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A. Introduction

  1. Types of Hematopoietic Stem Cell Transplantation (HSCT)
    1. Bone Marrow Transplantation (BMT)
    2. Peripheral Blood Stem Cell Transplantation (PBSC) - probably superior to BMT
    3. Cord (Placental) Blood Transplantation [2,7]
    4. In utero HSCT
    5. Autologous harvest with ex vivo stem (progenitor CD34+) cell expansion [8]
    6. Allogeneic (non-self donor) much more complicated than autologous transplantation
  2. Utility
    1. Treatment of congenital and acquired hematologic disorders including malignancies
    2. Rescue therapy after high dose chemotherapy and/or total body irradiation for malignancy
    3. Genetic diseases including immunodeficiencies, metabolic dysfunction [18]
    4. Severe autoimmune disorders including scleroderma, systemic juvenile arthritis (JCA) [12]
    5. Good efficacy in cyclophosphamide resistant systemic lupus erythematosus [13]
  3. Historical
    1. Allogeneic BMT was developed first in 1960s-70s
    2. Autologous BMT introduced in late 1970s
    3. PBSC was developed subsequently
  4. Costs [1]
    1. Autologous ~$80,000
    2. Allogeneic ~$150,000

B. Overview of Blood Cell Transplants

  1. Candidate recipient has major problem with hematologic cell lineage(s)
    1. This is due primarily to high expression of major histocompatibility antigens (MHC)
    2. The MHC and minor histocompatilibty antigens on donor cells signal recipient immune attack
    3. This causes a "host versus graft" situation and prevents engraftment
  2. Therefore, candidate recipient's immune system, even if deficient, must be suppressed
  3. Donor stem cells +/- other cell types are given to the recipient after immunosuppression
  4. Recipient will accept graft if the recipient's immune system is suppressed
  5. Donor stem cells engraft into recipient, but may cause graft versus host disease (GVHD)
  6. Degree of GVHD depends primarily on level of HLA matching between donor and recipient
  7. Recovery Following Transplantation [5]
    1. Most patients out of the hospital within 3-4 weeks
    2. Physical recovery to baseline can require more than 1 year
    3. Psychological recovery 3-5 years in many cases
    4. Depression following transplant is high

C. Obtaining Donor Hematopoietic Cells

  1. Bone Marrow (BM) Transplantation (BMT)
    1. Harvest from donor (autologous or allogeneic)
    2. Preharvest regimens - growth factors, chemotherapy, or nothing
    3. Repeated aspiration from posterior iliac crest for BMT only
    4. If cell harvest insufficient, try anterior iliac crest or sternum
    5. Need 100-300 million cells / kg recipient body weight
    6. Larger number of cells required for treatment of aplastic anemia
    7. PBSC are superior to BM derived cells in malignant hematologic disease
  2. Peripheral Blood Stem Cells (PBSC)
    1. Goal is to isolate hematopoietic stem cells from peripheral blood
    2. Surface protein CD34 appears to identify a population of these stem cells
    3. PBSC harvested after chemotherapy and growth factors (such as G-CSF)
    4. CD34+ stem cells are expanded ex vivo with growth factors [8]
    5. These ex vivo grown stem cells efficiently repopulate marrow [8]
    6. Stem cells are usually used to reconstitute marrow after very high dose chemotherapy
    7. These autologous PBSC transplants are better tolerated and more (cost) effective than standard autologous BMT [1,20]
    8. Expanded CD34+ cells showed ~1-2 day more rapid rescue of neutropenia and are very well tolerated [8]
    9. Transplanted T cells may home to adult thymus (thymic remnant) [35]
    10. PBSC appear to be able to differentiate to mature epithelial and liver cells [15]
  3. Umbilical Cord Blood Harvesting [3]
    1. Umbilical cord blood is rich in stem cells and can be used for transplant
    2. May be harvested, typed, and cryopreserved with no risk to "donor"
    3. Low likelihood of transmitting infections such as cytomegalovirus (CMV)
    4. Risk of acute or chronic graft versus host disease (GVHD) ~35% compared with BMT [36]
    5. Allogeneic unrelated donor transplantation provides reasonable graft acceptance and severe acute GVHD in 20% and chronic GVHD in ~30% [7]
    6. In children with acute leukemia, umbilical blood cell transplant with up to 2 HLA mismatches has similar 5 year outcomes to allogeneic transplant with less GVHD [4]
    7. In children with Hurler's disease, cord blood transplant with 1-3 HLA mismatches and a non-TBI preparative regimen had 20% acute GVHD and no significant chronic GVHD [16]
    8. In allogeneic matched cord blood transplants, repopulation of blood cells is delayed compared with BMT [36]
    9. HLA-mismatched cord blood can be used in adults with leukemia in the absence of an HLA-matched adult donor with similar outcomes [10,11]
    10. High levels of CD34+ cells in donor cord blood associated with improved outcomes [7]
    11. Cord blood harvested at delivery can be stored in public or private banks [2]
  4. In Utero Protocols
    1. For in utero procedure, T cell depleted or CD34+ enriched donors can be used
    2. Administration of cells should be carried out within 14 weeks for non-SCID fetuses
    3. For SCID fetuses, cells can be administred from 16.5 to 28 weeks
    4. Recipient ablation does not appear to be required
    5. Mixed chimerism can occur in successful cases (~20% success rate)
  5. Hepatocytes and epithelial cells of donor cell origin following PBSC transplant have been detected and are unrelated to severity of GVHD [15]

