Acute Lymphoblastic Leukemia Background

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children, accounting for 23 percent of cancer diagnoses among children younger than 15 years.¹⁵ An estimated 2,400 children and adolescents younger than 20 years are diagnosed with ALL annually in the United States. Although acute lymphoblastic leukemia is more common in children than in adults, the incidence shows a slight bimodal distribution, with a very high peak early in life (age 1 to 4 years) and a much lower peak after age 70 years.¹⁶ The incidence of ALL in children younger than 19 years of age in the United States in the year 2000 was 3.0 cases per 100,000. ALL is more common in white children than black children, with highest incidence among Hispanic children.¹⁵

Most cases of ALL do not have an identifiable genetic or environmental cause; it likely develops as a result of a combination of an environmental trigger (e.g., prenatal exposure to ionizing radiation, high postnatal dose of radiation) in individuals who have genetic susceptibilities such as upregulation of oncogenes or loss of inherent tumor suppressor proteins.^{15, 16} A number of germline genetic defects or clinical syndromes (e.g., Down syndrome, neurofibromatosis, Schwachman syndrome, Bloom syndrome, ataxia telangiectasia) have been associated with higher risk for developing acute lymphoblastic leukemia, but these collectively account for a small proportion of cases.

ALL typically presents with nonspecific signs and symptoms that include fever, anemia, fatigue, shortness of breath, petechiae or purpura, and CNS findings such as headache, nausea and vomiting, lethargy, and cranial nerve dysfunction.¹⁶ Total white blood count can be very low, or very high, ranging as high as greater than 100,000 per microliter. Patients may have low levels of neutrophils, erythrocytes, and platelets due to excessive acute lymphoblastic leukemia invasion of the bone marrow.

Morphologic, immunologic, and genetic methods are used to establish the diagnosis of any leukemia, its subtype, and specific type. For ALL, an individual prognostic risk profile is established.^17-23 Childhood acute cases are divided into three risk groups: low, intermediate, and high. These groups also are referred to as standard, high, and very high.²⁴ The Children's Oncology Group has used a four-category system that identifies patients with a very low probability of relapse.¹⁸ Infants fall into a special ALL subgroup that requires different treatment.²⁵ Prognostic risk factors¹⁸ used to direct ALL treatment are summarized in Table 4. Detailed discussion of risk factors is beyond the scope of this review.

Table 4

Prognostic factors in pediatric acute lymphoblastic leukemia.

Current management adjusts the intensity of ALL protocols according to specific presenting clinical and biologic features, as well as early treatment response, and is evolving with additional investigation. Therapy for most forms of ALL consists of four general phases: induction, intensification/consolidation, maintenance and early CNS prophylaxis. Induction therapy is started immediately, with the goal of achieving a CR, defined as fewer than 5 percent blast cells on morphological examination. Intensification or consolidation treatment is used after the patient achieves CR1, with the goal of long-term disease control and cure. Maintenance therapy typically continues in boys for 3 years and in girls for 2 years, with the goal to kill residual tumor cells.

ALL Evidence Base

The evidence base on the use of HSCT for treatment of pediatric ALL is summarized in Table 5. Evidence comprises systematic reviews, narrative reviews, genetically randomized clinical trials, as well as observational studies. A large number of HSCT procedures have been performed since the late 1960s. Two organizations, the European Group for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) maintain data registries on HSCT procedures.

Table 5

Evidence base for HSCT in pediatric leukemia.

ALL Guidelines

In 2005, the American Society for Blood and Marrow Transplantation (ASBMT) published a systematic review and expert consensus panel recommendations for the role of cytotoxic therapy and HSCT in children with ALL.²⁶ These remain the most comprehensive recommendations for this indication and population, and are summarized in Table 6. It should be noted, however, that revised guidelines were in preparation at the time this CER was submitted to AHRQ in 2011, and were unavailable for use here.

Table 6

ASBMT treatment recommendations for therapy of pediatric acute lymphoblastic leukemia.

ALL Summary

Contemporary treatment for newly diagnosed pediatric ALL aims to achieve complete first remission (CR1), with restoration of normal hematopoiesis, in about 1 to 1.5 months using chemotherapy.²³ In most study groups, this is achieved in approximately 98 percent of patients using three agents (a glucocorticoid, vincristine, and L-asparaginase) to which an anthracycline may be added.^{15, 18, 20} Long-term event-free survival can now be expected in some 80 percent of children overall who achieve CR1 with modern risk-adapted chemotherapy. However, outcomes vary, such that in children who meet good-risk criteria (e.g., age 1 to 9 years, white blood count less than 50,000 per μL), EFS rates exceed 85 percent, whereas in those with high-risk age and white blood count criteria EFS rates approximate 70 percent. Use of additional criteria to further stratify treatment can identify patient groups with expected EFS rates ranging from less than 40 percent to more than 95 percent.

Among children with standard or good-risk disease who are in CR1, physicians attempt to limit postremission use of alkylating agents or anthracyclines that are associated with increased risk of late toxic effects. HSCT is generally not indicated in these cases.^{21, 23, 26} High-risk cases require more intensive consolidation that may entail the use of higher cumulative doses of multiple agents, including anthracyclines or alkylating agents and combinations thereof. Some 10 to 20 percent of patients with ALL are classified as very high risk, including infants, those with adverse cytogenetic abnormalities (e.g., t[4;11]; t[9;22] or low hypodiploid) and those with poor response to induction therapy with high end-induction minimal residual disease or high absolute blast count. These patients receive multiple cycles of intensive induction and consolidation chemotherapy, often including agents not used upfront for standard and less high-risk cases.

Despite such intense regimens and reported long-term event-free survival rates in high-risk patients (Table 7), they may be considered for allogeneic HSCT in CR1.^{15, 21} Some patients with late bone marrow relapse and isolated extramedullary relapses may be successfully treated with chemotherapy.²⁷ However, HSCT is indicated for pediatric patients with ALL beyond CR1.^{21, 23, 26}

Table 7

Benefits and harms after treatment for pediatric leukemia.

As more pediatric ALL patients become long-term survivors, a host of treatment-related adverse events have assumed growing importance. These include cardiac late effects such as anthracycline-associated cardiomyopathy, neuropsychologic effects associated with methotrexate, endocrine deficits, and secondary malignancies such as AML associated with topoisomerase II inhibitor treatment or brain tumors associated with the use of radiotherapy.^{23, 28-30} Thus, leukemia survivors require regular examinations by physicians who are familiar with leukemia treatment and its associated risks and who are able to recognize early signs of adverse therapeutic sequelae. The Children's Oncology Group has published risk-based, exposure-related clinical practice guidelines intended to promote earlier detection of and intervention for complications secondary to treatment for pediatric malignancies.³¹ However, with the exception of GVHD, it is difficult to separate adverse effects associated with induction therapy and the subsequent consolidation treatment including HSCT.

