Hematopoietic Stem Cell Transplantation

Article Author:
Karam Khaddour
Article Editor:
Prerna Mewawalla
Updated:
3/2/2019 8:20:10 AM
PubMed Link:
Hematopoietic Stem Cell Transplantation

Introduction

Bone marrow transplant (hematopoietic stem cell transplant) (HPSCT) involves the administration of healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow. This helps to augment bone marrow function and allows, depending on the disease being treated, to either destroy tumor cells with malignancy or to generate functional cells that can replace the dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases.

History and Evolution

Hematopoietic stem cell transplantation (HSCT) was first explored in humans in the 1950s and 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 into humans when the first successful bone marrow transplant was performed in monozygotic twins in New York in 1957 (syngeneic transplant) in a patient with acute leukemia.[2] As a result, the physician Dr. Thomas who performed the procedure continued his research on the development of bone marrow transplantation and later received the Nobel Prize of physiology and medicine in appreciation of 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 transplant has increased in the United States and worldwide. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogenic transplants performed in the United States in 2016 with a higher number of autologous transplants with a steady and higher increase of autologous compared to allogenic.[4]

Definitions

Major Histocompatibility Complex (MHC)

The group of genes on the short arm of chromosome 6 (p6) that encodes human leukocyte antigens (HLA) which are considered being highly polymorphic leading to a large difference in the resultant expressed proteins on human cells. They are divided into MHC I and MHC II

Human Leukocyte Antigens (HLA)

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

Syngeneic Bone Marrow Transplantation

The donor and the recipient are identical twins. The advantages include no graft versus host disease (GVHD) and no graft failure. However, only a tiny number of transplant patients will have the ability to have an identical twin for transplantation.

Autologous Bone Marrow Transplantation

The bone marrow products are collected from the patient and are reinfused after purification methods. The advantages include no GVHD. The disadvantage is that the 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.

Allogenic Transplantation

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

Engraftment

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

Preparative Regimen

This is a regimen that comprises high-dose chemotherapy and/or total body irradiation (TBI) which are administered to the recipient prior to stem cell infusion to eliminate the largest number of malignant cells and to allow for immunosuppression in the recipient so that engraftment can occur.

Indications

Malignant Disease

Multiple Myeloma

Autologous stem cell transplant accounts for most hematopoietic stem cell transplants according to CIBMTR in 2016 in the United States. Studies have shown increased overall survival and progression free survival in patients younger than 65 years old when consolidation therapy with melphalan is initiated followed by autologous stem cell transplantation and lenalidomide maintenance therapy.[5] The study showed a favorable outcome of high-dose melphalan plus stem-cell transplantation when compared with consolidation therapy with melphalan, prednisone, lenalidomide (MPR). It also showed a better outcome in patients who received a maintenance therapy with lenalidomide.

Hodgkin and Non-Hodgkin Lymphoma

Studies have shown that chemotherapy followed by autologous stem cell transplantation in cases of recurrent lymphomas (HL and NHL) that do not respond to initial conventional chemotherapy have better outcomes. A randomized controlled trial by Schmitz N et al. showed a better 3-year outcome 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.[6] The number of hematopoietic stem cell transplant recipient comes second after multiple myeloma according to CIBMTR.

Acute Myeloid Leukemia

Allogenic stem cell transplant has shown to improve outcome in patients with AML who fail primary induction therapy and do not achieve compete response and may prolong overall survival.[7] The study recommended that early HLA typing for patients with AML can help if they fail induction therapy and are considered for bone marrow transplant.