D. Preparation of Recipient: Immunoablation

  1. Must deplete most or all active immune cells (to prevent engraftment failure)
  2. Must destroy as many neoplastic cells as possible (goal is destroy all cells)
  3. Myeloablative Regimens
    1. Either chemotherapy alone or chemotherapy + total body irradiation (TBI)
    2. One common preparative regimen: cyclophosphamide ± busulfan
    3. Another preparative regimen: TBI + cyclophosphamide
    4. Combination high dose chemotherapy (melphalan, mitoxandrone, cyclophosphamide) can be used in dose-intensified chemotherapeutic regimens with autologous transplant
    5. Cord blood transplantation with 1-3 HLA mismatches can be accomplished without TBI [16]
    6. TBI is not associated with cross-resistance to chemotherapy, and reaches sites not reached by chemotherapy
    7. However, TBI requires specialized sites for irradiation and is associated with more toxicity than non-TBI regimens
    8. Selective radiation using targeted drugs (such as radioactive monoclonal antibodies) are being evaluated
  4. Nonmyeloablative Regimens [6]
    1. Used in miniallogeneic transplants (see below)
    2. Sufficient immunosuppression to allow engraftment of donor cells
    3. Fludarabine, thiotepa or melphalan, cyclophosphamide often used
    4. Tacrolimus (FK506) usually used to reduce graft versus host disease (GVHD)
    5. May allow more rapid immune and hematopoietic recovery than standard transplants
    6. May be associated with higher relapse rates but are better tolerated, particularly in elderly
  5. Anti-T cell Reagents: Anti-thymocyte globulin, OKT3, others for allogeneic transplants
  6. Conditioning for Acute GVHD [9]
    1. Recipient treated with total lymphoid irradiation + antithymocyte serum
    2. Reduced risk of acute GVHD to 2 in 37 transplants
    3. Maintained potent anti-tumor responses
    4. Consider for patients at risk for GVHD
  7. Gene marking studies have shown that marrow often contains tumor cells
  8. Therefore, improved purging regimens or stem cell isolation are needed

