Hematopoietic Stem Cell Transplantation

Karam Khaddour; Caroline Hana; Prerna Mewawalla

Hematopoietic Stem Cell Transplantation

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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.

Introduction

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 performed between monozygotic twins in New York in 1957 to treat acute leukemia.[2] The performing physician, E. Donnell Thomas, continued his research on the development of bone marrow transplantation and later received the Nobel Prize for Physiology and Medicine for his work. The first successful allogeneic bone 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 even greater number 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), and are 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 few transplant 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 transplant is 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.

Indications

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 plus HPSCT 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 significantly different 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 allogeneic HPSCT 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, HPSCT is 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 considered the standard 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 with multiple blood transfusions.[15]

Sickle Cell Disease

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 of HPSCT 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]

Contraindications

There are no absolute contraindications for hematopoietic stem cell transplant.

Equipment

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

Personnel

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

Preparation

Preparation includes:

Preparative regimen: high-dose chemotherapy or total body irradiation (TBI) or both
Collection of hematopoietic stem cells
Instant infusion or cryopreservation followed by infusion

Technique or Treatment

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 then followed 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. Total body irradiation 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 and PSCT 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

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; Herpesviridae infections; and fungal infection with Candida and 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 prednisone in 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 are responsible 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 highest in 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 of a 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 of granulocytes, and CD3, which indicates the presence of T cells, and confirming that most of the cells present are from the donor. The importance of effective chimerism has been demonstrated 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 estimated using the Glucksberg scale, which classifies acute GVHD from grade I to VI. Treatment with either high-dose prednisone or methylprednisolone is indicated in higher-grade disease.[63]

Chronic GVHD occurs over three months after transplant and involves multiple organs, similar to collagen vascular diseases. Grading of chronic GVHD assesses the severity of the disease and has been developed by the National Institute of Health; grade determines the treatment modality and predicts survival [64]. Treatment is similar to acute GVHD, but the duration of treatment is usually more than two years.[65]

Toxicity

Chemotherapy and radiation of the preparative regimen and post-transplant immunosuppression can induce severe pancytopenia in the first week following infusion of hematopoietic stem cells, leading to life-threatening infection. This depends on the type and the dose of chemotherapy administered and factors related to the recipients. Chemotherapy causes the destruction of healthy, normal bone marrow products, including neutrophils, macrophages, monocytes, and lymphocytes. Also, chemotherapy-induced mucosal toxicity disrupts the barriers protecting against infectious agents, and the use of indwelling intravenous catheters provides another means for the entrance of infectious agents.

According to the guidelines, vaccination against the following agents is recommended: pneumococcus, tetanus, diphtheria, pertussis, Haemophilus influenzae, meningococcus, polio, Hepatitis B virus, influenza, measles, mumps, and rubella.[47] Several prophylaxis regimens have been proposed to prevent infections depending on the risk stratification of patients.

Many risk-scoring tools exist for evaluating hematopoietic stem cell transplant recipients to stratify risk so that proper preparation and treatment can be established to minimize the risks and toxicities before, during, and after transplantation. The most commonly utilized scoring tools in clinical practice are the European Group for Blood and Marrow Transplantation risk score, the hematopoietic cell transplantation-comorbidity index/age, and the Armand disease risk index.[66][67][68]

Enhancing Healthcare Team Outcomes

The use of HPSCT in clinical practice has expanded in the last decade, and there are many ongoing clinical trials to assess its efficacy in different medical conditions. However, given the lack of knowledge across most medical practices, an interprofessional team approach to care can help improve patient outcomes, where all team members can offer suggestions and guidance based on their knowledge and experience regarding potential stem cell transplant therapy for patients where it can benefit.

Details

References

[1]

BARNES DW, CORP MJ, LOUTIT JF, NEAL FE. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. British medical journal. 1956 Sep 15:2(4993):626-7 [PubMed PMID: 13356034]

[2]

THOMAS ED, LOCHTE HL Jr, LU WC, FERREBEE JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. The New England journal of medicine. 1957 Sep 12:257(11):491-6 [PubMed PMID: 13464965]

[3]

Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet (London, England). 1968 Dec 28:2(7583):1366-9 [PubMed PMID: 4177932]

[4]

