Hematopoietic Stem Cell Transplantation in Children and Adolescents

Hematopoietic stem cell transplantation (HSCT) indications and practices have changed significantly over the last 20 years. Evolving hematopoietic stem cell sources, less toxic conditioning regimens, and improving graft-versus-host disease prophylaxis and therapy have broadened the application of HSCT from malignant conditions to increasing numbers of nonmalignant diseases.After completing this article, the reader should be able to:A 1-year-old child is referred to your office for a developmental assessment due to delayed speech and gross motor skills. You notice coarse facial features and on physical examination document corneal clouding, hepatosplenomegaly, and numerous skeletal deformities. You suspect a metabolic disorder and request an urgent referral to a metabolic specialist. The specialist clinically diagnoses Hurler syndrome (mucopolysaccharidosis IH) and confirms α-L-iduronidase deficiency with urinary glycosaminoglycan testing and subsequently by enzyme deficiency in fibroblasts. While genetic testing results are pending, you discuss the case with the metabolic specialist and agree that an urgent referral to a pediatric hematopoietic stem cell transplantation (HSCT) specialist is warranted before genetic testing results are available. The best neurologic outcomes are seen when HSCT is performed as soon as possible, preferably before age 2 years. Having general knowledge about HSCT planning and complications, you help the family prepare for their meeting with the pediatric HSCT specialist, allowing for a more productive consultation, and offer to share ongoing care of the child both before HSCT and during subsequent follow-up.HSCT is the procedure of infusing blood stem cells from a donor into a recipient. When the donor and recipient are different people, the procedure is termed an allogeneic HSCT; if the donor and recipient is the same person, it is an autologous HSCT. Syngeneic HSCT describes a donation between identical twins.Hematopoietic stem cells (HSCs) may be collected from bone marrow, peripheral blood, or the umbilical cord/placental unit of a newborn (UCB).Human leukocyte antigens (HLAs) are tested at major histocompatibility loci: Class I (A, B, and C) and Class II (DR; DQ in some centers). At least 6 loci routinely are analyzed for a UCB product and 8 to 10 loci for a live donor product (ie, bone marrow or peripheral blood). The degree of matching is expressed as the numerator of matched loci over the denominator of loci tested. HLA matching may be tested at low (antigenic), medium, or high (allelic) levels of resolution.Graft-versus-host disease (GVHD) is a serious and potentially life-threatening complication of HSCT in which the donor T cells cause an inflammatory response in the recipient tissues. This complication is described in detail later, but the risk of its development has been historically reduced by the best possible HLA matching at major loci as well as the use of a related donor due to closer matching at untested minor histocompatibility antigens. Newer approaches to haploidentical HSCT (see definition later) and novel GVHD prevention strategies, however, are reducing GVHD rates, even in the setting of greater HLA disparity.Allogeneic HSC donors are further characterized in terms of the relationship between the donor and recipient (Table 1). Fully matched related donations can come from a minor or adult sibling or rarely a parent (often with a history of consanguinity). Haploidentical HSCT involves donation from a first-degree relative (usually a mother) who shares 1 haplotype, typically matched at 5 to 8 of 10 HLA loci. Unrelated HSC products may come from UCB donations or a living adult donor (not minors).Conditioning refers to the preparative chemotherapy, immunotherapy, and/or radiotherapy given to a recipient before stem cell infusion to facilitate engraftment of allogeneic donor HSCs and to prevent rejection. In this setting, the HSCs are a primary component of the curative therapy; in autologous HSCT, the conditioning is the actual therapy and the HSCs are administered to rescue the hematopoietic system. Myeloablative conditioning refers to intensive chemotherapy and/or radiation doses sufficient to cause bone marrow aplasia in the absence of HSC infusion. Reduced-intensity conditioning (RIC) describes nonmyeloablative or less intensive conditioning regimens.HSCs for UCB and autologous donation must be cryopreserved, whereas most allogeneic live donor products are donated during the conditioning of the recipient. Allogeneic products may also be manipulated to reduce plasma, red blood cells, or T cells, depending on the donor-recipient blood group matching/mismatching, the stem cell source, the routine practices of the HSCT center, and the indication for HSCT.Internationally, more than 2,000 allogeneic HSCTs were reported to have been performed in recipients younger than age 20 years in 2012. (1) The use of UCB has increased over the last 20 years, as have donations from unrelated live donors. These trends are affected by improvements in supportive care (including GVHD prevention and treatment) as well as donor availability, with expanded live donor and UCB registries.RIC was developed for older recipients who were ineligible for myeloablative conditioning due to comorbidities. Its use has expanded to many nonmalignant indications for children in whom a phenotype can be reversed with even relatively low numbers of engrafted donor HSCs (mixed donor