Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies

Abstract

Conventional myeloablative conditioning regimens prior to hematopoietic cell transplantation (HCT) are associated with significant transplant-related morbidity and mortality in children affected by primary immunodeficiency disorders. Reduced-intensity conditioning regimens have been extensively used without severe acute toxicity in patients with pre-HCT comorbidities, with the additional advantage of reducing or avoiding long-term sequelae such as infertility and growth retardation. Compared with myeloablative HCT, reduced-intensity conditioning regimens are associated with an increased incidence of mixed donor chimerism and graft rejection. While mixed donor engraftment is likely to correct the phenotypic expression of most children with primary immunodeficiency disorders, the use of donor lymphocyte infusion to increase donor chimerism or second HCT procedures may be required in some cases. Here we discuss the most recent data on the use of different reduced-intensity conditioning protocols in children with primary immunodeficiency disorders, highlighting significant clinical lessons and areas that need additional study.

Keywords::

• hematopoietic cell transplantation
• primary immunodeficiency diseases
• reduced-intensity conditioning

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Release date: 5 March 2012; Expiration date: 5 March 2013

Learning objectives

Upon completion of this activity, participants should be able to:

• • Compare outcomes of RIC and conventional myeloablative conditioning prior to HCT among children with primary immune deficiency

• • Evaluate differences in outcomes with use of different stem cell sources for RIC

• • Assess different protocols for RIC

• • Distinguish primary immune deficiency disorders that might respond particularly to RIC

Figure 1. A hierarchy of commonly used MIC, RIC and MAC regimens in PID patients.

ATG: Antithymocyte globulin; Bu(8): Busulfan 8 mg/kg; Bu(14–16): Busulfan 14–16 mg/kg; Cy: Cyclophosphamide; Cy(120–200): Cyclophosphamide 120–200 mg/kg; DLI: Donor lymphocyte infusion; Flu: Fludarabine; Gy: Gray; MAC: Myeloablative conditioning; MIC: Minimal-intensity conditioning; RIC: Reduced-intensity conditioning; TBI: Total-body irradiation; Treo: Treosulfan.

Adapted with permission from [7].

Figure 2. Kaplan–Meier analysis comparing overall survival in children with primary immunodeficiences receiving reduced-intensity conditioning or conventional conditioning (myeloablative conditioning or myeloablative therapy) stem cell transplantation.

(A) OS in all patients was significantly better in patients who received RIC (94% OS) compared with MAT (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 MAT compared with a 30% death rate following MAT for SCID).

(B) OS following either RIC or MAT in patients with SCID. (C) OS following RIC or MAT in patients with non-SCID.

OS: Overall survival; MAT: Myeloablative therapy; RIC: Reduced-intensity conditioning; SCID: Severe combined immunodeficiency.

Adapted with permission from [7].

Figure 3. Improvement in outcome of stem cell transplantation for T-cell immune deficiency.

^†Data taken from [7].

^‡Data taken from [51].

GOSH-RIC: Great Ormond Street Hospital reduced-intensity conditioning; Europe MAC: Myeloablative hematopoietic cell transplantation performed in European centers.

Figure 4. Comparison of disease-free survival of SCID patients <1 year of age transplanted using anti-CD45 monoclonal antibody-based MIC, fludarabine/melphalan-based RIC and Bu/Cy conditioning.

Kaplan–Meier curves showing disease-free survival (DFS; days) of SCID patients age <1 year conditioned with first, CD45 monoclonal antibody-based MIC regimen (n = 8; DFS 100%); second, fludarabine/melphalan-based RIC regimen (n = 21; DFS 71.4%); and third, Bu/Cy-based conditioning (n = 31; DFS 77.4%). The cohort conditioned with CD45-based MIC was transplanted between 2003 and 2007 (donor source 63% matched unrelated donor [MUD], 25% mismatched unrelated donor [MMUD], 13% matched sibling donor [MSD], 37% B^neg phenotype), the cohort conditioned with fludarabine/melphalan was transplanted between 1999 and 2003 (donor source 81% MUD, 19% MMUD, 57% B^neg phenotype) and the cohort transplanted with Bu/Cy was transplanted between 2003 and 2005 (donor source 57% MUD, 30% MSD, 13% matched family donor, 46% B^neg phenotype).

Bu: Busulfan; Cy: Cyclophosphamide; MIC: Minimal-intensity conditioning; RIC: Reduced-intensity conditioning; SCID: Severe combined immunodeficiency.

Reproduced with permission from [50].

Hematopoietic cell transplantation (HCT) from related or unrelated stem cell donors is the treatment of choice for most children with primary immunodeficiency diseases (PID), since the establishment of normal donor hematopoiesis in the recipient rapidly corrects defects in both lymphocyte and phagocyte cell lineages.

Traditional myeloablative preparation is associated with a high incidence of transplant-related morbidity and mortality (TRM), as well as long-term sequelae. Over the past decade reduced-intensity conditioning (RIC) prior to HCT has become a well-established strategy in adult patients with malignant diseases, therefore extending this curative approach to older individuals as well as to patients with comorbidities, otherwise ineligible for myeloablative procedures (reviewed in [1–3]). Because pediatric patients generally tolerate more intensive transplant approaches, myeloablative regimens have continued to be preferred in childhood malignancies, while RIC has become an attractive option for children with nonmalignant diseases particularly those with pretransplant infections and organ toxicties, both common in children with PID.