Acute Lymphocytic Leukemia

Allogenic stem cell transplant is indicated in refractory and resistant cases when induction therapy fails for a second time in inducing remission. Some studies suggest an increased benefit of allogenic hematopoietic stem cell transplant in patients with high risk ALL including patients with Philadelphia chromosome and those with t(4, 11).[8]

Myelodysplastic Syndrome

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

Chronic Myeloid Leukemia/Chronic Lymphocytic Leukemia

Recipients with these two diseases come at the bottom of the list of patients who received allogeneic stem cell transplant in 2016. Hematopoietic stem cell transplantation has shown high cure rates but with available treatments like tyrosine kinase inhibitors and high success rates with low adverse risk profile, HSCT is reserved for patients with the refractory disease to first-line agents in CML.

Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera

Allogenic stem cell transplant has shown to improve outcomes in patients with myelofibrosis and those who had a diagnosis of myelofibrosis that was preceded by essential thrombocytosis and polycythemia vera.[9]

Solid Tumors

Autologous stem cell transplant is considered the standard of care in patients with germ cell tumor (testicular tumors) that are refractory to chemotherapy (after the third recurrence with chemotherapy).[10] HSCT 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 hematopoietic stem cell transplant in acquired aplastic anemia when compared with conventional immunosuppressive therapy.[11] Allogenic stem cell transplant has shown better outcomes when it was collected from bone marrow compared to peripheral blood in a study that involved 1886 patients with acquired aplastic anemia.[12] Patients with aplastic anemia need preparative regimen given 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 at birth before the onset of infections.[13]

Thalassemia

Allogenic stems transplant from a matched sibling donor is considered an option to treat Thalassemia and has shown 15-year survival reaching 80%. However, recent retrospective data showed similar overall survival compared with conventional treatment that consists of multiple transfusions in the case of thalassemia.[14]

Sickle Cell Anemia

Allogenic stem cell transplant is recommended for the treatment of sickle cell disease.[15]

Other Nonmalignant Diseases

Stem cell transplant has been used in the treatment of chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan-Diamond anemia, and enzymatic disorders. Moreover, the role of stem cell transplant is being explored in autoimmune diseases including systemic sclerosis, systemic lupus erythematosus and has already shown promising results in cases like relapsing-remitting multiple sclerosis.[16]

Contraindications

There are no absolute contraindications for hematopoietic stem cell transplant.

Equipment

Special equipment exists for the collection, preservation, and administration of stem cell products.

Personnel

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

Preparation

Preparation includes:

  • Preparative regimen
  • Collection of hematopoietic stem cells
  • Instant infusion or cryopreservation followed by infusion

Technique

Mechanism of Action

The mechanism of action of stem cell transplant against malignancy 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 leukemia. These patients received stem cell transplantation and showed that the lowest rate of relapses was in patients who received non-T-cell-depleted bone marrow cells and in 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 plays a central role in the engraftment's efficacy against tumor cells.[17]

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

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

Administration

HLA Typing

HLA typing is an important step to determine the best donor suitable for stem cell collection. In theory, matched, related donors are the best candidates, followed by matched unrelated donors, cord blood, and then haploidentical donors. HLA typing is analyzed at either an intermediate-resolution level, which entails the detection of 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. PCR 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 eligibility of donors but according to studies that showed matching for HLA-A, B, C, and DRB1 at a high-resolution level were associated with improved survival and outcomes.[18] Recommendations about donor HLA assessment and matching have been proposed by the Blood and Marrow Transplant Clinical Trials Network (BM CTN).[19]

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. For example, the procedure consists of 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, and then this is followed by preparative regimen and finally, infusion.

Mobilization and collection involved the use of medication to increase the number of stem cells in the peripheral blood given that there are not enough stem cells in the peripheral blood. The agents used 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 lead to a break of vascular adhesion molecules and the release of hematopoietic stem cells from the bone marrow. Plerixafor blocks the binding of stromal cell-derived factor-1-alpha (SDF-1) to (CXCR4) which leads to the mobilization of stem cells to the peripheral blood.[20] 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 be used in some instances for mobilization of hematopoietic stem cells; this process is termed chemoembolization.

