Introduction

Allogeneic hematopoietic SCT (AlloSCT) from related or unrelated histocompatible donors has been well established as potentially curative therapy for children and adults with a variety of malignant and nonmalignant hematologic disorders, primary immunodeficiencies (PIDs) and metabolic diseases.¹ The concept underlying SCT with RIC in patients with malignant diseases involves a shift from the paradigm that eradicating tumors requires myeloablative chemoradiation to the concept that the donor's immune cells are utilized for tumor eradication, relying on allogeneic graft versus tumor effects. In contrast, in nonmalignant diseases with RIC-SCT, the aim is to create an immunologic platform of host–donor tolerance using pre- and post-transplantation immunosuppression. Once engrafted, these donor cells may partially or completely correct the underlying defect and, in many such disorders, mixed chimerism is sufficient for cure, thus obviating the need for myeloablative conditioning (MAC). Elimination of high-dose cytotoxic therapy allows medically infirm patients to be treated with SCT.² The goals of an RIC regimen are to prevent graft rejection, maintain stable donor-derived hematopoiesis and to provide a GVL effect, while decreasing the short- and long-term complications of MAC therapy.

Multiple RIC regimens have been developed in a variety of transplant centers ranging from predominantly immunosuppressive minimal intensity conditioning (MIC) regimens to those that are significantly myelosuppressive (Figure 1). Many such regimens incorporate in vivo T-cell depletion with serotherapy (alemtuzumab or antithymocyte globulin (ATG)) to achieve host immune suppression. A truly nonmyeloablative/MIC regimen should not eradicate host hematopoiesis and should allow relatively prompt hematopoietic recovery (<28 days) without a transplant, but be sufficient to enable either full or partial donor engraftment to occur post-SCT.² In contrast, RIC regimens require a SCT for hematologic recovery and if the graft is rejected, prolonged aplasia typically occurs.

Figure 1.

A hierarchy of commonly used minimal intensity, reduced intensity and myeloablative conditioning (MAC) regimens in pediatric patients. MMF, mycophenolate mofetil; Gy, gray; F, fludarabine; cyclo, cyclophosphamide; DXT, dexamethasone; BU8, busulfan 8 mg/kg; BU14–16, busulfan 14–16 mg/kg; CY120-200, cyclophosphamide 120–200 mg/kg; DLI, donor lymphocyte infusion; ATG, antithymocyte globulin.

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RIC-SCT in children with malignant disorders

There are multiple reports of the use of RIC-SCT in adults with malignant diseases. Initial studies were performed in elderly patients with malignant disorders who had HLA-matched sibling donors. However, over the last 10 years RIC-SCT studies have been conducted in young adults with alternative donor sources. These studies in adults with malignant disorders such as AML, CML, non-Hodgkin's lymphoma, Hodgkin's lymphoma (HD), multiple myeloma and renal cell carcinoma have clearly demonstrated that this approach is safe and feasible even in elderly patients and in those with preexisting comorbidity and suggested a graft versus malignancy effect.² Some studies have compared the outcomes of RIC-SCT versus MAC regimens and results are broadly comparable.^{3, 4}

