**2.5.2.1 Fanconi anemia (FA)**

FA is the most common IBMFS and consists of a complex disorder of increased sensitivity to DNA damage characterized by congenital anomalies, progressive BMF, and high risk of MDS, malignant transformation to acute leukemia and solid tumors. Significantly, a large percentage of affected persons (25% to 40%) have no visible anomalies, and FA cannot be excluded without specific testing for mutagen sensitivity. BMF in FA typically presents between the ages of 5 and 10 years, with an actuarial risk of developing bone marrow failure of 50% to 90% by age 40 years (Kutler et al., 2003; Rosenberg, 2008). The median age of patients who develop AML is 14 years (Alter, 2003), and cumulative incidence of hematologic malignancy by age 40 years is 22% to 33% (Kutler et al., 2003; Rosenberg, 2008). Symptomatic transfusion, G-CSF, and androgens can be used to treat cytopenias; however, HSCT is the only current definitive therapy to restore normal hematopoiesis.

Commonly agreed-upon indications for HSCT in these patients include evidence of severe marrow failure as manifested by an ANC less then 1000 x 109/L with or without G-CSF support, or hemoglobin of less than 8 g/dl or platelet count less than 50,000 x 109/L or requirement of blood transfusion on regular basis. HSCT is also indicated for FA patients with evidence of progression to MDS or AML. Patients with FA who have an HLA-identical related donor, early HSCT is now the first-line treatment of choice for BMF, and preferably before transfusion dependence develops, to limit the risk of graft failure.

Preparative regimens for HSCT in FA patients are modified from standard approaches because of the chromosomal instability present in all FA cells, including nonhematopoietic tissues. In vitro studies have shown that FA cells are hypersensitive to DNA cross-linking agents, such as cytoxan (Berger, 1980). In addition, patients with FA are at increased risk of severe GVHD compared with patients with severe AA because of defective DNA repair mechanisms, leading to prolonged tissue damage after targeting by an alloreactive response (Guardiola et al., 2004).

Elaine Gluckman's group at St Louis, Paris investigated the use of reduced-dose cytoxan (20 to 40mg/kg) and reduced-dose thoracoabdominal irradiation or total body irradiation (TBI) (400-450 cGy) and reported a long-term survival of 58.5% after sibling donor transplantation, although with high incidences of aGVHD (55%) and cGVHD (70%). Later series modified the Gluckman regimen with the addition of ATG, resulting in less aGVHD

family donor is not available, most patients are treated with high-dose immunosuppression, using antithymocyte globulin (ATG) plus cyclosporine, with or without granulocyte colonystimulating factor (G-CSF). Approximately 70-80% of patients respond to immunosuppression, although the actuarial 10-year survival rate is about 40%. Marrow transplantation from unrelated donors is reserved for those patients who do not respond to

IBMFS should be considered for all patients presenting with AA, regardless of the presence or absence of characteristic physical findings. IBMFS require specific approaches to management. Sensitive and specific diagnostic tests, including identification of mutations in

FA is the most common IBMFS and consists of a complex disorder of increased sensitivity to DNA damage characterized by congenital anomalies, progressive BMF, and high risk of MDS, malignant transformation to acute leukemia and solid tumors. Significantly, a large percentage of affected persons (25% to 40%) have no visible anomalies, and FA cannot be excluded without specific testing for mutagen sensitivity. BMF in FA typically presents between the ages of 5 and 10 years, with an actuarial risk of developing bone marrow failure of 50% to 90% by age 40 years (Kutler et al., 2003; Rosenberg, 2008). The median age of patients who develop AML is 14 years (Alter, 2003), and cumulative incidence of hematologic malignancy by age 40 years is 22% to 33% (Kutler et al., 2003; Rosenberg, 2008). Symptomatic transfusion, G-CSF, and androgens can be used to treat cytopenias; however,

Commonly agreed-upon indications for HSCT in these patients include evidence of severe marrow failure as manifested by an ANC less then 1000 x 109/L with or without G-CSF support, or hemoglobin of less than 8 g/dl or platelet count less than 50,000 x 109/L or requirement of blood transfusion on regular basis. HSCT is also indicated for FA patients with evidence of progression to MDS or AML. Patients with FA who have an HLA-identical related donor, early HSCT is now the first-line treatment of choice for BMF, and preferably

Preparative regimens for HSCT in FA patients are modified from standard approaches because of the chromosomal instability present in all FA cells, including nonhematopoietic tissues. In vitro studies have shown that FA cells are hypersensitive to DNA cross-linking agents, such as cytoxan (Berger, 1980). In addition, patients with FA are at increased risk of severe GVHD compared with patients with severe AA because of defective DNA repair mechanisms, leading to prolonged tissue damage after targeting by an alloreactive response

Elaine Gluckman's group at St Louis, Paris investigated the use of reduced-dose cytoxan (20 to 40mg/kg) and reduced-dose thoracoabdominal irradiation or total body irradiation (TBI) (400-450 cGy) and reported a long-term survival of 58.5% after sibling donor transplantation, although with high incidences of aGVHD (55%) and cGVHD (70%). Later series modified the Gluckman regimen with the addition of ATG, resulting in less aGVHD

HSCT is the only current definitive therapy to restore normal hematopoiesis.

before transfusion dependence develops, to limit the risk of graft failure.

or who relapse after immunosuppressive therapy.

specific genes, are available for many disorders.

**2.5.2.1 Fanconi anemia (FA)** 

(Guardiola et al., 2004).

**2.5.2 Inherited bone marrow failure syndromes (IBMFS)** 

and cGVHD and improved survival (Ayas et al., 2001). A recent series of 35 FA patients undergoing matched-related HSCT using this regimen along with peri transplantation ATG reported an excellent 10-year actuarial survival of 89%, with aGVHD in 23% of cases and cGVHD in 12% of cases (Farzin et al., 2007).

These studies have used low dose radiation because patients with FA have an increased risk of posttransplantation malignancy, but what about avoiding radiation altogether? A recent retrospective review of experience with matched related HSCT in FA patients in Saudi Arabia by Ayas et al (Ayas et al., 2008) found significantly greater OS in patients receiving non radiation, low dose cytoxan and ATG regimens compared with those undergoing preparative regimens with cytoxan and additional thoracoabdominal radiation (72.5% vs 96.9%; p=0.013). The availability of fludarabine, a highly immunosuppressive nucleoside analog that is well tolerated by patients with FA, has allowed the elimination of radiation with good results. Tan et al in 2006, recently reported an actual OS of 82%, transplant related mortality of 9% and minimal GVHD in a cohort of 11 patients who underwent transplantation with low dose cytoxan, fludarabine and ATG with T cell-depleted bone marrow or umbilical cord cells.