Acute Myelogenous Leukemia Background

Approximately 6,500 children younger than 20 years of age develop an acute leukemia annually in the U.S.; acute myelogenous leukemia (AML) represents about 15 percent, or about 1,000 cases per year. The incidence of AML is stable during childhood, except for a slight increase during adolescence and a peak in the neonatal period.⁶⁵ Some variation in the incidence of AML in children has been reported; for example, black children have an incidence of 5.8 cases per million compared to 4.8 cases per million among white children. The mortality rate from AML is estimated at 0.5 per 100,000 children younger than 10 years, and increases with age.

AML is a clonal malignancy that results from a series of somatic mutations in a hematopoietic multipotential cell, most commonly secondary to chromosomal translocations.⁶⁵ Rarely, it may stem from a more differentiated, lineage-restricted progenitor cell. It is characterized by accumulation of abnormal (leukemic) blast cells, principally in the bone marrow, and impaired production of normal blood cells. Classification of myeloid leukemia as acute requires greater than 20 percent leukemic blasts in the bone marrow. In general, the clinical presentation of AML varies as a function of the leukemic cell burden within the bone marrow, with anemia, thrombocytopenia, and a low or normal absolute neutrophil count depending on the total white blood cell count. Other signs and symptoms may stem from invasion of extramedullary sites such as soft tissues, skin, gingiva, orbit, and brain.

There is a high concordance rate of AML in identical twins, and an estimated 2- to 4-fold risk of fraternal twins both developing AML up to about 6 years of age, suggesting the disease has a genetic component. AML also has been associated with syndromes that predispose to its development secondary to chromosomal translocations or instabilities, DNA repair defects, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.⁶⁴

Treatment of AML consists of remission-induction, followed by a course of consolidation therapy and subsequent intensification, which may include autologous or allogeneic HSCT.^{65, 66} Because the AML stem cell is inherently drug resistant, improvements in outcomes have been achieved through escalation of induction regimens to maximally tolerated dose levels that necessitate intensive supportive care measures. Further escalation and improvements in outcomes in AML are thus limited on the therapeutic side.

The therapeutic approach to a newly diagnosed pediatric patient with AML is dictated by a number of prognostic risk factors, including cytogenetics, mutations of signal transduction pathways, response to induction therapy, and others that may be termed novel.^{66, 67} Detailed discussion of risk factors is beyond the scope of this review, but several are summarized in Table 8 and will be referred to in this discussion.

Table 8

Potential risk factors for pediatric acute myelogenous leukemia.

AML Evidence Base

The evidence base available on the use of HSCT for treatment of AML is summarized in Table 5. Published evidence comprises systematic reviews, narrative reviews, genetically randomized clinical trials, as well as observational studies. Two systematic reviews and one narrative review provide the basis for this evaluation. Also shown in Table 5, a large number of allogeneic HSCT procedures have been performed since the late 1960s. Two organizations, the European Group for Blood and Marrow Transplantation (EBMT), and in the U.S., the Center for International Blood and Marrow Transplant Research (CIBMTR), maintain data registries on HSCT procedures.

AML Guidelines

In 2007, the American Society for Blood and Marrow Transplantation (ASBMT) published a systematic review and expert consensus panel recommendations for the role of cytotoxic therapy and HSCT in children with AML.⁶⁸ These remain the most comprehensive recommendations for this indication and population, and are summarized in Table 9. It should be noted, however, that revised guidelines were in preparation at the time this CER was submitted to AHRQ in 2011, and were unavailable for use here.

Table 9

ASBMT treatment recommendations for therapy of pediatric acute myelogenous leukemia.

AML Summary

Survival rates in children with AML have increased with time as a result of numerous clinical trials conducted within pediatric cooperative cancer groups.^{30, 35-38, 69} About 50 to 60 percent of newly diagnosed pediatric AML patients experience long-term survival with modern treatment and supportive care, as shown in Table 7. Chemotherapy and autologous and allogeneic HSCT are established methods in this setting, but there is uncertainty about when to use each. Current practice in European groups limits use of allogeneic HSCT in CR1 to patients with poor risk prognostic factors; in the U.S., patients with a matched sibling donor typically receive allogeneic HSCT in CR1.³⁸ In general, patients who relapse and can be brought into CR2 will receive an allogeneic HSCT if a matched sibling donor is available, or if at very high risk, with an unrelated matched donor.³⁸

Although the data compiled in Table 7 were not stratified according to prognostic risk factors, the evidence generally supports use of allogeneic HSCT in children with poor- to intermediate-risk disease in CR1, and all who have refractory AML or who relapse. Substantial effort is being expended on identification of additional prognostic markers at the genetic level with the aim of personalizing AML therapy to improve survival rates. Risk stratification also has potential to reduce the burden of associated adverse effects of the procedure by targeting therapy intensification to appropriate groups, with less-intensive treatment for those who would not benefit.^{66, 67}

Adverse effects with HSCT in any disease are referable to all major organ systems including cardiovascular, CNS, endocrine, digestive, urinary, and reproductive, and include secondary malignancies and graft-versus-host disease.^{28, 29}

The Children's Oncology Group has published risk-based, exposure-related clinical practice guidelines intended to promote earlier detection of and intervention for complications secondary to treatment for pediatric malignancies.³¹ However, with the exception of GVHD and treatment-related mortality, it is difficult to separate adverse effects associated with induction therapy and the subsequent consolidation treatment including HSCT.

Chronic Myelogenous Leukemia Background

Chronic myelogenous leukemia (CML) is the most common of the chronic myeloproliferative disorders in children, but accounts for only 5 percent of childhood myeloid leukemia.⁶⁴ It occurs in very young children, but the majority is found in patients aged 6 years and older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. The white blood count may be extremely elevated in CML without evidence of excess leukemic blasts in the bone marrow, and is often associated with thrombocytosis. The Philadelphia chromosome, which is a translocation between chromosomes 9 and 22 (t[9, 22]), is nearly always present in CML. Bone marrow is hypercellular, with relatively normal granulocytic maturation. Biologically, CML in children is very similar to that in adults, so adult data are often extrapolated to children.³⁸ It is the malignancy for which a graft-versus-leukemia (GVL) effect has most clearly been shown.⁷⁰

CML occurs in three clinical phases: chronic, accelerated, and blast crisis. The chronic phase, which may last for 3 years, is associated with effects secondary to hyperleukocytosis, such as weakness, fever, night sweats, bone pain, and respiratory distress. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased proportion of peripheral and bone marrow blasts. In blast crisis, the bone marrow shows more than 30 percent blasts, with a clinical picture indistinguishable from acute leukemia. Patients who enter blast crisis will succumb to the disease within several months.⁷¹ This narrative review focuses on patients with chronic phase CML.

CML Evidence Base

The evidence base available on the use of HSCT for treatment of CML is summarized in Table 5. Published evidence comprises narrative reviews as well as observational studies. Allogeneic HSCT remains the only known curative modality for CML.

CML Guidelines

We identified no clinical guidelines for the use of HSCT in children with CML.