There are relatively few RIC-SCT studies in pediatric patients with malignant diseases. Pediatric patients who undergo intensive chemotherapy are at risk of developing comorbidities, which preclude them from receiving standard myeloablative AlloSCT. We at Columbia University Medical Center (CUMC) have previously reported the preliminary results in 14 children who received fludarabine (FLU)-based regimens followed by AlloSCT for various malignant diseases. The disease distribution in this study was as follows: six patients with HD (three patients were in second CR, one patient was in PR) and two patients had progressive disease (PD); one patient with non-HD in PR; two patients with neuroblastoma (one in CR and one with PD); one patient with Wilms' tumor with PD; one patient with CML in chronic phase; one patient with AML in first CR and two patients with myelodysplastic syndrome (MDS) in the refractory anemia stage. The majority of patients received BU (8 mg/kg)/FLU/ATG except one patient with CML who received BU (8 mg/kg)/FLU/alemtuzumab and one patient with HD who received CY/FLU/ATG. Tacrolimus and mycophenolate mofetil (MMF) were used for GVHD prophylaxis. The incidence of grade II–IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) was 38 and 0%, respectively. In this study we demonstrated a 1-year overall survival (OS) of 78% (Table 1).⁵ This study demonstrated that a high degree of sustained donor chimerism and myeloid engraftment can be achieved in children with malignant diseases following RIC therapy with either a matched family donor or unrelated cord blood donor. In another study, Gomez-Almaguer et al.⁶ reported their experience with RIC-SCT in 16 children and adolescents with malignant diseases who received allografts from matched sibling donors following RIC with BU/CY. Thirteen children had ALL (seven in second remission, one in third remission, one in first relapse, three in second relapse and one primarily refractory to therapy), one patient had AML and one had CML in accelerated phase. GVHD prophylaxis consisted of CsA/MTX, the incidence of aGVHD and cGVHD was 9.5 and 13%, respectively. In this study the 2-year OS rate was 44%. However, the event-free survival was 47% for high-risk ALL patients (Table 1). Overall, this regimen was very well tolerated and cost effective as half of the patients received RIC-SCT in an outpatient setting. The results of these studies should be interpreted with caution until larger groups of children with a homogenous diagnosis and disease status, uniform cell source and RIC regimens are utilized. There are only three disease-specific studies of RIC-SCT reported in children with malignancies. In the first study, 11 children with high-risk ALL received an FLU/BU/ATG-based RIC-SCT with GVHD prophylaxis consisting of CsA only (Table 1).⁷ A high degree of donor chimerism was achieved.⁷ In this very high-risk group of patients, who were ineligible for standard intensity conditioning, 36% of patients achieved remission following RIC-SCT. Two patients developed grade IV aGVHD. Two of five patients surviving more than 100 days developed cGVHD. Overall transplant-related mortality (TRM) was very high (50%).⁷ In the second study at CUMC, eight pediatric patients with CD33⁺ AML in CR1 (n=5) or CR2 (n=3) received targeted immunotherapy with gemtuzumab ozogamicin after RIC-SCT during the period of potential minimal residual disease.⁸ The RIC regimen consisted of BU (8 mg/kg)/FLUATG and tacrolimus/MMF were used for GVHD prophylaxis. The RIC regimen was well tolerated without any significant morbidity or mortality and the incidence of grade II–IV aGVHD and cGVHD was very low (12.5% each). In this study we demonstrated an OS of 63%, which is comparable to the standard intensity regimen. Claviez et al.⁹ reported a small study of six children with refractory (n=4)/relapsed (n=2) HD who received RIC consisting of BU (8 mg/kg)/FLUCY. In this difficult to treat group of patients, two of six patients responded and three of six survived following RIC-SCT.

Table 1 - Reduced intensity allogeneic stem cell transplant in children and adolescents with malignant disease.

Full table

The chimeric state after RIC-SCT provides an ideal platform for adoptive cellular immunotherapy. Donor lymphocyte infusion (DLI) can be given after RIC-SCT for conversion from mixed to full donor chimerism, as preemptive therapy to prevent relapse or for the treatment of relapse of hematologic malignancies and post-transplant lymphoproliferative disorder (LPD). Achievement of remission following DLI depends to a large extent on the underlying disease with best response demonstrated in the treatment of relapse of CML (70–80%)¹⁰ and in the pediatric setting in juvenile myelomonocytic leukemia and other myeloproliferative/myelodyplastic disorders and to a lesser extent in Ph⁺ ALL.¹¹ Data on the use of DLI for relapsed pediatric malignancies after RIC-SCT are limited, but in principle RIC-SCT may allow patients with such diseases who are not fit for conventional intensity conditioning to benefit from immunotherapy with DLI either preemptively or in relapse. For the majority of patients however, at present, the cytoreduction afforded by conventional MAC offers the best platform from which to exert a GVL effect after a primary transplant procedure. However, for patients with myeloid leukemias, MDS and Ph⁺ ALL who relapse after a myeloablative SCT having never developed significant GVHD, RIC may enable a second transplant procedure engineered to give GVH/GVL to be performed safely even within a few months of the initial SCT and the cytoreduction afforded by RIC may optimize the chance of a successful GVL effect. Raghuram et al.¹² reported long-term survival in 3/6 children with hematologic malignancies relapsing after initial myeloablative transplant and likewise Nagler et al.¹³ observed disease-free survival in 6/12 mostly adult patients receiving a second nonmyeloablative SCT for hematologic malignancies. A variety of maneuvers can be performed to enhance the likelihood of developing GVH/GVL in this setting: these include reduction in serotherapy, early withdrawal of immunosuppression, DLI and administration of cytokines such as interleukin-2 and IFN- post-SCT.

