|MP 8.01.22||Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/9:2014
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HSCTHSCT refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiotherapy. Allogeneic HSCT refers to the use of hematopoietic progenitor cells obtained from a donor. They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Cord blood is discussed in greater detail in Policy No. 7.01.50.
Immunologic compatibility between infused stem cells and the recipient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of HLA using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).
Preparative Conditioning for Allogeneic HSCT
The conventional practice of allogeneic HSCT involves administration of myelotoxic agents (eg, cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow failure. Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity. These regimens partially eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery. Patients who undergo RIC with allogeneic HSCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their intensity, from almost totally myeloablative to minimally myeloablative with lymphoablation.
Genetic Diseases and Acquired Anemias
The thalassemias result from mutations in the globin genes, resulting in reduced or absent hemoglobin production, reducing oxygen delivery. The supportive treatment of -thalassemia major requires life-long red blood cell transfusions that lead to progressive iron overload and the potential for organ damage and impaired cardiac, hepatic, and endocrine function.(3) The only definitive cure for thalassemia is to correct
the genetic defect with allogeneic HSCT.
Sickle cell disease is caused by a single amino acid substitution in the beta chain of hemoglobin and, unlike thalassemia major, has a variable course of clinical severity.(3) Sickle cell disease typically manifests clinically with anemia, severe painful crises, acute chest syndrome, stroke, chronic pulmonary and renal dysfunction, growth retardation, neurologic deficits, and premature death. The mean age of death for patients with sickle cell disease has been demonstrated as 42 years for males and 48 for females. Three major therapeutic options are available: chronic blood transfusions, hydroxyurea, and HSCT, the latter being the only possibility for cure.(3)
Bone Marrow Failure Syndromes
Aplastic anemia in children is rare and is most often idiopathic and less commonly due to a hereditary disorder. Inherited syndromes include Fanconi anemia, a rare, autosomal recessive disease characterized by genomic instability, with congenital abnormalities, chromosome breakage, cancer susceptibility, and progressive bone marrow failure leading to pancytopenia and severe aplastic anemia. Frequently this disease terminates in a myelodysplastic syndrome or acute myelogenous leukemia. Most patients with Fanconi anemia succumb to the complications of severe aplastic anemia, leukemia, or solid tumors, with a median survival of 30 years of age.(4) In Fanconi anemia, HSCT is currently the only treatment that definitively restores normal hematopoiesis. Excellent results have been observed with the use of HLA-matched sibling allogeneic HSCT, with cure of the marrow failure and amelioration of the risk of leukemia.(4)
Dyskeratosis congenita is characterized by marked telomere dysregulation with clinical features of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia.(5) Early mortality is associated with bone marrow failure, infections, pulmonary complications, or malignancy.(5)
Mutations affecting ribosome assembly and function are associated with Shwachman-Diamond syndrome, and Diamond-Blackfan anemia.5 Shwachman-Diamond has clinical features that include pancreatic exocrine insufficiency, skeletal abnormalities, and cytopenias, with some patients developing aplastic anemia. As with other bone marrow failure syndromes, patients are at increased risk of myelodysplastic syndrome and malignant transformation, especially acute myelogenous leukemia. Diamond-Blackfan anemia is characterized by absent or decreased erythroid precursors in the bone marrow, with 30% of patients also having a variety of physical anomalies.(5)
The primary immunodeficiencies are a genetically heterogeneous group of diseases that affect distinct components of the immune system. More than 120 gene defects have been described, causing more than 150 disease phenotypes.(1) The most severe defects (collectively known as severe combined immunodeficiency [SCID]) cause an absence or dysfunction of T lymphocytes and sometimes B lymphocytes and natural killer cells.1 Without treatment, patients with SCID usually die by 12 to 18 months of age. With supportive care, including prophylactic medication, the lifespan of these patients can be prolonged, but long-term outlook is still poor, with many dying from infectious or inflammatory complications or malignancy by early adulthood.(1) Bone marrow transplant is the only definitive cure, and the treatment of choice for SCID and other primary immunodeficiencies, including Wiskott-Aldrich syndrome and congenital defects of neutrophil function.(6)
Inherited Metabolic Diseases
Lysosomal storage disorders consist of many different rare diseases caused by a single gene defect, and most are inherited as an autosomal recessive trait.(7) Lysosomal storage disorders are caused by specific enzyme deficiencies that result in defective lysosomal acid hydrolysis of endogenous macromolecules that subsequently accumulate as a toxic substance. Peroxisomal storage disorders arise due to a defect
in a membrane transporter protein that leads to defects in the metabolism of long-chain fatty acids. Lysosomal storage disorders and peroxisomal storage disorders affect multiple organ systems, including the central and peripheral nervous systems. These disorders are progressive and often fatal in childhood due to both the accumulation of toxic substrate and a deficiency of the product of the enzyme reaction.(7) Hurler syndrome usually leads to premature death by 5 years of age.
Exogenous enzyme replacement therapy is available for a limited number of the inherited metabolic diseases; however, these drugs do not cross the blood-brain barrier, which results in ineffective treatment of the central nervous system. Stem-cell transplantation provides a constant source of enzyme replacement from the engrafted donor cells, which are not impeded by the blood-brain barrier.7 The donor-derived cells can migrate and engraft in many organ systems, giving rise to different types of cells, for example microglial cells in the brain and Kupffer cells in the liver.(7)
Allogeneic HSCT has been primarily used to treat the inherited metabolic diseases that belong to the lysosomal and peroxisomal storage disorders, as listed in the Table.(7) The first stem-cell transplant for an inherited metabolic disease was performed in 1980 in a patient with Hurler syndrome. Since that time, more than 1000 transplants have been performed worldwide.(7)
Table. Lysosomal and Peroxisomal Storage Disorders
Hurler, Scheie, H-S
Niemann-Pick disease C
GSD type II
Multiple enzyme deficiency
Lysosomal transport defects
Peroxisomal storage disorders
Infantile malignant osteopetrosis
Osteopetrosis is a condition caused by defects in osteoclast development and/or function. The osteoclast (the cell that functions in the breakdown and resorption of bone tissue) is known to be part of the hematopoietic family and shares a common progenitor with the macrophage in the bone marrow. (8) Osteopetrosis is a heterogeneous group of heritable disorders, resulting in several different types of variable severity. The most severely affected patients are those with infantile malignant osteopetrosis. Patients with infantile malignant osteopetrosis suffer from dense bone, including a heavy head with frontal bossing, exophthalmus, blindness by approximately 6 months of age, and severe hematologic malfunction with bone marrow failure. (8) Seventy percent of these patients die before the age of 6, often of recurrent infections. (8) HSCT is the only curative therapy for this fatal disease.
