Acute Lymphoblastic Leukemia (ALL)

Allogeneic HSCT is used for pediatric patients with acute lymphoblastic leukemia (ALL), either in the 1st complete remission when a child is considered to be at high risk of leukemia recurrence (such as, for example, those with Ph+ ALL or with high levels of minimal residual disease), or in 2nd or further complete remission after previous marrow relapse. ALL is the most common indication for HSCT in childhood (Chapter 489). Several patient-, donor-, disease-, and transplant-related variables may influence the outcome of patients with ALL given an allogeneic HSCT. The long-term probabilities of event-free survival for patients with ALL transplanted in the 1st or 2nd complete remission is 60-70% and 50%, respectively. Inferior results are obtained in patients transplanted in more advanced disease phases. The use of radiotherapy, total body irradiation (TBI), during the preparative regimen offers an advantage in terms of better event-free survival compared to a regimen consisting of cytotoxic drugs alone (Fig. 129-1). Less intensive GVHD prophylaxis is also associated with a better outcome. Bone marrow is still the preferred source of stem cells to be employed for transplantation.

Figure 129-1 Cumulative probability of leukemia-free survival after human leukocyte antigen–identical sibling bone marrow transplantation for childhood acute lymphoblastic leukemia, by pretransplant conditioning regimen of total body irradiation (TBI) plus cyclophosphamide (CY) (upper line) or busulfan (Bu) plus cyclophosphamide (lower line). There was superior survival with the total body irradiation plus cyclophosphamide regimen.

(Data from Davies S, Ramsay NK, Klein JP, et al: Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia, J Clin Oncol 18:340–347, 2000.)

Acute Myeloid Leukemia (AML)

Allogeneic HSCT from an HLA-identical sibling is largely employed as postremissional treatment of pediatric patients with acute myeloid leukemia (AML) (Chapter 489). Many studies have shown that children with AML in 1st complete remission given allogeneic HSCT as consolidation therapy have a better probability of event-free survival as compared to those treated with either chemotherapy alone or with autologous transplantation. Results obtained in patients given HSCT from an HLA-identical sibling after either a TBI-containing or a chemotherapy-based preparative regimen are similar, the probability of event-free survival being on the order of 60-70%. Children with acute promyelocytic leukemia in molecular remission at the end of treatment with chemotherapy and all-trans retinoic acid or with AML and either translocation t(8;21) or inversion of chromosome 16 (inv.16) are no longer considered eligible for allogeneic HSCT in 1st complete remission in view of their excellent prognosis with alternative treatments. Around 40% of pediatric patients with AML in the 2nd complete remission can be rescued by an allograft from an HLA-identical sibling.

Chronic Myelogenous Leukemia (CML)

Allogeneic HSCT is considered to be the only proven curative treatment for children with Philadelphia positive (Ph+) CML. Leukemia-free survival of CML patients after an allograft is 45-80%, the phase of disease (chronic phase, accelerated phase, blast crisis), recipient age, type of donor employed (either related or unrelated), and time interval between diagnosis and HSCT being the main factors influencing the outcome. The best results are obtained in children transplanted during the chronic phase from an HLA-identical sibling within 1 yr from diagnosis. Treatment with the specific Bcr-Abl tyrosine protein kinase inhibitors (imatinib mesylate, dasatinib, nilotinib), which target the enzymatic activity of the Bcr-Abl fusion protein, could modify the natural history of the disease and, thus, the indications for transplantation. Infusion of donor leukocytes can re-induce a state of complete remission in a large proportion of patients experiencing leukemia relapse.

Juvenile Myelomonocytic Leukemia (JMML)

This is a rare hematopoietic malignancy of early childhood, representing 2-3% of all pediatric leukemias. JMML is characterized by hepatosplenomegaly and organ infiltration, with excessive proliferation of cells of monocytic and granulocytic lineages. Hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and pathologic activation of the RAS-RAF-MAP (mitogen-activated protein) kinase signaling pathway play an important role in the pathophysiology. JMML usually runs an aggressive clinical course, with a median duration of survival for untreated children <12 mo from diagnosis. HSCT is able to cure approximately 50% of patients with JMML. Patients transplanted from an unrelated donor have comparable outcome to those given HSC from an HLA-compatible related donor. Leukemia recurrence represents the main cause of treatment failure in children with JMML after HSCT, the relapse rate being as high as 40-50%. Because children with JMML frequently have massive spleen enlargement, splenectomy has been performed before transplantation. Spleen size at the time of HSCT and splenectomy before HSCT do not appear to affect the posttransplant outcome. While donor leukocyte infusion is not useful for rescuing patients experiencing disease recurrence, a 2nd allograft can induce sustained remission in around one third of children with JMML relapsing after a 1st HSCT.