Reduced intensity SCT in nonmalignant pediatric diseases

The use of RIC-SCT has been more extensively studied in children with nonmalignant diseases. In a number of these disorders, the achievement of mixed chimerism can be curative, providing a strong rationale for the use of RIC regimens. This has also enabled SCT to be performed in children with preexisting comorbidities that preclude conventional conditioning. Furthermore the use of RIC may reduce both the short- and long-term toxicities of BMT, making this approach particularly attractive for children with nonmalignant disorders. Clearly, RIC has been used for many years in patients with severe aplasia, in whom myeloablation is not needed and with Fanconi anemia, in which high-dose chemo/radiotherapy was associated with unacceptable toxicity. A list of other conditions treated successfully with RIC-SCT is shown in Table 2.

Table 2 - Primary immunodeficiencies treated with RIC-SCT.

Full table

The principles behind SCT in patients with a nonmalignant disease are to prevent rejection of graft and create a niche for donor cell engraftment at a level sufficient for cure of the underlying genetic disease. In order to do this with an RIC regimen where less intensive chemo/radiotherapy is used, immune suppression is required to prevent rejection of the graft and donor versus graft alloreactivity is required in order to 'make space' for the donor stem cells. This is evidenced by the higher incidence of failure of engraftment following RIC-SCT from matched sibling donors,¹⁴ where the graft versus recipient alloreactivity is lower than in the unrelated donor setting. The level of engraftment needed for disease response is likely to be both disease-specific (for example, higher levels of donor engraftment are required to cure hemoglobinopathies and Hurler's syndrome than some immunodeficiencies) and lineage-specific (for example, myeloid/erythroid engraftment are required for cure of chronic granulomatous disease and hemoglobinopathies, whereas lymphoid engraftment may be sufficient to cure many forms of SCID).

Overall outcome

Although many centers now use RIC-SCT in children with nonmalignant diseases, the largest single center experience comes from Great Ormond Street Hospital. Our outcomes for treatment of nonmalignant diseases with RIC regimens compare favorably with conventional conditioning. Between 1998 and 2006, 113 patients with PIDs or hemophagocytic lymphohistiocytosis (HLH) (Table 2) have received RIC-SCT. A total of 20 patients received MIC and 93 an RIC regimen. Donor source was as follows: matched unrelated donors (MUD) (n=52), mismatched unrelated donors (n=29), matched sibling donors (n=14), matched family donors (n=7), mismatched umbilical cord blood (UCB) (n=4), UCB (n=1) and mismatched matched family donors (n=3). Eighteen patients had severe organ toxicity before transplant, including previous ventilation (n=12), significant liver or renal impairment (n=8) or total parental nutrition-dependent enteropathy (n=8). Five patients had DNA repair defects. At a median follow-up of 2.9 years (range 2 months to 8 years) the OS for these patients was 82% (93/113) and 91/133 (81%) had stable donor engraftment. Fourteen patients (12%) had or were likely to require additional procedures, including second SCT, marrow infusion, additional CD34⁺ cells or gene therapy. The survival curve for each disease is shown in Figure 2. Survival rates of 80% were observed in children receiving SCT for SCID, T-cell immune deficiency, X-linked LPD and HLH and Wiskott–Aldrich syndrome. Interestingly, as shown in Figure 3, there was no significant difference in survival for patients transplanted from single-antigen mismatched donors compared to 10/10 matched donors, highlighting the possibility that RIC may allow SCT from less than ideal donors. Causes of death were as follows: multiorgan failure (n=5), infection (n=4), pneumonitis (n=4), GVHD (n=2), recurrent disease, veno-occlusive disorder, transplant-related microangiopathy, iatrogenic and pulmonary hypertension (n=1 each).