Definition of RIC regimens

Conventional myeloablative preparative regimens are associated with significant toxicity and cause severe myelosuppression that, without stem cell rescue, results in prolonged and severe pancytopenia. In comparison, RIC regimens have been traditionally characterized by the following qualities [4]:

• • Reversible myelosuppression (typically within 28 days) in the absence of stem cell support;

• • Reduced regimen-related toxicity;

• • Higher incidence of mixed donor hematopoiesis.

In practice, the third European Group for Blood and Marrow Transplantation (EBMT) workshop on RIC HCT [5] have used one or more of the following criteria to define a RIC regimen:

• • Total-body irradiation (TBI) ≤200 cGy;

• • ≤8 mg/kg total busulfan dose;

• • ≤140 mg/m² total melphalan dose;

• • ≤10 mg/kg total thiotepa dose.

Two general approaches have been used to develop RIC regimens [6,7]; the terminology may be confusing but RIC protocols may be further subdivided into those with minimal-intensity conditioning (MIC) (Figure 1). RIC protocols still contain drugs capable of targeting stem cells (e.g., busulfan or melphalan), but at a reduced dose compared with conventional myeloablation. By contrast, MIC regimens are strictly nonmyeloablative and contain only immunosuppressive agents. A truly nonmyeloablative/MIC regimen should not eradicate host hematopoiesis and should allow relatively rapid autologous hematopoietic recovery without a transplant, but be sufficient to enable at least partial donor engraftment to occur post-HCT [8]. In this setting initial chimerism is often mixed. By contrast, RIC regimens require HCT for a rapid hematologic recovery and if the graft is rejected, aplasia may occur for up to 28 days. Initial chimerism following RIC HCT is frequently 100% donor, but may decline thereafter in the absence of an adequate graft-versus-marrow effect, as autologous hematopoiesis recovers.

RIC protocols for PID

Fludarabine & melphalan

Great Ormond Street Hospital (GOSH) in London (UK) first reported the combination of fludarabine, melphalan and in vivo T-cell depletion in eight children affected by PID: despite significant comorbidities prior to HCT, seven out of the eight children were surviving with donor cell engraftment 8–17 months after transplant [9]. The same group recently updated their results, reporting 113 patients with PID who had undergone RIC HCT between 1998 and 2006 [7].

Eighteen patients had severe organ toxicity before transplantation, including previous mechanical ventilation (n = 12), significant liver or renal impairment (n = 8) or total parental nutrition-dependent enteropathy (n = 8). The majority of children (93 out of 113) received a RIC regimen consisting of campath-1H 1 mg/kg (alemtuzumab), fludarabine 150 mg/m² and melphalan 140 mg/m², while 20 patients received a MIC HCT. Stem cell source was mainly unrelated (81 out of 113). The overall survival (OS) was 82% (93 out of 113) with a median follow-up of 2.9 years. Stable donor engraftment was achieved in 91 out of 133 patients (81%), while 14 children (12%) had or were likely to require additional procedures including a second HCT, marrow infusion, additional CD34⁺ cell top up or gene therapy.

There are no prospective randomized studies comparing RIC versus myeloablative HCT in PID; however, a London group has retrospectively compared their results in children with PID transplanted from unrelated donors (UDs) using fludarabine, melphalan and campath-RIC HCT or myeloablative HCT from an earlier time cohort. This study showed a reduced overall mortality in RIC HCT (two out of 33 RIC compared with four out of 19 myeloablative conditioning [MAC]; p < 0.01) [10], with improved OS, mainly through improved survival in patients with non-severe combined immunodeficiency (SCID) (Figure 2).

Interestingly, there was no difference in the incidence of acute graft-versus-host disease (GvHD), and although post-HCT immune reconstitution was similar in the two groups, there seemed to be an increased incidence of viral infections/reactivations in the RIC cohort (29% for RIC compared with 21% following MAC; p = 0.02). Viral infections in those receiving RIC HCT included CMV (n = 3), adenovirus (n = 5) and EBV (n = 10). As expected, there was an increased rate of mixed chimerism (MC) in RIC HCT when compared with MAC HCT (45% MC of which 13% had low-level donor chimerism for RIC vs 36% MC and 0% low-level donor chimerism for MAC); however, with withdrawal of the immunosuppression, MC after RIC appeared to stabilize or improve, and the rate of disease recurrence was low (two out of 23 patients).

The outcome of a larger cohort of PID patients undergoing RIC HCT from the London group was compared with that of PID patients undergoing largely MAC HCT and reported from European centers to the SCETIDE database [7]. In this comparison (Figure 3), the improvement in RIC HCT seems to be largely confined to children with T-cell deficiencies.