Hematopoietic stem-cell transplantation for autoimmune disease, such as rheumatoid arthritis or multiple sclerosis, is considered separately in policy No. 8.01.25.
Allogeneic hematopoietic stem cell transplantation is considered medically necessary for selected patients with the following disorders:
- Sickle cell anemia for children or young adults with either a history of prior stroke or at increased risk of stroke or end-organ damage.
- Homozygous beta-thalassemia (i.e., thalassemia major)
Bone marrow failure syndromes
- Aplastic anemia including hereditary (including Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond, Diamond-Blackfan) or acquired (e.g., secondary to drug or toxin exposure) forms.
- Absent or defective T cell function (e.g., severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome)
- Absent or defective natural killer function (e.g. Chediak-Higashi syndrome)
- Absent or defective neutrophil function (e.g. Kostmann syndrome, chronic granulomatous disease, leukocyte adhesion defect)
(See Policy Guideline # 1.)
Inherited metabolic disease
- Lysosomal and peroxisomal storage disorders except Hunter, Sanfilippo, and Morquio syndromes
(See Policy Guideline # 2)
Genetic disorders affecting skeletal tissue
- Infantile malignant osteopetrosis (Albers-Schonberg disease or marble bone disease)
1. The following lists the immunodeficiencies that have been successfully treated by allogeneic hematopoietic stem-cell transplantation (HSCT) (1):
Adenosine deaminase deficiency
Calcium channel deficiency
CD 40 ligand deficiency
Cernunnos/X-linked lymphoproliferative disease deficiency
CHARGE syndrome with immune deficiency
Common gamma chain deficiency
Deficiencies in CD 45, CD3, CD8
DNA ligase IV
Interleukin-7 receptor alpha deficiency
Janus-associated kinase 3 (JAK3) deficiency
Major histocompatibility class II deficiency
Purine nucleoside phosphorylase deficiency
Recombinase-activating gene (RAG) 1/2 deficiency
Winged helix deficiency
X-linked lymphoproliferative disease
Zeta-chain-associated protein-70 (ZAP-70) deficiency
Chronic granulomatous disease
Griscelli syndrome, type 2
Interferon-gamma receptor deficiencies
Leukocyte adhesion deficiency
Severe congenital neutropenias
Autoimmune lymphoproliferative syndrome
Cartilage hair hypoplasia
Hyper IgD and IgE syndromes
NF-κB inhibitor, alpha (IκB-alpha) deficiency
Nijmegen breakage syndrome
2. In the inherited metabolic disorders, allogeneic HSCT has been proven effective in some cases of Hurler, Maroteaux-Lamy, and Sly syndromes, childhood onset cerebral X-linked adrenoleukodystrophy, globoid-cell leukodystrophy, metachromatic leukodystrophy, alpha-mannosidosis, and aspartylglucosaminuria. Allogeneic HSCT is possibly effective for fucosidosis, Gaucher types 1 and 3, Farber lipogranulomatosis, galactosialidosis, GM1, gangliosidosis, mucolipidosis II (I-cell disease), multiple sulfatase deficiency, Niemann-Pick, neuronal ceroid lipofuscinosis, sialidosis, and Wolman disease. Allogeneic HSCT has not been effective in Hunter, Sanfilippo, or Morquio syndromes. (2)
The experience with reduced-intensity conditioning (RIC) and allogeneic HSCT for the diseases listed in this policy has been limited to small numbers of patients and have yielded mixed results, depending upon the disease category. In general, the results have been most promising in the bone marrow failure syndromes and primary immunodeficiencies. In the hemoglobinopathies, success has been hampered by difficulties with high rates of graft rejection, and in adult patients, severe graft versus host disease (GVHD). Several Phase II/III trials are ongoing examining the role of this type of transplant for these diseases, as outlined in the clinical trial section under each disease type.
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This policy was updated with an electronic search of the NCBI PubMed database from July 15, 2013 through July 31, 2014.
Two 2010 review articles summarize the experience to date with hematopoietic stem-cell transplant (HSCT) and the hemoglobinopathies. (9, 10)
More than 1,600 patients worldwide have been treated for -thalassemia with allogeneic HSCT(3) than Overall survival (OS) rates have ranged from 65% to 100% and thalassemia-free survival up to 73%.3 The Pesaro risk stratification system classifies patients with thalassemia who are to undergo allogeneic HSCT into risk groups I through III on the presence of hepatomegaly, portal fibrosis, or adequacy of chelation (class I having no risk factors, II with 2 risk factors, and III with all 3 risk factors).(11) The outcome of allogeneic HSCT in more than 800 patients with thalassemia according to risk stratification has shown overall and event-free survival (EFS) of 95% and 90% for Pesaro class I, 87% and 84% for class II, and 79% and 58% for class III.(11)
Most of the experience with allogeneic HSCT and sickle cell disease comes from 3 major clinical series. (3) The largest series to date consisted of 87 symptomatic patients, the majority of whom received donor allografts from siblings who are human leukocyte antigen (HLA) identical. The results from this series (12) and the other 2 (13, 14) were similar, with OS rates ranging from 92–94% and event-free survival from 82–86%, with a median follow-up ranging from 0.9–17.9 years. (3)
Experience with reduced-intensity preparative regimens (reduced intensity conditioning [RIC] and allogeneic HSCT for the hemoglobinopathies is limited to a small number of patients. Challenges have been with high rates of graft rejection (10–30%), (9) and, in adult patients, severe graft-versus-host-disease (GVHD) has been observed with the use of RIC regimens. (10)
In a recent report, 30 patients aged 16 to 65 years with severe sickle cell phenotype enrolled in a RIC allogeneic HSCT study, consisting of alemtuzumab (1 mg/kg in divided doses), total body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from HLA- matched siblings.(15) The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. Secondary end points included the level of donor leukocyte chimerism; incidence of acute and chronic GVHD; and sickle cell-thalassemia disease-free survival (DFS), immunologic recovery, and changes in organ function. Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. A total of 38 serious adverse events were reported: pain and related management, infections, abdominal events, and sirolimus-related toxic effects.