Figure 2.

Overall survival of pediatric patients undergoing RIC-SCT for PID/HLH stratified by disease. WAS, Wiskott–Aldrich Syndrome; phagocytic, neutrophil phagocytic defect; XLP, X-linked lymphoproliferative disorder; HLH, hemophagocytic lymphohistiocytocis; SCID, severe combined immunodeficiency syndrome; T-cell def, isolated T-cell immunodeficiencies; Imm Dys, immunodysregulatory disorders; CD40 ligand def, CD40 ligand deficiency.

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Figure 3.

Overall survival in pediatric patients undergoing RIC-SCT for PID/HLH stratified by HLA-matched versus -mismatched donor. There was no significant difference in survival for HLA-matched compared to -mismatched donors (P=0.2).

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Primary immune deficiency

Comparison of our results in children with primary immunodeficiency (PID) transplanted from unrelated donors using RIC versus conventional MAC15 showed a decreased overall mortality (2/33 RIC compared to 4/19 MAC, P<0.01). There was no difference in the incidence of aGVHD, but there was an increase in viral infections/reactivations (29% for RIC compared to 21% following MAC, P=0.02). Viral infections in those receiving an RIC included CMV (n=3), adenovirus (n=5) and EBV (n=10). There was also an increased rate of mixed chimerism when compared to MAC (45% mixed chimerism of which 13% had low-level donor chimerism for RIC versus 36% mixed chimerism and 0% low-level donor chimerism for MAC).¹⁵ However, in general, this appeared to stabilize or improve with withdrawal of immunosuppression and there were low rates of recurrent disease (2/23 patients). Immune reconstitution with RIC-SCT was similar to that seen after conventional intensity conditioning with similar kinetics of CD19, CD3 and CD4 recovery (Figure 4). OS was improved in the RIC group, mainly through improved survival in patients with non-SCID PID (Figure 5).

Figure 4.

Kinetics of recovery of CD3 (a), CD4 (b), CD19 (c) and PHA (d) after reduced intensity conditioning (RIC) and myeloablative transplantation (MAT) in children with primary immunodeficiencies. There was no statistical difference in speed of immune reconstitution between the two groups. This research was originally published in Blood (Rao et al.). Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using an RIC regimen (Blood 2005; 105: 879–85; The American Society of Hematology).

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Figure 5.

Kaplan–Meier analysis comparing overall survival (OS) in children with primary immunodeficiences receiving reduced intensity conditioning (RIC) or conventional conditioning (MAC or MAT) SCT. (a) OS in all patients was significantly better in patients who received RIC (94% OS) compared to MAC (53% OS). When divided into disease type, the improved survival following RIC was particularly marked in patients with non-SCID (who had a 54% death rate following MAC compared to a 30% death rate following MAC for SCID). (b) OS following either RIC or MAC in patients with SCID. (c) OS following RIC or MAC in patients with non-SCID.

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The Seattle group has investigated an MIC regimen without serotherapy in 14 patients (12 children and 2 adults) with PID and coexisting infections, organ toxicity or other factors precluding conventional SCT.¹⁶ The majority of patients received 200 cGy TBI plus FLU (30 mg/m² per day; days -4 to -2) as conditioning and all patients received HLA-matched grafts with intensive post-graft immunosuppression with CsA/MMF. Thirteen patients established mixed (n=5) or full (n=8) donor chimerism and one rejected the graft. OS (3 years) was 62% with a TRM of 23%. Eight of ten evaluable patients had correction of immune dysregulation with stable donor engraftment. However, there was a high rate of GVHD with 11/14 developing significant aGVHD (mostly grade II) and extensive cGVHD in eight patients, reflecting the use of peripheral blood as the stem cell source and the absence of serotherapy. While this approach may be associated with a lower incidence of viral infections/reactivations, notably EBV than RIC regimens utilizing serotherapy,¹⁷ the incidence of cGVHD is the major obstacle to broader use of this regimen in children with nonmalignant disorders.