HSCT from an unrelated donor for patients with FA remains a key treatment strategy. Historically, outcomes of alternative donor transplantation in FA have been discouraging, with high incidences of graft failure, aGVHD and cGVHD and organ toxicity related to preparative regimens. Many regimens have been looked at over the years for unrelated transplants including increasing the dose of radiation, adding ATG without significant improvement in overall survival. The advent of fludarabine based preparative regimens has resulted in considerable progress, improving engraftment without significant toxicity attributable to the drug. However, although fludarabine regimens have had some success in treating FA, concerns regarding reduced intensity conditioning (RIC) regimens persist; residual FA cells that survive the preparative regimen may present as AML as much as 10 years later (Ayas et al., 2001).Despite these data, (Chaudhury et al., 2008), in a study of 18 high-risk patients with transfusion dependent AA, MDS and AML receiving either related mismatched or unrelated matched or mismatched HSCT using fludarabine, TBI and cytoxan for preparative regimens with T-cell depleted stem cell sources, found 100% engraftment, OS 72.2% and DFS of 66.6% with a median follow up of 4.2 years, suggesting that a RIC preparative regimen might be sufficient to control malignancy in FA. Cord blood is an alternative stem cells source for patients with FA who lack an HLA-matched unrelated bone marrow donor, as umbilical cord blood transplant has decreased incidence of GVHD.

Despite the improved survival, identifying the ideal time for HSCT in FA patients requiring alternative donor transplantations remains challenging, given the still-significant peri transplantation mortality and the possibility of long lasting androgen response or survival with AA for a significant period without progression to MDS/AML. Referral and transplantation before exposure to large amounts of blood products or prolonged periods of severe neutropenia are likely to lead to the best outcomes.

#### **2.5.2.2 Shwachman-diamond syndrome (SDS)**

SDS is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, skeletal abnormalities and BMF with a predisposition to MDS and leukemia, especially AML. Although most patients with SDS have some hematologic abnormalities,

Hematopoietic Stem Cells Therapeutic Applications 361

A series of 36 patients from the DBA registry who underwent HSCT (main indication transfusion dependence) yielded 5-year survival rates of 72.7% in matched sibling donor recipients and 19% in alternative donor recipients (p=0.01) (Lipton et al., 2006). Similar results were reported in an international bone marrow transplant registry series of 61 patients with DBA undergoing HSCT with conventional cytoxan containing preparative regimens; 3-year survival was 76% after sibling donor transplantation compared with 39% after alternative donor transplantation (Roy et al., 2005)**.** In both studies, the alternative donor recipients were more likely to have received a TBI-containing regimen or to have a longer time from diagnosis to transplantation, suggesting that TBI should be avoided. In addition, patients with DBA have an increased risk of malignancy compared to the general population, another reason why TBI-containing regimens should be avoided in this population. There also are encouraging case reports of successful HSCT in DBA with RIC fludarabine containing preparative regimens; however, the data are scanty and reflect short

follow-up times; further study is needed in this area (Berndt, 2004; Ostronoff, 2004).

CAMT is a rare autosomal recessive disorder caused by mutations in the thrombopoietin receptor. It is usually diagnosed early in childhood, presenting with isolated nonimmune thrombocytopenia with decreased marrow megakaryocytes. Approximately 50% of CAMT

Although transient responses to steroids, cyclosporine and growth factors in CAMT have been documented, HSCT remains the only curative treatment. Good short-term survival has been reported after matched related donor HSCT in small case series. Reports of unrelated donor HSCT are largely case reports and describe significant engraftment challenges.

Primary cellular immunodeficiencies are a group of inherited disorders characterized by severe impairment of the innate or adaptive immune systems, which generally leads to early death from infectious complications. These disorders can be further categorized by the cell lineage primarily affected (table 6). Supportive care can extend the life span of patients affected by these diseases, definitive cure is generally only achieved by allogeneic hematopoietic stem cell transplantation, though recent advances in gene therapy hold significant promise that this may soon be a viable alternative. Allogeneic HSCT is indicated for severe primary immunodeficiencies from both HLA-identical and

**2.5.2.5 Congenital Amegakaryocytic Thrombocytopenia (CAMT)** 

patients develop marrow aplasia, and some develop MDS or leukemia.

Table 6. Primary Immunodeficiencies Potentially Treated with HSCT.

**2.6 Immunodeficiencies** 

alternative donors.

most of them do not require HSCT. In the largest reported series, 20% of cases developed pancytopenia and 6% progressed to MDS (Ginzberg et al., 1999).

HSCT is the only curative treatment for bone marrow dysfunction associated with SDS. However, the timing of HSCT remains a subject of controversy, and the apparent lack of genotype-phenotype correlation makes selection of patients for early preemptive HSCT difficult at present. In addition, SDS patients, like FA patients, have increased toxicity with intensive conditioning regimens. Overall, the available literature on HSCT in SDS patients is limited and consists mainly of case reports (Cesaro et al., 2001; Fleitz et al., 2002). Preliminary data indicates that HSCT with reduced intensity conditioning is feasible in patients with SDS and is associated with excellent donor cell engraftment and modest morbidity.

### **2.5.2.3 Dyskeratosis congenita (DS)**

DC is a disorder of diverse inheritance with chromosomal instability related to a defect in telomere maintenance, characterized by a triad of reticulate skin pigmentation, mucosal leukoplakia and nail dystrophy, along with BMF. Between 80% and 90% of persons with DC will develop hematopoietic abnormalities by age 30 years, and BMF is the leading cause of early mortality in this population (Dokal, 2000). In addition, DC patients are at increased risk for MDS/AML and solid tumors, especially squamous cell carcinomas, as well as progressive pulmonary fibrosis (Dokal, 2000).

Allogeneic HSCT remains the only curative approach for marrow failure in patients with DC; however outcomes have been poor due to early and late complications. Initial attempts at HSCT in DC patients with myeloablative regimens had poor results, with significant morbidity and mortality, including increased incidences of chronic pulmonary and vascular complications, likely related to these patients underlying tendency to develop restrictive pulmonary disease. Non-myeloablative transplants using low-dose Cytoxan and fludarabine and ATG have produced successful engraftment and good short term outcomes, largely in case reports (de laFuente, 2007)**.** Regardless of the potential reduction in toxicity associated with non-myeloablative regimens, preexisting conditions characteristic of DC (e.g. pulmonary disease) may ultimately limit the effectiveness of HSCT in DC patients.