Bernardo and colleagues reported the results of 60 thalassemia patients (median age, 7 years; range, 1-37) who underwent allogeneic HSCT after an RIC regimen based on the treosulfan. (16) Before transplant, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, one developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival were 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome.
In a recent report on RIC HSCT, 98 patients with class 3 thalassemia were transplanted with related or unrelated donor stem cells.(17) Seventy-six of the patients age 10 years or younger received a conventional myeloablative conditioning regimen (cyclophosphamide [Cy], busulfan, + fludarabine [Flu]). The remaining 22 patients who were older than 10 years, had hepatomegaly and in several instances additional comorbidity problems, underwent HSCT with a novel RIC regimen (fludarabine and busulfan). EFS (86% vs 90%, respectively), and OS (95% vs 90%, respectively) were not significantly different between the groups. However, a higher incidence of serious treatment-related complications was observed in the myeloablative conditioned group. Further, graft failures occurred in 6 patients in the myeloablated group (8%), but none occurred in the RIC group.
A Cochrane systematic review published in 2013 identified no randomized controlled trials (RCTs) that assessed a risk or benefit of any method of HSCT in patients with sickle cell disease. (18)
Bone marrow failure syndromes
Two 2010 review articles summarize the experience to date with HSCT and the bone marrow failure syndromes. (9, 19)
In a summary of allogeneic HSCT from matched related donors over the past 6 years in Fanconi anemia, totaling 103 patients, overall survival (OS) ranged from 83–88%, with transplant-related mortality ranging from 8–18.5% and average chronic GVHD of 12%. (20)
The outcomes in patients with Fanconi anemia and an unrelated donor allogeneic HSCT have not been as promising. The European Group for Blood and Marrow Transplantation (EBMT) working party has analyzed the outcomes using alternative donors in 67 patients with Fanconi anemia. Median 2-year survival was 28 +/- 8%. (5) Causes of death included infection, hemorrhage, acute and chronic GVHD, and liver veno-occlusive disease. (5) The Center for International Blood and Marrow Transplantation (CIBMTR) analyzed 98 patients transplanted with unrelated donor marrow between 1990 and 2003. Three-year OS rates were 13% and 52%, respectively, in patients who received nonfludarabine- versus fludarabine-based regimens. (5)
Zanis-Neto and colleagues reported the results of 30 patients with Fanconi anemia treated with RIC) regimens, consisting of low-dose cyclophosphamide. (21) Seven patients were treated with cyclophosphamide at 80 mg/kg and 23 with 60 mg/kg. Grade 2-3 acute GVHD rates were 57% and 14% for patients who received the higher and lower doses, respectively (p=0.001). Four of the 7 patients who received the higher dose were alive at a median of 47 months (range: 44-58 months), and 22 of 23 given the lower dose were alive at a median of 16 months (range: 3-52 months). The authors concluded that a lower dose of cyclophosphamide conditioning had lower rates of GVHD and was acceptable for engraftment.
In a retrospective study of 98 unrelated donor transplantations for Fanconi anemia reported to the CIBMTR, Wagner and colleagues reported that fludarabine-containing (reduced-intensity) regimens were associated with improved engraftment, decreased treatment-related mortality, and improved 3-year OS (52% vs. 13%, respectively; p<0.001) compared with nonfludarabine regimens. (22)
Results with allogeneic HSCT in dyskeratosis congenita have been disappointing due to severe late effects, including diffuse vasculitis and lung fibrosis.(5)Currently, nonmyeloablative conditioning regimens with Flu are being explored; however, very few results have been published.(5)
Outcomes after allogeneic HSCT were recently reported in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009.(23) The median age at transplantation was 13 years (range, 2-35). Approximately 50% of transplantations were from related donors. The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic GVHD were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n=6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with Cy-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.
Experience with allogeneic HSCT in Shwachman-Diamond syndrome is limited, as very few patients have undergone allogeneic transplants for this disease.(5) Cesaro et al reported 26 patients with Shwachman-Diamond syndrome from the EBMT registry given HSCT for treatment of severe aplastic anemia (n=16); myelodysplastic syndrome-acute myelogenous leukemia (MDS-AML) (n=9); or another diagnosis (n=1).(24) Various preparative regimens were used; most included either busulfan (54%) or total body irradiation (23%) followed by an HLA-matched sibling (n= 6), mismatched related (n= 1), or unrelated graft (n=19). Graft failure occurred in 5 (19%) patients, and the incidence of grade III to IV acute and chronic GVHD were 24% and 29%, respectively. With a median follow-up of 1.1 years, OS was 65%. Deaths were primarily caused by infections with or without GVHD (n=5) or major organ toxicities (n=3). The analysis suggested that presence of MDS-AML or use of total body irradiation–based conditioning regimens were factors associated with a poorer outcome.
In Diamond-Blackfan anemia, allogeneic HSCT is an option in corticosteroid-resistant disease.(5) In a report from the Diamond-Blackfan anemia registry, 20 of 354 registered patients underwent allogeneic HSCT, and the 5-year survival rates were 87.5% when recipients received HLA-identical sibling grafts but were poor in recipients of alternative donors.(5) The CIBMTR reported the results in 61 patients who underwent HSCT between 1984 and 2000.(25) Sixty-seven percent of patients were transplanted with an HLA-identical sibling donor. Probability of OS after transplantation for patients transplanted from an HLA-identical sibling donor (vs an alternative donor) was 78% versus 45% (p=0.01) at 1 year and 76% versus 39% (p=0.01) at 3 years, respectively.
A randomized phase 3 trial compared 2 different conditioning regimens in high-risk aplastic anemia patients (n=79) who underwent allogeneic HSCT.(26) Patients in the Cy plus anti-thymocyte globulin (ATG) arm (n=39) received Cy at 200 mg/kg; those in the Cy-Flu-ATG group (n=40) received Cy at 100 mg/kg and Flu at 150 mg/m2. No difference in engraftment rates was reported between arms. Infection with an identified causative organism and sinusoidal obstruction syndrome, hematuria, febrile episodes, and death from any cause tended to be more frequent in the Cy-ATG arm but did not differ significantly between arms. OS at 4 years did not differ between the Cy-ATG and Cy-Flu-ATG arms (78% vs 86%, respectively, p=0.41). Although this study was underpowered to detect real differences between the conditioning regimens, the results suggest an RIC regimen with Cy-Flu-ATG appears to be as safe as a more traditional myeloablative regimen comprising Cy-ATG in allogeneic HSCT.