HLH and Langerhans cell histiocytosis

Primary HLH is a disorder of immune dysregulation caused by at least four different genetic defects. SCT is the only curative therapy and it is clear that mixed chimerism with donor-derived T cells is sufficient for cure. Further, patients often present late and have high rates of comorbidity. With conventional SCT regimens, there is high morbidity and mortality in such patients. We recently reported our data on 12 patients with HLH transplanted with RIC regimens.¹⁸ As of August 2007, we have transplanted 21 patients with HLH using RIC. Seventeen patients (81%) are alive and in remission at a median follow-up of 28 months. This compares well to historical control data from the HLH 94 registry, reporting a 64% OS at 3 years using conventional conditioning.¹⁹ Table 3 shows a comparison of survival data between our RIC cohort and published data using conventional regimens by donor type. Five of twenty-one patients in the RIC cohort had mixed chimerism, including one patient who had only donor T- but not NK-cell engraftment, but none have relapsed.

Table 3 - Comparison of overall survival of patients with HLH receiving a RIC regimen versus historical data using myeloablative conditioning.

Full table

We and others have also successfully transplanted small numbers of children with refractory Langerhans cell histiocytosis (LCH) using RIC. Steiner et al.²⁰ reported seven of nine children with high-risk LCH failing conventional chemotherapy survived disease-free at a median follow-up of 1 year after receiving RIC-SCT with FLU/melphalan-based regimens. This approach is now being studied as salvage therapy for patients with resistant disease in the current LCH hematopoietic cell transplantation 2006 study.

Hemoglobinopathies

The available experience from the transplantation of patients with sickle cell disease (SCD) and thalassemia indicates that stable mixed hematopoietic chimerism is sufficient to cure the disease phenotype^{21, 22} raising the possibility that RIC regimens could be used in these diseases. Even with MAC, graft failure is frequently problematic in patients with hemoglobinopathies, as these patients have often been heavily transfused and have not received prior chemo/radiotherapy. The available data on RIC-SCT, mostly in small numbers of adult patients,^{23, 24, 25, 26} suggest that RIC is feasible in patients with hemoglobinopathies but that there is a high rate of primary or secondary graft failure in such patients.^{23, 27} For example, in the largest study in children, Iannone et al.²³ report engraftment with minimal toxicity in 6/7 patients with hemoglobinopathies (SCD=6, -thalassemia=1) transplanted from HLA-identical siblings using the Seattle minimal intensity FLU/2 Gy TBI regimen (two patients also received ATG). However, all six patients progressed to autologous reconstitution when immunosuppression was tailed. The optimal stem cell source for such patients is uncertain. While the increased stem cell dose from PBSC may make rejection less likely, the use of PBSC may be associated with an increased incidence of cGVHD. Mixed T-cell chimerism is likely to be associated with a reduced incidence of aGVHD²⁸ and may enable at least a reduction in the sickle percent, allowing a normal phenotype. It may therefore be advantageous to choose a regimen that induces early mixed chimerism in the majority of patients, in association with rigorous post-transplant immunosuppression to stabilize host–donor tolerance. Likewise, it is not clear how to manage patients who achieve mixed hematopoietic chimerism but show declining levels of donor contribution; while withdrawal of immunosuppression is sometimes effective, the use of DLI in this setting has been associated with fatal GVHD. Thus, while this approach has the potential for major therapeutic benefits, RIC-SCT for hemoglobinopathies remains experimental and should be performed in the context of well-constructed clinical trials in centers with expertise in SCT for these diseases.

