HLA-haploidentical hematopoietic SCT (HSCT) is an option for severe aplastic anemia (SAA) patients. Here, we evaluated the outcomes of 26 adult-SAA patients who received HLA-haploidentical HSCT in five transplant centers in southwestern China. Most of the patients in this study failed prior therapy and were transfused heavily before the transplantation. The patients received fludarabine+cyclophosphamide+antithymocyte globulin as conditioning regimens and then unmanipulated peripheral blood plus marrow transplantation. Micafungin, i.v. Ig and recombinant human TPO were used for post-grafting infection prevention and supportive care. Of 26 patients, 25 achieved engraftment at a median of 13 days (range, 11–19 days) after HSCT. One of 25 patients experienced graft rejection and did not achieve sustained engraftment after second HSCT. Therefore, the final engraftment rate was 92.3%. Three of 25 (12%) patients developed acute GVHD, 10 of 25 (40%) patients developed chronic GVHD (9 with limited whereas the other with extensive). The OS rate was 84.6% and the average follow-up time was 1313.2 (738–2005) days for surviving patients. This encouraging result suggests that HLA-haploidentical HSCT is an effective therapeutic option for adults with acquired SAA if an HLA-identical donor is not available.
Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for patients with severe aplastic anemia (SAA). The best outcomes for allo-HSCT have been obtained in patients receiving allografts from a HLA identical sibling or matched-alternative donor.1 However, the chance of finding an HLA genotypically identical sibling donor is only 25%, and unrelated donors matched at the allelic level cannot be found in time for all patients who need an allograft.2 The interest in transplantation using haploidentical donors arises from the immediate availability of a suitable HLA-haplotype-matched donor for virtually all patients within an appropriate period. Progress has been made in haploidentical HSCT, and it is now used to treat patients with hematological malignancies.3, 4 However, only a few cases of mismatched, related donor transplants in SAA are reported.5, 6, 7 Recently, new therapeutics for haploidentical transplantation from unmanipulated grafts have been developed. Huang et al.8 reported their experience with HLA-haploidentical HSCT using grafts without in vitro T-cell depletion in 19 patients with acquired SAA. All 19 patients achieved primary engraftment, but 2 patients developed late graft failure (GF) and 6 died from transplantation related causes (GVHD, infection and late GF). The 2-year OS rate was 64.5%. This retrospective analysis suggests that HLA-haploidentical HSCT for SAA patients without an HLA-identical sibling donor might be feasible. However, further research to improve OS by decreasing TRM while maintaining stable engraftment is needed in SAA.
To improve the therapeutic effect of HLA-haploidentical HSCT for SAA, a long-term retrospective clinical study of HLA-haploidentical HSCT for SAA patients was conducted in five transplant centers in southwestern China. We successfully applied a modified conditioning regimen involving fludarabine (Flu) and modified post-grafting supportive care, including regeneration of platelets with recombinant human TPO (rhTPO), drastic infection prevention with micafungin and i.v. Ig (IVIG).
Patients and methods
Between June 2007 and December 2010, 26 consecutive adult patients (>18 years old) with SAA who underwent HLA-haploidentical HSCT at five transplant centers in Southwestern China were enrolled in this study. SAA or very SAA (VSAA) was defined by the Education Program of the American society of hematology.9 In addition, all the patients met the following criteria: (1) voluntary participation in HSCT; (2) absence of uncontrolled infections and severe liver, renal, lung and heart diseases; (3) lack of available HLA-identical-related sibling or unrelated donor; (4) no clonal evolution. Written informed consent was obtained from the patients or their guardians and donors. This study was approved by the ethics committees of the participating institutions and was conducted in accordance with the Declaration of Helsinki.
Donors, stem cell mobilization and collection
HLA-A, HLA-B and HLA-DR typing was performed using a high-resolution DNA technique.10 For the 26 haploidentical transplantation patients, 18 donors were full haplotype mismatches, and 8 donors were haploidentical with two-loci-mismatched.
All the patients received peripheral blood (PB) combined with BM HSCT. The donor PB and BM cells were collected using standard mobilization protocols.10 Periphery blood monocytes were>2.0 × 108/kg, BM nucleated cells were >4.0 × 108/kg and CD34+ cells were >6.0 × 106/kg. The surface markers of the graft cells were determined by flow cytometry.