Two 2010 review articles summarize experience to date with HSCT and the primary immunodeficiencies.(27,28) Additional individual studies are reported next.
Outcomes of HSCT in patients with chronic granulomatous disease (CGD) were compared with those in patients with CGD who were given conventional treatment.(29) Forty-one patients in Sweden were diagnosed with CGD between 1990 and 2012. From 1997 to 2012, 14 patients with CGD, aged 1 to 35 years, underwent HSCT and received grafts either from an HLA-matched sibling donor or a matched unrelated donor. Thirteen of the 14 (93%) transplanted patients were reported alive and well at publication. The mean age at transplantation was 10.4 years, and the mean survival time was 7.7 years. In contrast, 7of 13 men or boys with X-linked CGD who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remaining patients suffered life-threatening infections.
A prospective study in 16 centers in ten countries worldwide enrolled patients aged 0 to 40 years with CGD treated with RIC HSCT consisting of high-dose Flu, serotherapy or low-dose alemtuzumab, and low-dose (50% to 72% of myeloablative dose) or targeted busulfan administration.(30) Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary end points were OS and EFS, probabilities of OS and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. A total 56 patients (median age 12.7 years) with chronic granulomatous disease were enrolled; 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). Median time to engraftment was 19 days for neutrophils and 21 days for platelets. At median follow-up of 21 months, OS was 93% (52/56) and EFS was 89% (50/56). The 2-year probability of OS was 96% (95% confidence interval [CI], 86.46 to 99.09) and of EFS was 91% (79.78 to 96.17). Graft-failure occurred in 5% (3/56) of patients. The cumulative incidence of acute GVHD of grade III to IV was 4% (2/56) and of chronic GVHD was 7% (4/56). Stable (>/=90%) myeloid donor chimerism was documented in 52 (93%) surviving patients.
HSCT using HLA-identical sibling donors can correct underlying primary immunodeficiencies, such as severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and other prematurely lethal X- linked immunodeficiencies, in approximately 90% of cases.31 According to a European series of 475 patients collected between 1968 and 1999, survival rates for SCID were approximately 80% with a matched sibling donor, 50% with a haploidentical donor, and 70% with a transplant from an unrelated donor.(31) Since 2000, OS for patients with SCID who have undergone HSCT is 71%.(1)
Hassan et al reported a multicenter retrospective study, which analyzed the outcome of HSCT in 106 patients with adenosine deaminase deficient-SCID who received a total of 119 transplants.32 HSCT from matched sibling and family donors had significantly better OS (86% and 81%) in comparison with HSCT from matched unrelated (66%; p<0.05) and haploidentical donors (43%; p<0.001). Superior OS was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; p<0.003) although in unconditioned haploidentical donor HSCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T cell numbers were similar, although a faster rate of T cell recovery was observed following matched sibling and family donor HSCT. Humoral immunity and donor B cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HSCT.
For Wiskott-Aldrich syndrome, an analysis of 170 patients transplanted between 1968 and 1996 demonstrated the impact of donor type on outcomes.33 Fifty-five transplants were from HLA-identical sibling donors, with a 5-year probability of survival of 87% (95% CI, 74% to 93%); 48 were from other relatives, with a 5-year probability of survival of 52% (37% to 65%); and 67 were from unrelated donors with a 5-year probability of survival of 71% (58% to 80%; p<0.001).
Moratto et al retrospectively reported the long-term outcome and donor-cell engraftment in 194 patients with Wiskott-Aldrich syndrome treated by HSCT in the period 1980 to 2009.(34) OS was 84.0% and was even higher (89.1% 5-year survival) for those who received HSCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HSCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical condition had a lower rate of post-HSCT complications. Retrospective analysis of lineage-specific donor-cell engraftment showed that stable full-donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HSCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte counts and post-HSCT autoimmunity, and myeloid donor cell chimerism below 50% was associated with persistent thrombocytopenia.
For patients with genetic immune/inflammatory disorders, such as hemophagocytic lymphohistiocytosis, the current results with allogeneic HSCT are 60% to 70% 5-year DFS.
For patients with other immunodeficiencies, OS rates are 74%, with even better results (90%) with well-matched donors for defined conditions, such as chronic granulomatous disease.(1)
Studies so far indicate that RIC regimens may have an important role in treating patients with primary immunodeficiency.28 In the absence of prospective or larger registry studies, it is not possible to prove superiority of RIC in more stable patients with primary immunodeficiency; however, RIC does offer the advantage that long-term sequelae, eg, infertility and growth retardation, may be avoided or reduced.
Currently, RIC HSCT using unrelated donors may offer a survival advantage in patients with T cell deficiencies, hemophagocytic lymphohistiocytosis, Wiskott-Aldrich syndrome (>5 years of age), and chronic granulomatous disease with ongoing inflammatory or infective complications. Minimal intensity conditioning HSCT may be particularly suited to unrelated donor HSCT in young SCID patients with significant comorbidities.
X-linked lymphoproliferative disease type 1 (XLP1) is a rare, deadly immune deficiency caused by mutations in SH2D1A. Allogeneic HSCT is often performed because of the morbidity and mortality associated with XLP1. There is limited experience using RIC regimens for these patients. A recent study reported an 8-year single-center experience.(35) Sixteen consecutive patients diagnosed with XLP1 underwent allogeneic HSCT between 2006 and 2013 after an RIC regimen consisting of alemtuzumab, Flu, and melphalan. Fourteen of 16 patients received 8/8 HLA-matched unrelated or related bone marrow grafts, whereas 2 patients received mismatched unrelated grafts. All patients had hematopoietic recovery. No cases of hepatic veno-occlusive disease or pulmonary hemorrhage were reported. One patient (6%) developed acute GVHD and later also developed chronic GVHD (6%). Five patients (31%) developed mixed chimerism. One-year survival estimated by Kaplan-Meier analysis was 80%, with long-term survival estimated at 71%. There were no occurrences of lymphoma after HSCT.