E. Allogeneic Transplant

  1. Indications for Allogeneic Transplant
    1. Aplastic Anemia - 50% long term survival
    2. Severe marrow infiltration by metastatic tumor, especially leukemias (AML, ALL)
    3. Chronic myelogenous leukemia
    4. Thalassemia
    5. Severe Combined Immunodeficiency - Adenosine Deaminase Deficiency and Others
    6. Wiskott-Aldrich Syndrome
    7. Chediak-Higashi Syndrome
    8. Graft versus leukemia effect may lead to improved disease free survival
    9. Fanconi's Anemia
    10. Especially effective in children
  2. Consideration in Allogenetic Transplants [6]
    1. Recipients are generally <55-60 years old
    2. Poorly tolerated procedure on older persons
    3. In standard allogeneic transplant, recipient's hematopoietic system is completely ablated
    4. Nonmyeloablative conditioning of recipient is increasing in safety and utility
    5. In these "miniallogeneic" transplants, nonablative chemotherapy is used to permit engraftment of donor cells without completely destroying host hematopoietic cells
    6. Result is chimeric hematopoietic system with reduced GVHD and good anticancer effect
    7. Nonmyeloablative transplants are better tolerated and may apply to older persons
    8. Nonmyeloablative transplants with T-cell depletion have been effective in lymphomas [22]
  3. Mortality Risk Score []
    1. 50 point risk score derived and validated includes 4 categories of increasing risk
    2. Major Risk Factors:
    3. Age >60 years
    4. Donor type: related mismatch > unrelated matched > related matched risk
    5. Disease risk: high > intermediate > low
    6. Conditioning Regimen: high radiation > low radiation > non-total body radiation > nonablative
    7. Carbon monoxide diffusing capacity (DLCO): low > high
    8. Serum alanine aminotransferase (ALT) level: high > low (borderline significance)
    9. Serum creatinine and FEV1 also of borderline significance
  4. Donors
    1. Twins permit a "syngeneic" transplant which behaves more like autologous (see below)
    2. HLA Matched Sibling Donors are available to ~30% of patients
    3. Chance of matched sibling ~ 1-(0.75)>N where N=number of siblings
    4. "Matched" unrelated donors (with T cell depletion)
    5. National Marrow Donor Program established to improve matches in USA
    6. Umbilical cord blood - HLA mismatches are acceptable and better tolerated with reduced GVHD and outcomes similar to matched allogeneic transplants [7,10,11]
    7. Allogeneic peripheral blood stem cells can be used in place of bone marrow transplants [40]
    8. Allogeneic peripheral blood stem cells have improved platelet reconstitution over BMT [40]
    9. Used for stem cell disease, cancer with severe marrow involvement, other
    10. CD28-blocked histoincompatible transplants may now be possible (see above) [29]
    11. T cell depleted allogeneic transplant has reduced GVHD, more rapid neutrophil recovery, reduced duration of initial hospitalization compared with cyclosporin/methotrexate [31]
    12. T cell depleted allogeneic transplant has less graft versus leukemia effect with higher leukemia relapse rates and trend to poorer survival than cyclosporin/methotrexate [31]
    13. Recipients treated with total lymphoid irradiation + anti-thymocyte serum have reduced risk of acute GVHD after allogeneic transplant [9]
  5. Graft Versus Host Disease (GVHD)
    1. Major problem with allogeneic transplant
    2. GVHD risk reduced with cord blood transplanteven with HLA mismatches [10,11]
    3. GVHD risk may be slightly increased in recipients of peripheral allogeneic stem cells [40]
    4. Degree of match inversely correlates with GVHD incidence
    5. GVHD may be acute (<1 month) and/or chronic (2-3 months)
    6. GVHD is a T cell mediated destruction of recipient organs
    7. Donor T cells are sometimes removed prior to transplant in some centers
    8. This reduces GVHD but increases rate of tumor relapses and graft failure
    9. Increasing dose of infused, T-cell depeleted donor cells increases engraftment [25]
    10. T cell depleted stem cells will engraft without GVHD even with HLA mismatch [25]
    11. Mismatches at HLA-A and HLA-C, but not HLA-D associated with GVHD [24]
  6. Induction of Anergy [29]
    1. Treatment of donor marrow with CD28 blockers in presence of irradiated recipient
    2. This provides first-signal stimulation, without coactivation signals
    3. Donor marrow becomes anergic specifically to recipient HLA/non-HLA antigens
    4. Incidence of GVHD is substantially reduced with this treatment
    5. Engraftment of treated donor bone marrow was not affected by treatment
    6. This kind of BMT is useful for patients without matched donors and with recurrent lymphoprofiliferative diseases
  7. Graft Failure
    1. Rejection usually due to host cell destruction of graft
    2. Usually in patients with aplastic anemia without TBI preparative regimen
    3. Increased failure risk correlates with number of blood transfusions prior to transplant
    4. In addition, T cell depleted grafts also have increased failure rate
    5. More immunosuppressive regimens given to recipient reduce failure rate
  8. Pneumonitis
    1. Acutely: fever, infiltrates, hypoxia, ARDS, alveolar hemorrhage
    2. Glucocorticoids are effective acutely in diffuse alveolar hemorrhage (DAH)
    3. Chronic: CMV infection probably responsible for a proportion of ARDS-like symptoms
    4. Treat with ganciclovir and/or foscarnet
  9. Other Problems
    1. Prolonged myelosuppression (infections in ~90% of cases; see below)
    2. Difficulty finding donor
    3. Poorer outcomes in elderly patients: increase in GVHD and poor tolerance
    4. Hepatic Venoocclussive Disease
    5. Hepatic complications reduced with ursodiol (Actigal®) treatment peritransplant [23]
    6. Mortality 10-20% depending on center and underlying disese
    7. Mortality may be >30% in older, high risk patients (usually with AML)
  10. Transplanted patients disease free after 2 years (CML, AML, ALL, aplastic anemia) are probably cured of the disease, but overall mortality higher than general population [30]