The conditioning therapy consists of Flu (Fludara, Schering AG, Berlin, Germany), cyclophosphamide (CY) and antithymocyte globulin (ATG; Genzyme, Boston, MA, USA). All the patients were treated with the following regimen: Flu: 30 mg/m2 once daily i.v. for 4 consecutive days on days −5 to −2; CY: 45 mg/kg once daily i.v. for 2 consecutive days on days −3 and −2; and ATG: 2.5 mg/kg once daily i.v for 4 consecutive days on days −5 to −2 (as shown in Figure 1).
Evaluation of engraftment and transplantation-related toxicity
Neutrophil engraftment was defined as an ANC ⩾0.5 × 109/L for 3 consecutive days. Platelet engraftment was defined as a platelet count ⩾20 × 109/L for 3 consecutive days without transfusion. Hematopoietic chimerism was evaluated by FISH for sex-mismatched patient–donor pairs and by PCR amplification of STRs for sex-matched pairs using PB samples from the donor and the recipient. After HSCT, recipient BM samples were drawn monthly for the first 3 months, every 3 months for the first year and then every 6 months for the second year. Complete donor chimerism was defined as the presence of only donor-type hematopoietic cells after allo-HSCT.
GF was defined as either primary GF, which is the absence of hematologic recovery in patients surviving ⩾21 days after transplantation or transient engraftment. Transient engraftment was defined as complete or partial recovery of donor hematopoiesis followed by recurrent pancytopenia with a markedly hypocellular BM in the absence of moderate to severe acute GVHD (aGVHD).11
Transplantation-related toxicity was evaluated by common criteria set by the National Cancer Institute (NCIC, www.ecog.org/general/ctc.pdf). The time of onset of grades III–IV toxicities was defined as occurring within 40 days following HSCT. Any organ damage due to GVHD and/or infectious complications was excluded.
GVHD prophylaxis and management
The haploidentical SAA patients required intensive immunosuppressive treatment. In addition to the basic treatment with ATG, all transplant recipients received CsA, mycophenolate mofetil (MMF) and short-term MTX for aGVHD prophylaxis.10 Detailed usage was described in Figure 1.
aGVHD and chronic GVHD (cGVHD) were defined according to the Fred Hutchinson Cancer Research Center criteria.10, 12 aGVHD was treated with 1–2 mg/kg of methylprednisolone. The second-line immunosuppressive therapy, such as tacrolimus (FK506), MMF and CD25 MoAb (daclizumab; Roche, Basel, Switzerland), or MTX was given for steroid-refractory aGVHD. cGVHD was treated with 1–2 mg/kg of prednisolone equivalents and resumption of full-dose CsA administration.
Infection prevention and surveillance
All patients were cared for in a laminar air-flow room and received prophylactic antibiotics when their ANC was <0.5 × 109/L. Norfloxacin, trimethoprim sulfamethoxazole and ganciclovir were routinely administered according to the reported method.10 In this study, SAA patients also received micafungin (50 mg/day) from day +1 before engraftment to prevent invasive fungal infection (IFI). At the same time, all SAA patients were given IVIG (0.4 g/kg once weekly, before +100 days; 0.4 g/kg once monthly, after +100 days) to increase passive immunity (Figure 1). The patients were monitored for CMV DNA weekly by PCR and CMV-positive patients were treated with either ganciclovir or foscarnet. CMV-related interstitial pneumonia was defined according to reported criteria.13
All blood products were irradiated and filtered. Red cell and platelet transfusions were given to maintain Hb of >80 g/L and platelet count >20 × 109/L. All patients received recombinant human G-CSF and rhTPO (Sansheng Pharmaceutical Co., Ltd, Shenyang, China) from day 01 after hematopoietic stem cell infusion to donor engraftment (Figure 1).
The primary end point of the study was the OS rate after transplantation. The secondary end points included engraftment rate, TRM, incidence of infection and GVHD. aGVHD and cGVHD were analyzed as time-dependent variables. The date of the last follow-up for all surviving patients was 31 December 2012. Statistical software packages (SPSS 16.0, Chicago, IL, USA) were used for the analyses.