D'Souza A, Fretham C, Lee SJ, Arora M, Brunner J, Chhabra S, Devine S, Eapen M, Hamadani M, Hari P, Pasquini MC, Perez W, Phelan RA, Riches ML, Rizzo JD, Saber W, Shaw BE, Spellman SR, Steinert P, Weisdorf DJ, Horowitz MM. Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020 Aug:26(8):e177-e182. doi: 10.1016/j.bbmt.2020.04.013. Epub 2020 May 11 [PubMed PMID: 32438042]

[5]

Pasquini MC, Wang Z, Horowitz MM, Gale RP. 2010 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clinical transplants. 2010:():87-105 [PubMed PMID: 21696033]

[6]

Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. The New England journal of medicine. 2014 Sep 4:371(10):895-905. doi: 10.1056/NEJMoa1402888. Epub [PubMed PMID: 25184862]

[7]

Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Müller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V, German Hodgkin's Lymphoma Study Group, Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet (London, England). 2002 Jun 15:359(9323):2065-71 [PubMed PMID: 12086759]

Level 1 (high-level) evidence

[8]

Othus M, Appelbaum FR, Petersdorf SH, Kopecky KJ, Slovak M, Nevill T, Brandwein J, Larson RA, Stiff PJ, Walter RB, Tallman MS, Stenke L, Erba HP. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015 Mar:21(3):559-64. doi: 10.1016/j.bbmt.2014.10.025. Epub 2014 Dec 20 [PubMed PMID: 25536215]

[9]

Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer. 2006 Jun 15:106(12):2657-63 [PubMed PMID: 16703597]

[10]

Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M, Bacigalupo A, Rambaldi A, Scarano M, Klisovic RB, Gupta V, Andreasson B, Mascarenhas J, Wetzler M, Vannucchi AM, Prchal JT, Najfeld V, Orazi A, Weinberg RS, Miller C, Barosi G, Silverman LR, Prosperini G, Marchioli R, Hoffman R. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014 Aug 14:124(7):1183-91. doi: 10.1182/blood-2014-04-572545. Epub 2014 Jun 24 [PubMed PMID: 24963042]

[11]

Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. The New England journal of medicine. 2007 Jul 26:357(4):340-8 [PubMed PMID: 17652649]

[12]

Peinemann F, Grouven U, Kröger N, Bartel C, Pittler MH, Lange S. First-line matched related donor hematopoietic stem cell transplantation compared to immunosuppressive therapy in acquired severe aplastic anemia. PloS one. 2011 Apr 25:6(4):e18572. doi: 10.1371/journal.pone.0018572. Epub 2011 Apr 25 [PubMed PMID: 21541024]

[13]

Bacigalupo A, Socié G, Schrezenmeier H, Tichelli A, Locasciulli A, Fuehrer M, Risitano AM, Dufour C, Passweg JR, Oneto R, Aljurf M, Flynn C, Mialou V, Hamladji RM, Marsh JC, Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation (WPSAA-EBMT). Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica. 2012 Aug:97(8):1142-8 [PubMed PMID: 22315497]

[14]

Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, O'Reilly RJ. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. The New England journal of medicine. 2014 Jul 31:371(5):434-46. doi: 10.1056/NEJMoa1401177. Epub [PubMed PMID: 25075835]

[15]

Caocci G, Orofino MG, Vacca A, Piroddi A, Piras E, Addari MC, Caria R, Pilia MP, Origa R, Moi P, La Nasa G. Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. American journal of hematology. 2017 Dec:92(12):1303-1310. doi: 10.1002/ajh.24898. Epub 2017 Sep 25 [PubMed PMID: 28850704]

[16]

Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle JH, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C, EBMT Inborn Error and EBMT Paediatric Working Parties. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May:99(5):811-20. doi: 10.3324/haematol.2013.099747. Epub [PubMed PMID: 24790059]

[17]

Henes J, Oliveira MC, Labopin M, Badoglio M, Scherer HU, Del Papa N, Daikeler T, Schmalzing M, Schroers R, Martin T, Pugnet G, Simoes B, Michonneau D, Marijt EWA, Lioure B, Olivier Bay J, Snowden JA, Rovira M, Huynh A, Onida F, Kanz L, Marjanovic Z, Farge D. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica. 2021 Feb 1:106(2):375-383. doi: 10.3324/haematol.2019.230128. Epub 2021 Feb 1 [PubMed PMID: 31949011]

[18]