F. Autologous Transplant

  1. Used to reconstitute (rescue) bone marrow following intensive chemo- (radio-) therapy
    1. Dose intensive chemotherapy destroys marrow
    2. Unclear if dose intensive chemotherapy prolongs survival for many tumors
  2. Major problem is purging of neoplastic cells from marrow
    1. Detection of invading neoplastic cells has been a problem in the past
    2. Histologic identification is unreliable
    3. Polymerase chain reaction (PCR) has allowed highly sensitive detection
    4. Various "purging" regimens are used to remove neoplastic cells
  3. Purging Regimens
    1. Previously, chemotherapeutic agents were used (now out of favor)
    2. Monoclonal Abs very effective when available for deletion of tumor cells
    3. Positive selection of "stem" cells now possible
    4. Detection of residual neoplastic cells by culture and PCR
    5. Purging appears to reduce relapse in AML and Non-Hodgkin's Lymphoma (B cell types)
  4. Generally well tolerated
    1. Essentially no GVHD, little graft failure
    2. Can be done in patients >55 yeaars old
  5. Growth Factors
    1. Significantly reduce times to engraftment of marrow
    2. Currently, G-CSF, GM-CSF, and erythropoietin are used fairly routinely
    3. Studies using thrombopoietin and lymphocyte stimulators are increasing
    4. Stem cell factor (SCF, ancestim) may stimulate all lines including platelets [39]
    5. Growth factors may be used to expand progenitor cells ex vivo prior to infusion
    6. Large numbers of CD34+ progenitors are needed for ex vivo expansion
  6. Utility
    1. CML, CLL, Myelodysplastic Syndromes, Multiple Myeloma
    2. Intermediate and High Grade Non-Hodgkin's Lymphoma, Relapsing Hodgkin's Disease
    3. Autologous Marrow Transplant for Solid Tumor High Dose Chemotherapy

G. Early Side Effects [1]

  1. Mucositis
    1. Most common problem in short term
    2. Associated with myeloablative regimens and methotrexate
    3. Oropharyngeal mucositis is very painful and if extensive, can require intubation
    4. Intestinal mucositis causes nausea, cramping, diarrhea
    5. Parenteral nutrition may be required
    6. Opiates are often required for pain
    7. Palifermin (recombinant keratinocyte growth factor, Kepivance®) reduces mucositis and clinical complications associated with autologous transplantation [48]
  2. Hepatic Veno-Occlusive Disease (VOD)
    1. Second most common acute adverse effect
    2. Potentially fatal syndrome of painful hepatomegaly, jaundice, fluid retention
    3. Due to damage to sinusoidal endothelium, obstructing hepatic circulation
    4. Most strongly associated with cyclophosphamide+busulfan combinations
    5. Fludarabine associated with less VOD than cyclophosphamide
    6. In BMT, hepatic VOD reduced from 40% to 15% with ursodiol treatment [49]
  3. Transplantation Related Lung Injury
    1. Occurs within 4 months after the procedure
    2. Mortality exceeds 60%
    3. TBI, allogeneic transpant, and acute GVHD increase risk
    4. High levels of tumor necrosis factor alpha (TNFa) are found
    5. Treatment with etanercept (Enbrel®) and glucocorticoids advocated
  4. GVHD and Infections (see below)