Metabolic disorders

Data reporting the use of RIC-SCT in children with inborn errors of metabolism, including Hurler's syndrome,²⁹ autosomal recessive osteopetrosis³⁰ and adrenoleukodystrophy³¹ have been reported in small numbers of patients. Tolar et al.³⁰ reported sustained engraftment in 6/6 children with osteopetrosis transplanted using an FLU/BU/total lymphoid irradiation regimen when bone marrow or peripheral blood was used as a source of stem cells, but 0/5 patients transplanted using UCB. Clearly however, given the high rates of graft failure are observed even with conventional intensity conditioning in some of these disorders (notably Hurler's syndrome and autosomal recessive osteopetrosis), further data is needed before RIC-SCT can be recommended for children with such disorders.

Other indications

Animal data and anecdotal clinical case reports suggest that a variety of other inherited and autoimmune hematologic disorders, including Glanzmann's thrombasthenia,³² refractory Evan's syndrome and Kostmann syndrome may also be successfully treated with RIC regimens. In children with systemic autoimmune disorders, such as refractory juvenile inflammatory arthritis, the role of RIC allogeneic SCT has yet to be established and this is currently reserved for patients who fail both conventional immunosuppression and autologous SCT.

RIC for cord blood transplantation

There has been increasing interest in the use of RIC in UCB transplantation (UCBT). UCB has the advantage of immediate access and a lower rate of GVHD. Several papers have been published in the last few years using RIC UCBT in more than 300 adults.³³ The largest series treated 110 adults with a CY/FLU/TBI regimen with CsA/MMF for post-transplant immune suppression. They report neutrophil recovery in 92% of patients at a median of 12 days, and while there is early mixed chimerism, most patients achieved 100% donor chimerism at day 100 and at 1 year. TRM was 26% at 3 years. OS was 45% at 3 years with an incidence of grade III–IV aGVHD of 22% and cGVHD of 23%. They noted a trend toward lower relapse rate and higher event-free survival in patients receiving double cords.³⁴ It appears that modifications of protocol, including use of double cords to increase total nucleated cells, using CY rather than BU and giving ATG to patients who have received minimum chemotherapy before transplant may improve the outcome. There is considerably less experience in the use of RIC with UCB in children. Our group has described the outcome of 21 children, median age 9 years (range 0.33–20 years) with malignant (n=14) and nonmalignant conditions (n=7) transplanted using heterogeneous RIC regimens. Six patients (29%) had primary graft failure following transplant and five of these had received no prior chemotherapy (CML, -thalassemia, HLH and MDS). A total of 14 patients had neutrophil engraftment at a median of 17.5 days (range 9–45), 13 with >90% donor chimerism. Importantly, the TRM was low (14%) compared to myeloablative unrelated cord blood transplant. Six patients with high-risk malignancies died of disease. The incidence of >grade II aGVHD was 28%; cGVHD 16%.³⁵ The 5 year OS was 60%, (78% for those with average risk malignancy and 69% for nonmalignant diseases). These early reports indicate RIC UCBT may have a role, particularly in children with nonadvanced hematologic malignancies, but larger cohorts and longer follow-up in defined diseases are required to establish the role and efficacy of this combination in children. For children who have undergone minimal cytotoxic pretreatment, novel approaches such as the use of double cords to increase cell dose or alternate conditioning regimens may be required to overcome the problem of graft rejection.

Discussion

While there are no randomized studies comparing RIC-SCT with conventional intensity conditioning in children, as outlined above, sufficient data now exist in patients with PID and HLH to support the routine use of RIC for these diseases, at least in the MUD setting. Further potential indications include other nonmalignant disorders in which mixed chimerism may be sufficient for cure including refractory LCH, Glanzmann's thrombasthenia and some inherited and refractory autoimmune cytopenias. In these disorders, outcomes with RIC-SCT need to be studied prospectively in larger series with standardized protocols and long-term outcomes compared to results with conventional intensity conditioning. For certain disorders, including hemoglobinopathies, Hurler's syndrome and autosomal recessive osteopetrosis, novel protocols may be required to overcome the higher graft rejection rates in these patients and in these disorders, studies of RIC-SCT should initially only be performed in patients with comorbidity precluding the use of MAC. The role of RIC-SCT is less established for children with hematologic malignancies and there is a need to perform randomized, well-controlled clinical trials in well-defined disease groups to evaluate the role of RIC-SCT more fully. At present, this approach is most appropriate in selected patients with juvenile myelomonocytic leukemia and other myelodysplastic/myeloproliferative disorders, CML and Ph⁺ ALL in patients with significant comorbidity who are not candidates for conventional intensity conditioning or as conditioning for a second transplant procedure designed to achieve GVL in these disorders.