Some of the outcomes associated with the use of fludarabine, melphalan and in vivo T-cell depletion in PID have been studied in more detail. RIC HCT recipients seem to experience a higher incidence of EBV reactivations [11]: the increased rate of EBV viremia was thought to reflect the profound immunosuppression following RIC HCT, together with the incomplete ablation of recipient-derived B cells [12]. By contrast, the combination of alemtuzumab, fludarabine, melphalan and rituximab or the use of EBV-specific cytotoxic T lymphocytes has been successful in curing all eight patients with EBV-driven lymphoproliferative disease complicating PID and immunodysregulatory syndromes [13]. This suggests that close monitoring of EBV by PCR and pre-emptive therapy (mainly rituximab), can overcome complications associated with EBV viremia following RIC HCT.

Similarly, in adult patients a high incidence of CMV reactivation has been described following fludarabine, melphalan and campath-RIC HCT [14].

In 2005, Shenoy and colleagues [15] used a fludarabine/melphalan-RIC HCT in 16 patients with nonmalignant disorders including two PID patients. Campath-1H was given proximally pre-HCT (from day -21 to day -19) at the dose of 33 or 48 mg. The study included sibling bone marrow (BM; n = 5), sibling peripheral blood (PB; n = 5), unrelated BM (n = 3) and unrelated cord blood (CB; n = 3) donors. All 14 evaluable patients had complete or high level (>50%) donor engraftment in all cell lineages, suggesting that lower doses of campath-1H or its early administration may increase donor chimerism in the HLA-matched setting.

The benefit from fludarabine, melphalan and campath-RIC HCT was most evident in children over 1 year of age, since children with SCID below 1 year of age experienced high TRM even with RIC HCT (28% in the London series) [16]. Occasionally, very young patients appear to develop a fatal ‘melphalan shock’ syndrome with massive capillary leak syndrome within hours of receiving melphalan [Rao K, Personal Observation] although the mechanism of this is not understood. An alternative RIC or MIC protocol (e.g., fludarabine and treosulfan, see later) might be preferable for this group of patients.

Fludarabine, melphalan & radioimmunotherapy

Recently, Schulz and colleagues have reported their results on RIC HCT with the combination of fludarabine, melphalan and radiolabeled monoclonal antibodies in children with PID [17].

Twelve children affected by PID underwent HCT from a matched UD (MUD)/mismatched family donor (n = 8), matched family donor (MFD; n = 2) or haploidentical donor (n = 2) after conditioning with mostly fludarabine (160 mg/m²), melphalan (70–140 mg/kg; n = 9 out of 12) and an anti-CD66 monoclonal antibody conjugated with the radioisotope Yttrium-90 (⁹⁰Y-anti-CD66). CD66 is an antigen expressed at a high density on normal myeloid cells, and anti-CD66 antibody has been utilized to target radioimmunotherapy in older adults with malignancies with encouraging results in terms of engraftment and toxicity profile [18]. The median absorbed dose in the BM in this group of children with PID was 17 Gy (range: 16–20). Eleven patients engrafted, while one patient rejected the graft after a haploidentical HCT and eventually died of adenovirus pneumonia. Nine patients achieved 100% donor engraftment at last follow-up, while two out of 12 children were MC. Regimen-related toxicity was low and ten out of 12 children were alive and disease-free at the last follow-up. These results show that radioimmunotherapy is effective in achieving myeloablation with low additional toxicity when used in combination with RIC in young children affected by PID.

Fludarabine & busulfan

The combination of fludarabine and full dose of busulfan has gradually replaced the standard myeloablative combination of busulfan and cyclophosphamide in most BMT centers, due to the increased transplant-related toxicity of the latter scheme, such as veno-occlusive disease (VOD) and mucositis [19]. A reduced dose of busulfan in combination with fludarabine has also been used as a RIC regimen in adults and children with malignant and nonmalignant diseases undergoing HCT. Jacobsohn and colleagues [20] reported the outcome of RIC HCT in patients with nonmalignant disorders using a scheme with fludarabine, busulfan and antithymocyte globulin (ATG) modeled after Slavin and colleagues [21]. Six children with PID underwent matched sibling donor (MSD) peripheral blood stem cell (PBSC; n = 2), MUD PBSC (n = 2) and unrelated CB (n = 2) HCT. Patients received fludarabine 180 mg/m², and intravenous (iv.) busulfan 6.4 mg/kg in eight doses on days -5 to -4 or pharmacokinetic monitoring to achieve an area under the curve (AUC) of 3800–4200 micromol × min with single daily dosing of busulfan. Two patients with X-linked hyper-IgM were phenotypically cured, off iv. immunoglobulins, and experienced reversal of their cholangiopathy: one patient had full donor and one 30% donor chimerism. One patient with XLP was also alive and well, with 98% donor engraftment. One child with SCID was too early to evaluate and two patients, one with chronic granulomatous disease (CGD) and one with Omenn’s syndrome died within 100 days of HCT. There was little acute or chronic GvHD in evaluable patients.

Dennison and colleagues described their experience with a combination of fludarabine (150 mg/kg), low-dose iv. busulfan (7.8 mg/kg, once daily) and ATG in six children affected by PID [22]. The stem cell donor was a matched sibling in five cases and a matched family donor in one case. All children engrafted, with four out of six patients being MC at the last follow-up and two out of six children achieving complete donor engraftment. Transplant-related toxicity was low and six out of six children were alive and free from their original disease at the last follow-up.