chimerism) and there is a mix of hematopoietic cells of donor and recipient origin. Several conditions, such as severe combined immune deficiency, hemophagocytic lymphohistiocytosis, and hemoglobinopathies, are known to be cured with stable mixed-donor chimerisms as low as 20% to 30%. (2) The appeal of RIC lies in reduced rates of GVHD and transplant-related mortality (TRM) in addition to fewer acute and late toxicities due to lower doses of conditioning agents.The increased use of RIC and haploidentical HSCT has also influenced the growing proportion of HSCT recipients with nonmalignant diseases. This trend toward HSCT for nonmalignant conditions is due to improved outcomes with upfront non-HSCT childhood leukemia therapies as well as advancements in the safety of HSCT. As the risks of morbidity and mortality decrease, the potential application of HSCT as a curative option for various nonmalignant diseases broadens.Expertise in haploidentical HSCT is increasing worldwide, particularly in Europe and the United States. Its appeal lies in the almost universal availability of a donor, particularly for potential recipients whose HLA haplotypes are underrepresented on existing volunteer registries. Risks of GVHD and infection (due to T-cell depletion) as well as required laboratory infrastructure complicate its application, but improved supportive care options have increased the practice of haploidentical HSCT. Newer techniques such as the use of cyclophosphamide after HSC infusion have resulted in markedly improved rates of engraftment and reduced rates of GVHD and infectious complications. (3)Allogeneic HSCT involves the replacement of the deficient recipient hematopoietic system with that of the donor. The best possible HLA-matched donor is used, with a preference for matched sibling, followed by matched related donors. HLA testing and matching is currently limited to 8 to 10 major histocompatibility loci for living donors, yet minor histocompatibility (H) antigens also influence the risk of GVHD. Minor H antigens are potentially immunogenic peptides genetically coded outside of the major histocompatibility complex (MHC). (4) The coding loci for H antigens are scattered throughout the genome in contrast to the MHC being coded on chromosome 6. As a result, a related fully HLA-matched donor is almost always preferred to an unrelated donor with the same number of matched loci. Unrelated donors may be identified through international live donor registries or accredited public UCB banks. Identifying an unrelated donor and proceeding with HSCT usually takes 1 or more months, depending on the rarity of the recipient HLA-typing, donor availability to proceed with donation, and medical clearance of both donor and recipient. This process is generally shorter for UCB products because the donation has already been made and the product has been cryopreserved.Allogeneic stem cells can be donated as 1 of 3 stem cell sources:Table 2 describes the method of donation as well as advantages and disadvantages of each source of allogeneic HSCs. Peripheral blood stem cells are less commonly used in pediatric HSCT recipients due to higher risks of chronic GVHD; they are typically only used for malignant indications or as part of a RIC protocol. Many considerations are balanced in choosing a stem cell source: the recipient’s underlying condition, the degree of HLA matching, the urgency of the HSCT, the risk to the donor (particularly for minor sibling donors who cannot consent for themselves), donor preference for method of donation, donor health status (which may preclude a method of donation), ABO status of donor and recipient, and size discrepancy between donor and recipient. The stem cell dose (ie, number of donor HSCs) required for the HSCT recipient is calculated based on recipient weight, which may not be achievable based on the size of a prospective living donor. Donations from living donors are almost always collected within 2 days of infusion to ensure that the HSCT is not subsequently cancelled due to a change in the recipient’s eligibility status and to avoid cell loss with cryopreservation. UCB products contain a fixed number of cryopreserved stem cells. A given UCB unit may have sufficient stem cells for a smaller recipient but may be inadequate for a larger patient.Additional considerations include the age of the donor, the donor sex, and any pregnancies (if applicable). Younger donors generally have more cellular bone marrows and produce greater HSC yields. In addition, their donations are associated with lower GVHD rates in recipients. Donations from females, particularly with increasing parity, are associated with higher rates of GVHD. Male recipients with female donors are at highest risk. (10)Autologous stem cell collections are almost always from peripheral blood, with bone marrow harvests usually reserved for failed peripheral blood collections. Such collections are typically timed at the point of initial hematopoietic recovery following myelosuppressive chemotherapy, in combination with granulocyte colony-stimulating factor (G-CSF). “Steady-state” collections can also be performed with G-CSF administration alone. The HSCs are then cryopreserved to be used later to rescue the patient following high doses of chemotherapy or radiation, allowing for more rapid hematopoietic recovery.HSCs are infused into the recipient after conditioning chemotherapy and/or radiation (see next section). Such cells are infused into the venous system using a central vascular access device