Burt RK, Han X, Gozdziak P, Yaung K, Morgan A, Clendenan AM, Henry J, Calvario MA, Datta SK, Helenowski I, Schroeder J. Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome. Bone marrow transplantation. 2018 Jun:53(6):692-700. doi: 10.1038/s41409-018-0173-x. Epub 2018 May 31 [PubMed PMID: 29855561]

[19]

Bruera S, Sidanmat H, Molony DA, Mayes MD, Suarez-Almazor ME, Krause K, Lopez-Olivo MA. Stem cell transplantation for systemic sclerosis. The Cochrane database of systematic reviews. 2022 Jul 29:7(7):CD011819. doi: 10.1002/14651858.CD011819.pub2. Epub 2022 Jul 29 [PubMed PMID: 35904231]

Level 1 (high-level) evidence

[20]

Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE, SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. The New England journal of medicine. 2018 Jan 4:378(1):35-47 [PubMed PMID: 29298160]

[21]

Huang X, Chen W, Ren G, Zhao L, Guo J, Gong D, Zeng C, Hu W, Liu Z. Autologous Hematopoietic Stem Cell Transplantation for Refractory Lupus Nephritis. Clinical journal of the American Society of Nephrology : CJASN. 2019 May 7:14(5):719-727. doi: 10.2215/CJN.10570918. Epub 2019 Apr 12 [PubMed PMID: 30979713]

[22]

Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, Hiepe F, Lisukov I, Musso M, Ou-Yang J, Marsh J, Wulffraat N, Besalduch J, Bingham SJ, Emery P, Brune M, Fassas A, Faulkner L, Ferster A, Fiehn C, Fouillard L, Geromin A, Greinix H, Rabusin M, Saccardi R, Schneider P, Zintl F, Gratwohl A, Tyndall A, European Group for Blood and Marrow Transplantation, European League Against Rheumatism Registry. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus. 2004:13(3):168-76 [PubMed PMID: 15119545]

[23]

Ceglie G, Papetti L, Valeriani M, Merli P. Hematopoietic Stem Cell Transplantation in Neuromyelitis Optica-Spectrum Disorders (NMO-SD): State-of-the-Art and Future Perspectives. International journal of molecular sciences. 2020 Jul 26:21(15):. doi: 10.3390/ijms21155304. Epub 2020 Jul 26 [PubMed PMID: 32722601]

Level 3 (low-level) evidence

[24]

Burt RK, Balabanov R, Han X, Burns C, Gastala J, Jovanovic B, Helenowski I, Jitprapaikulsan J, Fryer JP, Pittock SJ. Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica. Neurology. 2019 Oct 29:93(18):e1732-e1741. doi: 10.1212/WNL.0000000000008394. Epub 2019 Oct 2 [PubMed PMID: 31578302]

[25]

Zhang P, Liu B. Effect of autologous hematopoietic stem cell transplantation on multiple sclerosis and neuromyelitis optica spectrum disorder: a PRISMA-compliant meta-analysis. Bone marrow transplantation. 2020 Oct:55(10):1928-1934. doi: 10.1038/s41409-020-0810-z. Epub 2020 Feb 4 [PubMed PMID: 32020080]

Level 1 (high-level) evidence

[26]

Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelson F, Barreira AA, Carlson K, Han X, Moraes D, Morgan A, Quigley K, Yaung K, Buckley R, Alldredge C, Clendenan A, Calvario MA, Henry J, Jovanovic B, Helenowski IB. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15:321(2):165-174. doi: 10.1001/jama.2018.18743. Epub [PubMed PMID: 30644983]

Level 1 (high-level) evidence

[27]

Bertolotto A, Martire S, Mirabile L, Capobianco M, De Gobbi M, Cilloni D. Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Standard of Care for Relapsing-Remitting Multiple Sclerosis Patients. Neurology and therapy. 2020 Dec:9(2):197-203. doi: 10.1007/s40120-020-00200-9. Epub 2020 Jun 16 [PubMed PMID: 32548740]

[28]

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringdén O, Rozman C, Speck B. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990 Feb 1:75(3):555-62 [PubMed PMID: 2297567]

[29]

Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, Fernandez-Vina M, Flomenberg N, Horowitz M, Hurley CK, Noreen H, Oudshoorn M, Petersdorf E, Setterholm M, Spellman S, Weisdorf D, Williams TM, Anasetti C. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007 Dec 15:110(13):4576-83 [PubMed PMID: 17785583]

[30]