CML Summary

The EBMT reported outcomes in 314 children who received allogeneic HSCT in the pre-imatinib era. As shown in Table 7, the best results were achieved among children in chronic phase who received a matched sibling donor transplant (75 percent 3-year OS, 63 percent leukemia-free survival).⁶¹ Among patients who received an unrelated donor HSCT, procedural mortality reached 35 percent versus 20 percent with a MSD. Severe graft-versus-host disease (grades 2-3) occurred in 52 percent of unrelated donor HSCT recipients compared to 37 percent of recipients with a matched sibling donor. Similar results were reported by other groups who used allogeneic HSCT to treat children with chronic phase CML.^{72, 73}

The introduction of imatinib mesylate (and newer tyrosine kinase inhibitors dasatinib and nilotinib) altered the paradigm of CML treatment, particularly in adults.⁷⁴ However, there is no consensus how to treat newly diagnosed children with CML if a matched sibling donor is available.^{38, 75} Allogeneic HSCT may be delayed until imatinib fails to produce a major cytogenetic or molecular response, or if secondary resistance develops. However, relapse occurs in previously responding patients who stop imatinib. Thus, children with CML who achieve molecular disease control are typically managed individually. The decision and timing to proceed to allogeneic HSCT given the necessity for life-long imatinib therapy and the prospect of resistance developing remain uncertain.³⁰

Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia Background

In children, the myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by a constellation of ineffective hematopoiesis, impaired maturation of myeloid precursors with dysplastic morphologic features, and cytopenias.⁶⁴ Myelodysplastic disorders have been defined by their predilection to evolve into AML, yet not all cases terminate in leukemia. Mortality in myelodysplasia syndrome results from bleeding, recurrent infection, and leukemic transformation. In the absence of treatment, myelodysplasia syndrome can be rapidly fatal, with or without the transformation to AML.

The exact incidence of MDS in childhood has been difficult to estimate because of controversies regarding its classification, the heterogeneity of presentation, and the heterogeneity of risk factors in the population. MDS may occur either de novo or secondary to previous therapy for cancer. The annual incidence internationally is estimated at 0.5 to 4 per million population, and myelodysplasia syndrome accounts for about 2 to 5 percent of hematologic malignancies in children.⁷⁶ Fewer than 100 new cases of myelodysplasia are reported in the U.S. each year in children. The male-to-female ratio varies from 1.7 to 4.8:1 in different series.⁷⁷

The significance of this male predominance is unclear but is attributed, in part, to the increased prevalence of juvenile myelomonocytic leukemia (JMML), which was previously termed “juvenile chronic myelogenous leukemia” (JCML), in boys and monosomy 7 syndrome in children.⁷⁸ JMML is very rare, accounting for less than 1 percent of all childhood leukemias.

MDS/JMML Evidence Base

Given the rarity of MDS in children, randomized trials have not been performed specifically for this disease. Children with MDS have been included in AML studies, with allogeneic HSCT representing the only curative therapy.³⁸ JMML historically has been fatal in more than 90 percent of patients despite the use of chemotherapy.⁶⁴ Allogeneic HSCT is the only intervention that can provide long-term disease control.³⁰ As shown in Table 5, available evidence includes narrative reviews that include information on MDS and JMML, and observational studies.

Outcomes data abstracted from recent narrative review articles on the use of HSCT to treat children with high-risk leukemias are summarized in Table 7.

MDS/JMML Guidelines

We identified no clinical guidelines for the use of HSCT in children with MDS, or JMML.

MDS Summary

Given the rarity of MDS in children, randomized trials have not been performed specifically for this disease. However, allogeneic HSCT is the only curative therapy.³⁸ Children with MDS have been included in AML studies.⁶² This trial enrolled 77 patients with MDS or AML with antecedent MDS, randomly allocated to standard or intensively timed induction and subsequently to allogeneic HSCT if there was a suitable matched related donor, or to autologous HSCT or chemotherapy in the absence of a donor.⁶² Patients with refractory anemia (RA) or RA with excess blasts (RAEB) had a 45 percent remission rate and 6-year OS rate of 28 percent. Those with RAEB in transformation had a 69 percent remission rate and 30 percent 6 year OS rate. Patients with AML and history of MDS experienced an 81 percent remission rate and 50 percent OS rate with allogeneic HSCT, which was marginally significant compared to chemotherapy (p=0.08). The Children's Cancer Study Group investigators conclude that children with a history of MDS who present with AML (excluding those with monosomy 7) and a proportion with RAEB in transformation will do as well with AML chemotherapy remission induction and HSCT consolidation as those with AML. Among MDS patients who achieve remission following induction, but for whom a suitable stem cell donor is not available, optimum therapy is not established.⁶⁴

JMML Summary

JMML historically has been fatal in more than 90 percent of patients despite the use of chemotherapy.⁶⁴ Allogeneic HSCT is the only intervention that can provide long-term disease control.³⁰ In a study of 100 JMML patients, OS of 64 percent has been reported at 5 years.⁶³ Among patients who had disease recurrence, 7 of 15 who underwent a second allogeneic HSCT survived free of disease. In a retrospective National Marrow Donor Program registry analysis, 46 JMML patients who underwent unrelated donor allogeneic HSCT achieved a 2-year DFS rate of 24 percent with relapse probability of 58 percent.⁷⁹

Hodgkin's Lymphoma Background

Hodgkin's lymphoma, which comprises 6 percent of childhood cancers, shows a bimodal age incidence with most patients diagnosed between the ages of 15 and 30, and a second peak in adults 55 years of age and older. In the pediatric population, the incidence is highest among 15 to 19 year olds (29 per million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having threefold, eightfold, and thirtyfold lower rates, respectively.⁸¹

Hodgkin's lymphoma, a B-cell lymphoma, is divided into two distinct subcategories, classical (which is characterized by multinucleated tumor cells known as Reed-Sternberg cells) and nodular lymphocyte predominant type (with large mononuclear tumor cells known as lymphocytic and histiocytic, or “L & H” cells), both with a background of inflammatory cells. Subtypes of classical HL include lymphocytic rich, nodular sclerosis, mixed cellularity and lymphocytic depleted. The most common subtypes seen in the pediatric population are the mixed cellularity, nodular lymphocyte predominant and nodular sclerosis.⁸⁰

Most patients with Hodgkin's lymphoma present with painless adenopathy, commonly in the supraclavicular or cervical area. Whereas mediastinal involvement is present in approximately 75 percent of adolescents and adults, only about 35 percent of young children with Hodgkin's lymphoma have mediastinal presentation, in part because of the tendency of these patients to have disease with mixed cellularity or lymphocyte-predominant histology.⁸¹ Approximately 80 to 85 percent of children and adolescents with Hodgkin's lymphoma have involvement of lymph nodes and/or the spleen only (stages I-III), with the remaining 15 to 20 percent having noncontiguous extranodal involvement (stage IV).⁸¹ The most common extranodal sites include the lung, liver, bone, and bone marrow.⁸¹

Contemporary treatment programs use a risk-adapted approach in which patients receive multi-agent chemotherapy with or without low-dose involved field radiation.⁸¹ Prognostic factors considered include stage, presence or absence of B symptoms, and/or bulky disease.⁸¹ With current therapy, the long-term disease-free survival (DFS) in children with newly diagnosed localized and advanced-stage Hodgkin's lymphoma ranges between 85 to 100 percent and 70 to 90 percent, respectively.⁸⁰

However, high-risk patients with Hodgkin's lymphoma whose disease is refractory to initial therapy or relapse after primary initial chemotherapy (particularly with early relapse at 12 months or earlier) have a minimal chance for long-term survival with salvage chemotherapy alone (with 5-year OS rates of 20 to 25 percent).⁸⁰ Approximately 10 to 15 percent of patients with HL fail to achieve a complete remission (CR) or relapse, and it is in this population that more aggressive treatment strategies like HSCT are utilized.