Horn and colleagues [23] also reported the use of fludarabine, busulfan and ATG in six children with PID. The conditioning regimen consisted of iv. busulfan from day -9 to -6, to a total of 16 doses targeting continuous steady state concentration of 600 ng/ml. Fludarabine 40 mg/m²/day was given from day -5 to -2 (total dose 160 mg/m²) and rabbit ATG 0.5 mg/kg/day on day -4 and 2.5 mg/kg on days -3 to -1 (total dose 8 mg/kg). Donors were MUD BM (3) matched related BM (2) and umbilical CB (UCB). Three patients achieved >95% donor chimerism and three were mixed chimeras. One patient with Wiskott–Aldrich syndrome (WAS) died of CMV pneumonitis, while the others are alive and disease-free. There were 13 other non-PID patients included in the study and overall MC was more common with BM as a stem cell source and graft rejection was more common in patients receiving mismatched UDs (MMUDs). Four patients experienced graft failure, all underwent second HCT and three out of four are alive and disease-free at the time of writing, illustrating how second HCT after failed first RIC HCT is well-tolerated and frequently successful. A similar protocol was used in five further children with PID [24]: all patients are alive and disease-free at the time of writing: one patient with CGD required donor lymphocyte infusions (DLI) for low level donor chimerism, while three patients had stable MC. One child with complete donor chimerism experienced significant acute and chronic GvHD. Interestingly, in this study investigators prolonged immunosuppression for mixed donor chimerism rather than tailing it as the usual course of action; this did not appear to increase graft rejection although it might have reduced donor chimerism in this group. Further work may establish an AUC for iv. busulfan that is tailored to disease, donor type and stem cell source in order to achieve lineage-specific donor engraftment with the minimum amount of acute and long-term toxicity. A successful example of this kind of approach is provided by Güngör et al.[25] in the treatment of CGD (see later).

Fludarabine & treosulfan

For many years, preparative regimens prior to HCT have been based on the combination of alkylators such as busulfan, cyclophosphamide or melphalan. Side effects such as severe mucosal damage, VOD or cardio-toxicity has led to the search for alternative drugs that might further improve the outcomes after HCT, minimizing its toxicity. Treosulfan (L-treitol-1,4-bis-methanesulphonate) is the pro-drug of L-epoxybutane, an alkylator with myeloablative and immunosuppressive features [26,27].

Recently, results on treosulfan-based conditioning regimens prior to HCT in adults affected by malignancies have shown a high success rate with a low risk of VOD when compared with busulfan [28–30]. Early studies have shown a linear pharmacokinetics of treosulfan up to the clinically effective dose of 42 g/m²[30].

Eighteen patients with PID with a mean age < 1 year underwent HCT, with a variety of donors and stem cell sources, using treosulfan 14 g/m² × 3 days, fludarabine 30 mg/m² × 5 days and campath-1H (n = 14) or ATG (n = 2) [28]. One patient received cyclophosphamide 50 mg/m² × 4 days and ATG. Thirteen patients achieved 100% donor chimerism which remained stable in 10 out of 13 patients. Three children achieved stable MC (90–99% donor, n = 2; 30% donor in PB, but 80% donor in T cells, n = 1) which was sufficient to cure the underlying disease. Two patients achieved low-level donor engraftment (<50%) and are under consideration of a second HCT. Toxicity was tolerable particularly given such a young group of patients and may be preferable to the combination of fludarabine, melphalan and campath-1H in this cohort.

Recently, the UK experience of treosulfan-based conditioning regimen for HCT in children with PID has been published [31]. Forty children were treated with a combination of treosulfan (36–42 g/m²), fludarabine (150 mg/m²) and alemtuzumab (n = 35) or ATG (n = 3). Patients received a graft from an UD (n = 30), MFD (n = 8), MSD (n = 1) or haploidentical donor (n = 1). Thirty-eight patients engrafted, while one patient rejected the graft from a MSD and was successfully re-transplanted using busulfan and cyclophosphamide, while another child rejected the graft after a haploidentical HCT. Twenty-four children (54%) had 100% donor chimerism in all cell lineages, while 13 patients presented mixed donor engraftment. The majority of children with MC had ≥95% donor engraftment in the T-cell compartment (n = 11 out of 13), with complete resolution of the disease phenotype. Interestingly, when compared with a similar group of children affected by PID, but treated with treosulfan and cyclophosphamide, patients given fludarabine and treosulfan had significantly better T-cell chimerism (p = 0.038). Also of note from a combined group of children receiving treosulfan and fludarabine or cyclophosphamide, there were significantly fewer under 1-year olds admitted to intensive care in this study (12 out of 44) compared with children with PID receiving fludarabine and melphalan (17 out of 30; p = 0.0155).