#### **2.5.2.4 Diamond-blackfan anemia (DBA)**

DBA is a rare inherited form of pure red blood cell aplasia that presents early in infancy. Mutations in one of a number of ribosomal proteins have been identified in approximately 50% of DBA patients, implicating ribosomal biogenesis or function in the disorder. Clinically, DBA is associated with macrocytosis, reticulocytopenia, and normal marrow cellularity with erythroblastopenia. Characteristically, these patients have elevated fetal hemoglobin and erythrocyte adenosine deaminase activity, and up to 35% have an associated congenital anomaly, with craniofacial and thumb abnormalities the most common.

Corticosteroids remain the mainstay of initial therapy in DBA, with 80% response rate. Only 20% of patients achieve remission; 40% require continued therapy with steroids, which can have significant side effects, and another 40% remain transfusion and chelation dependent (Vlachos et al., 2008)**.** Steroid-intolerant or transfusion-dependent patients may be considered for HSCT, which although curative for DBA, remains controversial, because most of these patients can achieve long-term survival with supportive therapy alone.

most of them do not require HSCT. In the largest reported series, 20% of cases developed

HSCT is the only curative treatment for bone marrow dysfunction associated with SDS. However, the timing of HSCT remains a subject of controversy, and the apparent lack of genotype-phenotype correlation makes selection of patients for early preemptive HSCT difficult at present. In addition, SDS patients, like FA patients, have increased toxicity with intensive conditioning regimens. Overall, the available literature on HSCT in SDS patients is limited and consists mainly of case reports (Cesaro et al., 2001; Fleitz et al., 2002). Preliminary data indicates that HSCT with reduced intensity conditioning is feasible in patients with SDS and is associated with excellent donor cell engraftment and modest

DC is a disorder of diverse inheritance with chromosomal instability related to a defect in telomere maintenance, characterized by a triad of reticulate skin pigmentation, mucosal leukoplakia and nail dystrophy, along with BMF. Between 80% and 90% of persons with DC will develop hematopoietic abnormalities by age 30 years, and BMF is the leading cause of early mortality in this population (Dokal, 2000). In addition, DC patients are at increased risk for MDS/AML and solid tumors, especially squamous cell carcinomas, as well as

Allogeneic HSCT remains the only curative approach for marrow failure in patients with DC; however outcomes have been poor due to early and late complications. Initial attempts at HSCT in DC patients with myeloablative regimens had poor results, with significant morbidity and mortality, including increased incidences of chronic pulmonary and vascular complications, likely related to these patients underlying tendency to develop restrictive pulmonary disease. Non-myeloablative transplants using low-dose Cytoxan and fludarabine and ATG have produced successful engraftment and good short term outcomes, largely in case reports (de laFuente, 2007)**.** Regardless of the potential reduction in toxicity associated with non-myeloablative regimens, preexisting conditions characteristic of DC (e.g. pulmonary disease) may ultimately limit the effectiveness of HSCT in DC patients.

DBA is a rare inherited form of pure red blood cell aplasia that presents early in infancy. Mutations in one of a number of ribosomal proteins have been identified in approximately 50% of DBA patients, implicating ribosomal biogenesis or function in the disorder. Clinically, DBA is associated with macrocytosis, reticulocytopenia, and normal marrow cellularity with erythroblastopenia. Characteristically, these patients have elevated fetal hemoglobin and erythrocyte adenosine deaminase activity, and up to 35% have an associated congenital

Corticosteroids remain the mainstay of initial therapy in DBA, with 80% response rate. Only 20% of patients achieve remission; 40% require continued therapy with steroids, which can have significant side effects, and another 40% remain transfusion and chelation dependent (Vlachos et al., 2008)**.** Steroid-intolerant or transfusion-dependent patients may be considered for HSCT, which although curative for DBA, remains controversial, because

most of these patients can achieve long-term survival with supportive therapy alone.

anomaly, with craniofacial and thumb abnormalities the most common.

pancytopenia and 6% progressed to MDS (Ginzberg et al., 1999).

morbidity.

**2.5.2.3 Dyskeratosis congenita (DS)** 

progressive pulmonary fibrosis (Dokal, 2000).

**2.5.2.4 Diamond-blackfan anemia (DBA)** 

A series of 36 patients from the DBA registry who underwent HSCT (main indication transfusion dependence) yielded 5-year survival rates of 72.7% in matched sibling donor recipients and 19% in alternative donor recipients (p=0.01) (Lipton et al., 2006). Similar results were reported in an international bone marrow transplant registry series of 61 patients with DBA undergoing HSCT with conventional cytoxan containing preparative regimens; 3-year survival was 76% after sibling donor transplantation compared with 39% after alternative donor transplantation (Roy et al., 2005)**.** In both studies, the alternative donor recipients were more likely to have received a TBI-containing regimen or to have a longer time from diagnosis to transplantation, suggesting that TBI should be avoided. In addition, patients with DBA have an increased risk of malignancy compared to the general population, another reason why TBI-containing regimens should be avoided in this population. There also are encouraging case reports of successful HSCT in DBA with RIC fludarabine containing preparative regimens; however, the data are scanty and reflect short follow-up times; further study is needed in this area (Berndt, 2004; Ostronoff, 2004).

#### **2.5.2.5 Congenital Amegakaryocytic Thrombocytopenia (CAMT)**

CAMT is a rare autosomal recessive disorder caused by mutations in the thrombopoietin receptor. It is usually diagnosed early in childhood, presenting with isolated nonimmune thrombocytopenia with decreased marrow megakaryocytes. Approximately 50% of CAMT patients develop marrow aplasia, and some develop MDS or leukemia.

Although transient responses to steroids, cyclosporine and growth factors in CAMT have been documented, HSCT remains the only curative treatment. Good short-term survival has been reported after matched related donor HSCT in small case series. Reports of unrelated donor HSCT are largely case reports and describe significant engraftment challenges.

#### **2.6 Immunodeficiencies**

Primary cellular immunodeficiencies are a group of inherited disorders characterized by severe impairment of the innate or adaptive immune systems, which generally leads to early death from infectious complications. These disorders can be further categorized by the cell lineage primarily affected (table 6). Supportive care can extend the life span of patients affected by these diseases, definitive cure is generally only achieved by allogeneic hematopoietic stem cell transplantation, though recent advances in gene therapy hold significant promise that this may soon be a viable alternative. Allogeneic HSCT is indicated for severe primary immunodeficiencies from both HLA-identical and alternative donors.