Hodgkin's Lymphoma Evidence Base

The evidence compiled includes one review article, which summarizes the experience with autologous HSCT and childhood Hodgkin's lymphoma.⁸⁰ There have been no randomized trials in the pediatric population with Hodgkin's lymphoma using HSCT, and the data consist of several small, retrospective case series as summarized in Table 10. Outcomes with the use of autologous HSCT and pediatric Hodgkin's lymphoma show a wide range, with an overall survival (OS) from 43 to 95 percent and event-free survival (EFS) from 31 to 62 percent (Table 11).^82-86

Table 10

Pediatric lymphomas and the evidence base.

Table 11

Benefits and harms after treatment for childhood Hodgkin's lymphoma.

National Comprehensive Cancer Network (NCCN) clinical practice guidelines exist.⁸⁷ No health technology assessments were identified in the search.

A case-matched comparison of autologous HSCT in the pediatric population (n=81) versus adult patients (n=81) with Hodgkin's lymphoma suggested that pediatric and adult patients with HL have similar EFS and OS.⁸⁶

There have been two randomized trials in adult patients with relapsed or refractory Hodgkin's lymphoma, comparing standard-dose salvage chemotherapy and high-dose chemotherapy with autologous HSCT.^{88, 89} Both trials demonstrated significantly improved EFS and longer time to treatment failure in the HSCT group, but no significant difference in OS was observed between the two groups. Whether survival data from the adult population with Hodgkin's lymphoma can be extrapolated to the pediatric population is somewhat controversial.

In patients with Hodgkin's lymphoma who undergo HSCT, harms include secondary malignancies, including breast cancer and myelodysplastic syndrome/secondary acute myelogenous leukemia (MDS/sAML). In patients with recurrent lymphoma who undergo high-dose chemotherapy and autologous HSCT, the incidence of MDS/sAML is 4 to 20 percent at 5 years.⁸⁰

Hodgkin's Lymphoma Guidelines

NCCN guidelines⁸⁷ for the treatment of Hodgkin's lymphoma with HSCT state the best option for patients with progressive disease or relapse is high-dose therapy with autologous stem-cell rescue and that allogeneic transplant may be an option in select patients with progressive or relapsed disease.

Hodgkin's Lymphoma Summary

Overall there appears to be a favorable risk-benefit profile for the treatment of Hodgkin's disease with HSCT in patients with progressive disease or relapse, with OS and EFS rates ranging from 43 to 95 percent and 31 to 62 percent, respectively.⁸⁰ Patients who fail following autologous HSCT or for patients who cannot mobilize sufficient numbers of autologous stem cells, allogeneic HSCT is an option.

Current recommendations are based on small numbers from five case series. Future challenges in the treatment of Hodgkin's lymphoma include the development of risk-stratified treatment approaches for patients with high-risk disease and the possible use of allogeneic HSCT where graft versus lymphoma has been demonstrated.⁸⁰

Non-Hodgkin's Lymphoma Background

Non-Hodgkin's lymphoma (NHL) accounts for approximately 7 percent of cancers in children younger than 20 years of age.⁹⁰ Whereas NHL in adults is more commonly low or intermediate grade, in the pediatric population almost all non-Hodgkin's lymphomas are high grade, and differ from disease in adults with respect to disease types, staging system, biology, treatment, and outcome.⁹¹ NHLs are broadly classified as being of B-cell, T-cell, or natural killer (NK) cell origin and by differentiation (precursor versus mature cell). NHLs in children and adolescence fall into three therapeutically relevant categories: (1) mature B-cell NHL: Burkitt and Burkitt-like lymphoma/leukemia (BL, 50 percent of pediatric NHL) and diffuse large B-cell lymphoma (DLBCL, 10-20 percent of pediatric NHL); (2) lymphoblastic lymphoma (LBL) primarily precursor T-cell and less frequently precursor B-cell (20 to 30 percent of pediatric NHL); and (3) anaplastic large cell lymphoma (ALCL), mature T-cell or null-cell lymphoma (10 percent). The other 10 percent of NHL observed in the pediatric population are comprised of diseases commonly seen in adults, such as follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, cutaneous lymphoma, primary central nervous system lymphoma or mature T-cell or natural killer-cell lymphoma.⁹¹ Approximately 100 of the 1,000 cases of childhood NHL that occur annually in the U.S. occur in children or adolescents with a primary or secondary immunodeficiency, and the majority are associated with Epstein-Barr virus.⁹¹ The ultimate goal in treating these patients is improving immune function.

Burkitt and Burkitt-like lymphoma (BL) consistently exhibit very aggressive clinical behavior and show overlapping characteristics with acute lymphoblastic leukemia. BL exhibits rapid growth rate, and a tendency to involve extranodal sites and to disseminate to the bone marrow and meninges. Common primary sites include the abdomen and pelvis and the head and neck. The diagnosis of Burkitt-like lymphoma is somewhat controversial due to overlapping histologic features with DLBCL. Cytogenetic evidence of C-MYC rearrangement is the gold standard for the diagnosis of BL. BL can be sporadic or endemic, with endemic cases being Epstein-Barr virus-related and occurring commonly in equatorial Africa.

Diffuse large B-cell lymphoma (DLBCL) in the pediatric population occurs more commonly in the second decade of life than the first. DLBCL differs biologically in children and adolescents than in adults (except for those that present as primary mediastinal disease, which represents approximately 20 percent of pediatric DLBCL). The characteristic chromosomal translocation seen in adult DLBCL, t(14;18), is rarely observed in pediatric DLBCL. Outcomes for children with DCBCL are more favorable than those seen in adults.

Lymphoblastic lymphoma (LBL) occurs most commonly in young men as an anterior mediastinal mass. Chromosomal abnormalities in LBL are not well characterized. The disease course is aggressive with frequent involvement of the bone marrow and/or central nervous system. Patients with limited disease may fare well, but those with poor-risk disease (defined as bone marrow or central nervous system involvement or LDH greater than 300 IU/L) or recurrent disease have less favorable outcomes.⁹²

Anaplastic large cell lymphoma (ALCL) has a broad range of clinical presentations, including involvement of lymph nodes and extranodal sites, particularly skin and bone. More than 90 percent of cases have a characteristic chromosomal translocation t(2;5) which leads to expression of a fusion protein NPM/ALK, although variant ALK translocations also occur. ALCL is classified as a peripheral T-cell lymphoma (PTCL); however, ALK-positive ALCL has a superior prognosis to other forms of PTCL.

