem cell transplants are used to put blood stem cells back into the body after the bone marrow has been destroyed by disease, chemotherapy (chemo), or radiation. Depending on where the stem cells come from, the transplant procedure may go by different names:

All of these can also be calledhematopoietic stem cell transplants.

In a typical stem cell transplant for cancer, a person first gets very high doses of chemo, sometimes along with radiation therapy, to try to kill all the cancer cells. This treatment also kills the stem cells in the bone marrow. This is called myeloablation or myeloablative therapy.

Soon after treatment, blood stem cells are given (transplanted) to replace those that were destroyed. The replacement stem cells are given into a vein, much like ablood transfusion. The goal is that over time, the transplanted cells will settle in the bone marrow, where they will begin to grow and make healthy new blood cells. This process is called engraftment.

There are 2 main types of transplants. They are named based on who donates the stem cells.

In this type of transplant, the first step is to remove or harvest your own stem cells. Your stem cells are removed from either your bone marrow or your blood, and then frozen. (You can learn more about this process at Whats It Like to Donate Stem Cells?) After you get high doses of chemo and/or radiation as your myeloablative therapy, the stem cells are thawed and given back to you.

This kind of transplant is mainly used to treat certain leukemias, lymphomas, and multiple myeloma. Its sometimes used for other cancers, like testicular cancer and neuroblastoma, and certain cancers in children. Doctors can use autologous transplants for other diseases, too, like systemic sclerosis, multiple sclerosis (MS), Crohn's disease, and systemic lupus erythematosus (lupus).

An advantage of an autologous stem cell transplantis that youre getting your own cells back. When you get your own stem cells back, you dont have to worry about them (called the engrafted cells or the graft) being rejected by your body. You also dont have to worry about immune cells from the transplant attacking healthy cells in your body (known as graft-versus-host disease), which is a concern with allogeneic transplants.

An autologous transplant graft might still fail, which means the transplanted stem cells dont go into the bone marrow and make blood cells like they should.

Also, autologous transplants cant produce the graft-versus-cancer effect, in which the donor immune cells from the transplant help kill any cancer cells that remain.

Another possible disadvantage of an autologous transplant is that cancer cells might be collected along with the stem cells and then later be put back into your body.

To help prevent any remaining cancer cells from being transplanted along with stem cells, some centers treat the stem cells before theyre given back to the patient. This may be called purging. While this might work for some patients, there haven't been enough studies yet to know if this is really a benefit. A possible downside of purging is that some normal stem cells can be lost during this process. This may cause your body to take longer to start making normal blood cells, and you might have very low and unsafe levels of white blood cells or platelets for a longer time. This could increase the risk of infections or bleeding problems.

Another treatment to help kill cancer cells that might be in the returned stem cells involves giving anti-cancer drugs after the transplant. The stem cells are not treated. After transplant, the patient gets anti-cancer drugs to get rid of any cancer cells that may be in the body. This is called in vivo purging. For instance, lenalidomide (Revlimid) may be used in this way for multiple myeloma. The need to remove cancer cells from transplanted stem cells or transplant patients and the best way to do it continues to be researched.

Doing 2 autologous transplants in a row is known as a tandem transplant or a double autologous transplant. In this type of transplant, the patient gets 2 courses of high-dose chemo as myeloablative therapy, each followed by a transplant of their own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each transplant. Usually, the 2 courses of chemo are given within 6 months. The second one is given after the patient recovers from the first one.

Tandem transplants have become the standard of care for certain cancers. High-risk types of the childhood cancer neuroblastoma and adult multiple myeloma are cancers where tandem transplants seem to show good results. But doctors dont always agree that these are really better than a single transplant for certain cancers. Because this treatment involves 2 transplants, the risk of serious outcomes is higher than for a single transplant.

Sometimes an autologous transplant followed by an allogeneic transplant might also be called a tandem transplant. (See Mini-transplants below.)

Allogeneic stem cell transplants use donor stem cells. In the most common type of allogeneic transplant, the stem cells come from a donor whose tissue type closely matches yours. (This is discussed in Matching patients and donors.) The best donor is a close family member, usually a brother or sister. If you dont have a good match in your family, a donor might be found in the general public through a national registry. This is sometimes called a MUD (matched unrelated donor) transplant. Transplants with a MUD are usually riskier than those with a relative who is a good match.