Table 6. Primary Immunodeficiencies Potentially Treated with HSCT.

Hematopoietic Stem Cells Therapeutic Applications 363

decade of life. The only curative strategy is allogeneic HSCT. The international bone marrow registry and national marrow donor program demonstrated in 170 patients that while the 5 year OS of patients transplanted from HLA-identical siblings was 87%, the results for unrelated HSCT were significantly related to the age at transplant (Filipovich et al., 2001). Unrelated donors less than 5 years of age had an 85% 5-year OS, while all 15 patients greater than 5 years of age died (Filipovich et al., 2001)**.** Haploidentical related transplants have

Table 8. Survival Following HSCT For SCID Based on Stem Cell Source and Conditioning

Familial HLH is characterized by episodes of fever, hepatosplenomegaly and cytopenias. An autosomal recessive defect in one of the several genes including those encoding perforin or Munc 13, causes reduced NK and T cell cytotoxicity. This leads to a widespread accumulation of lymphocytes and mature macrophages with hypercytokinemia. Familial HLH is invariably fatal. The only curative strategy for treatment of familial HLH is allogeneic HSCT. A report from a multicenter prospective trial, HLH-94, demonstrated a 62% 3-year EFS in 65 children undergoing allogeneic HSCT with a variety of stem cell

CGD is characterized by recurrent pyogenic infections in patients with normal neutrophil numbers. A defect in one of the four genes encoding subunits of the nicotinamide adenine dinucleotide phosphate-oxidase complex leads to insufficient production of free protons from which to make hydrogen peroxide. With good supportive care, including therapy with interferon gamma, affected individuals can live up to the fourth decade of life, but suffer

Allogeneic HSCT is the only curative strategy. A report from the European group for Blood and Marrow Transplantation demonstrated in 23 patients that myeloablative conditioning prior to matched sibling HSCT can be safely performed (85%OS), especially if the patient were free of infection at the time of HSCT (100% OS) (Seger et al., 2002). Given the current success rates, some favor transplantation in all patients with CGD who have an appropriate

Recent data, (Kuhn's et al., 2010) showed that patients with very low superoxide production had worse long-term survival than those with higher levels of NADPH oxidase activity

**2.6.3 Familial hemophagocytic lymphohistiocytosis (HLH)** 

been less successful with an OS of 45-52%.

Regimen.

sources (Henter et al., 2002)**.** 

donor at the earliest opportunity.

**2.6.4 Chronic granulomatous disease (CGD)** 

early mortality from recurrent pulmonary infections.

#### **2.6.1 Severe combined immunodeficiency (SCID)**

SCID is a rare disorder caused by a group of genetic disorders with a shared phenotype of deficient T and B lymphocyte infunction (with or without abnormal natural killer (NK) cell development) that leads to early death from recurrent infections in affected children **(**table 7). Except for those patients with SCID due to deficiency of adenosine deaminase (ADA), for which replacement enzyme exists, the only curative therapy for SCIS is allogeneic HSCT. However, early results with gene insertion into autologous hematopoietic stem cells for children with x-linked SCID and ADA deficiency (Cavazzana-Calco, 2007) suggest that eventually this will become a more common form of curative treatment for many primary immunodeficiency diseases.


Table 7. Genetic Sub-Types of Severe Combined Immunodeficiency.

HSCT should be done as soon as the diagnosis is confirmed because these patients are at risk of developing a life-threatening infection, particularly pulmonary infections. For all stem cell sources, successful outcomes are more likely to be achieved when the patient is still very young, preferably less than 6 months of age.( Buckley et al., 1999)**,** demonstrated that infants transplanted less than 3.5 months of age had a 95% overall survival compared to only 76% overall survival in older children. The preferred choice of stem cell donor for a patient with SCID is an HLA-identical sibling, in which the overall survival now exceeds 90%, if the transplant is performed promptly. In patients without a matched sibling, the choice is whether to use an immediately available T cell depleted haplocompatible family member or to perform a search for an HLA matched unrelated donor or cord blood unit. Table 8 lists the reports on transplantation with different stem cell sources.

#### **2.6.2 Wiskott-Aldrich syndrome (WAS)**

WAS is characterized by a trial of thrombocytopenia with small platelets, eczema and recurrent infections. The T cell immunodeficiency predisposes to the development of autoimmune phenomena and lymphoma. Affected males rarely survive past the second

SCID is a rare disorder caused by a group of genetic disorders with a shared phenotype of deficient T and B lymphocyte infunction (with or without abnormal natural killer (NK) cell development) that leads to early death from recurrent infections in affected children **(**table 7). Except for those patients with SCID due to deficiency of adenosine deaminase (ADA), for which replacement enzyme exists, the only curative therapy for SCIS is allogeneic HSCT. However, early results with gene insertion into autologous hematopoietic stem cells for children with x-linked SCID and ADA deficiency (Cavazzana-Calco, 2007) suggest that eventually this will become a more common form of

**2.6.1 Severe combined immunodeficiency (SCID)** 

curative treatment for many primary immunodeficiency diseases.

Table 7. Genetic Sub-Types of Severe Combined Immunodeficiency.

Table 8 lists the reports on transplantation with different stem cell sources.

**2.6.2 Wiskott-Aldrich syndrome (WAS)** 

HSCT should be done as soon as the diagnosis is confirmed because these patients are at risk of developing a life-threatening infection, particularly pulmonary infections. For all stem cell sources, successful outcomes are more likely to be achieved when the patient is still very young, preferably less than 6 months of age.( Buckley et al., 1999)**,** demonstrated that infants transplanted less than 3.5 months of age had a 95% overall survival compared to only 76% overall survival in older children. The preferred choice of stem cell donor for a patient with SCID is an HLA-identical sibling, in which the overall survival now exceeds 90%, if the transplant is performed promptly. In patients without a matched sibling, the choice is whether to use an immediately available T cell depleted haplocompatible family member or to perform a search for an HLA matched unrelated donor or cord blood unit.

WAS is characterized by a trial of thrombocytopenia with small platelets, eczema and recurrent infections. The T cell immunodeficiency predisposes to the development of autoimmune phenomena and lymphoma. Affected males rarely survive past the second decade of life. The only curative strategy is allogeneic HSCT. The international bone marrow registry and national marrow donor program demonstrated in 170 patients that while the 5 year OS of patients transplanted from HLA-identical siblings was 87%, the results for unrelated HSCT were significantly related to the age at transplant (Filipovich et al., 2001). Unrelated donors less than 5 years of age had an 85% 5-year OS, while all 15 patients greater than 5 years of age died (Filipovich et al., 2001)**.** Haploidentical related transplants have been less successful with an OS of 45-52%.