The St. Jude (Murphy) staging system is the most widely used for pediatric NHL, and differs from the Ann Arbor staging system (used in adult NHL) in the classification of abdominal, intrathoracic, and paraspinal/epidural disease.⁹¹ The most important prognostic variable in pediatric NHL is tumor burden, evaluated by staging and serum lactate dehydrogenase (LDH) level. Patients with stage III/IV disease and serum LDH greater than 400 U/L have significantly worse outcomes than those with LDH less than 400 U/L.

Unlike adults with NHL, who usually present with lymph node disease, most pediatric patients present with extranodal disease. Approximately 70 percent of children with NHL present with advanced disease and/or have involvement of the bone marrow, central nervous system and/or bone.⁸⁰ The primary therapy for childhood NHL is multi-agent chemotherapy, with the length and intensity of therapy determined by the subtype and stage of disease.⁸⁰ Children with limited stage NHL have an excellent prognosis with conventional chemotherapy with or without radiation, with estimated event-free survival of 90 to 95 percent.⁸⁰ Patients with advanced stage disease have a variable prognosis depending upon disease subtype, with 5-year event-free survival rates ranging from 60 to 90 percent.⁸⁰

If remission can be achieved in children and adolescents with recurrent or refractory B-cell NHL, HSCT is usually pursued.⁹¹ Most pediatric transplant programs reserve the use of HSCT in children with NHL for after first relapse, with disease progression or induction failure.⁸⁰

NHL Evidence Base

The evidence compiled includes one review article which summarizes the experience with autologous HSCT and childhood NHL.⁸⁰ There have been no randomized trials in the pediatric population with NHL using HSCT, and the data consist of five small, retrospective case series^93-97 and one nonrandomized, comparative study ⁹⁸, as summarized in Table 12. Several of the studies report survival data combined for patients with different histologies, with median EFS of 50 percent (range: 27 to 59 percent).^{93-96, 98} Studies that report survival data for one histologic type of NHL include ALCL: EFS 75 percent at 3 years⁹⁷ and OS 95 percent at 7 years;⁹⁹ LL: EFS 39 percent and 5-year OS of 44 percent for autologous HSCT, EFS 36 percent and 5-year OS 39 percent for allogeneic HSCT;⁹² BL: EFS 57 percent.¹⁰⁰

Table 12

Benefits and harms after treatment for childhood Non-Hodgkin's lymphoma.

NCCN clinical practice guidelines (for all subtypes of pediatric NHL) and guidelines from the American Society for Blood and Marrow Transplantation (for DLBCL only) exist. No health technology assessments were identified in the search.

Harms associated with HSCT include secondary malignancies, which are a well-recognized complication in patients with lymphoma who undergo chemotherapy and/or radiation treatment. In patients with recurrent lymphoma who undergo high-dose chemotherapy and autologous HSCT, the incidence of myelodysplastic syndrome/secondary acute myelogenous leukemia is 4 to 20 percent at 5 years.⁸⁰

NHL Guidelines

The American Society for Blood and Marrow Transplantation (ASBMT) issued a position statement on the use of HSCT in the treatment of diffuse large cell B-cell non-Hodgkin's lymphoma recommending its use in first chemotherapy-sensitive relapse, first complete remission in high/intermediate-high risk international prognostic index (IPI) patients, and as high-dose sequential therapy in intermediate-high/high risk IPI untreated patients.¹⁰¹

Guidelines from the ASBMT specifically addressing NHL and HSCT in the pediatric population were not identified.

NCCN clinical practice guidelines¹⁰² for BL recommend that patients be considered for a clinical trial, which may include autologous or allogeneic stem-cell rescue. The recommendations for DLBCL are for autologous HSCT for relapsed or refractory disease in patients with either partial or complete response to second line therapy. Recommendations for LBL include consolidation of high-dose therapy with autologous or allogeneic stem-cell rescue in poor risk patients, allogeneic HSCT for patients with an initial CR who relapse and for patients with an initial partial response. Finally, recommendations for peripheral T-cell lymphomas, noncutaneous (including ALCL) include high-dose therapy and stem-cell rescue as first-line consolidation in all patients except those considered low risk (by age adjusted IPI), and autologous or allogeneic HSCT in patients with relapsed or refractory disease with a partial or complete response to additional therapy.

NHL Summary

Overall there appears to be a favorable risk-benefit profile for the treatment of NHL with HSCT in patients with primary refractory or chemosensitive relapse. EFS for the various subtypes of NHL (except for ALCL) range from 27 to 59 percent,^{92-94, 96, 98, 100} and for ALCL, EFS of 75 percent at 3 years⁹⁷ and OS 95 percent at 7 years⁹⁹ have been reported.

Current recommendations are based on small studies which have included heterogeneous patient populations with various tumor histologies and a mixture of adult and pediatric patients.

Future challenges in the treatment of NHL include the development of risk-stratified treatment approaches for patients with high-risk disease, defining the use of autologous HSCT as upfront consolidation for certain groups of high-risk NHL, and the possible use of allogeneic HSCT where graft versus lymphoma has been demonstrated.⁸⁰

Background

Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for 8 to 10 percent of all childhood cancers and for approximately 15 percent of cancer deaths in children.¹⁰³ At least 40 percent of all children with neuroblastoma are designated as high-risk patients, based on adverse features including age 18 months or older at presentation, the presence of disseminated disease, unfavorable histologic features, and amplification of the MYCN oncogene.¹⁰³

Low-risk patients are managed with surgery alone because excellent cure rates are achieved even when some tumor is left behind.¹⁰³ Intermediate-risk patients are still at low risk of succumbing to disease but require limited chemotherapy and/or surgery.^{103, 104} The amount of chemotherapy is determined in part by the biological features. High-risk patients receive treatment with an aggressive regimen of combination high-dose chemotherapy (HDC); long-term survival with current treatments is about 30 percent.¹⁰⁴ Children with aggressively treated, high-risk disease may develop late recurrences, some more than 5 years after completion of therapy.^{103, 104} Many centers have used HDC with HSCT in the setting of high-risk or recurrent disease.^{103, 105-108} Survivors have an increased rate of second malignant neoplasms, relative to the age- and sex-comparable U.S. population, and of chronic health conditions, relative to their siblings, which underscores the need for long-term medical surveillance.¹⁰⁹

Evidence Base

The evidence compiled for this narrative review includes one systematic review,¹¹⁰ of three randomized controlled trials (RCTs).^{105, 107, 108} A followup analysis of one RCT¹¹¹ and reports from two European registries^{112, 113} were also found (Table 13). No health technology assessments or clinical practice guidelines for the treatment of childhood neuroblastoma with HSCT were identified in the literature search.

Table 13

Neuroblastoma evidence base.

The systematic review was a report published by the Cochrane Collaboration in May 2010, comparing the effectiveness of HDC with autologous HSCT versus conventional therapy in children with high-risk disease.¹¹⁰ A meta-analysis of the three RCTs including 739 patients, independently identified in our search, showed a significant difference in both event-free and overall survival in favor of the transplant group (Table 14). Overall, no significant differences in the occurrence of adverse effects between treatment groups were identified in the Cochrane review (Table 14). These findings were further validated in a subsequent analysis of one RCT (not included in the Cochrane Review) with an 8-year median followup period (Table 14).¹¹¹

Table 14

Benefits and harms after treatment for neuroblastoma.