H. Graft Versus Host Disease (GVHD) [14,26]

  1. Major current problem with BMT
    1. May be acute (<1 month) and/or chronic (>2-3 months) post BMT
    2. GVHD is caused by T cell mediated destruction of host (recipient) organs
    3. Basis of destruction is immune mediated attack by graft on host cells
  2. Allogeneic grafts are far more likely to cause GVHD than autologous grafts
    1. Matches at major histocompatibility loci (MHC) are major determinant of GVHD
    2. Degree of HLA match inversely correlates with GVHD incidence
    3. Mismatches at HLA-A and HLA-C, but not HLA-D, increase risk of GVHD [24]
    4. Mismatches at minor histocompatibility loci also increase GVHD risk
    5. Chronic GVHD due to graft cytotoxic T lymphocytes (CTL) killing host endothelial cells, leading to microvessel damage and loss [46]
    6. Large doses of T-cell depleted graft cells after conditioning led to graft acceptance with no GVHD even with one HLA mismatch [25]
    7. Blockade of donor marrow with CD28 inhibitors can induce host specific tolerance [29]
    8. Ex vivo deplation of alloreactive T cells using anti-CD25 Abs leads to reduced risk of GVHD and no cases of severe (Grade III or IV) GHVD [27]
    9. In recipients of stem cells from HLA-identical sibling, interleukin 10 -529A allele is a marker of good outcome (reduced GVHD and mortality) after transplantation [34]
  3. Acute GVHD
    1. Skin, Liver, and gastrointestinal tract are primarily affected
    2. Pancytopenia or neutropenia may occur due to bone marrow attack by grafted cells
    3. Infection, particularly fungal, is common and prophylaxis is required
    4. Kidney is usually spared
    5. Prophylaxis for acute GVHD with cyclosporin ± methotrexate, glucocorticoids is used
    6. Donor T cells are sometimes removed prior to transplant with anti-T cell Antibodies
    7. T cell depleted stem cells will engraft without GVHD even with HLA mismatch [25]
    8. Treat exacerbations with high dose glucocorticoids, anti-thymocyte globulin, monoclonal Abs, and infection prophylaxis
    9. Haploidenitical allogeneic mesenchymal stem cells induced remission of severe acute GVHD in patient following allogeneic stem cell transplantation [43]
    10. In patients with severe, steroid-resistant acute GVHD after allogeneic transplant, infusion of mesenchymal stem cells from allogeneic source improved overall survival at 1 and 2 years [3]
  4. Chronic GVHD Symptoms [26]
    1. "Lichenoid" changes (white plaques, striae) in skin and mucous membranes
    2. Vitiligo
    3. Periorbital hyperpigmentation
    4. Odynophagia (esophageal involvement)
    5. Nail dysplasia
    6. Keratoconjunctivitis sicca and xerostomia
    7. Alopecia
    8. Scleroderma or morphea; may be fatal if untreated
    9. Cholestasis
    10. Susceptibility to infection (major risk for morbidity and mortality)
    11. Nearly every body system can be effected by chronic GVHD
  5. Treatment of Chronic GVHD [26]
    1. Treat with glucocorticoids (prednisone) ± cyclosporine standard
    2. Alternatives: Tacrolimus (Prograf®), Sirolimus (Rapamycin), myophenolate (CellCept®), thalidomide, anti-T cell or anticytokine antibodies, photopheresis, others
    3. Very slow tapering of agents begun ~6 months after complete resolution of symptoms
    4. Adverse prognostic signs: thrombocytopenia, hyperbilirubinemia
  6. Chronic GVHD significantly reduces long term positive outcomes [26]
    1. About 60% of patients respond to immunosuppressive therapy and can be tapered
    2. About 20% with chronic GVHD will die, mainly from infection
    3. About 20% will require long term immunosuppression
  7. Infection prophylaxis, vaccination, and careful surveilance are essential in GVHD