Inherited Metabolic Diseases
Two 2010 review articles summarize the experience to date with HSCT and the inherited metabolic diseases.(36,37)
In the past 25 years, HSCT has been performed in approximately 20 of the approximately 40 known lysosomal storage disorders and peroxisomal storage disorders.(7) Most (>80%) have been in patients with mucopolysaccharidosis I (MPS I; Hurler syndrome), other MPS syndromes (MPS II, MPS IIIA and B, MPS VI), adrenoleukodystrophy, metachromatic leukodystrophy, and globoid leukodystrophy.(7) With the exception of Hurler and globoid cell leukodystrophy, most published data are single-case reports or small series with short follow-up.(38) The benefit of allogeneic HSCT appears limited to select subsets of patients with few types of lysosomal storage diseases and is not effective in patients who have developed overt neurologic symptoms or in those with aggressive infantile forms.(38)
Impressive results have been observed with allogeneic HSCT in Hurler syndrome. The benefits that have been observed include improvement of neurocognitive functioning, joint integrity, motor development, linear growth, corneal clouding, cardiac function, and others.7 Survival of engrafted Hurler syndrome patients has been radically changed from that of untransplanted patients, with long-term survival data indicating that lifespan will be extended many decades.(2) An analysis of nearly 150 transplanted patients with Hurler syndrome showed an OS rate of more than 80%.(39)
Experience with allogeneic HSCT and a reduced-intensity preparative regimen has been reported in 7 patients with Hurler syndrome.(40) Six of the patients received transplants from unrelated donors, and 1 received the transplant from a sibling. All patients had initial donor engraftment at 100 days, and there were no reports of severe acute GVHD. Six of the 7 children were alive at a median of 1014 days (range,
726–2222 days) posttransplant.
The few patients with Maroteaux-Lamy and Sly syndrome who have received transplants have shown promising results, with clinical improvement posttransplant.(2)
Outcomes with the leukodystrophies and allogeneic HSCT have been variable but somewhat promising. In boys and men with X-linked adrenoleukodystrophy; outcomes have depended on disease status at transplant and transplant-related complications,(2) but reports of preservation of neuropsychologic and neurologic function have been made.
Miller et al reported the results of 60 boys who underwent allogeneic HSCT for cerebral adrenoleukodystrophy between 2000 and 2009. The median age at HSCT was 8.7 years; conditioning regimens and allograft sources varied. At HSCT, 50% demonstrated a Loes radiographic severity score of 10 or more, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n=47) are alive at a median 3.7 years after HSCT. The estimate of 5-year survival for boys with Loes score less than 10 at HSCT was 89%, whereas that for boys with Loes score of 10 or more was 60% (p=0.03). The 5-year survival estimate for boys absent of clinical cerebral disease at HSCT was 91%, whereas that for boys with neurologic dysfunction was 66% (p=0.08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Posttransplantation progression of neurologic dysfunction depended significantly on the pre-HSCT Loes score and clinical neurologic status.
Fewer than 40 patients with globoid-cell leukodystrophy have undergone allogeneic HSCT; however, there have been reports of dramatic improvements in neurologic, neuropsychologic, and neurophysiologic function.(2)
Many patients with metachromatic leukodystrophy who have undergone allogeneic HSCT and had long-term engraftment have had amelioration of the disease signs and symptoms and prolonged survival.(2)
Mynarek et al reported the results of a retrospective, multicenter analysis of 17 patients with - mannosidosis who underwent allogeneic HSCT.(41) Patients were diagnosed with the disease at a median age of 2.5 years (range, 1.1-23 years) and underwent HSCT at a median age of 3.6 years (1.3-23.1 years). After a median follow-up of 5.5 years (2.1-12.6 years), OS was 88%. One patient died 76 days after HSCT from sepsis, GVHD, and pulmonary hemorrhage, and another patient died on day 135 due to viral infections and multi-organ failure. Before HSCT, the extent of developmental delay in the 17 patients varied over a wide range. After HSCT, patients made developmental progress; however, normal development was not achieved. Hearing ability improved in some but not all of the patients.
Hunter syndrome is composed of 2 distinct clinical entities, a severe and an attenuated form. The attenuated form is characterized by a prolonged lifespan, minimal to no central nervous system involvement, and a slow progression.(2) Experience with allogeneic HSCT in patients with severe Hunter syndrome has shown that it has failed to alter the disease course favorably or significantly.(2) Some authors suggest that HSCT would not be justifiable in the attenuated form because the risks outweigh the possible benefits.(2)
Eight patients with Hunter syndrome received an allogeneic HSCT between the ages of 3 and 16 years.(42) In 6 cases, the donor was a sibling with identical HLA status, in 1 case, the donor was unrelated HLA-compatible, and in 1 case, the donor was a mismatched unrelated donor. The severity of disease before transplant was rated by assessing the age at diagnosis, behavior, and intelligence quotient (IQ) at the time of graft and genotype. Five patients were considered to have severe central nervous system involvement (ie, diagnosis before the age of 4 years and an IQ <80), 2 were considered to have the attenuated form (ie, diagnosis at 5 years and normal IQ), and 1 as intermediate (ie, diagnosis after the age of 4 years and IQ between 80 and 90). After follow-up ranging from 7 to 17 years, all were still alive with the exception of 1 patient who died of unrelated causes. Successful engraftment was achieved in all patients and cardiovascular abnormalities stabilized in all patients, hepatosplenomegaly resolved, and joint stiffness improved. Perceptual hearing defects remained stable, and transmission hearing defects improved. Neuropsychological outcome was variable: the 2 patients with the attenuated phenotype reached adulthood with normal IQ, social and scholastic development, and no language impairment. Four patients with the severe form of the syndrome deteriorated after the graft, and their IQ/developmental quotient had declined below 50 at the time of the last evaluation. Of the patients with the severe form, 3 lost the ability to walk in their early teens, 2 lost language at 9 and 11 years, and 2 developed epilepsy.
The remaining 2 patients with the severe form required special schooling and had poor social and language skills.