Guidelines

No guidelines for the treatment of neuroblastoma were identified in the search.

Summary

Overall there appears to be a favorable risk-benefit profile for the role of HDC with autologous HSCT in children with high-risk disease, although possible higher levels of adverse effects should be kept in mind. Interpretation of these data is subject to the clinical context of the complete therapy which includes the effect of the induction regimen, the sources of stem cells, and presence and type of consolidation chemotherapy.

Background

Germ-cell tumors represent 3 percent of all childhood neoplasms.^{114, 115} In the U.S., approximately 900 children and adolescents younger than 20 years of age are diagnosed with these tumors each year.^{115, 116} Childhood germ-cell tumors are composed primarily of extragonadal neoplasms (e.g., mediastinal or retroperitoneal) whereas gonadal (ovarian and testicular) tumors are more common in adults.^115-118 Prognosis and appropriate treatment depend on factors such as histology (e.g., seminomatous vs. nonseminomatous), age (young children vs. adolescents), stage of disease, and primary site.^{117, 118}

Germ-cell tumors are highly sensitive to chemotherapy.^{114, 117, 118} Cisplatin-based combination chemotherapy, followed by appropriate surgical resection of residual disease, is curative in 80 percent of patients.^{114, 118, 119} Reports of salvage treatment strategies used in adult recurrent germ-cell tumors include larger numbers of patients, but the differences between children and adults regarding the location of the primary tumor site, pattern of relapse, and the biology of childhood disease may limit the applicability of adult salvage approaches to children. Many centers have used HDC with HSCT in the setting of recurrent disease.^{114, 119, 120}

Evidence Base

The evidence compiled for this review (Table 15) includes one cohort study,¹²⁰ two reports based on registry data,^{114, 119} and two NCCN guidelines.^{117, 118} A review of the NCI's PDQ® Cancer Clinical Trials Registry identified at least one ongoing trial involving HSCT in the setting of relapsed childhood germ-cell tumors.¹²¹ No RCTs, systematic reviews or health technology assessments for childhood germ-cell tumors were identified in the literature search.

Table 15

Germ-cell tumor evidence base.

Agarwal and colleagues¹²⁰ reported their experience at Stanford University Medical Center in treating 37 consecutive patients who received HDC and autologous HSCT between 1995 and 2005 for relapsed disease (Table 16). Only four patients (11 percent) in this cohort were in the pediatric age group. Twenty-nine patients had received prior standard salvage chemotherapy. Three-year overall and event-free survival was 57 and 49 percent, respectively. Treatment-related mortality was reported at 3 percent. In terms of ongoing trials, there is a pilot study underway to assess the feasibility of HDC followed by autologous HSCT in patients with newly diagnosed or relapsed solid tumors (including GCTs). Twenty patients (6 months to 40 years of age) are expected to be enrolled in this single-center U.S. study with the expected final data collection date of December 2010.¹²¹

Table 16

Benefits and harms after treatment for germ-cell tumors.

Guidelines

Our search identified two guidelines for the treatment of GCT. Both guidelines were from NCCN and were not specific to childhood disease.^{117, 118} The NCCN testicular cancer guidelines¹¹⁸ recommend HDC with HSCT as the preferred third-line option for metastatic disease if the patient experiences an incomplete response or relapses after second-line conventional dose chemotherapy. This recommendation is based on lower-level evidence and uniform NCCN consensus (Category 2A) In addition, HDC with HSCT is recommended as one therapeutic option for patients with poor prognostic features including an incomplete response to first-line therapy, high levels of serum markers, high-volume disease and presence of extratesticular primary tumor. This recommendation is based on lower-level evidence, including clinical experience and nonuniform NCCN consensus, but no major disagreement (Category 2B) Alternatively, the patients may be put on best supportive care or salvage surgery if feasible.¹¹⁸ The NCCN ovarian cancer guidelines,¹¹⁷ on the other hand, recommend HDC with HSCT as one therapeutic option for patients having persistently elevated alpha-fetoprotein and/or beta-human chorionic gonadotropin levels after first-line chemotherapy. This recommendation is based on lower-level evidence and uniform NCCN consensus (Category 2A)

Summary

Although there is not sufficient literature to firmly establish the role of HDC with autologous HSCT for relapsed pediatric germ-cell tumor, studies in adult patients with similar tumors show efficacy in poorly responsive or relapsed disease. Further study is needed in young children and adolescents to determine whether the efficacy noted in adult studies can be extrapolated to pediatric patients.

Background

Classification of brain tumors is based on both histopathologic characteristics of the tumor and location in the brain.¹²² Central nervous system (CNS) embryonal tumors are the most common malignant brain tumor in childhood. Embryonal tumors of the CNS include medulloblastoma, ependymoblastoma, supratentorial primitive neuroectodermal tumors (PNETs), medulloepithelioma, and atypical teratoid/rhabdoid tumor (AT/RT).¹²²

Medulloblastomas account for 20 percent of all childhood CNS tumors.^{123, 124} The other types of embryonal tumors are rare by comparison ¹²². Surgical resection is the mainstay of therapy with the goal being gross total resection with adjuvant radiation therapy, as medulloblastomas are very radiosensitive tumors.^{124, 125} Treatment protocols are based on risk stratification, as average or high risk. HSCT is used in high-risk disease, including metastatic, and recurrent or residual following surgery and chemotherapy. The average-risk group includes children older than 3 years, without metastatic disease, and with tumors that are totally or near totally resected (i.e., less than 1.5 cm² of residual disease).¹²⁴ In addition, patients with non-anaplastic medulloblastoma are considered to be at average (or standard) risk, and those with anaplastic disease at high risk. The high-risk group includes children aged 3 years or younger, or with metastatic disease, and/or subtotal resection (i.e., more than 1.5 cm² of residual disease).¹²⁴ The treatment of medulloblastoma continues to evolve, and, especially in children younger than 3 years because of the concern of the deleterious effects of craniospinal radiation on the immature nervous system, therapeutic approaches have attempted to delay and sometimes avoid the use of radiation, and have included trials investigating different chemotherapy regimens to improve outcome.¹²²

PNETs are a heterogeneous group of highly malignant neoplasms comprising 3 to 5 percent of all childhood brain tumors, most commonly located in the cerebral cortex and pineal region.^{123, 125} AT/RT, on the other hand, is a tumor of early childhood, with nearly two-thirds of cases diagnosed before the age of 3 years.^{123, 125, 126} The prognosis for these tumors is worse than for medulloblastoma, despite identical therapies.^{122, 123, 125} Recurrence of all forms of CNS embryonal tumors is not uncommon, usually occurring within 18 months of treatment; however, recurrent tumors may develop many years after initial treatment.¹²² Many centers have used HDC with HSCT in the setting of high-risk disease.