Howard CA, Fernandez-Vina MA, Appelbaum FR, Confer DL, Devine SM, Horowitz MM, Mendizabal A, Laport GG, Pasquini MC, Spellman SR. Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015 Jan:21(1):4-7. doi: 10.1016/j.bbmt.2014.09.017. Epub 2014 Sep 30 [PubMed PMID: 25278457]

Level 3 (low-level) evidence

[31]

Cashen A, Lopez S, Gao F, Calandra G, MacFarland R, Badel K, DiPersio J. A phase II study of plerixafor (AMD3100) plus G-CSF for autologous hematopoietic progenitor cell mobilization in patients with Hodgkin lymphoma. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2008 Nov:14(11):1253-61. doi: 10.1016/j.bbmt.2008.08.011. Epub [PubMed PMID: 18940680]

[32]

Dominietto A, Lamparelli T, Raiola AM, Van Lint MT, Gualandi F, Berisso G, Bregante S, Di Grazia C, Soracco M, Pitto A, Frassoni F, Bacigalupo A. Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation. Blood. 2002 Dec 1:100(12):3930-4 [PubMed PMID: 12393584]

[33]

Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG, Scott BL, Deeg HJ, Appelbaum FR, Storb R. Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Sep 20:25(27):4246-54 [PubMed PMID: 17724349]

[34]

Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, Chauncey TR, Pulsipher MA, Petersen FB, Sahebi F, Agura ED, Hari P, Bruno B, McSweeney PA, Maris MB, Maziarz RT, Langston AA, Bethge W, Vindeløv L, Franke GN, Laport GG, Yeager AM, Hübel K, Deeg HJ, Georges GE, Flowers ME, Martin PJ, Mielcarek M, Woolfrey AE, Maloney DG, Sandmaier BM. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 Apr 20:31(12):1530-8. doi: 10.1200/JCO.2012.45.0247. Epub 2013 Mar 11 [PubMed PMID: 23478054]

[35]

Gopal R, Ha CS, Tucker SL, Khouri IF, Giralt SA, Gajewski JL, Andersson BS, Cox JD, Champlin RE. Comparison of two total body irradiation fractionation regimens with respect to acute and late pulmonary toxicity. Cancer. 2001 Oct 1:92(7):1949-58 [PubMed PMID: 11745270]

[36]

Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R, Kashyap A, Flowers ME, Lilleby K, Chauncey TR, Storb R, Appelbaum FR. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. The New England journal of medicine. 2001 Jan 18:344(3):175-81 [PubMed PMID: 11172139]

[37]

Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL, Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors. The New England journal of medicine. 2012 Oct 18:367(16):1487-96. doi: 10.1056/NEJMoa1203517. Epub [PubMed PMID: 23075175]

[38]

Lee SJ, Logan B, Westervelt P, Cutler C, Woolfrey A, Khan SP, Waller EK, Maziarz RT, Wu J, Shaw BE, Confer D, Horowitz MM, Anasetti C. Comparison of Patient-Reported Outcomes in 5-Year Survivors Who Received Bone Marrow vs Peripheral Blood Unrelated Donor Transplantation: Long-term Follow-up of a Randomized Clinical Trial. JAMA oncology. 2016 Dec 1:2(12):1583-1589. doi: 10.1001/jamaoncol.2016.2520. Epub [PubMed PMID: 27532508]

Level 1 (high-level) evidence

[39]

Locatelli F, Kabbara N, Ruggeri A, Ghavamzadeh A, Roberts I, Li CK, Bernaudin F, Vermylen C, Dalle JH, Stein J, Wynn R, Cordonnier C, Pinto F, Angelucci E, Socié G, Gluckman E, Walters MC, Rocha V, Eurocord and European Blood and Marrow Transplantation (EBMT) group. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. 2013 Aug 8:122(6):1072-8. doi: 10.1182/blood-2013-03-489112. Epub 2013 May 21 [PubMed PMID: 23692854]

[40]

Eapen M, Klein JP, Ruggeri A, Spellman S, Lee SJ, Anasetti C, Arcese W, Barker JN, Baxter-Lowe LA, Brown M, Fernandez-Vina MA, Freeman J, He W, Iori AP, Horowitz MM, Locatelli F, Marino S, Maiers M, Michel G, Sanz GF, Gluckman E, Rocha V, Center for International Blood and Marrow Transplant Research, Netcord, Eurocord, and the European Group for Blood and Marrow Transplantation. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014 Jan 2:123(1):133-40. doi: 10.1182/blood-2013-05-506253. Epub 2013 Oct 18 [PubMed PMID: 24141369]