MIC protocols for PID

Fludarabine & low-dose total-body irradiation

The Seattle (USA) group described a MIC regimen in 14 patients (12 children and two adults) with PID and coexisting infections, organ toxicity or other factors precluding HCT with a more intensive preparative regimen [32]. The majority of patients received 200 cGy TBI and fludarabine (90 mg/m²) as conditioning and all patients received HLA-matched grafts with GvHD prophylaxis consisting of cyclosporine and mycophenolate mofetil. No in vivo T-cell depletion (ATG or campath) was given. Thirteen patients established either mixed (n = 5) or full (n = 8) donor engraftment, while one child rejected the graft. Overall survival at 3 years was 62% with a TRM of 23%. Eight of ten evaluable patients achieved correction of their immune defect with stable donor engraftment. However, the rate of GvHD was high, with 11 out of 14 patients developing significant acute GvHD (mostly grade II) and extensive chronic GvHD in eight patients, reflecting both the use of PB as the stem cell source and the absence of in vivo T-cell depletion. This approach was associated with a lower incidence of viral infections/reactivations (notably EBV) compared with RIC regimens utilizing in vivo T-cell depletion; however, the high incidence of chronic GvHD would be a significant limitation to a broader use of this preparative regimen in children with nonmalignant disorders.

Fludarabine, cyclophosphamide & monoclonal antibodies

The GOSH group in London has explored a MIC protocol combining fludarabine (30 mg/m² × 5 day, from day -8 to -4) and low-dose cyclophosphamide (300 mg/m²/day × 4 days, from day -7 to -4) with two rat anti-CD45 monoclonal antibodies to provide additional myelosuppression and campath-1H either 0.6 mg/kg or 0.3 mg/kg with UD or MSD, respectively [16]. Patients enrolled in this study were at particularly high risk from HCT-related toxicity even with RIC protocols due to severe pre-existing organ toxicity, age <1 year, or the presence of DNA/telomere repair disorders. In total, 16 children underwent a MIC HCT from MSD (5), MUD (9) and MMUD (2). Conditioning was well tolerated with only two cases of grade III and no grade IV toxicity. Six out of 16 patients (38%) developed significant acute GvHD (three children with grade II skin and three children with grade III skin/gut GvHD). Five children (31%) developed chronic GvHD (limited in three and extensive in two), which resolved in all cases. Of note, the incidence of GvHD was reduced when BM was used as a stem cell source (two out of ten BM recipients compared with four out of four evaluable PBSC recipients developed acute GvHD >grade II). Similarly the incidence of chronic GvHD was lower in recipients of BM (two out of ten) as compared with PBSC (three out of four). Myeloid recovery occurred at a median of 9.5 days (range 1–15). One patient failed to engraft and experienced autologous reconstitution, while one patient who received a mismatched UCB transplantation (UCBT) engrafted with stable MC. Analysis of chimerism showed that of 15 engrafted patients, six achieved complete donor engraftment, and five achieved stable high-level MC in both myeloid and lymphoid lineages (57–93%). In three patients, engraftment was restricted to the T-cell lineage. One patient achieved very low level donor engraftment and required a second HCT. At a median of 37 months post-HCT, 13 out of 16 patients in this high-risk cohort were alive and cured from their underlying disease. Patients affected by SCID and <1 year of age appeared to gain particular benefit from this MIC HCT protocol (Figure 4).

Stem cell source

The use of PBSCs as opposed to BM in reduced-intensity transplantation (RIT) appears to be associated with improved donor chimerism in recipents with PID [11,16,32], but at the cost of increased rates of GvHD; in this setting OS appears to be similar between the two groups. An unpublished study from GOSH [Rao K et al., Unpublished Data] has recently examined lineage-specific chimerism and long-term outcome by donor type and stem cell source in 146 children undergoing 149 transplant procedures using fludarabine- and melphalan-based RIC for predominantly PID. Donors were MUD (n = 66), MMUD (n = 45), MSD (n = 17) and family donors (n = 21). Stem cell source was BM (n = 108) or PBSC (n = 41). Overall survival at a median follow-up of 7.4 years was excellent at 74% irrespective of stem cell source or donor type. When BM was used as stem cell source there was a high incidence of rejection (14%) and of very low level myeloid MC. This was especially evident in the MSD (44% rejection) and MMUD (14% rejection) groups. Event-free survival was poor (21%) in children with very low level MC. With the use of PBSC, 95% of children achieved complete donor chimerism or high level MC. With matched donors, GvHD was equivalent in the BM and PBSC groups. MMUDs had a higher incidence of acute and chronic GvHD with PBSC (50% grade III and IV acute GvHD, 50% chronic GvHD). GOSH therefore recommends the use of PBSC with alemtuzumab, fludarabine and melphalan in the MUD setting, but is currently examining the use of CD34⁺ cell selection (CliniMACS, Miltenyi Biotech) from MMUDs, with addback of 1 × 10⁸ CD3⁺ cells/kg to see whether the excellent engraftment rate of PBSC can be maintained with a GvHD incidence equivalent to the use of BM.