I. Infection and BMT [14,28]

  1. Pre-transplant screening
    1. Titers of HSV, CMV Antibodies
    2. Toxoplasmosis Titers
    3. Hepatitis Serologies
    4. HIV Serology
    5. Syphilis Testing
    6. Epstein-Barr Virus (EBV) may cause post-transplant lymphoproliferative syndrome
  2. Infections Post-BMT
    1. Early (day 0-30): bacteremia (>80% gram positive), HSV, Fungi (Candida, Asergillus)
    2. Middle (day 31-120): Nocardia, CMV, Candida, Aspergillus, Pneumocystis (PCP), Toxoplasmosis
    3. Late (day 120+): S. pneumoniae, H. influenzae, Varicella Zoster (VZV), PCP, Toxoplasmosis
    4. Late infections occur in ~25% of patients after PBSC [28]
    5. Cell-wall-deficient bacteria (mainly staphylococcus or baccilus) cause a substantial portion of "culture-negative" febrile episodes in BMT patients [41]
    6. Intravenous immunoglobulin (IVIg) does not reduce infection or complication risk when used prophylactically in allogeneic transplant [17]
  3. Vaccinations [14,21]
    1. Reimmunization of adults following HSCT is a critical part of infection prevention
    2. Children should complete primary immunizations and titers checked
    3. For adults after HSCT, two doses of each vaccine are currently recommended
    4. Diphtheria-tetanus (or DaPT) should be given (at least two doses)
    5. Pneumococcus and Haemophilus inlfuenza type B
    6. Inactived poliovirus and MMR (measles-mumps-rubella) should be used
    7. Hepatitis B (HBV) vaccine is currently used in about 50% of BMT centers
    8. Influenza vaccinations are also recommended
    9. Heat-inactivated VZV vaccine reduces risk of zoster in transplanted patients [47]
    10. Full immunizations are strongly recommended
    11. Live virus vaccines such as live VZV should be avoided in most cases
    12. Live Measles/Mumps/Rubella can usually be given safely at 24 months
  4. Additional Prophylaxis Against Infection
    1. Bacterial Infections - Quinolone antibiotic (bid) with penicillin 250mg po bid
    2. Fungal Infections
    3. Fluconazole (Diflucan®) 200-400mg po or IV qd [45]
      1. Itraconazole (Sporanox®) 200mg po bid or 200mg IV qd
      2. Posaconazole (Noxafil®) [51] 200mg po tid
      3. Antifungals discontinued after neutrophil recovery or post-transplant day 100
    4. Itraconazole 200mg po bid (or 200mg IV qd) is more effective than fluconazole 400mg po or IV qd through day 100 post-transplant (invasive infections 9% versus 25%) [37]
      1. Posaconazole is superior to fluconazole for preventing invasive aspergillosis and reducing fungal-related deaths in patients with allotransplant and severe GVHD []
    5. Cytomegalovirus (CMV)
    6. Prophylaxis in CMV Ab negative patients
      1. Valganciclovir preferred over ganciclovir
    7. Herpes Simplex Virus (HSV)
    8. Acyclicovir 250mg/m2 IV q8 hours OR
      1. Valacyclovir
    9. Pneumocystis (PCP) and/or Toxoplasmosis
    10. TMP/SMX (Bactrim®) DS po 3X/week
      1. Atovoquone can be used for pneumocystis and/or toxoplasmosis also
    11. Aggressive use of G-CSF (GM-CSF) ± additional growth factors in prolonged neutropenia
  5. IVIg does not reduce infection risk when used prophylactically in allogeneic transplant [17]