The usual site of bone marrow collection is the anterior or posterior iliac crest. The procedure can be performed under local or general anesthesia. Complications include pain, fever, and serious iatrogenic complications can occur in less than 1% of cases. Multiple aspirations are done with each aspirate containing 15 mL. The goal is to collect up to 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 as studies showed that overall survival and long-term engraftment is strongly influenced by cell dose in allogeneic hematopoietic stem cell transplantation.[21]

The preparative regimen consists of 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 only limited to patients with malignancies but also extends to cases like aplastic anemia and hemoglobinopathies given that these patients have an intact immune system that could cause graft failure if there is no conditioning.

The preparative regimen is divided into myeloablative conditioning and reduced intensity conditioning. The preparative regimen depends on the disease being treated, existing comorbidities, and the source of the harvested hematopoietic stem cells. The preparative regimen consists of chemotherapy, total body irradiation, or both. There are different combination regimens used in the preparative period, and the choice of the regimen depends on the disease being treated, existing comorbidities, and previous exposure to radiation.

In the special case of SCID, there is no need for preparative regimen in patients receiving from HLA-matched siblings given that there are no abnormal cells that are needed to be eliminated and because immunosuppression caused by SCID can prevent graft rejection. Reduced-intensity conditioning is preferred in patients with prior radiotherapy, older age, the presence of comorbidities, and history extensive chemotherapy before BMT.[22] The advantages of using reduced-intensity conditioning include less need for transfusion due to the transient post-transplant pancytopenia and less damage to the liver in cases of chemotherapy and lung due to radiation.[23] However, the relapse rates are higher, but these regimens are more tolerated with a better safety profile in a specific patient population. Most of the chemotherapies used in preparative regimens consist of either potent immunosuppressive agents (high doses of cyclophosphamide 60 mg/kg IV), alkylating agents especially busulfan 130 mg/m2 IV, nucleoside analogs (fludrabine 40 mg/m2) and other agents like melphalan, antithymocyte globulin, rituximab, gemcitabine, and many others. Total body irradiation (TBI) is performed using fractionated doses because it has shown less pulmonary toxicity when compared with one dose regimen.[24] The administration of the preparative regimen should immediately precede the bone marrow transplantation, and as a general rule, the effect of the regimen should produce bone marrow suppression within 1 to 3 weeks of administration.

Reinfusion of either fresh or cryopreserved stem cells can occur in an ambulatory setting and takes up to 2 hours. Before the infusion begins, quality measures are performed to ensure the number of CD34+ cells is sufficient.

Advantages and Disadvantages of Different Hematopoietic Stem Cells

The advantages of peripheral blood stem cells transplant (PBSCTs) include more rapid engraftment rate compared to bone marrow where it takes about 2 weeks of recovery in the former and is delayed for 5 days more in the latter,[25] but the use of post-transplant immunosuppressive regimen to prevent GVHD can prolong the increase in bone marrow products. Moreover, the rate of acute GVHD appears to be similar when compared with bone marrow transplantation in HLA- identical matched related donors.[25] However, chronic GVHD appears to be encountered more after peripheral blood stem cell transplant which could lead to more complications.[26] In the study by Anasetti et al., the primary endpoint was the difference in the 2-year overall survival seemed to be non-significant in the two groups. However, secondary end points showed more stable grafts with decreased graft failure in the group which received peripheral blood stem cell transplant but also this group had a higher incidence of chronic GVHD.[26] Other similar studies comparing both bone marrow transplant and peripheral blood SCTs concluded that the psychological burden due to chronic GVHD and the 5-year ability to restore normal activities including going back to work were better in the bone marrow transplanted group.[27]