Evidence Base

The evidence compiled for this review includes seven case series published since 2005.^127-133 No RCTs, registry reports, or clinical practice guidelines for the treatment of childhood CNS embryonal tumors with HSCT were identified in the literature search. In addition, no systematic reviews or health technology assessments were found on CNS embryonal tumors (Table 17). Published information on outcome for children with CNS embryonal tumors is based on small series and is retrospective in nature (Table 18).

Table 17

CNS embryonal tumors evidence base.

Table 18

Benefits and harms after treatment for CNS embryonal tumors.

Guidelines

No guidelines on the treatment of CNS embryonal tumors were identified in the search.

Summary

Overall, there is a favorable risk-benefit profile for the role of HDC with HSCT in young children with high-risk or recurrent medulloblastoma supported by case series published in the past 5 years. Data is limited regarding the use of this therapy for other childhood CNS embryonal tumors. Comparison of the effects of HSCT between treatment trials remains challenging given the heterogeneity of these tumors, use of different combinations of chemotherapy as well as radiation therapies, and varied patient selection.

Sickle-Cell Disease

Evidence Base

The evidence compiled for this review includes two literature reviews^{139, 140} and one systematic review on the use of hydroxyurea containing data from one RCT and 22 observational studies.¹⁴¹ One clinical practice guideline for the treatment of sickle-cell disease with HSCT¹⁴² and no health technology assessments were identified in the literature search.

For patients in whom HSCT is indicated, the review of the literature (Table 20) shows for median followup ranging from 0.9 to 17.9 years overall survival of greater than 92 percent and event free survival of greater than 82 percent have been observed. Cord blood and marrow donations from family donations have been used with equal success; although current numbers are small.^{143, 144}

Table 20

Benefits and harms after treatment for hemoglobinopathies.

β-Thalassemia Major

Acquired Bone Marrow Failure Syndrome

Acquired Aplastic Anemia

Background

Acquired aplastic anemia is a failure of the bone marrow to produce red and white blood cells, as well as platelets. Approximately 80 percent of all cases of aplastic anemia are acquired versus congenital. While disease onset can occur at any age, it preferentially occurs in young adults and individuals over 60 years of age.¹⁶⁹ Patients with acquired aplastic anemia are classified according to the severity of marrow aplasia.¹⁷⁰ The urgency of treatment is dictated by the patient's absolute neutrophil count and the duration of severe neutropenia, which is correlated to survival.

The standard of care for treatment of aplastic anemia is immunosuppression and/or HSCT. The patient's age, medical history (such as number of prior blood transfusions and infections) and the availability of a matched sibling donor guide treatment decisions.¹⁷²

Evidence Base

The evidence compiled for this review includes one literature review.¹⁶⁸ One clinical practice guideline¹⁷² but no health technology assessments for the treatment of childhood acquired aplastic anemia with HSCT were identified in the literature search. The evidence base on the use of HSCT for treatment of acquired aplastic anemia is summarized in Table 22.

Table 22

Benefits and harms after treatment for bone marrow failure syndromes.

The literature review¹⁶⁸ reports for patients without a matched sibling donor immunosuppression can offer 89 percent 10-year survival among responders. Seventeen to 34 percent will eventually require HSCT as salvage therapy and the long term use of immunosuppressants leave the patient at higher risk for infection and an increased rate of MDS/AML of 8 to 25 percent. For patients with a matched sibling donor survival rates after transplant are far better reaching 98 percent in some series. A matched sibling bone marrow transplant may offer better survival 85 percent versus 73 percent with peripheral blood stem cells and a lower risk of graft versus host disease. Various conditioning regimens are available and are associated with varied rates of adverse events.

Guidelines

Guidelines for the treatment of acquired aplastic anemia with HSCT were published by Bagby et al.¹⁷²

The treatment algorithm recommends:

• patients younger than 35 years with a matched sibling donor, HSCT as first-line therapy,
• patients older than 35 years or no matched sibling donor, immunosuppressive therapy as first-line therapy,
• HSCT as treatment for those refractory to immunosuppression.

Summary

Overall there appears to be a favorable risk-benefit profile for the treatment of acquired aplastic anemia with HSCT. Clinical management entails immunosuppression and HSCT. In general younger patients with a matched sibling donor are encouraged to pursue HSCT, while older patients who are less tolerant of transplant or those without a matched sibling donor are first put on immunosuppressive therapy. For those receiving transplant, control of graft-versus-host disease is essential in achieving high rates of survival. Selection of a conditioning regimen influences the harms associated with transplantation.

Inherited/Congenital Bone Marrow Failure Syndromes

Background

The primary immunodeficiencies are a genetically heterogeneous group of diseases that affect distinct components of the immune system (Table 23). More than 120 gene defects have been described, causing more than 150 disease phenotypes.²⁵⁰ The most severe defects (collectively known as “severe combined immunodeficiency” or SCID) cause an absence or dysfunction of T lymphocytes, and sometimes B lymphocytes and natural killer cells.²⁵⁰

Table 23

Primary immunodeficiencies successfully treated with HSCT.

Without treatment, patients with severe combined immunodeficiency 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.²⁵⁰

Evidence Base

The evidence compiled for this review (Table 24) includes three literature reviews (Table 25).^250-252 No health technology assessments or clinical practice guidelines for the treatment of primary immunodeficiencies with HSCT were identified in the literature search.

Table 24

Evidence base for HSCT in primary immunodeficiencies.

Table 25

Benefits and harms after treatment for primary immunodeficiency.

HSCT using HLA-identical sibling donors can provide correction of underlying primary immunodeficiencies such as SCID, Wiskott-Aldrich syndrome, and other prematurely lethal X-linked immunodeficiencies in approximately 90 percent of cases where a donor is available.²⁵¹ According to a European series of 475 patients collected between 1968 and 1999, 3-year survival rates for SCID were 81 percent with a matched sibling donor, 50 percent with a haploidentical donor, and 70 percent with a transplant from an unrelated donor.²⁵³ Since 2000, overall survival for patients with SCID who have undergone HSCT is 71 percent.²⁵⁰ For non-SCID patients, 3 year survival rates were 71 percent, 42 percent, and 59 percent for genotypically HLA-matched, phenotypically HLA-matched and HLA-mismatched related, and HLA-mismatched unrelated, respectively.²⁵³

For Wiskott-Aldrich syndrome, which has a median survival of 15 years, an analysis of 170 patients transplanted between 1968 and 1996 demonstrated the impact of donor type on outcomes.²⁵⁴ Fifty-five transplants were from HLA-identical sibling donors, with a 5-year probability of survival of 87 percent (95 percent CI: 74–93 percent); 48 were from other relatives, with a 5-year probability of survival of 52 percent (37 to 65 percent); and 67 were from unrelated donors with a 5-year probability of survival of 71 percent (58 to 80 percent; p=0.0006). In patients with genetic immune/inflammatory disorders such as hemophagocytic lymphohistiocytosis the current results with allogeneic HSCT are 60 to 70 percent 5-year disease-free survival. Survival rates for patients with other immunodeficiencies are similar at 74 percent, with even better results (90 percent) when well-matched donors are used for defined conditions such as chronic granulomatous disease. Survival after HSCT for primary immunodeficiencies is good, and data show that patients surviving 12-24 months post-transplant generally have good long-term outcomes since relapse does not occur, as it may with hematologic malignancy.²⁵⁰

Guidelines

No guidelines for the treatment of primary immunodeficiencies were identified in the search.