Table 8. Survival Following HSCT For SCID Based on Stem Cell Source and Conditioning Regimen.

#### **2.6.3 Familial hemophagocytic lymphohistiocytosis (HLH)**

Familial HLH is characterized by episodes of fever, hepatosplenomegaly and cytopenias. An autosomal recessive defect in one of the several genes including those encoding perforin or Munc 13, causes reduced NK and T cell cytotoxicity. This leads to a widespread accumulation of lymphocytes and mature macrophages with hypercytokinemia. Familial HLH is invariably fatal. The only curative strategy for treatment of familial HLH is allogeneic HSCT. A report from a multicenter prospective trial, HLH-94, demonstrated a 62% 3-year EFS in 65 children undergoing allogeneic HSCT with a variety of stem cell sources (Henter et al., 2002)**.** 

#### **2.6.4 Chronic granulomatous disease (CGD)**

CGD is characterized by recurrent pyogenic infections in patients with normal neutrophil numbers. A defect in one of the four genes encoding subunits of the nicotinamide adenine dinucleotide phosphate-oxidase complex leads to insufficient production of free protons from which to make hydrogen peroxide. With good supportive care, including therapy with interferon gamma, affected individuals can live up to the fourth decade of life, but suffer early mortality from recurrent pulmonary infections.

Allogeneic HSCT is the only curative strategy. A report from the European group for Blood and Marrow Transplantation demonstrated in 23 patients that myeloablative conditioning prior to matched sibling HSCT can be safely performed (85%OS), especially if the patient were free of infection at the time of HSCT (100% OS) (Seger et al., 2002). Given the current success rates, some favor transplantation in all patients with CGD who have an appropriate donor at the earliest opportunity.

Recent data, (Kuhn's et al., 2010) showed that patients with very low superoxide production had worse long-term survival than those with higher levels of NADPH oxidase activity

Hematopoietic Stem Cells Therapeutic Applications 365

psychomotor retardation, severe skeletal malformations, life-threatening cardiopulmonary

Data from the CIBMTR and EBMT indicate that more than 500 allogeneic HSCTs have been performed worldwide for children with MPS IH since 1980, making it the most commonly transplanted IMD. HSCT is effective, resulting in increased life expectancy and improvement of clinical parameters if performed early in the disease course before the onset of irreversible damage. Donor engraftment after HSCT has resulted in improvement of the following clinical symptoms: rapid reduction of obstructive airway symptoms, and hepatomegaly; improvement in cardiovascular function as well as hearing, vision and linear growth; finally hydrocephalus is either prevented or stabilized. In addition, cerebral damage already present before HSCT seems to be irreversible, but HSCT is able to prevent progressive psychomotor deterioration and improve cognitive function (Peters, 1998;

complications, and early death.

Table 9. IMD for which HSCT may be indicated

Vellodi et al., 1997).

suggesting that these patients should be considered appropriate candidates for early HSCT, particularly if a sibling matched donor is available. An increased alkaline phosphatase level, a history of liver abscesses, and a decrease in platelet count reflecting portal hypertension are adverse prognostic indicators (Feld et al., 2008)**.** These patients might also be considered for early transplantation. Even with improved survival and longevity caused by better infection and inflammation management, complications and their consequences can accumulate over time. However, HSCT is probably better before infections and inflammatory damage accumulates. Transplantation has aloes reversed some of the inflammatory and autoimmune complications associated with CGD and might prevent their development (Seger et al., 2002)**.** Allogeneic HSCT has improved dramatically over the last decade because of improved conditioning regimens and GVHD prophylaxis, highresolution sequence-based matching and improved pre transplantation, peri transplantation and post transplantation management and as a result it has become a successful and sensible option for many patients with CGD.

#### **2.7 Inherited metabolic diseases (IMD)**

IMD is a diverse group of diseases arising from genetic defects in lysosomal enzymes or peroxisomal function. The lysosome is an intracellular sorting, recycling and digestion of organic molecules. Loss of functional activity of lysosomal enzymes results in accumulation of substrates, such as glycoprotein or mucopolysaccharides (MPS). The clinical manifestations vary depending on the specific enzymatic deficiency, level of residual activity, and site of substrate accumulation.

Allogeneic HSCT can prolong life and improve its quality in patients with IMD. HSCT offers a permanent source of enzyme replacement therapy and also might mediate nonhematopoietic cell regeneration or repair. The likely processes responsible for the effectiveness of HSCT for IMD includes cytoreduction to ablate myeloid and immune elements, engraftment of donor-derived hematopoietic and immune system, donor leukocytes production of enzyme, distribution of enzyme through blood circulation, migration of cells to brain, cross blood-brain barrier, many develop microglia, replacement of enzyme in the brain by cross-correction and nonhematopoietic cell engraftment (Prasad and Kurtzberg, 2008).HSCT has been performed in almost 20 of the 40 known lysosomal storage disorders and peroxisomal storage disorders. However, the majority of transplant experience to date is in patients with MPS I (Hurler Syndrome), other MPS syndromes (MPSII, MPSIII, A & B, MPSVI), adrenal leukodystrophy (ALD), metachromic leukodystrophy (MLD), and globoid leukodystrophy (Krabbe disease), accounting for more than 80% of the cases. Table 9 identifies the IMD for which allogeneic HSCT is currently indicated or under investigation. The response to HSCT varies from disease to disease, within patients with same disease, and within different organ systems in the same patient.

#### **2.7.1 Hurler syndrome (MPS IH)**

MPS IH, the most sever phenotype of alpha-l-iduronidase deficiency, is an autosomal recessive disorder characterized by progressive accumulation of stored glycosaminoglycans (GAGs). Hurler and other phenotypes of MPS I are a broad continuous clinical spectrum. Accumulation of GAGs results in progressive, multisystem dysfunction that includes

suggesting that these patients should be considered appropriate candidates for early HSCT, particularly if a sibling matched donor is available. An increased alkaline phosphatase level, a history of liver abscesses, and a decrease in platelet count reflecting portal hypertension are adverse prognostic indicators (Feld et al., 2008)**.** These patients might also be considered for early transplantation. Even with improved survival and longevity caused by better infection and inflammation management, complications and their consequences can accumulate over time. However, HSCT is probably better before infections and inflammatory damage accumulates. Transplantation has aloes reversed some of the inflammatory and autoimmune complications associated with CGD and might prevent their development (Seger et al., 2002)**.** Allogeneic HSCT has improved dramatically over the last decade because of improved conditioning regimens and GVHD prophylaxis, highresolution sequence-based matching and improved pre transplantation, peri transplantation and post transplantation management and as a result it has become a successful and