The advantages of cord blood transplant include the rapid collection and administration which serves in treating urgent conditions, less frequency of infections, lower rates of GVHD with the same rate of GVT, less need for a stringent identical HLA. The disadvantages include delayed engraftment with a higher possibility of graft rejection and higher rates of disease relapses. The cord blood transplant is most used in patients without matched related or unrelated donors. A major study by Locatelli et al. demonstrated the utility of cord blood transplant in patients with thalassemia major and sickle cell anemia and showed similar 6-year overall survival in the CBT and BMT groups.[28] The most important factors that affect the outcome of CBT are the total nucleated cell dose and HLA matching with a recommended minimum dose of total nucleated cells of 2 x 10*7 cells/kg for successful engraftment. Theoretically, strict HLA matching is not required in the case of cord blood transplant given it 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.[29] Given that a single blood cord unit might not contain the required amount of nucleated cells an approach using double cord transplant is used to overcome this problem. However, only one cord blood transplant product will predominate within 3 months of infusion. Further, randomized controlled trials failed to show a significant difference in terms of outcome benefits or risks between double cord blood and a single cord blood transplant.[30][31]

Haploidentical stem cell transplantation refers to the administration of bone marrow products from a first degree related haplotype-mismatched donor.[32] This helps in non-white patients like African American, Hispanics, and patients from countries where there is no wide access to resources as they have fewer chances of having a matched unrelated donor.[33] The advantages include lower cost and rapid availability of the hematopoietic cell products. However, the disadvantages include hyperacute GVHD which increases mortality and graft rejection.[34] This has been overcome by 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 when compared to conventional ex vivo depletion of large T-cell populations.[35]

Complications

Complications after bone marrow transplant can be divided into acute and chronic. Many factors can affect the occurrence of these adverse events including the age of the patient, baseline performance status, the source of stem cell transplant the type and intensity of the preparative regimen. Acute complications can occur in the first 90 days and include myelosuppression with neutropenia, anemia, thrombocytopenia, sinusoidal obstruction syndrome (SOS), mucositis, acute graft versus host disease, gram-positive/gram-negative infections, HSV, CMV, Candida, and Aspergillus. Chronic complications include chronic GVHD, infection with encapsulated bacteria and VZV. Levofloxacin is usually given by mouth or intravenously (IV) at day 1 post-transplant and is continued until absolute neutrophil count (ANC) is more than 1000 cells/uL or until the discontinuation of prednisone in cases of GVHD.[36] PCP prophylaxis is warranted given the immunosuppression following hematopoietic stem cell transplant.[37] Trimethoprim-sulfamethoxazole (TMP-SMX) is usually used, and several dosing regimens have been proposed. TMP-SMX is given 2 days per week until the patient is off immunosuppression.[38] Antifungal infection prophylaxis with fluconazole is recommended for 1 month following transplant as it has shown to decrease the incidence of fungal infections and no difference was seen when fluconazole was compared to voriconazole.[39][40] However, voriconazole is used in patients with a high-risk profile of developing severe forms of antifungal infection. Prevention against HSV and VZV is achieved with acyclovir that is continued for 1 month for the prevention against HSV and for 1 year for preventions against VZV. [41] Prophylaxis against CMV is only recommended in patients who test positive for CMV 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[42] which usually responds to a course of metronidazole or levofloxacin. 

Sinusoidal Obstruction Syndrome (SOS)

Also known as veno occlusive disease (VOD) is the result of chemotherapy during preparative regimen and occurs within 6 weeks of hematopoietic stem cell transplant. 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.[43] The pathophysiology consists of endothelial damage to the hepatic sinusoids leading to obstruction and necrosis of the centrilobular liver.[44] 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. The use of IV busulfan has shown to decrease the occurrence of SOS.[45] The diagnosis is clinical and is based on hyperbilirubinemia greater than 2 mg/dL with the other clinical findings of tender hepatomegaly and fluid retention. Treatment consists of ursodeoxycholic acid (UDCA) which has shown to significantly decrease the occurrence of SOS when given pre and post-transplant.[46] Another medication, defibrotide, has shown efficacy in the treatment of SOS when it occurs.[47][48]

Idiopathic Pneumonia Syndrome (IPS)