The balance of host-versus-graft and graft-versus-host/graft-versus-marrow reflects the complex interactions of stem cell source with disease type, conditioning regimen, in vivo T-cell depletion, graft content (CD34⁺, CD3⁺, NK–KIR alloreactivity) and GvHD prophylaxis, and has to be more finely balanced in RIT rather than MAC HCT. The optimal combinations for PID remain to be determined, but even then there is likely to remain a risk of rejection with RIT and early warning of future graft rejection, as suggested by recipient chimerism status in NK cells on day +28 [33] or increasing MC >30% host cells [24], might enable timely intervention by withdrawal of immune suppression or DLI.

There is less experience using UCB and RIT in PID. Bradley et al.[34] 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/MIC regimens. Five patients affected by hemophagocytic lymphohistiocytosis (HLH; n = 2), SCID (n = 2) and WAS received four to six (out of six) HLA-matched unrelated UCB following MIC conditioning with fludarabine, cyclophosphamide and ATG. Children with HLH received additional VP16, but both rejected; one underwent a successful second MAC HCT. Two of the three remaining patients died from viral pneumonitis and GvHD-related complications. GOSH have transplanted three patients with PID using a MIC protocol as described by Wagner and colleagues [35]. Only one out of three survived, one dying from disseminated cryptosporidiosis and the other child from idiopathic pneumonitis [Rao K, Pers. Comm.]. Based on very few patients therefore, the combination of MIC and unrelated UCB does not initially appear to offer any survival advantage to PID patients.

More recently Morio and colleagues [36] have published their experience with the use of unrelated UCBT in 88 patients with PID: children would receive MAC (n = 43), RIC (n = 31) or no conditioning (n = 14). Patients treated with RIC received different preparative regimens including: fludarabine and melphalan ± low-dose TBI; fludarabine and busulfan; and fludarabine and low-dose TBI. No difference was observed in the incidence of neutrophil recovery between the MAC and RIC groups (84 vs 87% at day 100) and no difference was observed in platelet recovery. RIC was associated with a decreased overall mortality compared with MAC (p = 0.017): 87% of patients on the RIC regimen and 66% on the MAC regimen remained alive at the last follow-up. RIC was selected preferentially in SCID and CGD patients, with good survival rates: 17 out of 18 SCID patients and three out of four CGD patients remain alive. Eight out of nine patients with PID who underwent UCBT following preparation with treosulfan and fludarabine are alive and well [31].

Taken together these results suggest that unlike the use of MIC protocols, the combination of RIC and UCBT is an attractive approach to HCT in PID.

RIT in specific PID diseases

Hemophagocytic lymphohistiocytosis

Patients with HLH often have significant pretransplant comorbidities and require intensive cardio-respiratory support pre-HCT. This toxicity results in a high TRM with conventional MAC, mostly from noninfectious pulmonary toxicity and VOD. The use of RIC has therefore been examined closely in HLH [37,38]. Twenty-five consecutive patients with primary HLH underwent RIC HCT in London using MUD (n = 8), MMUD (n = 11), MFD (n = 2) and haploidentical (n = 4) donors. Most patients were conditioned with fludarabine 150 mg/m², melphalan 140 mg/m² and alemtuzumab 1 mg/kg. Following RIC HCT, 21 out of 25 (84%) children were alive and in complete remission: these results compare positively with historical data, especially for children undergoing transplant from a mismatched donor. In the RIC group, seven of eight patients (87%) undergoing MUD HCT and nine of 11 (82%) children undergoing MMUD HCT survived in complete remission, as opposed to corresponding figures of 70 and 54% using a fully myeloablative HCT in the HLH 94 study [39].

In 2010, Marsh and colleagues reported the results of 26 children with HLH who underwent allogeneic HCT using alemtuzumab, fludarabine and melphalan: the authors noted a remarkable improvement in 3-year OS of patients receiving RIC HCT (92%), compared with MAC HCT patients treated at the same institution (43%) [40]. Interestingly, there were no cases of VOD and no deaths prior to day +100 in the RIC group. There was a high incidence of MC in the RIC group, occurring in 65% of patients and many children were treated with DLI and/or stem cell boost to stabilize or increase the donor engraftment.

RIC HCT therefore appears to be a promising approach for children with HLH.

Wiskott–Aldrich syndrome

The finding that MC post-HCT for WAS might be associated with an increased incidence of autoimmunity [41] might deter the use of RIT in WAS. Conversely, WAS patients >5 years old who have accumulated more comorbidities have a poor outcome following MAC HCT [42], and RIT may offer some advantages in this setting. Investigators in London have explored the use of RIC HCT in WAS (updated from [43]). Between 1995 and 2007, 17 patients with WAS with a median age of 27 months underwent MSD (n = 5) or UD HCT (n = 12). MAC (busulfan/cyclophosphamide) was used in six patients, while RIC HCT was used in 11: treosulfan/fludarabine was used in five and fludarabine/melphalan was used in six. Among the 11 patients receiving RIC, ten had WAS and one had X-linked thrombocytopenia. The mean age in this group was 70 months (15–194 months) and the mean Ochs score was 4.8. Donor source was MUD (n = 10) and MMUD (n = 1). Eight patients received BM and three patients recieved PBSCs. All patients survived with a median follow-up of 4 years. Five of the 17 patients have mixed/split chimerism all following UD HCT: one out of two following MAC UD HCT, and four out of 11 (36%) following RIC UD HCT. All four of these patients received in vivo T-cell depletion with campath-1H (alemtuzumab) 1 mg/kg total dose from day 8–4. Only one of these patients has so far developed definite autoimmune disease. Three subsequent patients underwent UD HCT with RIT with reduced campath-1H 0.6 mg/kg total dose day 8–6, and all achieved 100% donor chimerism with only one patient experiencing acute GvHD grade II skin. Of interest, three out of four patients with MC developed acute GvHD > grade II, as opposed to three out of 15 with full donor chimerism (p < 0.05). Comparative incidence of mixed/split chimerism following MAC HCT in other studies is 28 [41] and 38% [44]. RIC HCT protocols may be suitable for UD HCT in WAS, particularly in older children with comorbidities; however, some graft-versus-marrow reaction is required to secure 100% donor chimerism in all patients.