but may also be infused into a peripheral intravenous catheter. No filters can be placed on the tubing, which could block the HSCs from entering the circulation. Premedication is required for cryopreserved products to avoid reaction to the preservative required for the cells to tolerate freezing, and such premedication is also used for ABO incompatibilities with bone marrow products. The HSCs enter the marrow via adhesion molecule recognition and start to grow and mature immediately. However, 2 to 3 weeks generally is required for measurable neutrophil counts (or engraftment) and for red blood cell and platelet transfusion independence. The fastest rates of HSC engraftment are seen with autologous rescues and with peripheral blood stem cell products; UCB products are often the slowest to engraft. (9)Conditioning, or the preparative regimen, refers to the combination of chemotherapy, immunotherapy, and/or radiation therapy given to an HSCT recipient before the HSC infusion. Such conditioning is usually administered over 1 to 2 weeks before HSC infusion. Immune suppression, notably reduction or ablation of innate immune and T cells, is necessary to prevent rejection of the HSCs in the setting of allogeneic HSCT. Conditioning may also serve as disease-directed therapy in allogeneic HSCT for malignant disease. Serotherapy is a form of immunotherapy typically involving antithymocyte globulin or alemtuzumab (monoclonal antibody to CD52) that is intended to address host immune cell depletion, although it is primarily administered for in vivo GVHD prophylaxis. Total body irradiation (TBI) is highly myelosuppressive but is associated with many undesirable acute and late toxicities.Myeloablative conditioning is standard for malignant disease HSCT indications and has been used historically for nonmalignant conditions as well. The goal of myeloablation is to replace all cell lines of the hematopoietic system (eg, lymphoid, myeloid) completely with donor HSCs. Although most experts consider eradication of all recipient blood cells to be essential for a person with leukemia, as few as 20% donor cells in the deficient cell line can reverse the abnormal phenotype in a nonmalignant condition. (2) The ability to cure a nonmalignant disease in the setting of mixed-chimerism following RIC has greatly increased the safety and application of HSCT to a broader number of nonmalignant diseases. Graft failure after RIC often results in autologous recovery of the recipient’s original HSCs.Autologous HSCT conditioning regimens are almost exclusively composed of high-dose combinations of chemotherapy with or without radiation therapy targeted at the underlying disease (usually malignant). The goal is to rescue the patient after otherwise intolerable doses of these agents given to intensify therapy.HSCT is associated with numerous acute and long-term toxicities. The conditioning, its intensity (myeloablative versus RIC), preexisting comorbidities, prior chemotherapy exposure, and the stem cell source all influence the risks of complications and TRM. Children and adolescents generally tolerate myeloablative conditioning better than adults, but TRM rates are still typically 5% to 10%. RIC was initially designed to offer HSCT to patients with comorbidities, so TRM rates are inherently lower, as are rates of many toxicities. HSCT adverse effects on growth, development, and fertility are especially pertinent in children and adolescents (Table 3). (11)(12) A detailed discussion of these late effects is beyond the scope of this article, but comprehensive follow-up by general pediatricians and a team with expertise in HSCT late effects care and surveillance is recommended. Surveillance guidelines have been published by the Children’s Oncology Group and other research bodies. (11)(12)(13)HSCT usually involves myelosuppression as well as functional impairment of adaptive immunity. (14) As mentioned previously, neutrophil engraftment typically occurs 2 to 3 weeks after HSC infusion, which is an important milestone for innate immune protection against bacteria and fungi. Natural killer cell recovery usually is complete by 1 month post-HSCT, offering additional protection against infection. T-cell function is impaired by intent during periods of prophylaxis or therapy for GVHD, and GVHD in itself is a dysregulated immune state, with poor function and protection against infection. For those HSCT recipients who can stop GVHD prophylaxis by 6 months post-HSCT, lymphocyte class switching (producing immunoglobulin [Ig]G after IgM production) can be seen between 6 and 8 months after HSC infusion.Children must be monitored for opportunistic infections after HSCT. Bacteremia and sepsis are frequent, particularly during the neutropenic phase before engraftment. Fungal infections are also a concern during neutropenic phases or corticosteroid therapy. Respiratory viruses such as respiratory syncytial virus and adenovirus can be devastating in an immunocompromised host. infection or with and virus surveillance and based on international guidelines and can be associated with prophylaxis for in recipients is generally administered for to 1 and may also some protection against virus is a virus that is generally in an host. However, it can cause and in HSCT recipients if is prophylaxis is also immune has been for and in with international HSCT have guidelines for infectious and international guidelines also for the of and in pediatric HSCT recipients. children after HSCT, but must the of live for the of for children