This usually happens in the first 90 days post-transplant. The incidence is low and is related to direct chemotoxicity due to preparative regimen. Treatment with steroids is usually used although no randomized controlled clinical trials have been done to support their efficacy. Recently, etanercept has been studied in a randomized control trial in patients who develop this syndrome. The study assessed the addition of soluble TNF inhibitors to steroids in the treatment and has not shown added efficacy with combination therapy.[49]

Graft Rejection

The process of which there is a loss of bone marrow function after reconstitution following infusion of hematopoietic stem cells or if there is no gain of function after infusion and is termed graft failure or rejection. The incidence of failure is highest when there is a high HLA disparity that usually occurs in the case of cord blood and haploidentical donors and is 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. Checking for chimerism is an important step in ensuring engraftment and success of the transplantation. The physician does this by checking the expression of CD33 which indicates the presence of granulocytes and CD3 which indicate the presence of T cells and confirming that most of the present cells 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.[50]

Graft Versus Host Disease

The graft versus host disease (GVHD) consists of the reaction between T-cells from the donor in allogeneic transplant and recipient’s HLA polymorphic epitopes that leads to a constellation of symptoms and manifestations. GVHD can be categorized into acute and chronic which are both sub-categorized into classic and late onset, classic, and chronic overlap respectively.[51] Acute GVHD usually develops within three months. However, it can develop after 3 months and is termed delayed acute GVHD. Prophylaxis is usually achieved with calcineurin inhibitors, methotrexate, and anti-thymocyte globulins. Severity is estimated based on Glucksberg scale which classifies acute GVHD from grade I to VI, and treatment with either high dose prednisone or methylprednisolone is indicated in higher grades.[52]

Chronic GVHD occurs after three months and is represented by the involvement of multiple organs in a similar fashion to collagen vascular diseases. Grading has been developed by NIH (Global Grading System) to assess the severity of GVHD which determines the treatment modality and predicts survival [53]. Treatment is similar to that of acute GVHD, but the duration is usually over 2two years.[54]

Toxicity

Chemotherapy and radiation of preparative regimen along with post-transplant immunosuppression can induce severe pancytopenia in the first week following infusion of hematopoietic stem cells which can lead to life-threatening infection. This depends on the type and the dose of chemotherapy administered and factors related to the recipients. Chemotherapy causes a destruction of healthy, normal bone marrow products including neutrophils, macrophages, monocytes, and lymphocytes. Also, mucositis toxicity due to chemotherapy disrupts the barriers protecting against infectious agents, and use of indwelling intravenous catheters provides another mean of the entrance of infectious agents. Vaccination is recommended for the following agents according to the guidelines: pneumococcal conjugate (PCV), TDaP, Haemophilus influenzae, meningococcal conjugate, onactivated polio, recombinant hepatitis B, inactivated influenza, and MMR.[36] Several regimens of prophylaxis have been proposed to prevent infections depending on the risk stratification of patients (low-risk, high-risk, treatment of ongoing GVHD.

Many risk scoring tools exist for the evaluation of recipients of hematopoietic stem cell transplant and stratification of risks so that proper preparation and treatment can be established to minimize the risks and toxicities before, during, and after transplantation. Some of the most commonly utilized scores in clinical practice are the European Group for Blood and Marrow Transplantation (EBMT) risk score,[55] hematopoietic cell transplantation-comorbidity index/age,[56] and Armand disease risk index (DRI).[57]

Enhancing Healthcare Team Outcomes

Hematopoietic stem cell transplant use in clinical practice has been expanding in the last decade, and many clinical trials are still ongoing to assess its efficacy in different medical conditions.