Patient and donor characteristics
The characteristics of patients and donors before transplantation are shown in Table 1. The average age of patients was 25.4 (ranging from 18 to 41) years. Ten (38.5%) of these patients were VSAA cases. All patients had failed to respond to previous immunosuppressive therapy before HSCT, including CsA+andriol±corticosteroid regimen (17 patients) and CsA+ATG+andriol±corticosteroid regimen (9 patients). In all, 18 of 26 patients were heavily transfused and received RBCs and/or platelet preparations >20 times. The median time from diagnosis to transplantation was 6.7 (ranging from 2 to 72) months.
All donors tolerated the procedures well and showed no severe side effects during PB leukapheresis and BM harvest. The cell transplantation data are shown in Table 2.
Engraftment and transplantation-related toxicity
One patient could not achieve myeloid recovery and died of intracranial hemorrhage on day 54 post transplantation. The other patients achieved myeloid recovery and full donor chimerism by day 30 after HSCT. The patients had ANC exceeding 0.5 × 109/L within 13 days (range, 11–19) and PLT exceeding 20 × 109/L within 13 days (range, 10–21). Of these patients, secondary granulocytopenia and thrombocytopenia occurred in three patients. One patient recovered after treatment with recombinant human G-CSF and platelet transfusions. Two patients developed late GF on days +72 and +130, respectively. These patients were treated with CY (50 mg/kg × 2 days) followed by an infusion of PBSCs from the original donor after on days +104 and +165. The first patient did not recover and died of infection on day +184. The second patient recovered 1 month after treatment (on day +197).
All patients received the conditioning regimen on schedule. The grades II through IV organ toxicity that occurred within the first 40 days after HSCT were evaluated. There was no significant cardiovascular, renal or liver toxicity, and no deaths resulted from lethal organ toxicity.
GVHD incidence and severity
Patients in this study had a lower risk of aGVHD than in other studies of allo-HSCT treatment for SAA.14 Of the 25 evaluable patients, 21 (84.0%) cases had no aGVHD, 1 (4.0%) case had grade II aGVHD and 1 (4.0%) case had grade III aGVHD (as shown in Table 3). Two patients had frequent micturition and urgent urination on days +45 and +60. After examination and treatment, one patient was diagnosed with CMV infection. The other patient developed a secondary rash, diarrhea and hepatic functional lesions. The patient was diagnosed with grade III aGVHD. At 100 days after transplantation, the cumulative incidence of grades II–IV and III–IV aGVHD were 12.0% and 8.0%, respectively. (Figure 2a). Corticosteroids (2 mg/kg once daily) were given i.v. and tapered as scheduled or based on the therapeutic response. One patient with grade III aGVHD who was resistant to corticosteroids received a second line of immunosuppressive drugs (tacrolimus and daclizumab).
There were 25 patients who survived more than 100 days after HSCT who were evaluated for the incidence of cGVHD. cGVHD developed in 10 (40.0%) patients. Nine (36.0%) showed limited cGVHD when they were tapered off CsA at the scheduled time and one (4.0%) showed extensive cGVHD (as shown in Table 3). The cumulative incidences of cGVHD and extensive cGVHD were 40.0% and 4.0%, respectively (Figure 2b). The patient with extensive cGVHD remained on tacrolimus and steroids (long-term taper), showed recurrent episodes of cGVHD and died from infection on day +370.
Immune reconstitution and infections
The immune reconstitution of all 25 patients who had sustained stable engraftment was examined, including the patient who received successful salvage transplantation. As controls, twenty donors also had detected CD3, CD4, CD8, CD19 and CD56 cells in the blood. CD3+, CD19+ and CD56+ cells in the blood recovered within 12 months. The CD4+ cells recovered relatively more slowly, but reached above a 0.41 × 109/L level in 12 months and became normal within 18 months after transplant (Table 4).
The major infection types noted in transplant patients were bacterial infections and CMV reactivation. There were 6 of 26 patients who experienced CMV viremia. In addition, one patient developed CMV pneumonia. A fever developed in 10 patients after transplantation. Seven patients with bacterial infections, one patient with IFIs and two patients with bacterial and CMV mixed infections.
OS and TRM
There were four patient deaths by 31 December 2012. The TRM at +100 days, +1 year and +2 years was 3.8%, 11.5% and 15.4%, respectively. The causes of TRM included GVHD in one case, severe mixed infection in one case and GF in two cases. A total of 22 patients survived at an average follow-up of 1313.2 days (range, 738–2005), with an OS rate of 84.6% (Figure 3). All of the 22 surviving patients achieved stable myeloid recovery and transfusion independence.