Chronic granulomatous disease

Horwitz and colleagues [45] reported their results on the use of MIC HCT and DLI in ten patients affected by CGD. Conditioning regimen consisted of cyclophosphamide (120 mg/kg), fludarabine (125 mg/m²) and ATG, followed by infusion of CD34⁺-selected PBMCs from matched sibling donors. Delayed DLI was given at intervals of 30 or more days to increase the level of donor engraftment. After a median follow-up of 17 months donor myeloid chimerism in eight out of ten patients ranged from 33–100%, a level that should provide normal host immunity. Two patients presented graft rejection. Significant acute GvHD developed in three out of four patients, one of whom subsequently had extensive chronic GvHD. Seven patients were alive at the last follow-up: two patients died of transplant-related toxicity, while one patient who rejected the graft died after a second stem cell transplant.

Güngör and colleagues have recently updated their results on the use of low-dose iv. busulfan, full dose of fludarabine (180 mg/m²) and in vivo T-cell depletion (ATG or campath) in 30 high-risk pediatric and adult patients with CGD [25].

Busulfan was given at 50–65% of the myeloablative dose in adults (6.4–12 mg/kg), while children received an adjusted dose of busulfan with a targeted cumulative AUC of 45–65 mg/l × h. The majority of the patients were refractory to treatment and suffering from infections and/or inflammatory complications. Stem cell donors were 14 matched sibling/related donors, 11 MUD and five MMUD. BM was the preferred stem cell source. Twenty eight out of 30 patients achieved donor engraftment, while two out of 30 patients with a low cumulative busulfan exposure (AUC: 45 mg/l × h) rejected the graft with autologous reconstitution and were re-transplanted. At last follow-up 28 patients were alive, with good myeloid engraftment (95–100%) and cured of the original disease. This RIC regimen showed to be efficacious and well tolerated in both pediatric and adult patients with CGD and busulfan targeting was regarded to be of major importance to prevent rejection.

Another type of RIC HCT (cyclophosphamide 50 mg/kg, fludarabine 200 mg/m², TBI 4 Gy) followed by two mismatched unrelated UCB units in an adult patient with McLeod phenotype and CGD with active aspergillosis also showed full donor chimerism and cure [46].

Leukocyte adhesion deficiency

The transplant experience for 36 children with leukocyte adhesion deficiency undertaken at 14 centers worldwide between 1993 and 2007 was recently surveyed [47]. At a median follow-up of 62 months OS was 75%. MAC was used in 28 patients, and the remaining eight patients received RIC (fludarabine, melphalan, campath = 5, fludarabine, treosulfan, campath/ATG = 2). Survival after MFD and UD transplants was similar, with 11 out of 14 MFD and 12 out of 14 UD recipients surviving; mortality was greatest after haplo-identical HCT, where four out of eight children did not survive. Full donor chimerism was achieved in 17 of the survivors, mixed multilineage chimerism in seven patients, and mononuclear cell restricted chimerism in a further three cases. Causes of death in the nine patients that died included pneumonitis (n = 2), infection (n = 5), VOD (n = 3), malignancy (n = 1; some had >1 contributing factor) and all had received MAC HCT. Overall the use of RIC regimens appeared to be associated with reduced toxicity, with all eight patients surviving, although two patients have low-level donor chimerism, not requiring second HCT to date.

Fertility & late effects

One major impetus for performing RIT in children is the avoidance or reduction of long-term sequelae associated with MAC HCT including growth failure, gonadal failure, secondary malignancies and myelodysplasia [48]. However, the true incidence of late effects following RIT in children with PID awaits well-planned and well-executed follow-up studies as the first cohorts of survivors approach adulthood. Intact fertility and uncomplicated pregnancies have been reported in dogs with canine leukocyte adhesion deficiency following MIC HCT [43]. There have been several reports of successful pregnancies in adults following fludarabine, melphalan and campath-RIC and fludarabine, busulfan and ATG-RIC protocols for malignant disease; one adult CGD patient fathered a child after fludarabine, busulfan and ATG [49]; however, the impact of the same drugs on the pediatric gonadal and endocrine systems may be very different.