IMD is a diverse group of diseases arising from genetic defects in lysosomal enzymes or peroxisomal function. The lysosome is an intracellular sorting, recycling and digestion of organic molecules. Loss of functional activity of lysosomal enzymes results in accumulation of substrates, such as glycoprotein or mucopolysaccharides (MPS). The clinical manifestations vary depending on the specific enzymatic deficiency, level of residual

Allogeneic HSCT can prolong life and improve its quality in patients with IMD. HSCT offers a permanent source of enzyme replacement therapy and also might mediate nonhematopoietic cell regeneration or repair. The likely processes responsible for the effectiveness of HSCT for IMD includes cytoreduction to ablate myeloid and immune elements, engraftment of donor-derived hematopoietic and immune system, donor leukocytes production of enzyme, distribution of enzyme through blood circulation, migration of cells to brain, cross blood-brain barrier, many develop microglia, replacement of enzyme in the brain by cross-correction and nonhematopoietic cell engraftment (Prasad and Kurtzberg, 2008).HSCT has been performed in almost 20 of the 40 known lysosomal storage disorders and peroxisomal storage disorders. However, the majority of transplant experience to date is in patients with MPS I (Hurler Syndrome), other MPS syndromes (MPSII, MPSIII, A & B, MPSVI), adrenal leukodystrophy (ALD), metachromic leukodystrophy (MLD), and globoid leukodystrophy (Krabbe disease), accounting for more than 80% of the cases. Table 9 identifies the IMD for which allogeneic HSCT is currently indicated or under investigation. The response to HSCT varies from disease to disease, within patients with same disease, and within different organ systems in the same patient.

MPS IH, the most sever phenotype of alpha-l-iduronidase deficiency, is an autosomal recessive disorder characterized by progressive accumulation of stored glycosaminoglycans (GAGs). Hurler and other phenotypes of MPS I are a broad continuous clinical spectrum. Accumulation of GAGs results in progressive, multisystem dysfunction that includes

sensible option for many patients with CGD.

**2.7 Inherited metabolic diseases (IMD)** 

activity, and site of substrate accumulation.

**2.7.1 Hurler syndrome (MPS IH)** 

psychomotor retardation, severe skeletal malformations, life-threatening cardiopulmonary complications, and early death.


#### Table 9. IMD for which HSCT may be indicated

Data from the CIBMTR and EBMT indicate that more than 500 allogeneic HSCTs have been performed worldwide for children with MPS IH since 1980, making it the most commonly transplanted IMD. HSCT is effective, resulting in increased life expectancy and improvement of clinical parameters if performed early in the disease course before the onset of irreversible damage. Donor engraftment after HSCT has resulted in improvement of the following clinical symptoms: rapid reduction of obstructive airway symptoms, and hepatomegaly; improvement in cardiovascular function as well as hearing, vision and linear growth; finally hydrocephalus is either prevented or stabilized. In addition, cerebral damage already present before HSCT seems to be irreversible, but HSCT is able to prevent progressive psychomotor deterioration and improve cognitive function (Peters, 1998; Vellodi et al., 1997).

Hematopoietic Stem Cells Therapeutic Applications 367

(Gungor,1995; Vellodi et al., 1992). On the other hand, the results of HSCT for Maroteaux-Lamy Syndrome (MPS VI) have been promising. MPS VI has multiple clinical phenotypes, but generally patients live into the second to fourth decade. HSCT in 4 patients with MPS VI lead to improvement in cardiopulmonary function, facial features, and quality of life (Herskhovitz et al., 1999). HSCT can be considered a therapeutic option for patients with

X-ALD is a peroxisomal disorder involving defective beta-oxidation of very long chain fatty acids (VLCFA). The affected gene in X-ALD is ABCD1 and the peroxisomal membrane protein for which it codes is ALDP. More than 500 mutations in the gene are described, but there is no relationship between the nature of the mutation and the clinical presentation of illness. X-ALD has a variable clinical presentation. Patients can be asymptomatic or present with adrenal insufficiency and/or non inflammatory axonopathy (AMN) and/or cerebral disease. The clinical course is so variable with some individuals never developing symptoms so therefore, HSCT can not be recommended based on the presence or absence of the genetic mutation. HSCT is indicated only in those patients with clear evidence of early cerebral inflammatory disease as determined by a gadolinium enhanced MRI. (Peters, 2003)**.** Cerebral disease may manifest itself during childhood or adolescence. Approximately 40% of genetically affected boys develop childhood cerebral X-ALD. Many of the remainder develops AMN. Cerebral disease is usually progressive, although clinical stabilization without HSCT can occur. HSCT is not currently indicated for asymptomatic individuals as prophylaxis. In view of the natural history of the disease such a practice would mean that some boys would undergo HSCT ( with its short-term mortality and long-term morbidity risks) who might otherwise have been healthy. Nor is indicated for those individuals with advanced cerebral disease because HSCT does not reverse and may even worsen,

In this disease, judicious timing of the transplant is paramount. Asymptomatic boys should be regularly screened for signs of inflammatory brain disease, a potential donor identified, and HSCT rapidly performed if and when such symptoms appear. The presence of brain MRI abnormalities and the presence or absence of enhancement with gadolinium has been shown to be of prognostic value. A 34-point MRI scoring system specific for X-ALD that was designed by Loes and colleagues (Loes et al., 1994; Loes et al., 2003) is now used worldwide for patient evaluation and treatment decisions. An MRI severity score as low as 1 with gadolinium enhancement in a young boy is highly predictive of subsequent progressive demyelination and is an indication for transplant. However, the identification of an HSCT donor for asymptomatic boys should not await MRI anomalies, but should done immediately after diagnosis to prevent delays if a follow up MRI indicates disease

Review of the literature supports that most boys that have been transplanted from the best available donor have received full intensity chemotherapy-only preparative regimen (Peters, 2004); most unrelated donors have been adult bone marrow donors, but some CB donors have been used (Beam, 2007); donor-derived engraftment rates seem higher than seen in patients transplanted for MPS IH syndrome (86% of 93 evaluable patients at a median follow-up of 11 months; 93% of related donor transplants; 80% of unrelated donor

MPS VI that are intolerant or fail ERT.

**2.7.3 Adrenal leukodystrophy (ALD)** 

established disease.

progression.