Myelodysplastic Syndromes Other Than JMML

Myelodysplastic syndromes are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenia and a propensity to evolve toward AML. HSCT is the treatment of choice for children with refractory anemia with excess of blasts (RAEB) and for those with RAEB in transformation (RAEB-t). The probability of survival without evidence of disease for these children is 50-60% if the donor is an HLA-identical sibling, whereas that of patients transplanted from an alternative donor is slightly lower. It is still unclear whether patients with myelodysplastic syndromes and a blast percentage >20% benefit from pretransplant chemotherapy. HSCT from an HLA-identical sibling is also the preferred treatment for all children with refractory cytopenia. Transplantation from an alternative donor is also employed in children with refractory cytopenia associated to either monosomy 7, complex karyotype, life-threatening infections, or transfusion dependency. For children with refractory cytopenia, the probability of event-free survival after HSCT may be as high as 80%, disease recurrence being rarely observed. This observation has provided the rationale for testing reduced-intensity regimens in these patients.

Non-Hodgkin Lymphoma and Hodgkin Disease

Childhood non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) are quite responsive to conventional chemoradiotherapy, but some of these patients are at high risk for relapse. HSCT can cure a proportion of patients with relapsed NHL and HD and should be offered early after relapse, while the disease is still sensitive to therapy. If an HLA-identical sibling is available, allogeneic transplant should be offered to take advantage from the GVL effect. Patients with sensitive disease and limited tumor burden have favorable outcomes, with event-free survival rates of 50-60%.

Acquired Aplastic Anemia

HSCT from an HLA-identical sibling is the treatment of choice for children with the severe form of acquired aplastic anemia, defined as two of the following: platelet count <20,000/mm³, absolute neutrophil count <500/mm³, or reticulocyte count <1% when anemia is present, together with hypoplastic bone marrow (<20% total cellularity) (Chapter 463). The probability of survival with sustained donor engraftment for these patients is >80%, with younger patients having even better outcomes. Every child diagnosed with severe acquired aplastic anemia should undergo HLA-typing as early as possible in order to identify a suitable HLA-compatible family donor. Graft rejection represents the most important cause of treatment failure. Blood transfusion should be avoided whenever possible because sensitization to blood products increases the likelihood of graft rejection. GVHD prophylaxis combining cyclosporine and short-term methotrexate is associated with a better outcome as compared to cyclosporine alone (Fig. 129-2). Some studies have suggested that the addition of antithymocyte globulin to the classical conditioning regimen consisting of cyclophosphamide (200 mg/kg) can reduce the risk of graft rejection, particularly in patients with previous heavy sensitization to blood products. The use of G-CSF mobilized peripheral blood progenitors has provided inferior results with respect to the infusion of bone marrow cells.

Figure 129-2 Cumulative probability of survival after human leukocyte antigen–identical sibling bone marrow transplantation (BMT) for aplastic anemia, by graft versus host disease (GVHD) prophylaxis with cyclosporin alone (dotted line) or cyclosporine plus methotrexate (continuous line). GVHD prophylaxis combining cyclosporin and short-term methotrexate was associated with superior outcome compared to cyclosporin alone. EV, number of events occurring in each arm of randomization; N, number of patients in each arm of randomization.

(From Locatelli F, Bruno B, Zecca M, et al: Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis I patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EMBT randomized trial, Blood 96:1690–1697, 2000.)

Constitutional Aplastic Anemia

Fanconi anemia and dyskeratosis congenita are genetic disorders associated with a high risk of developing pancytopenia (Chapter 462). Fanconi anemia is an autosomal recessive disease characterized by spontaneous chromosomal fragility, which is increased after exposure of peripheral blood lymphocytes to DNA cross-linking agents, including clastogenic compounds, such as diepoxybutane, mitomycin C, and melphalan. Besides being at risk of pancytopenia, patients with Fanconi anemia show a high propensity to develop clonal disorders of hematopoiesis, such as myelodysplastic syndromes and acute myeloid leukemia. HSCT can rescue aplastic anemia and prevent the occurrence of clonal hematopoietic disorders. In view of their defects in DNA repair mechanisms, which are responsible for the chromosomal fragility, Fanconi anemia patients have an exquisite sensitivity to alkylating agents. Thus, they must be prepared for the allograft with reduced doses of cyclophosphamide. Many patients were once successfully transplanted after receiving low-dose cyclophosphamide and thoraco-abdominal irradiation. However, the use of this regimen is associated with an increased incidence of post-transplant head and neck cancers. Either reduced doses of cyclophosphamide alone or low-dose cyclophosphamide with fludarabine are currently employed for preparing Fanconi anemia patients to the allograft. Using these regimens, the success rate of HSCT from an HLA-identical sibling is on the order of 70-80%.