who have HSCT can be and are all children who myeloablative HSCT This of the is due to from conditioning agents and is by a inflammatory in the setting of can between the and and intensive with and therapies is often with typically after neutrophil engraftment. As the intensity of the conditioning is the of is commonly required is The risk of the of the and and infections are a children due to which may be related to or when many other complications many children and adolescents to ensure and In addition, metabolic are often increased due to a state, with required HSCT often have the and most method of and with potential due to or GVHD, should be when about In the absence of has potential to the in which is important because the is at risk of from conditioning, syndrome GVHD, and is particularly for more intensive conditioning of and may reduce complications as and is for patients with high stable engraftment has research is the of on after HSCT. is a serious seen in to of HSCT with risk increased for those with preexisting allogeneic HSCT children with and those who or involves of due to with and and is with of enzyme Although prevention is can from in to agents such as in severe with has yet to from the and of complications after HSCT is with being infection and considerations include from radiation or and chronic GVHD. Respiratory failure and is associated with rates of mortality in immunocompromised recipients of HSCT. is an complication seen almost exclusively in allogeneic HSCT. involves and exposure, and of donor T cells against recipient tissues. GVHD the or and these are to chemotherapy and radiation and are in cells. the of each affected with an the to with and potentially additional Although some degree of GVHD can be associated with better for those with (due to a there is in nonmalignant and GVHD a to the application of HSCT for many nonmalignant conditions, particularly if matched family donor GVHD is often seen months after HSCT at 6 and can be a devastating this or and can in and disease. and can also of immune is required for more severe which can in opportunistic infection. particularly of and is a major GVHD can replace the for which HSCT was and although less in children than in adults, must always be during the process for between the donor T cells and the HSCT recipient results in the ability to reduce and usually of immune occurs at after HSC infusion in the absence of GVHD, with periods of prophylaxis and higher levels for nonmalignant HSCT disease For those who GVHD, the GVHD is for a sufficient of immune is and subsequently For this HSCT recipients are not to immune suppression, in contrast to patients who most allogeneic HSCT in children were for malignant diseases such as and improving cure rates using chemotherapy for such the proportion of nonmalignant disease indications for pediatric HSCT to malignant disease indications for allogeneic HSCT in children are acute and some and features or are usually (Table a with risk of to acute leukemia, is almost always with HSCT in leukemia is often with so fewer affected children and adolescents are to HSCT is performed routinely for children with and for Many are high-dose chemotherapy and autologous HSCT, particularly for children younger than age 3 years, in an to or radiation therapy to the research is the use of autologous HSCT in children and adolescents with such as who have HSCT is performed for nonmalignant disease indications as rates of TRM and GVHD are These diseases risks of morbidity or mortality and often complex supportive care (Table for are associated with risks of and complications. For some of these conditions, the risks of HSCT are affected by the of donor and the for HSCT may be immune such as severe combined immune deficiency, chronic and syndrome are of nonmalignant diseases for which HSCT is commonly A body of the safety and of HSCT for severe with increasing to in for bone marrow failure major has an for related and unrelated HSCT, with a phenotype of transfusion and risk of cell disease is as a disease with limited and of best supportive As a result, is growing in the application of HSCT to those with Although a history of complications of been in the to HSCT, the HSCT techniques have increasing from and HSCT to before notably neurologic and metabolic diseases such as are routine indications for HSCT, although the potential are less for other metabolic diseases. 5 some of the more standard with an that HSCT is performed in some for life-threatening metabolic diseases with fewer potential HSCT can help prevent neurologic in a metabolic disease due to replacement of the deficient enzyme by from the HSCs following engraftment. HSCT generally only and not reverse neurologic and that enzyme replacement can months to the central system due to of into the HSCT is for other of the metabolic are not reversed with HSCT. about the of HSCT should relatively soon after a and those who such conditions routinely should be of indications for this group of practice of autologous HSCT for nonmalignant conditions is relatively results for those with severe that some patients may in terms of or reduced disease of the bone marrow and peripheral blood with fewer in addition to the use of agents such as cyclophosphamide as part of the conditioning, may this of therapy for are autologous HSC and vivo with following conditioning designed to the manipulated cells a The use of autologous HSCT for and is an of but these indications are at

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