An allogeneic transplant works about the same way as an autologous transplant. Stem cells are collected from the donor and stored or frozen. After you get high doses of chemo and/or radiation as your myeloablative therapy, the donor's stem cells are thawed and given to you.

Allogeneic transplants are most often used to treat certain types of leukemia, lymphomas, multiple myeloma, myelodysplastic syndromes, and other bone marrow disorders such as aplastic anemia.

Blood taken from the placenta and umbilical cord after a baby is born can also be used for an allogeneic transplant. This small volume of cord blood has a high number of stem cells in it.

Cord blood transplants can have some advantages. For example, there are already a large number of donated units in cord blood banks, so finding a donor match might be easier. These units have already been donated, so they dont need to be collected once a match is found. A cord blood transplant is also less likely to be rejected by your body than is a transplant from an adult donor.

But cord blood transplants can have some downsides as well. There arent as many stem cells in a cord blood unit as there are in a typical transplant from an adult donor. Because of this, cord blood transplants are used more often for children, who have smaller body sizes. These transplants can be used for adults as well, although sometimes a person might need to get more than one cord blood unit to help ensure there are enough stem cells for the transplant.

Cord blood transplants can also take longer to begin making new blood cells, during which time a person is vulnerable to infections and other problems caused by having low blood cell counts. For a newer cord blood product, known as omidubicel (Omisirge), the cord blood cells are treated in a lab with a special chemical, which helps them get to the bone marrow and start making new blood cells quicker once theyre in the body.

A major benefit of allogeneic transplants is that the donor stem cells make their own immune cells, which could help kill any cancer cells that remain after high-dose treatment. This is called the graft-versus-cancer or graft-versus-tumor effect.

Other advantages are that the donor can often be asked to donate more stem cells or even white blood cells if needed (although this isn't true for a cord blood transplant), and stem cells from healthy donors are free of cancer cells.

As with any type of transplant, there is a risk that the transplant, or graft, might not take that is, the transplanted donor stem cells could die or be destroyed by the patients body before settling in the bone marrow.

Another risk is that the immune cells from the donor could attack healthy cells in the patients body. This is called graft-versus-host disease, and it can range from mild to life-threatening.

There is also a very small risk of certain infections from the donor cells, even though donors are tested before they donate.

Another risk is that some types of infections you had previously and which your immune system has had under control may resurface after an allogeneic transplant. This can happen when your immune system is weakened (suppressed) by medicines called immunosuppressive drugs. Such infections can cause serious problems and can even be life-threatening.

For some people, age or certain health conditions make it more risky to do myeloablative therapy that wipes out all of their bone marrow before a transplant. For those people, doctors can use a type of allogeneic transplant thats sometimes called a mini-transplant. Your doctor might refer to it as a non-myeloablative transplant or mention reduced-intensity conditioning (RIC). Patients getting a mini transplant typically get lower doses of chemo and/or radiation than if they were getting a standard myeloablative transplant. The goal in the mini-transplant is to kill some of the cancer cells (which will also kill some of the bone marrow), and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow.

Unlike the standard allogeneic transplant, cells from both the donor and the patient exist together in the patients body for some time after a mini-transplant. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patients own bone marrow cells. These new cells can then develop an immune response to the cancer and help kill off the patients cancer cells the graft-versus-cancer effect.

One advantage of a mini-transplant is that it uses lower doses of chemo and/or radiation. And because the stem cells arent all killed, blood cell counts dont drop as low while waiting for the new stem cells to start making normal blood cells. This makes it especially useful for older patients and those with other health problems. Rarely, it may be used in patients who have already had a transplant.

Mini-transplants treat some diseases better than others. They may not work well for patients with a lot of cancer in their body or people with fast-growing cancers. Also, although there might be fewer side effects from chemo and radiation than those from a standard allogeneic transplant, the risk of graft-versus-host disease is the same. Some studies have shown that for some cancers and some other blood conditions, both adults and children can have the same kinds of results with a mini-transplant as compared to a standard transplant.

This is a special kind of allogeneic transplant that can only be used when the patient has an identical sibling (twin or triplet) someone who has the exact same tissue type. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. Also, there are no cancer cells in the transplanted stem cells, as there might be in an autologous transplant.

A disadvantage is that because the new immune system is so much like the recipients immune system, theres no graft-versus-cancer effect. Every effort must be made to destroy all the cancer cells before the transplant is done to help keep the cancer from coming back.