Summary

Overall there appears to be a favorable risk-benefit profile for the treatment of SCID and other primary immunodeficiencies, including Wiskott-Aldrich syndrome and congenital defects of neutrophil function.²⁵⁷

While primary immunodeficiency diseases are heterogeneous, it is universally accepted that HSCT offers the only chance of cure. The best outcomes have been reported to occur when children are transplanted in infancy, prior to the development of organ damage.^{258, 259} Conventional therapies including treatment with IVIG may decrease morbidity and mortality but do not address the underlying problem or alter the long-term outcome.²⁵⁰ Gene therapy has been performed for over a decade now for ADA deficiency, X-linked SCID and WAS. It is, however, considered experimental.²⁶

Hurler Syndrome (MPS I)

Maroteaux-Lamy Syndrome (MPS VI)

Sly Syndrome (MPS VII)

Gaucher Disease Type I

Niemann-Pick Disease Type B

Globoid Cell Leukosystrophy (Krabbe Disease)

Metachromatic Leukodystrophy

Fucosidosis

Evidence Base

The evidence compiled for this review (Table 31) includes two literature reviews,^{270, 325} which describe three patients with fucosidosis undergoing HSCT, two reports in the literature and one conference abstract.^{326, 327} No health technology assessments or clinical practice guidelines for the treatment of fucosidosis with HSCT were identified in the literature search.

Table 31

Treatment benefits and harms for fucosidosis and α-mannosidosis.

Both cases reported in the literature were diagnosed early because of disease in an older sibling. Transplantations were performed prior to the onset of symptoms, and the success of the transplants is attributed to the timing of the procedures. Leukocyte enzyme levels rose quickly following engraftment, and remained in the normal range 1 to 3 years post-procedure. Most promising is the detection of enzyme activity in cerebrospinal fluid, indicating that the enzyme had reached the central nervous system.³²⁷ MRIs from 1 to 3 years post-procedure showed a consistent progression of myelination following the transplants. Both cases reported in the literature showed better mental and physical development and improved quality of life compared to their affected siblings. Complications included GVHD and infections.^{326, 327}

α-Mannosidosis

Adrenoleukodystrophy

Evidence Base

The evidence compiled for this review (Table 32) includes two literature reviews.^{270, 337} One clinical practice guideline²⁹¹ but no health technology assessments for the treatment of adrenoleukodystrophy with HSCT were identified in the literature search.

Table 32

Evidence base for HSCT in adrenoleukodystrophy.

Outcomes following HSCT have varied from complete resolution of symptoms to having no effect (Table 33). Disease status prior to the procedure is the best predictor of outcomes.^{338, 339} The most successful outcomes are when the HSCT has been performed prior to the onset of neurologic symptoms. In a report on 94 boys with X-linked adrenoleukodystrophy receiving HSCT, 5-year survival rates were 70 percent with no neurological deficits, 67 percent with one neurological deficit, and 35 percent with two or more neurological deficits. The 5-year survival rates of boys with X-linked adrenoleukodystrophy not receiving HSCT have been reported as less than 40 percent.³³⁹

Table 33

Treatment benefits and harms for adrenoleukodystrophy.

Background

Osteopetrosis is a group of rare inherited disorders of the skeleton characterized by a defect in the form or function of osteoclasts. Osteoclasts degrade bone in the bone remodeling process, so a decrease in osteoclast activity causes an increase in bone density, an impairment of longitudinal growth of the bone, and bone marrow failure.³⁴³ There is a wide spectrum of presentation and severity of symptoms, which have been classified into three primary clinical types: autosomal recessive infantile (“malignant”) osteopetrosis, autosomal recessive “intermediate” osteopetrosis, and autosomal dominant osteopetrosis. The estimated incidence of the autosomal recessive type is 1 in 250,000–300,000 births, though in Costa Rica the incidence is three times as high, and for the autosomal dominant type, the estimated incidence is 1 in 20,000 births.³⁴⁴ The autosomal recessive infantile form is the most severe and is characterized by hepatosplenomegaly, cranial-nerve dysfunction, hearing loss in about one-third of cases, and visual deficits in a majority of the cases, all of which are detected within the first several months of life.

Because of neutrophil defects, anemia, and complications of the ear, nose, and throat, patients with osteopetrosis are susceptible to frequent infections, usually affecting the respiratory tract.³⁴⁵ Life expectancy is less than 10 years, with cause of death most commonly thrombocytopenia, anemia, or infectious complications.³⁴³ There are rare variants of the autosomal recessive type, a neuronopathic form characterized by seizures and a milder form exhibiting renal tubular acidosis are two examples. There is also a rare X-linked form characterized by severe immunodeficiency. Symptoms of the more common, but less severe autosomal dominant form are primarily skeletal, such as fractures, scoliosis, and osteomyelitis, with onset in late childhood or adolescence and a normal life expectancy.³⁴⁴

Clinical management of osteopetrosis is supportive, with fractures and arthritis treated by experienced orthopedic surgeons due to the brittleness of the bone, hypocalcemic seizures treated with calcium and vitamin D supplements, and bone marrow failure treated with red blood cell and platelet transfusions.³⁴⁵

Evidence Base

The evidence compiled for this review (Table 34) includes four literature reviews^345-348 of osteopetrosis and HSCT (Table 35). In a retrospective study of over 100 osteopetrosis patients undergoing HSCT, 5-year disease free survival rates ranged from 24 percent with a mismatched unrelated donor to 73 percent with a matched sibling donor.³⁴⁹ Some patients experienced improvements in visual symptoms and either stable or improved growth.³⁴⁹ Risks related to HSCT include hypercalcemia, graft versus host disease, and infections.^{349, 350}

Table 34

Evidence base for HSCT in osteopetrosis.

Table 35

Treatment benefits and harms for osteopetrosis.

Age at transplantation and availability of a suitable HLA matched donor determine the quality and durability of engraftment, which in turn affects the extent of benefit of HSCT.^{345, 350} Engraftment can significantly alter the course of the disease, and prolong life expectancy from less than 10 years of age, to adulthood. Despite successful engraftment, some patients may still experience growth retardation, visual impairment, and damage to permanent teeth.³⁴⁶ Additionally, susceptibility to fractures is expected for some time after successful transplantation. Monitoring of symptoms continues, by a multidisciplinary team including a pediatrician, an ophthalmologist, an audiologist, and a dentist.³⁴⁵

Guidelines

No guidelines for the management of osteopetrosis were identified in the search.

Summary

Overall there appears to be a favorable risk-benefit profile for the use of HSCT in the severe autosomal recessive infantile malignant form of osteopetrosis. For this indication HSCT is the only curative treatment. HSCT is performed as early as possible, once symptoms clearly indicate the severe form, usually before 3 months of age.^{346, 348} Symptom-specific treatment is recommended for the milder autosomal recessive form and the autosomal dominant form.