Experience with allogeneic HSCT in patients with MPS III (Sanfilippo syndrome) has shown no alteration in the course of neuropsychologic deterioration seen in these patients.(2) The literature addressing the use of HSCT in Sanfilippo disease consists of 2 case reports.(43,44) Vellodi et al reported the outcomes of twin girls diagnosed with MPS III who underwent allogeneic HSCT and were followed up for 9 years.(43) At the time of transplant, both girls were functioning in the low average range of intellectual development. Over the next 8 years, both girls had a steady decline in cognitive development, and both functioned in the area of significant developmental delay. The authors postulated that a possible reason for continued deterioration in the twins, despite the demonstration of full chimerism, was a very low level of enzyme throughout the years after transplant. One other patient with MPS III who had received a transplant was 5.3 years old at the time of the transplant and continued to regress posttransplant.(44)
Infantile Malignant Osteopetrosis
A 2010 review article summarizes the experience to date with HSCT and osteopetrosis.(45)
The success of allogeneic HSCT in infantile malignant osteopetrosis has depended greatly on the type of donor, with patients receiving grafts from HLA-identical siblings having a 5-year DFS of 73% to 79% versus transplantation with an unrelated or mismatched donor of 13% to 45%.(8)
A retrospective analysis of 122 children who received an allogeneic HSCT for autosomal recessive osteopetrosis between 1980 and 2001 reported 5-year DFS of 73% for recipients of a genotype HLA- identical HSCT (n=40), 43% for those of a phenotype HLA-identical or 1 HLA-antigen mismatch graft from a related donor (n=21), 40% for recipients of a graft from a matched unrelated donor (n=20), and 24% for
patients who received an HLA-haplotype-mismatch graft from a related donor (n=41).(46)
Ongoing and Unpublished Clinical Trials
The online site ClinicalTrials.gov was searched to identify clinical trials in progress. These are summarized next.
A nonrandomized phase 2/3 trial is recruiting patients with a high-risk hemoglobinopathy to undergo an allogeneic HSCT using a preparative regimen to achieve stable mixed chimerism. Patients will either receive a myeloablative preparative regimen or a nonmyeloablative one if they do not have an HLA-identical sibling donor or are otherwise ineligible for a myeloablative regimen. Primary outcome measure is regimen-related toxicity, and secondary outcome measures include incidence of chimerism and GVHD, quality of life, and OS and DFS. Estimated enrollment is 30 with a study completion date of June 2016 (NCT00176852). Several phase 2 trials are also recruiting patients with a hemoglobinopathy for allogeneic HSCT, including with RIC.
An open-label phase 2/3 trial is recruiting participants to determine toxicity, risk of disease progression, immune reconstitution, and GVHD using a RIC regimen in select patients with nonmalignant diseases (including those with bone marrow failure, osteopetrosis, and SCID). Estimated enrollment is 50, with an estimated study completion date of May 2013 (NCT01019876). No results are available.
A nonrandomized phase 2/3 trial is recruiting participants to determine the efficacy of a preparative regimen of busulfan, Cy, and ATG plus allogeneic HSCT in the treatment of immune deficiencies and histiocytic disorders. Outcome measures include time to transplant engraftment, severe toxicities, DFS, GVHD, and graft failure. Estimated enrollment is 22, with estimated study completion date of September
2015 (NCT00176826). No results are available.
A phase 3 trial has been completed comparing the health and well-being of children treated with a reduced-intensity allogeneic HSCT for chronic granulomatous disease with that of children receiving standard of care treatment. Patients underwent reduced-intensity allogeneic HSCT with peripheral blood stem cells from an HLA identical family member and were compared with patients who were considered
transplant-eligible but lacked an HLA identical family member. The latter group of patients was treated using the current standard of care. Estimated enrollment was 60, with a completion date of June 2004 (NCT00023192). Study listed as completed but no results posted (last verified in June 2004).
An open-label phase 2/3 trial is recruiting participants to determine the toxicity, risk of disease progression, immune reconstitution, and GVHD using an RIC regimen in select patients with nonmalignant diseases (including those with bone marrow failure, osteopetrosis, SCID). Estimated enrollment is 50, with an estimated study completion date of May 2013 (NCT01019876). No results are posted.
A nonrandomized, open-label, uncontrolled, phase 2/3 study is completed, which used HSCT for Hurler syndrome, Maroteaux-Lamy syndrome, mannosidosis, or I cell disease, to determine the safety and engraftment of donor hematopoietic cells using a certain conditioning regimen. Secondary outcome measures include survival. The estimated enrollment was 41, with an estimated study completion date of May 2010 (NCT00176917). Results are posted.
An open-label, nonrandomized phase 2 study for allogeneic HSCT for high-risk inherited inborn errors using an RIC regimen is currently recruiting patients. Outcome measures are to evaluate the ability to achieve donor cell engraftment and to determine the toxicity associated with this regimen. The estimated enrollment is 30, and the estimated study completion date is September 2013 (NCT00383448). No results
Two open-label nonrandomized phase 2/3 trials are recruiting participants, 1 assessing survival and GVHD after allogeneic HSCT for osteopetrosis, with an estimated enrollment of 10 and estimated study completion date of December 2012 (NCT01087398) and the other assessing engraftment, mortality, toxicity, and GVHD with an RIC regimen, with an estimated enrollment of 23 and estimated study
completion date of October 2016 (NCT00775931). No results are posted.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received from 3 reviewers from 1 physician specialty society and 3 academic medical centers while this policy was under review for September 2009. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. There was general agreement with the policy statements. In particular, the reviewers were specifically asked to address the issue of the use of HSCT in the inherited metabolic diseases, except for Hunter, Sanfilippo, and Morquio syndromes; 4 reviewers agreed with the current policy statement, 1 disagreed, and 1 did not address this specific question.
Summary of Evidence
As of July 31, 2014, no trials have been published that would alter the current policy statements; allogeneic HSCT is considered medically necessary for all the listed indications, with the exception of the inherited metabolic diseases Hunter, Sanfilippo, and Morquio syndromes.
Practice Guidelines and Position Statements
No guidelines or statements were identified.
U.S. Preventive Services Task Force Recommendations
Allogeneic HSCT is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
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- Mehta P. Metabolic diseases. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:233-258.
- Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant. 2008;41(2):109-117. PMID
- Mehta P. Hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:281-316.