[41]

Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, Bunin N, Delaney C, Haut P, Margolis D, Peres E, Verneris MR, Walters M, Horowitz MM, Kurtzberg J, Blood and Marrow Transplant Clinical Trials Network. One-unit versus two-unit cord-blood transplantation for hematologic cancers. The New England journal of medicine. 2014 Oct 30:371(18):1685-94. doi: 10.1056/NEJMoa1405584. Epub [PubMed PMID: 25354103]

[42]

Scaradavou A, Brunstein CG, Eapen M, Le-Rademacher J, Barker JN, Chao N, Cutler C, Delaney C, Kan F, Isola L, Karanes C, Laughlin MJ, Wagner JE, Shpall EJ. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013 Jan 31:121(5):752-8. doi: 10.1182/blood-2012-08-449108. Epub 2012 Dec 9 [PubMed PMID: 23223509]

[43]

Ciurea SO, Bayraktar UD. "No donor"? Consider a haploidentical transplant. Blood reviews. 2015 Mar:29(2):63-70. doi: 10.1016/j.blre.2014.09.009. Epub 2014 Sep 30 [PubMed PMID: 25307958]

[44]

Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, Hartzman R, Rizzo JD, Horowitz M, Confer D, Maiers M. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. The New England journal of medicine. 2014 Jul 24:371(4):339-48. doi: 10.1056/NEJMsa1311707. Epub [PubMed PMID: 25054717]

[45]

Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, Sanders JE, Stewart P, Buckner CD, Storb R. Marrow transplantation from related donors other than HLA-identical siblings. The New England journal of medicine. 1985 Sep 26:313(13):765-71 [PubMed PMID: 3897863]

[46]

Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood. 2014 Jul 31:124(5):822-6. doi: 10.1182/blood-2014-03-563817. Epub 2014 May 28 [PubMed PMID: 24869942]

[47]

Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JA, Boeckh MJ, Center for International Blood and Marrow Research, National Marrow Donor program, European Blood and MarrowTransplant Group, American Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Disease Canada, Centers for Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2009 Oct:15(10):1143-238. doi: 10.1016/j.bbmt.2009.06.019. Epub [PubMed PMID: 19747629]

Level 3 (low-level) evidence

[48]

Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone marrow transplantation. 1992 Sep:10(3):267-72 [PubMed PMID: 1422481]

[49]

Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. The Cochrane database of systematic reviews. 2007 Jul 18:(3):CD005590 [PubMed PMID: 17636808]

Level 1 (high-level) evidence

[50]

Girmenia C, Barosi G, Piciocchi A, Arcese W, Aversa F, Bacigalupo A, Bandini G, Bosi A, Busca A, Castagnola E, Caselli D, Cesaro S, Ciceri F, Locasciulli A, Locatelli F, Mikulska M, Pagano L, Prete A, Raiola AM, Rambaldi A. Primary prophylaxis of invasive fungal diseases in allogeneic stem cell transplantation: revised recommendations from a consensus process by Gruppo Italiano Trapianto Midollo Osseo (GITMO). Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014 Aug:20(8):1080-8. doi: 10.1016/j.bbmt.2014.02.018. Epub 2014 Feb 26 [PubMed PMID: 24582783]

Level 3 (low-level) evidence

[51]

Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA, Blood and Marrow Transplant Clinical Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9:116(24):5111-8. doi: 10.1182/blood-2010-02-268151. Epub 2010 Sep 8 [PubMed PMID: 20826719]

Level 1 (high-level) evidence

[52]

Erard V, Guthrie KA, Varley C, Heugel J, Wald A, Flowers ME, Corey L, Boeckh M. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007 Oct 15:110(8):3071-7 [PubMed PMID: 17515400]

[53]

Bhatt AS, Freeman SS, Herrera AF, Pedamallu CS, Gevers D, Duke F, Jung J, Michaud M, Walker BJ, Young S, Earl AM, Kostic AD, Ojesina AI, Hasserjian R, Ballen KK, Chen YB, Hobbs G, Antin JH, Soiffer RJ, Baden LR, Garrett WS, Hornick JL, Marty FM, Meyerson M. Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. The New England journal of medicine. 2013 Aug 8:369(6):517-28. doi: 10.1056/NEJMoa1211115. Epub [PubMed PMID: 23924002]

[54]

Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, Guinan E, Vogelsang G, Krishnan A, Giralt S, Revta C, Carreau NA, Iacobelli M, Carreras E, Ruutu T, Barbui T, Antin JH, Niederwieser D. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2010 Feb:16(2):157-68. doi: 10.1016/j.bbmt.2009.08.024. Epub 2009 Sep 18 [PubMed PMID: 19766729]

[55]

Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995 Jun 1:85(11):3005-20 [PubMed PMID: 7756636]

[56]

Andersson BS, Madden T, Tran HT, Hu WW, Blume KG, Chow DS, Champlin RE, Vaughan WP. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2000:6(5A):548-54 [PubMed PMID: 11071260]

[57]

Cheuk DK. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies. World journal of transplantation. 2012 Apr 24:2(2):27-34. doi: 10.5500/wjt.v2.i2.27. Epub [PubMed PMID: 24175193]

[58]

Chao N. How I treat sinusoidal obstruction syndrome. Blood. 2014 Jun 26:123(26):4023-6. doi: 10.1182/blood-2014-03-551630. Epub 2014 May 15 [PubMed PMID: 24833355]

[59]

Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, Martin PL, Steinbach G, Murray KF, Vogelsang GB, Chen AR, Krishnan A, Kernan NA, Avigan DE, Spitzer TR, Shulman HM, Di Salvo DN, Revta C, Warren D, Momtaz P, Bradwin G, Wei LJ, Iacobelli M, McDonald GB, Guinan EC. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2010 Jul:16(7):1005-17. doi: 10.1016/j.bbmt.2010.02.009. Epub 2010 Feb 16 [PubMed PMID: 20167278]

Level 1 (high-level) evidence

[60]

Yanik GA, Horowitz MM, Weisdorf DJ, Logan BR, Ho VT, Soiffer RJ, Carter SL, Wu J, Wingard JR, Difronzo NL, Ferrara JL, Giralt S, Madtes DK, Drexler R, White ES, Cooke KR. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014 Jun:20(6):858-64. doi: 10.1016/j.bbmt.2014.02.026. Epub 2014 Mar 7 [PubMed PMID: 24607553]

Level 1 (high-level) evidence

[61]

Reshef R, Hexner EO, Loren AW, Frey NV, Stadtmauer EA, Luger SM, Mangan JK, Gill SI, Vassilev P, Lafferty KA, Smith J, Van Deerlin VM, Mick R, Porter DL. Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014 Nov:20(11):1758-66. doi: 10.1016/j.bbmt.2014.07.003. Epub 2014 Jul 10 [PubMed PMID: 25016197]

[62]

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2005 Dec:11(12):945-56 [PubMed PMID: 16338616]

Level 3 (low-level) evidence

[63]

Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, Litzow MR, Nieto Y, Savani BN, Schriber JR, Shaughnessy PJ, Wall DA, Carpenter PA. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2012 Aug:18(8):1150-63. doi: 10.1016/j.bbmt.2012.04.005. Epub 2012 Apr 14 [PubMed PMID: 22510384]

[64]

Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015 Mar:21(3):389-401.e1. doi: 10.1016/j.bbmt.2014.12.001. Epub 2014 Dec 18 [PubMed PMID: 25529383]

Level 3 (low-level) evidence

[65]

Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, Appelbaum FR, Carpenter PA, Sanders JE, Kiem HP, Nash RA, Petersdorf EW, Moravec C, Morton AJ, Anasetti C, Flowers ME, Martin PJ. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004 Dec 1:104(12):3501-6 [PubMed PMID: 15292060]

[66]

Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D, Ruutu T, Vernant JP, de Witte T, Apperley J. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet (London, England). 1998 Oct 3:352(9134):1087-92 [PubMed PMID: 9798583]

[67]

Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, Bhatia S, Ostronoff F, Deeg HJ, Syrjala KL, Estey E, Maloney DG, Appelbaum FR, Martin PJ, Storer BE. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Oct 10:32(29):3249-56. doi: 10.1200/JCO.2013.53.8157. Epub 2014 Aug 25 [PubMed PMID: 25154831]

[68]

Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP, Ritz J, Sorror ML, Lee SJ, Deeg HJ, Storer BE, Appelbaum FR, Antin JH, Soiffer RJ, Kim HT. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012 Jul 26:120(4):905-13. doi: 10.1182/blood-2012-03-418202. Epub 2012 Jun 18 [PubMed PMID: 22709687]