A matched normal sibling is the preferred HSCT donor. In the past decade an unrelated cord blood (CB) has been used with increasing frequency in patients without a sibling donor. CB offers several potential advantages compared with bone marrow or peripheral blood for HSCT, including better availability, greater tolerance for HLA mismatches, lower incidence and severity of GVHD and reduced likelihood of transmitting viral infections (Staba et al., 2004; Prasad et al., 2008)**.** The use of CB for children with MPS IH has been associated with high rates of chimerism, engraftment and overall survival (Staba et al., 2004; Prasad et al., 2008)**.** Similar results are noted for CB in other selected IMD (Escolar et al., 2005). As a result of this data, the EBMT developed transplantation guidelines for patients with MPS IH in 2005. These guidelines are widely used today and include a standardized busulfan/cytoxan (BU/CY) conditioning regimen, an enzymatically normal matched sibling bone marrow donor if available, and if not, cord blood as the preferred graft source. A recent EUROCORD- Duke university MPS IH collaborative study showed that early transplant (i.e., within 4.6 months from diagnosis) with CB and BU/Cy conditioning was associated with improved engraftment and overall survival. Furthermore, 94% of engrafted survivors achieved full donor chimerism. (Boelens et al., 2007).

Despite the overall success from HSCT, some disease manifestations persists or can even progress after HSCT, and this includes the musculoskeletal disorders secondary to the IMD that does not resolve and often requires orthopedic surgical intervention. In addition, neurocognitive dysfunction and corneal clouding that developed before HSCT may be irreversible. The outcome of HSCT for children with MPS IH is promising, yet variable from child to child. The variability is presumably caused by factors such as genotype, age and clinical status before HSCT, donor enzyme activity level, donor chimerism (mixed or full) stem cell source (CB, BM,PB) and resultant enzyme activity level in the recipient (Aldenhoven, 2008). An international long-term follow up study involving Europe and North America is underway to evaluate the influence of these various factors. Overall progress has been made. HSCT for children with MPS IH has become a safer procedure, with recent survival rates exceeding 90%.

#### **2.7.2 Other mucopolysaccharidosis syndromes**

Compared with MPS IH, experience with HSCT for treatment of other MPS disorders is limited. Small numbers and lack of detailed functional outcome data hamper the development of specific therapy guidelines. Conceptually, the basis for the effectiveness of HSCT in these children is the same as those with MPS IH. However, the kinetics of cellular migration, differentiation, distribution, and effective enzyme delivery may differ. Also, there is wide clinical variability within and across specific MPS diseases. As with HSCT for other IMD, important factors in the outcome may be timing of transplant, graft source, and the underlying severity of the phenotype in a given child. To date, most of the published experience is in recipients of BMT (Guffon et al., 2009). Recently, survival has been reported in small cohorts undergoing CBT, but their functional outcomes are not yet published.

The role of HSCT in MPS II remains controversial because of lack of convincing evidence of neurocognitive benefit. The status of HSCT for Sanfilippo Syndrome (MPS III) is similar to that of MPS II with inadequate data and inability to make specific recommendations about timing of transplant, graft source, and potential neurological benefit. Eleven long-term survivors of BMT have been reported, but all showed declined in neurocognitive function

A matched normal sibling is the preferred HSCT donor. In the past decade an unrelated cord blood (CB) has been used with increasing frequency in patients without a sibling donor. CB offers several potential advantages compared with bone marrow or peripheral blood for HSCT, including better availability, greater tolerance for HLA mismatches, lower incidence and severity of GVHD and reduced likelihood of transmitting viral infections (Staba et al., 2004; Prasad et al., 2008)**.** The use of CB for children with MPS IH has been associated with high rates of chimerism, engraftment and overall survival (Staba et al., 2004; Prasad et al., 2008)**.** Similar results are noted for CB in other selected IMD (Escolar et al., 2005). As a result of this data, the EBMT developed transplantation guidelines for patients with MPS IH in 2005. These guidelines are widely used today and include a standardized busulfan/cytoxan (BU/CY) conditioning regimen, an enzymatically normal matched sibling bone marrow donor if available, and if not, cord blood as the preferred graft source. A recent EUROCORD- Duke university MPS IH collaborative study showed that early transplant (i.e., within 4.6 months from diagnosis) with CB and BU/Cy conditioning was associated with improved engraftment and overall survival. Furthermore, 94% of engrafted

Despite the overall success from HSCT, some disease manifestations persists or can even progress after HSCT, and this includes the musculoskeletal disorders secondary to the IMD that does not resolve and often requires orthopedic surgical intervention. In addition, neurocognitive dysfunction and corneal clouding that developed before HSCT may be irreversible. The outcome of HSCT for children with MPS IH is promising, yet variable from child to child. The variability is presumably caused by factors such as genotype, age and clinical status before HSCT, donor enzyme activity level, donor chimerism (mixed or full) stem cell source (CB, BM,PB) and resultant enzyme activity level in the recipient (Aldenhoven, 2008). An international long-term follow up study involving Europe and North America is underway to evaluate the influence of these various factors. Overall progress has been made. HSCT for children with MPS IH has become a safer procedure,

Compared with MPS IH, experience with HSCT for treatment of other MPS disorders is limited. Small numbers and lack of detailed functional outcome data hamper the development of specific therapy guidelines. Conceptually, the basis for the effectiveness of HSCT in these children is the same as those with MPS IH. However, the kinetics of cellular migration, differentiation, distribution, and effective enzyme delivery may differ. Also, there is wide clinical variability within and across specific MPS diseases. As with HSCT for other IMD, important factors in the outcome may be timing of transplant, graft source, and the underlying severity of the phenotype in a given child. To date, most of the published experience is in recipients of BMT (Guffon et al., 2009). Recently, survival has been reported in small cohorts undergoing CBT, but their functional outcomes are not yet published.

The role of HSCT in MPS II remains controversial because of lack of convincing evidence of neurocognitive benefit. The status of HSCT for Sanfilippo Syndrome (MPS III) is similar to that of MPS II with inadequate data and inability to make specific recommendations about timing of transplant, graft source, and potential neurological benefit. Eleven long-term survivors of BMT have been reported, but all showed declined in neurocognitive function

survivors achieved full donor chimerism. (Boelens et al., 2007).

with recent survival rates exceeding 90%.

**2.7.2 Other mucopolysaccharidosis syndromes** 

(Gungor,1995; Vellodi et al., 1992). On the other hand, the results of HSCT for Maroteaux-Lamy Syndrome (MPS VI) have been promising. MPS VI has multiple clinical phenotypes, but generally patients live into the second to fourth decade. HSCT in 4 patients with MPS VI lead to improvement in cardiopulmonary function, facial features, and quality of life (Herskhovitz et al., 1999). HSCT can be considered a therapeutic option for patients with MPS VI that are intolerant or fail ERT.