Allogeneic HSCT remains the only potentially curative approach for severe bone marrow failure associated with dyskeratosis congenita, a rare congenital syndrome characterized also by atrophy and reticular pigmentation of the skin, nail dystrophy, and leukoplakia of mucosa membrane. Results of allograft in these patients have been relatively poor, due to occurrence of both early and late complications, reflecting increased sensitivity of endothelial cells to radiotherapy and alkylating agents.

Thalassemia

Conventional treatment (blood transfusion and iron chelation therapy) has dramatically improved both the survival and quality of life of patients with thalassemia, changing a previously fatal disease with early death to a chronic, slowly progressive disease compatible with prolonged survival (Chapter 456.9). HSCT remains the only curative treatment for patients with thalassemia. In these patients the risk of dying from transplant-related complications is primarily dependent on patient age, iron overload, and concomitant hepatic viral infections. Adults, especially when affected by chronic active hepatitis, have a poorer outcome than children. Among children, 3 classes of risk have been identified on the basis of 3 parameters, namely regularity of previous iron chelation, liver enlargement, and presence of portal fibrosis. In pediatric patients without liver disease who have received regular iron chelation (class 1 patients), the probability of survival with transfusion independence is >90%, whereas for patients with low compliance with iron chelation and signs of severe liver damage (class 3 patients), the probability of survival is 60% (Fig. 129-3). As in other nonmalignant disorders the best pharmacologic combinations (such as that including cyclosporine A and methotrexate) should be employed to prevent GVHD.

Figure 129-3 Kaplan-Meier estimates of survival and thalassemia-free survival, and cumulative incidences of rejection and nonrejection mortality for 122 thalassemic patients <17 yr of age given a myeloablative preparative regimen including busulfan and cyclophosphamide.

(Courtesy of Dr. Emanuele Angelucci.)

Sickle Cell Disease

Disease severity varies greatly among patients with sickle cell disease (SCD), with 5-20% of the overall population suffering significant morbidity from vaso-occlusive crises and pulmonary, renal, or neurologic damage (Chapter 456.1). Despite the fact that hydroxyurea, an agent favoring the synthesis of HbF, has been demonstrated to reduce the frequency and severity of vaso-occlusive crises and to improve the quality of life for patients with sickle cell disease, allogeneic HSCT is the only curative treatment for this disease. Although HSCT can cure homozygous HbS disease, selecting appropriate candidates for transplantation is difficult. Patients with SCD may survive for decades, but some patients have a poor quality of life, with repeated hospitalizations for painful vaso-occlusive crises and central nervous system infarcts. The main indications for performing HSCT in patients with sickle cell disease are history of strokes, magnetic resonance imaging of central nervous system lesions associated with impaired neuropsychologic function, failure to respond to hydroxyurea as shown by recurrent acute chest syndrome, and/or recurrent vaso-occlusive crises and/or severe anemia and/or osteonecrosis. The results of HSCT are best, with a probability of cure of 80-90%, when performed in children with an HLA-identical sibling. The use of antithymocyte globulin during the preparative regimen has been shown to improve patient outcomes, preventing graft failure.

Immunodeficiency Disorders

HSCT is the treatment of choice for children affected by severe combined immunodeficiency (SCID) and other inherited immunodeficiencies (see Table 129-1). With an HLA-identical sibling, the probability of survival approaches 100%, with less favorable results for patients transplanted from an unrelated volunteer or an HLA-partially matched relative. Some children with SCID may be transplanted without receiving any preparative regimen, in particular those without residual NK activity or maternal T-cell engraftment. Sustained donor engraftment is more difficult to achieve in children with Omenn syndrome, hemophagocytic lymphohistiocytosis, or leukocyte adhesion deficiency. Life-threatening opportunistic fungal and viral infections occurring before the allograft adversely affect the patient’s outcome after HSCT. Patients with the most severe immunodeficiencies must be transplanted as early as possible.