J. Prognosis

  1. Short term complications remain a major problem but now cause less mortality
  2. Most patients who survived >5 years were in good health and returned to school or work
  3. Long Term Poor Prognostic Factors
    1. Recurrence of primary disease
    2. Secondary cancer (may be linked to immunosuppression)
    3. Chronic GVHD and its sequellae remain major problems
    4. True recovery to physical and psychological baseline in 3-5 years [5]
  4. Outcome with Cord Blood [2]
    1. One year survival was 63% in 1997 study
    2. GVHD grade II or worse occurred in 50% of HLA mismatches, 10% of matches
    3. CMV negative serologic status was a good predictor of survival and lack of GVHD
    4. Neutrophil recovery occurred in 94% of recipients receiving >37 million cell/kg
  5. Bone Loss [33]
    1. Osteoporotic fractures are a frequent complication
    2. Lack of vitamin D from the liver is a major contributing factor
    3. Glucocorticoids, cyclosporine and bed rest also contribute
    4. The vitamin D receptor has a polymorphism
    5. Commonly, BB, Bb, and bb genotypes are found
    6. Patients with genotypes Bb and BB had a substantially higher bone loss within 3 months of transplantation
    7. From 3-24 months after transplant, all groups gained equal bone mass
  6. Increased risk of avascular necrosis (mainly of hip) likely due to glucocorticoids
  7. Increased risk of Solid Tumors after BMT [19,32]
    1. Overall BMT patients, solid tumor risk versus general population 2.7-3.8 fold increase
    2. For patients with BMT who survived 10 years or more, risk about 8 fold (8X)
    3. Cumulative risk was 2.2-3.5% at 10 years and 6.7-12.8% at 15 years
    4. Major increases in bone (13X), buccal cavity (11X), fibroblastic (8X), brain/CNS (7X)
    5. Also increases in liver (7X), thyroid (6X), and melanoma (5X)
    6. Non-melanoma skin tumors were considerably increased
    7. Higher doses of irradiation were major risk factor for solid tumor development [19]
    8. Increased age and use of cyclosporin for GVHD were risk factors [32]
  8. Insulin resistance and dyslipidemia late after BMT in childhood [38]
  9. Infertily
    1. Common after pelvic radiation or high dose chemotherapy
    2. For men, storage of frozen semen is commonly effective
    3. In vitro fertilization of crytopreserved eggs may be employed
    4. Egg harvest is difficult and time consuming (may delay BMT therapy)
    5. Cryopreserved ovarian cortical strips have been used to restore ovulation after high dose chemotherapy for HD [42]