#### **2.7.3 Adrenal leukodystrophy (ALD)**

X-ALD is a peroxisomal disorder involving defective beta-oxidation of very long chain fatty acids (VLCFA). The affected gene in X-ALD is ABCD1 and the peroxisomal membrane protein for which it codes is ALDP. More than 500 mutations in the gene are described, but there is no relationship between the nature of the mutation and the clinical presentation of illness. X-ALD has a variable clinical presentation. Patients can be asymptomatic or present with adrenal insufficiency and/or non inflammatory axonopathy (AMN) and/or cerebral disease. The clinical course is so variable with some individuals never developing symptoms so therefore, HSCT can not be recommended based on the presence or absence of the genetic mutation. HSCT is indicated only in those patients with clear evidence of early cerebral inflammatory disease as determined by a gadolinium enhanced MRI. (Peters, 2003)**.** Cerebral disease may manifest itself during childhood or adolescence. Approximately 40% of genetically affected boys develop childhood cerebral X-ALD. Many of the remainder develops AMN. Cerebral disease is usually progressive, although clinical stabilization without HSCT can occur. HSCT is not currently indicated for asymptomatic individuals as prophylaxis. In view of the natural history of the disease such a practice would mean that some boys would undergo HSCT ( with its short-term mortality and long-term morbidity risks) who might otherwise have been healthy. Nor is indicated for those individuals with advanced cerebral disease because HSCT does not reverse and may even worsen, established disease.

In this disease, judicious timing of the transplant is paramount. Asymptomatic boys should be regularly screened for signs of inflammatory brain disease, a potential donor identified, and HSCT rapidly performed if and when such symptoms appear. The presence of brain MRI abnormalities and the presence or absence of enhancement with gadolinium has been shown to be of prognostic value. A 34-point MRI scoring system specific for X-ALD that was designed by Loes and colleagues (Loes et al., 1994; Loes et al., 2003) is now used worldwide for patient evaluation and treatment decisions. An MRI severity score as low as 1 with gadolinium enhancement in a young boy is highly predictive of subsequent progressive demyelination and is an indication for transplant. However, the identification of an HSCT donor for asymptomatic boys should not await MRI anomalies, but should done immediately after diagnosis to prevent delays if a follow up MRI indicates disease progression.

Review of the literature supports that most boys that have been transplanted from the best available donor have received full intensity chemotherapy-only preparative regimen (Peters, 2004); most unrelated donors have been adult bone marrow donors, but some CB donors have been used (Beam, 2007); donor-derived engraftment rates seem higher than seen in patients transplanted for MPS IH syndrome (86% of 93 evaluable patients at a median follow-up of 11 months; 93% of related donor transplants; 80% of unrelated donor

Hematopoietic Stem Cells Therapeutic Applications 369

difficult to draw firm conclusions regarding the efficacy of HSCT in MLD. In addition, data suggest that outcomes are less promising than those for MPS IH. It is not clear if MLD patients, or which phenotypes, might benefit from HSCT. For presymptomatic juvenile and adult onset patients there is positive evidence. Improved transplantation techniques and the prompt availability of CB grafts may positively influence long-term outcomes. An international registry would facilitate comparative evaluation of therapeutic options, leading to improved guidelines.

HSCT has been explored in a number of malignant and nonmalignant diseases. Currently, research is rapidly expanding in areas not historically considered for HSCT. Also, as morbidity and mortality decrease, HSCT is being reconsidered for many diseases in which HSCT was previously considered and rejected. Several potential indications are reported in

Thalassemias result from mutations of the globin genes that cause reduced or absent hemoglobin production, reducing oxygen delivery. To treat the anemia and restore oxygen delivery to tissues, chronic lifelong transfusions are required in those who have thalassemia major. However, this promotes progressive iron overload and organ damage. The only definitive cure for thalassemia is to correct the genetic defect by HSCT. Transplantation is recommended early, if an allogeneic healthy related sibling donor or a related CB is available. Several studies have suggested that umbilical cord blood transplant (UCBT) recipients benefit from a lower risk of GVHD (Gluckman, 1997; Wagner, 1995) and a recent analysis comparing 113 children who received a UCBT from a compatible sibling with 2052 HLA-identical sibling marrow transplant recipients showed that children receiving UCB experienced a significantly reduced risk of developing aGVHD and cGVHD (Rocha, 2000). Prior to transplant, the patient should be assigned to 1 of 3 Pesaro risk class to assess risk factors for BMT. This classification is based upon clinical features of thalassemia that include: (1) adherence to a program of regular iron chelation therapy, (2) the presence or absence of hepatomegaly and (3) the presence or absence of portal fibrosis observed by liver biopsy. The conditioning regimen is uniform for classes 1 and 2 patients, but is modified for those who have class 3 features due to an increased risk of transplant-related mortality (Lucarelli, 1990). As a result of this risk classification and the development of new conditioning regimens, the outcome of thalassemia patients have improved with thalassemia-free survival and EFS over 70% reported worldwide. When stratifying patients, initially those with Pesaro Class 1 characteristics < 17 years had a superior thalassemia-free survival; however, recent updates show that outcomes are very similar across all three risk categories after employing risk-based conditioning regimens (Bhatia, 2008). Unrelated donor transplants are also used in selected patients (Bhatia, 2008). Following transplant, iron overload may still be a problem;

SCD contrasts with thalassemia major by its variable course of clinical severity. Its typical clinical manifestation include anemia, severe painful crisis, acute chest syndrome, splenic

**3. Expanding Indications for transplant** 

consequently, chelation or phlebotomy may still be necessary.

**3.2 Sickle cell disease (SCD)** 

this section.

**3.1 Beta-thalassemia** 

transplant) (Peters,1998,2004); outcome is affected by disease status, donor source and HLA matching (Peters, 2004). The most common causes of death are progressive cerebral X-ALD disease and GVHD. TRM is 10% in related donors and 18% in unrelated donors. Five-year survival rates for recipients of related donor and unrelated donor transplants have been reported at 64% and 53%, respectively (Peters, 2004); and finally, survival is clearly affected by disease status at time of transplant as assessed by the number of neurologic deficits and MRI severity score. In those with 0 or 1 neurologic deficit and MRI score of less than 9, the 5-year survival was 92% compare to 45% in all other patients (Peters, 2004).