Conclusion & expert commentary

Studies so far indicate that RIC HCT may have an important role in treating children with PID: unlike more standard approaches, such regimens can be used without severe toxicity in patients with pretransplant infections or severe pulmonary or hepatic disease. Accordingly, RIC has extended the role of allogeneic transplantation to many patients who until recently were considered ineligible for this procedure. RIC HCT is associated with an increased incidence of mixed donor chimerism and graft rejection compared with fully myeloablative HCT; while mixed donor engraftment is likely to correct the phenotypic expression of most children with PID, the use of DLI to increase donor chimerism or second HCT may be required in some cases.

It is difficult to make specific recommendations as to which RIC protocol should be used in which disease and with which donor. As a generalization the combination of alemtuzumab, fludarabine and melphalan is very applicable to children aged >1 year undergoing unrelated HCT for immunodeficiency disorders with the greatest benefit realized in T-cell deficiencies and HLH. If the donor is fully matched then PB is the preferred stem cell source. Compared to other RIC protocols the combination of fludarabine and melphalan is likely to be associated with the least long-term side effects. The outcome of procedures following treosulfan and fludarabine or reduced busulfan and fludarabine is likely to be equivalent. Further preference may be guided by the differing incidence of late effects between the two protocols: such studies are urgently required.

The use of RIC protocols in combination with matched sibling donors requires further analysis and in particular the role of in vivo T-cell depletion in this context needs to be defined. Finally, the use of a MIC protocol is best suited for PID children with significant comorbidities or DNA repair disorders.

Five-year view

PIDs are a heterogeneous group of diseases that result in high susceptibility to infection. In most cases HCT is the only curative treatment. However, many patients with PID have severe comorbidities due to chronic infections, autoimmune phenomena or nonhematological features of their primary disease. Since organ toxicity is a major cause of death after HCT, several groups of investigators have developed RIC regimens to minimize regimen-related complications.

These least intensive regimens rely on pre- and post-transplant immunosuppression to establish mutual graft–host tolerance and initial mixed donor–host hematopoietic chimerism, which is often sufficient to correct the underlying genetic abnormality.

Future therapeutic strategies should aim at further reducing regimen-related toxicity after RIC HCT in children with PID. Such strategies might include a more frequent use of targeted therapies with minimal toxicity like monoclonal antibodies (especially in children with PID associated with disorders of DNA repair) or the use of therapeutic drug monitoring to achieve a targeted drug systemic exposure to maximize efficacy while limiting morbidity.

Key issues

• • Reduced-intensity conditioning (RIC) regimens have enabled the performance of hematopoietic cell transplantation (HCT) in children with primary immunodeficiency diseases and pre-existing comorbidities that would preclude conventional conditioning.

• • The goal of RIC HCT is to reduce acute and long-term regimen-related toxicity, while establishing donor-derived hematopoiesis at a level sufficient to cure the underlying disease.

• • Different RIC regimens (mostly fludarabine-based) have been used and more studies are needed using drug pharmacokinetic monitoring (e.g., busulfan, treosulfan) and varying stem cell sources to optimize graft-versus-marrow reactions and minimize graft-versus-host disease.

• • In some primary immunodeficiency disease patients, RIC HCT is the first step towards establishing donor engraftment and donor lymphocyte infusions or second HCT procedures may be necessary in some children with low-level donor engraftment.

• • Minimal-intensity protocols are best suited for primary immunodeficiency disease children with significant comorbidities or DNA repair defects.

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Editorial Director, Future Science Group, London, UK

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD,Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure:Charles P. Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

Robert Chiesa, MD,Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, UK

Disclosure:Robert Chiesa, MD, has disclosed no relevant financial relationships.

Paul Veys, FRCP,Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, UK

Disclosure:Paul Veys, FRCP, has disclosed no relevant financial relationships.

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Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies

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1. Which of the following outcomes is most associated with reduced-intensity conditioning (RIC) vs myeloablative hematopoietic cell transplant (HCT)?

• □ A Worse overall survival

• □ B Higher rate of mixed donor chimerism

• □ C Lower risk for viral infections

• □ D Higher incidence of acute graft-vs-host disease (GvHD)

2. Which of the following statements regarding the source of stem cells in RIC is most accurate?

• □ A Peripheral blood stem cells (PBSCs) are associated with lower rates of donor chimerism and GvHD compared with bone marrow

• □ B PBSCs are associated with higher rates of donor chimerism and GvHD compared with bone marrow

• □ C PBSCs are associated with lower rates of donor chimerism but higher rates of GvHD compared with bone marrow

• □ D PBSCs are associated with higher rates of donor chimerism but lower rates of GvHD compared with bone marrow

3. Which of the following statements regarding different RIC protocols is most accurate?

• □ A Treosulfan and fludarabine are superior to reduced busulfan and fludarabine

• □ B Reduced busulfan and fludarabine are superior to treosulfan and fludarabine

• □ C RIC is most sensible among children younger than 1 year of age

• □ D There is no one accepted RIC protocol to recommend above others

4. RIC is most effective for which of the following disease indications?

• □ A DiGeorge syndrome

• □ B Hemophagocytic lymphohistiocytosis (HLH)

• □ C Bruton agammaglobulinemia

• □ D Leukocyte adhesion deficiency