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;     [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;     [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;     [PubMed PMID: 4177932]
[4] 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;     [PubMed PMID: 21696033]
[5] 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;     [PubMed PMID: 25184862]
[6] 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, 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;     [PubMed PMID: 12086759]
[7] 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;     [PubMed PMID: 25536215]
[8] 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;     [PubMed PMID: 16703597]
[9] 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;     [PubMed PMID: 24963042]
[10] 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;     [PubMed PMID: 17652649]
[11] 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;     [PubMed PMID: 21541024]
[12] 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, 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;     [PubMed PMID: 22315497]
[13] 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;     [PubMed PMID: 25075835]
[14] 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;     [PubMed PMID: 28850704]
[15] 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, Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May;     [PubMed PMID: 24790059]
[16] Burt RK,Balabanov R,Han X,Sharrack B,Morgan A,Quigley K,Yaung K,Helenowski IB,Jovanovic B,Spahovic D,Arnautovic I,Lee DC,Benefield BC,Futterer S,Oliveira MC,Burman J, Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015 Jan 20;     [PubMed PMID: 25602998]
[17] 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;     [PubMed PMID: 2297567]
[18] 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;     [PubMed PMID: 17785583]
[19] 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;     [PubMed PMID: 25278457]
[20] 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;     [PubMed PMID: 18940680]
[21] 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;     [PubMed PMID: 12393584]
[22] 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;     [PubMed PMID: 17724349]
[23] 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;     [PubMed PMID: 23478054]
[24] 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;     [PubMed PMID: 11745270]
[25] 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;     [PubMed PMID: 11172139]
[26] 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, Peripheral-blood stem cells versus bone marrow from unrelated donors. The New England journal of medicine. 2012 Oct 18;     [PubMed PMID: 23075175]
[27] 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;     [PubMed PMID: 27532508]
[28] 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, Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. 2013 Aug 8;     [PubMed PMID: 23692854]
[29] 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, Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014 Jan 2;     [PubMed PMID: 24141369]
[30] 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, One-unit versus two-unit cord-blood transplantation for hematologic cancers. The New England journal of medicine. 2014 Oct 30;     [PubMed PMID: 25354103]
[31] 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;     [PubMed PMID: 23223509]
[32] Ciurea SO,Bayraktar UD,     [PubMed PMID: 25307958]
[33] 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;     [PubMed PMID: 25054717]
[34] 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;     [PubMed PMID: 3897863]
[35] 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;     [PubMed PMID: 24869942]
[36] Tomblyn M,Chiller T,Einsele H,Gress R,Sepkowitz K,Storek J,Wingard JR,Young JA,Boeckh MJ, 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;     [PubMed PMID: 19747629]
[37] Tuan IZ,Dennison D,Weisdorf DJ, Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone marrow transplantation. 1992 Sep;     [PubMed PMID: 1422481]
[38] 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;     [PubMed PMID: 17636808]
[39] 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;     [PubMed PMID: 24582783]
[40] 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, Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9;     [PubMed PMID: 20826719]
[41] 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;     [PubMed PMID: 17515400]
[42] 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;     [PubMed PMID: 23924002]
[43] 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;     [PubMed PMID: 19766729]
[44] Bearman SI, The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995 Jun 1;     [PubMed PMID: 7756636]
[45] 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;     [PubMed PMID: 11071260]
[46] Cheuk DK, Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies. World journal of transplantation. 2012 Apr 24;     [PubMed PMID: 24175193]
[47] Chao N, How I treat sinusoidal obstruction syndrome. Blood. 2014 Jun 26;     [PubMed PMID: 24833355]
[48] 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;     [PubMed PMID: 20167278]
[49] 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;     [PubMed PMID: 24607553]
[50] 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;     [PubMed PMID: 25016197]
[51] 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;     [PubMed PMID: 16338616]
[52] 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;     [PubMed PMID: 22510384]
[53] 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;     [PubMed PMID: 25529383]
[54] 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;     [PubMed PMID: 15292060]
[55] 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;     [PubMed PMID: 9798583]
[56] 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;     [PubMed PMID: 25154831]
[57] 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;     [PubMed PMID: 22709687]