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Stem cell transplantation for children with nonmalignant disorders
The concept of stem cell transplant was first performed in 1956 in a patient with leukemia; however, this was quickly applied to nonmalignant disorders only a decade later in a patient with severe combined immunodeficiency. In patients with nonmalignant conditions, the goal is to replace a missing gene or enzyme in the hematopoietic/immune systems or to replete a bone marrow that is not functioning. Historically, conditioning regimens have been myeloablative, mimicking those used in malignant conditions, but myeloablative conditioning regimens are associated with numerous short- and long-term complications such as acute and chronic graft versus host disease (GVHD), infections, infertility, and organ damage. Full-donor chimerism levels are usually associated with success in the malignant setting, but in the nonmalignant setting, mixed-donor chimerism levels can be curative. Lowering the intensity of conditioning regimens has been used in an attempt to decrease complications, but this can also be associated with higher rates of graft failure and rejection. When approaching transplantation for nonmalignant disorders, careful consideration must be made regarding conditioning regimens. The goal is to decrease toxicity but at the same time provide enough ablation for cure.
1
What special considerations should be accounted for when performing a bone marrow transplant in a patient with Fanconi anemia?
Fanconi anemia (FA) is an inherited DNA repair disorder with heterogeneous clinical manifestations, including congenital anomalies, progressive cytopenias to frank bone marrow (BM) failure, and both hematologic and solid malignancies. FA patients are particularly sensitive to chemotherapy and radiation therapy, as first demonstrated by Gluckman et al. This study reported the dismal outcomes for 5 FA patients undergoing human leukocyte antigen (HLA)–matched sibling donor (MSD) BM transplant (BMT) with “standard dose” cyclophosphamide (CY). All 5 patients experienced severe acute GVHD, leading to death in 4. The current goal of conditioning regimens for FA patients is to eliminate radiation and minimize the use of CY by including fludarabine and busulfan as alternatives. In terms of graft source, BM from an HLA-MSD is the graft of choice when it is available; however, sibling cord blood units can also be used as a source, and the first successful cord blood transplant occurred in a patient with FA. For FA patients without an HLA-MSD, an HLA-matched unrelated donor (MUD) is the second best option, and for those without an HLA-matched unrelated marrow donor, there is no clear next best choice.
2
What complications related to FA still need to be monitored even after BMT?
Compared with the general population, FA patients have a markedly higher risk of malignancy, particularly squamous cell carcinomas of the aeroesophageal and/or anogenital tracts, in addition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In contrast to the general population, the peak hazard for solid tumors increases in a linear manner after the age of 10 years, increasing by over 10% per year after the age of 40. Because of this increased risk of epithelioid tumor risk, all patients should undergo frequent evaluations of the aeroesophageal tract (biannual dental evaluations and annual direct endoscopic laryngoscopy) and anogenital tracts (annual Pap smears and evaluations). Patients should additionally be encouraged to reduce risk by avoiding environmental exposures such as alcohol, tobacco products, and ultraviolet radiation.
3
What are the indications to proceed to BMT in a patient with Kostmann syndrome?
Kostmann syndrome is an inherited hematological disorder with severe neutropenia with an absolute neutrophil count (ANC) less than 0.2 × 10 9 /L and early onset of severe bacterial infections. BMT is the only curative option for Kostmann syndrome, but the successful reduction in infections with the use of GCSF has improved the overall long-term survival in those unable to receive a transplant. Nevertheless, these patients have a higher risk of transforming events, such as MDS or leukemia. Patients who do not respond to GCSF or who need very high doses of GCSF (15–20 micrograms/kg/day) to see a response should be considered for MSD or MUD BMT. In addition, patients who have BM dysplasias or cytogenetic abnormalities, including an isolated GCSFr mutation, should be considered for BMT.
4
How do you diagnose a patient with acquired severe aplastic anemia?
Acquired severe aplastic anemia (SAA) is regarded as the result of an immune-mediated destruction of hematopoietic cells. It is defined as pancytopenia with a hypocellular BM in the absence of an abnormal infiltrate or marrow fibrosis. The diagnosis of acquired SAA is based on the exclusion of other disorders that can cause pancytopenia and on the well-known Camitta criteria. To diagnose SAA, there must be two of the following: hemoglobin concentration less than 100 g/L, platelet count less than 50 × 10 9 /L, neutrophil count less than 1.5 × 10 9/ L. The modified Camitta criteria is used to assess severity. A BM biopsy is mandatory and will confirm an empty marrow; it should also exclude MDS, leukemia, or marrow metastasis from solid tumors. Cytogenetics and/or fluorescence in situ hybridization (FISH) analysis should also be sent to determine any chromosomal abnormalities.
5
What is the treatment for a newly diagnosed patient with SAA?
For newly diagnosed patients with SAA, the standard of care in those with an MSD is BMT. Event-free survival (EFS) rates in pediatric patients with an MSD are estimated in various studies to be between 85 and 100%. For those without a sibling donor, immunosuppressive therapy (IST) is given consisting of equine antithymocyte globulin (ATG) and cyclosporine, with hematological recovery in 50% to 70% of patients and excellent long-term survival among responders. For those who do not respond, alternate donor transplants are recommended. Additionally, some are considering alternate donor transplants as upfront therapy in those without sibling donors if they have a well-matched donor. Dufour et al. recently reported on the outcome of 29 children with acquired SAA treated with unrelated grafts as first-line treatment. The 2-year overall survival (OS) and EFS were 96% and 92%, respectively. These results appeared equal to a historical matched group of HLA identical sibling BMT and superior to patients receiving either an MSD or MUD transplant after failure of IST. In addition, results using haplo-identical related donors have been promising in patients who fail IST, with a recent study showing a 100% OS at 21 months post-BMT with minimal GVHD, 6 and trials are ongoing evaluating the use of haplo-identical related BMT as upfront therapy.
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