Improvements have been made in the use of family members as donors. This kind of transplant is called ahalf-match (haploidentical) transplant for people who dont have fully matching or identical family member. This can be another option to consider, along with cord blood transplant and matched unrelated donor (MUD) transplant.

If possible, it is very important that the donor and recipient are a close tissue match to avoid graft rejection. Graft rejection happens when the recipients immune system recognizes the donor cells as foreign and tries to destroy them as it would a bacteria or virus. Graft rejection can lead to graft failure, but its rare when the donor and recipient are well matched.

A more common problem is that when the donor stem cells make their own immune cells, the new cells may see the patients cells as foreign and attack their new home. This is called graft-versus-host disease. (See Stem Cell Transplant Side Effects for more on this). The new, grafted stem cells attack the body of the person who got the transplant. This is another reason its so important to find the closest match possible.

Many factors play a role in how the immune system knows the difference between self and non-self, but the most important for transplants is the human leukocyte antigen (HLA) system. Human leukocyte antigens are proteins found on the surface of most cells. They make up a persons tissue type, which is different from a persons blood type.

Each person has a number of pairs of HLA antigens. We inherit them from both of our parents and, in turn, pass them on to our children. Doctors try to match these antigens when finding a donor for a person getting a stem cell transplant.

How well the donors and recipients HLA tissue types match plays a large part in whether the transplant will work. A match is best when all 6 of the known major HLA antigens are the same a 6 out of 6 match. People with these matches have a lower chance of graft-versus-host disease, graft rejection, having a weak immune system, and getting serious infections. For bone marrow and peripheral blood stem cell transplants, sometimes a donor with a single mismatched antigen is used a 5 out of 6 match. For cord blood transplants a perfect HLA match doesnt seem to be as important, and even a sample with a couple of mismatched antigens may be OK.

Doctors keep learning more about better ways to match donors. Today, fewer tests may be needed for siblings, since their cells vary less than an unrelated donor. But to reduce the risks of mismatched types between unrelated donors, more than the basic 6 HLA antigens may be tested. For example, sometimes doctors to try and get a 10 out of 10 match. Certain transplant centers now require high-resolution matching, which looks more deeply into tissue types and allow more specific HLA matching.

There are thousands of different combinations of possible HLA tissue types. This can make it hard to find an exact match. HLA antigens are inherited from both parents. If possible, the search for a donor usually starts with the patients brothers and sisters (siblings), who have the same parents as the patient. The chance that any one sibling would be a perfect match (that is, that you both received the same set of HLA antigens from each of your parents) is 1 out of 4.

If a sibling is not a good match, the search could then move on to relatives who are less likely to be a good match parents, half siblings, and extended family, such as aunts, uncles, or cousins. (Spouses are no more likely to be good matches than other people who are not related.) If no relatives are found to be a close match, the transplant team will widen the search to the general public.

As unlikely as it seems, its possible to find a good match with a stranger. To help with this process, the team will use transplant registries, like those listed here. Registries serve as matchmakers between patients and volunteer donors. They can search for and access millions of possible donors and hundreds of thousands of cord blood units.

Be the Match (formerly the National Marrow Donor Program)Toll-free number: 1-800-MARROW-2 (1-800-627-7692)Website: http://www.bethematch.org

Blood & Marrow Transplant Information NetworkToll-free number: 1-888-597-7674Website: http://www.bmtinfonet.org

Depending on a persons tissue typing, several other international registries also are available. Sometimes the best matches are found in people with a similar racial or ethnic background. When compared to other ethnic groups, white people have a better chance of finding a perfect match for stem cell transplant among unrelated donors. This is because ethnic groups have differing HLA types, and in the past there was less diversity in donor registries, or fewer non-White donors. However, the chances of finding an unrelated donor match improve each year, as more volunteers become aware of registries and sign up for them.

Finding an unrelated donor can take months, though cord blood may be a little faster. A single match can require going through millions of records. Also, now that transplant centers are more often using high-resolution tests, matching is becoming more complex. Perfect 10 out of 10 matches at that level are much harder to find. But transplant teams are also getting better at figuring out what kinds of mismatches can be tolerated in which particular situations that is, which mismatched antigens are less likely to affect transplant success and survival.

Keep in mind that there are stages to this process there may be several matches that look promising but dont work out as hoped. The team and registry will keep looking for the best possible match for you. If your team finds an adult donor through a transplant registry, the registry will contact the donor to set up the final testing and donation. If your team finds matching cord blood, the registry will have the cord blood sent to your transplant center.

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