Much of the data above in pediatric patients relates to the MUD setting. Higher rates of low-level mixed chimerism and autologous reconstitution have been observed in patients receiving matched sibling/family donor grafts using RIC-SCT14, reflecting reduced alloreactivity. For this reason, at our center, we generally use conventional intensity conditioning for matched sibling donor grafts. Potentially reducing the dose or altering the timing of serotherapy of alemtuzumab may improve outcomes with RIC in the matched sibling donor setting and further studies are warranted. Another group in which a high rate of low-level mixed chimerism and autologous reconstitution were problematic initially was patients transplanted from single-antigen mismatched unrelated donors.¹⁴ However, to a large extent this problem has been overcome by using peripheral blood as the stem cell source and more intensive post-SCT immunosuppression using both CsA and MMF.¹⁴

Regular monitoring of chimerism (ideally in separated cell lineages) is integral to the use of RIC-SCT. When mixed chimerism does occur, if this is stable and in the appropriate cell lineage, it may not be detrimental in patients with nonmalignant conditions such as PID and HLH where this may establish long-term cure. Withdrawal of immunosuppression in such patients generally stabilizes or improves the level of donor hematopoeisis in patients transplanted from unrelated donors, but this is less effective in the matched sibling setting and patients who progress to autologous reconstitution may require a second SCT procedure with conventional conditioning. In patients with malignancy, however, mixed chimerism may be associated with a higher risk of relapse.³⁶ In such patients, aggressive withdrawal of immune suppression and consideration of DLI may be important to restore full donor hematopoeisis and ensure a GVL effect.

Another potential concern following RIC is the possible increase in infectious complications. The incidence of EBV reactivation and LPD appears higher in patients receiving RIC-SCT when serotherapy, particularly with ATG is used in the conditioning regimen.³⁷ In contrast, when no serotherapy is used to T deplete the graft, as in the Seattle FLU/low-dose TBI regimen, the risk of EBV-associated LPD appears low.¹⁷ Likewise, CMV reactivation may also be more frequent following RIC-SCT.^{38, 39} Data on adenoviral infections after RIC-SCT are conflicting: there does not appear to be any difference in the incidence of adenoviremia between RIC and full intensity conditioning regimens in children⁴⁰ but Avivi et al.⁴¹ have reported a high incidence of adenovirus-associated disease in adults undergoing RIC-SCT. These data are likely to reflect the increased intensity of immunosuppression with RIC-SCT. The impact of RIC-SCT on the incidence of invasive fungal infections is unknown, although mortality in patients who develop such infections may in fact be reduced.⁴² Awareness of the increased susceptibility to certain infections and vigorous monitoring of viremia with reduction in immunosuppression and preemptive ganciclovir/rituximab in patients who develop viremia is crucial in the management of these patients.

One of the major impetus for performing RIC-SCT in children has been the anticipated reduction in late effects, such as growth and pubertal failure, infertility and secondary malignancies compared to MAC. Data on this are as yet disappointingly scanty. It is clear that the FLU/melphalan regimen is significantly gonadotoxic in adults, resulting in elevation of both luteinizing hormone and follicle-stimulating hormone, implying damage to both germ cells and Leydig cells,⁴³ but the clinical effects of this on pubertal development and fertility are as yet unknown. Clearly such effects are very likely to be regimen specific. Given the crucial importance of such late effects when transplanting children, there is a pressing need for well-planned and executed follow-up studies to evaluate the effects of RIC on growth, fertility, cGVHD and secondary malignancies in pediatric allograft recipients.

References

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Acknowledgements

This research was supported in part by grants from the Pediatric Cancer Research Foundation, Marisa Fund, Sonia Scaramella Fund, Brittany Barron and Bevanmar Foundation.