- Gluckman E, Wagner JE. Hematopoietic stem cell transplantation in childhood inherited bone marrow failure syndrome. Bone Marrow Transplant. 2008;41(2):127-132. PMID
- Porta F, Forino C, De Martiis D, et al. Stem cell transplantation for primary immunodeficiencies. Bone Marrow Transplant. 2008;41(suppl 2):S83-86. PMID
- Prasad VK, Kurtzberg J. Emerging trends in transplantation of inherited metabolic diseases. Bone Marrow Transplant. 2008;41(2):99-108. PMID
- Askmyr MK, Fasth A, Richter J. Towards a better understanding and new therapeutics of osteopetrosis. Br J Haematol. 2008;140(6):597-609. PMID
- MacMillan ML, Walters MC, Gluckman E. Transplant outcomes in bone marrow failure syndromes and hemoglobinopathies. Semin Hematol. 2010;47(1):37-45. PMID
- Smiers F, Krishnamurti L, Lucarelli G. Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends. Pediatr Clin N Am. 2010;57(1):181-205. PMID
- Mehta P. Hematopoietic stem cell transplantation for hemoglobinopathies. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett Publishers; 2004:259-279.
- Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related, myeloablative stem cell transplantation to cure sickle cell disease. Blood. 2007;110(7):2749-2756. PMID
- Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996;335(6):369-376. PMID
- Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease an interim report: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood. 2000;95(6):1918-1924. PMID
- Hsieh MM, Fitzhugh CD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. Jul 2 2014;312(1):48-56. PMID 25058217
- Bernardo ME, Piras E, Vacca A, et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. Jul 12 2012;120(2):473-476. PMID 22645178
- Anurathapan U, Pakakasama S, Mekjaruskul P, et al. Outcomes of Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplantation by Using a Standard Myeloablative versus a Novel Reduced Toxicity Conditioning Regimen According to a New Risk Stratification. Biol Blood Marrow Transplant. Jul 23 2014. PMID 25064743
- Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev. 2013;5:CD007001. PMID 23728664
- Mehta P, Locatelli F, Stary J, et al. Bone marrow transplantation for inherited bone marrow failure syndromes. Pediatr Clin N Am. 2010;57(1):147-170. PMID
- Dufour C, Svahn J. Fanconi anaemia: new strategies. Bone Marrow Transplant. 2008;41(suppl 2):S90-95. PMID
- Zanis-Neto J, Flowers ME, Medeiros CR, et al. Low-dose cyclophosphamide conditioning for haematopoietic cell transplantation from HLA-matched related donors in patients with Fanconi anaemia. Br J Haematol. 2005;130(1):99-106. PMID
- Wagner JE, Eapen M, MacMillan ML, et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood. 2007;109(5):2256–2262. PMID
- Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. Biol Blood Marrow Transplant. Aug 2013;19(8):1238-1243. PMID 23751955
- Cesaro S, Oneto R, Messina C, et al. Haematopoietic stem cell transplantation for Shwachman-Diamond disease: a study from the European Group for Blood and Marrow Transplantation. Br J Haematol. 2005;131(2):231-236. PMID
- Roy V, Perez WS, Eapen M, et al. Bone marrow transplantation for Diamond-Blackfan anemia. Biol Blood Marrow Transplant. 2005;11(8):600-608. PMID
- Kim H, Lee JH, Joo YD, et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol. Sep 2012;91(9):1459-1469. PMID 22526363
- Smith AR, Gross TG, Baker KS. Transplant outcomes for primary immunodeficiency disease. Semin Hematol. 2010;47(1):79-85. PMID
- Szabolcs P, Cavazzana-Calvo M, Fischer A, et al. Bone marrow transplantation for primary immunodeficiency diseases. Pediatr Clin N Am. 2010;57(1):207-237. PMID
- Ahlin A, Fugelang J, de Boer M, et al. Chronic granulomatous disease-haematopoietic stem cell transplantation versus conventional treatment. Acta Paediatr. Nov 2013;102(11):1087-1094. PMID 23937637
- Gungor T, Teira P, Slatter M, et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet. Feb 1 2014;383(9915):436-448. PMID 24161820
- Filipovich AH. Hematopoietic cell transplantation for correction of primary immunodeficiencies. Bone Marrow Transplant. 2008;42(suppl 1):S49-52. PMID
- Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase deficient severe combined immunodeficiency. Blood. Jul 12 2012. PMID 22791287
- Filipovich AH, Stone J, Tomany SC, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97(6):1598-1603. PMID
- Moratto D, Giliani S, Bonfim C, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. Aug 11 2011;118(6):1675-1684. PMID 21659547
- Marsh RA, Bleesing JJ, Chandrakasan S, et al. Reduced-Intensity Conditioning Hematopoietic Cell Transplantation Is an Effective Treatment for Patients with SLAM-Associated Protein Deficiency/X-linked Lymphoproliferative Disease Type 1. Biol Blood Marrow Transplant. Jun 9 2014. PMID 24923536
- Boelens JJ, Prasad VK, Tolar J, et al. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am. 2010;57(1):123-145. PMID
- Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol. 2010;47(1):59-69. PMID
- Rovelli AM. The controversial and changing role of haematopoietic cell transplantation for lysosomal storage disorders: an update. Bone Marrow Transplant. 2008;41(suppl 2):S87-89. PMID
- Boelens JJ, Wynn RF, O’Meara A, et al. Outcomes of haematopoietic cell transplantation for MPS-1 in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant. 2007;40(3):225-233. PMID
- Hansen MD, Filipovich AH, Davies SM, et al. Allogeneic hematopoietic cell transplantation (HCT) in Hurler’s syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant. 2008;41(4):349-353. PMID
- Mynarek M, Tolar J, Albert MH, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. Mar 2012;47(3):352-359. PMID 21552297
- Guffon N, Bertrand Y, Forest I, et al. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr. 2009;154(5):733-737. PMID
- Vellodi A, Young E, New M, et al. Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Dis. 1992;15(6):911-918. PMID
- Bordigoni P, Vidailbet M, Lena M, et al. Bone marrow transplantation for Sanfilippo syndrome. In: Hobbs JR, ed. Correction of Certain Genetic Diseases by Transplantation. London: Cogent; 1989:114-119.