References

  1. Copelan EA. 2006. NEJM. 354(17):1813 abstract
  2. Cord Blood Banks. 2004. Med Let. 46(1178):21
  3. Le Blanc K, Frassoni F, Ball L, et al. 2008. Lancet. 371(9624):1579 abstract
  4. Eapen M, Rubinstein P, Zhang M, et al. 2007. Lancet. 369(9577):1947 abstract
  5. Syrjala KL, Langer SL, Abrams JR, et al. 2004. JAMA. 291(19):2335 abstract
  6. Ball ED. 2003. Ann Intern Med. 139(11):916 abstract
  7. Laughlin MJ, Barker J, Bambach B, et al. 2001. NEJM. 344(24):1815 abstract
  8. Reiffers J, Cailliott C, Dazey B, et al. 1999. Lancet. 354(9185):1092
  9. Lowsky R, Takahashi T, Liu YP, et al. 2005. NEJM. 353(13):1321 abstract
  10. Laughlin MJ, Eapen M, Rubinstein P, et al. 2004. NEJM. 351(22):2265 abstract
  11. Rocha V, Labopin M, Sanz G, et al. 2004. NEJM. 351(22):2276 abstract
  12. Wulffraat N, van Royen A, Bierings M, et al. 1999. Lancet. 353(9152):550 abstract
  13. Traynor AE, Schroeder J, Rosa RM, et al. 2000. Lancet. 356(9231):701 abstract
  14. Antin JH. 2002. NEJM. 347(1):36 abstract
  15. Korbling M, Katz RL, Khanna A, et al. 2002. NEJM. 346(10):738 abstract
  16. Staba SL, Escolar ML, Poe M, et al. 2004. NEJM. 350(19):1960 abstract
  17. Cordonnier C, Chevret S, Legrand M, et al. 2003. Ann Intern Med. 139(1):8 abstract
  18. Neven B, Valayannopoulos V, Quartier P, et al. 2007. NEJM. 356(26):2700 abstract
  19. Curtis RE, Rowlings PA, Deeg HJ, et al. 1997. NEJM. 336(13):897 abstract
  20. Hartmann O, Le Corroller AG, Blaise D, et al. 1997. Ann Intern Med. 126(8):600 abstract
  21. Henning KJ, White MH, Sepkowitz KA, Armstrong D. 1997. JAMA. 277(14):1148 abstract
  22. Peggs KS, Hunter A, Chopra R, et al. 2005. Lancet. 365(9475):1934 abstract
  23. Essell JH, Schroeder MT, Harman GS, et al. 1998. Ann Intern Med. 128(12):975 abstract
  24. Sasazuki T, Juji T, Morishima Y, et al. 1998. NEJM. 339(17):1177 abstract
  25. Aversa F, Tabiliio A, Velardi A, et al. 1998. NEJM. 339(17):1186 abstract
  26. Blushan V and Collins RH Jr. 2003. JAMA. 290(19):2599
  27. Andre-Schmutz I, Le Deist F, Hacein-Bay-Abina S, et al. 2002. Lancet. 360(9327):130 abstract
  28. Ketterer N, Espinouse D, Chomarat M, et al. 1999. Am J Med. 106(2):191 abstract
  29. Guinan EC, Boussiotis VA, Neuberg D, et al. 1999. NEJM. 340(22):1704 abstract
  30. Socie G, Stone JV, Wingard JR, et al. 1999. NEJM. 341(1):14 abstract
  31. Wagner JE, Thompson JS, Carter SL, Kernan NA. 2005. Lancet. 366(9487):733 abstract
  32. Kolb HJ, Socie G, Duell T, et al. 1999. Ann Intern Med. 131(10):739
  33. Buardiola J, Xiol X, Sallie R, et al. 1999. Ann Intern Med. 131(10):753
  34. Lin MT, Storer B, Martin PJ, et al. 2003. NEJM. 349(23):2201 abstract
  35. Douek DC, Vescio RA, Betts MR, et al. 2000. Lancet. 355(9218):1875
  36. Rocha V, Wagner JE Jr., Sobocinski KA, et al. 2000. NEJM. 342(25):1846 abstract
  37. Winston DJ, Maziarz RT, Chandrasekar PH, et al. 2003. Ann Intern Med. 138(9):705 abstract
  38. Taskinen M, Saarinen UM, Hovi L, Lipsanen-Nyman M. 2000. Lancet. 309(9234):993
  39. Blaise D, Faucher C, Vey N, et al. 2000. Lancet. 356(9138):1325
  40. Bensinger WI, Martin PJ, Storer B, et al. 2001. NEJM. 344(3):175 abstract
  41. Woo PCY, Wong SSY, Lum PNL, et al. 2001. Lancet. 357(9256):675
  42. Radford JA, Lieberman BA, Brison DR, et al. 2001. Lancet. 357(9263):1172 abstract
  43. La Blanc K, Rasmusson I, Sundberg B, et al. 2004. Lancet. 363(9419):1439
  44. Cord Blood Banks. 2001. Med Let. 43(1114):84
  45. MacMillan ML, Goodman JL, DeFor TE, Weisdorf DJ. 2002. Am J Med. 112(5):369 abstract
  46. Biedermann BC, Sahner S, Gregor M, et al. 2002. Lancet. 359(9323):2078 abstract
  47. Hata A, Asanuma H, Rinki M, et al. 2002. NEJM. 347(1):26 abstract
  48. Palifermin. 2005. Med Let. 47(1207):33 abstract
  49. Essell JH, Schroeder MT, Harman GS, et al. 1998. Ann Intern Med. 128(12):975 abstract
  50. Posaconazole. 2006. Med Let. 48(1248):93 abstract
  51. Ullmann AJ, Lipton JH, Vesole DH, et al. 2007. NEJM. 356(4):335 abstract