- Steward CG. Hematopoietic stem cell transplantation for osteopetrosis. Pediatr Clin N Am. 2010;57(1):171-180. 46. Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of hematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 2003;32(7):657-663.
|CPT||38204||Management of recipient hematopoietic cell donor search and cell acquisition|
|38205||Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic|
|38208||Thawing of previously frozen harvest|
|38209||Washing of harvest|
|38210||Specific cell depletion with harvest, T cell depletion|
|38212||Red blood cell removal|
|38214||Plasma (volume) depletion|
|38215||Cell concentration in plasma, mononuclear, or buffy coat layer|
|38220||Bone marrow, aspiration only|
|38221||Biopsy, needle or trocar|
|38230||Bone marrow harvesting for transplantation|
|38240||Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic|
|38242||Allogeneic donor lymphocyte infusions|
|86812, 86813, 86816, 86817, 86821, 86822||Histocompatibility studies code range|
|ICD-9 Procedure||41.02||Allogeneic bone marrow transplant with purging|
|41.03||Allogeneic bone marrow transplant without purging|
|41.05||Allogeneic hematopoietic stem-cell transplant|
|41.08||Allogeneic hematopoietic stem-cell transplant with purging|
|41.91||Aspiration of bone marrow from donor for transplant|
|99.79||Other therapeutic apheresis (includes harvest of stem cells)|
|ICD-9 Diagnosis||272.7||Lipidoses (includes mucolipidosis)|
|279.2||Combined immunity deficiency|
|282.41–282.49||Thalassemia code range|
|284.0–284.9||Aplastic anemia code range|
|288.01||Congenital neutropenia (includes Kostmann’s syndrome)|
|HCPCS||G0265||Cryopreservation, freezing and storage of cells for therapeutic use, each cell line|
|G0266||Thawing and expansion of frozen cells for therapeutic use, each cell line|
|G0267||Bone marrow or peripheral stem-cell harvest, modification or treatment to eliminate cell type(s) (e.g., T cells, metastatic carcinoma)|
|Q0083, Q0084, Q0085||Chemotherapy administration code range|
|J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9040, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9395, J9600, J9999||Chemotherapy drug code range|
|S2140||Cord blood harvesting for transplantation, allogeneic|
|S2142||Cord blood-derived stem-cell transplantation, allogeneic|
|S2150||Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical, surgical, diagnostic and emergency services)|
|ICD-10-CM (effective 10/1/15)||D56.1||Beta thalassemia|
|D57.00 – D57.819||Sickle-cell disorders code range|
|D61.01 – C61.89||Other aplastic anemias and other bone marrow failure syndromes code range (includes Fanconi anemia)|
|D70.0||Congenital agranulocytosis (includes Kostmann’s disease)|
|D71||Functional disorders of polymorphonuclear neutrophils (includes chronic granulomatous disease)|
|D81.0 – D81.9||Combined immunodeficiencies code range|
|D82.0 – D82.9||Immunodeficiency associated with other major defects code range (includes Wiskott-Aldrich and X-linked lymphoproliferative syndromes)|
|<71.50 – E71.548||Peroxisomal disorders code range (includes childhood cerebral X-linked adrenoleukodystrophy)|
|E76.29||Other mucopolysaccharidoses (includes Maroteaux-Lamy syndrome)|
|E77.01||Defects in glycoprotein degradation (includes aspartylglucosaminuria, mannosidosis and fucosidosis)|
|Q78.2||Osteopetrosis (includes Albers-Schonberg syndrome)|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services.|
|30243G1, 30243X1, 30243Y1||Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list|
|07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ||Surgical, lymphatic and hemic systems, extraction, bone marrow, code list|
|Type of Service||Therapy|
|Place of Service||Inpatient/Outpatient|
Aplastic Anemia, Stem Cell Transplant
High-dose Chemotherapy, Aplastic Anemia
High-dose Chemotherapy, Inborn Errors of Metabolism
High-dose Chemotherapy, Mucolipidoses
High-dose Chemotherapy, Mucopolysaccharidoses
High-dose Chemotherapy, Osteopetrosis
High-dose Chemotherapy, Severe Combined Immunodeficiencies
High-dose Chemotherapy, Sickle Cell Disease
High-dose Chemotherapy, Thalassemia
Inborn Errors of Metabolism, Stem Cell Transplant
Mucolipidoses, Stem Cell Transplant
Mucopolysaccharidoses, Stem Cell Transplant
Osteopetrosis, Stem Cell Transplant
Positron emission tomography
Severe Combined Immunodeficiencies (SCID), Stem Cell Transplant
Sickle Cell Disease, Stem Cell
Thalassemia, Stem Cell Transplant
|12/01/99||Add to Therapy section||New policy
Policy represents revision of original policy No. 7.03.10. Discussion of myelofibrosis, originally included in this policy, is now addressed in policy No. 8.01.21. Policy statement on remaining indications is unchanged
|7/12/02||Replace policy||Policy reviewed without literature review; new review date only|
|12/18/02||Replace policy||Update CPT codes only|
|4/16/04||Replace policy||Policy updated with literature search; no change in policy statement.|
|4/1/05||Replace policy||Policy updated with literature search; no change in policy statement; no further review scheduled|
|12/12/06||Replace policy||Policy updated with literature search for March 2005 through October 2006; no change in policy statement. Policy update changed to annual review with literature search|
|12/13/07||Replace policy||Policy updated with literature search; no change in policy statement.|
|09/10/09||Replace policy||Policy updated and extensively edited based on literature search. Except for one change, the intent of the policy statements is unchanged. The change in the policy statement is that treatment of Hunter, Sanfilippo, and Morquio syndromes are not included in the list of lysosomal and peroxisomal storage diseases where allo-HSCT may be considered medically necessary. Clinical input reviewed; references 21 and 22 added.|
|09/16/10||Replace policy||Policy updated and extensively edited (with information on use of reduced-intensity conditioning) based on literature search; policy statements are unchanged. References 9, 10, 15, 18, 19, 21, 22, 25, 26, 30, 33 added|
Policy updated with literature search; reference 30 added; no change in policy statement.
|9/13/12||Replace policy||Policy updated with literature search; references 15, 25 and 27 added; no change in policy statements.|
|9/12/13||Replace policy||Policy updated with literature search through July 15, 2013; references 16 and 23 added; no change in policy statements.|
|9/11/14||Replace policy||Policy updated with literature review through July 31, 2014;
references 15, 17, 23, 29-30, and 35 added; no change in policy statements.