In this study, the results showed that HLA-haploidentical HSCT with modified conditioning and supportive therapy had a favorable outcome for patients with SAA. Most of the patients in this study had a long history of SAA and had been heavily transfused. Several unique aspects of our protocol may help to improve the 2-year OS.
The first obstacle to successful haploidentical HSCT is GF. GF after haploidentical HSCT occurs in 5–20% of patients.15, 16 Compared with patients with acute leukemia, GF is more common in patients with SAA, especially heavily transfused cases.17, 18 The Seattle group study showed that TBI 2 × 200 cGy was sufficient for successful engraftment of transplantations from HLA-nonidentical donors in patients with SAA. However, there are only four cases in this group of patients. Moreover, when the TBI dose increased 3 × 200 cGy the GF rate reached 50%.19 Therefore, increased TBI does not improve engraftment of haploidentical stem cells. Flu is a purine antimetabolite, which was initially used for the treatment of acute myelocytic leukemia and CLL.20, 21 Owing to the profound immune suppression associated with Flu, a number of cytoreductive regimens include this drug to facilitate engraftment, especially in the context of related HLA-mismatched transplants.22 EBMT-SAA Working Party developed a reduced-intensity conditioning regimen for patients with SAA undergoing alternative donor transplants, which includes Flu (120 mg/m2), CY (1200 mg/m2) and ATG (7.5 mg/kg). In all, 18% patients (7/38) had evidence of GF. The actuarial 2-year survival is 73%, with a median follow-up of 621 days.23 As a result of this, we increase the dosage and modulate the administration of this regimen and use it on HLA-haploidentical HSCT for SAA. In this study, only 3 of 26 patients experienced GF, including early graft rejection in 1 patient. Three patients were all heavily transfused before transplantation. One of three patients was rescued by a second HSCT with the same donor and treated with CY. So, the final rate of GF was minimized to 7.7% (2 of 26).
A high dose of hematopoietic stem cells is also crucial for overcoming the barrier of residual anti-donor cytotoxic T-lymphocyte precursors during haploidentical transplantation. A combination of G-CSF mobilized marrow and PBSC grafts (G-BMPB) work synergistically to enhance engraftment.10 In addition, all patients in this study received rhTPO and recombinant human G-CSF to treat pancytopenia. TPO is the key cytokine regulating proliferation, differentiation and maturation of megakaryocytes.24 Patients undergoing allogeneic HSCT may have poor platelet engraftment. However, it has been found that platelet numbers recover substantially in patients undergoing allogeneic HSCT for hematological malignancies when rhTPO is administered.25 In this study, we also found that early administration of rhTPO before engraftment was effective and well tolerated in patients. The recovery time of platelets is equivalent to the ANC recovery. It will be beneficial to reduce the possibility of lethal intracranial hemorrhage.
The second barrier to successful haploidentical HSCT is the development of fatal GVHD. We observed the cumulative incidence of aGVHD in SAA patients in this trial is lower than previously reported for malignant hematology patients with haploidentical HSCT.10, 26 Although the incidence rates of cGVHD were higher in our trial, most cases of cGVHD were limited and well controlled. However, SAA patients received no additional protection from GVHD compared with patients with other malignant hematological diseases.10 Flu could increase donor engraftment and susceptibility to GVHD from small numbers of residual T cells in the donor inoculum, possibly by depleting recipient regulatory T cells. This could attenuate the graft-versus-host response and reduce GVHD.27 Li JM et al.28 found that Flu had the greatest ability to inhibit the GVHD activity of allogeneic lymphocytes and preserved the GVL activity and ability to engraft recipients. At the same time, reduced-intensity conditioning regimens can reduce the activity and damage of endothelial cells. It will also do good to reduce aGVHD.29
Infection is another major barrier to the wider application of haploidentical HSCT, especially for Aspergillosis and CMV reactivation. The delayed immune reconstitution is a main problem. In this study, CD3+, CD19+ and CD56+ cells in the blood were recovered within12 months. The CD4+ cells were recovered relatively slower within 18 months after transplant. In order to reduce the incidence of infection after HSCT, all SAA patients were given timely IVIG and micafungin on the basic infection prevention. There were 23.1% (6/26) patients who experienced CMV viremia. It is significantly lower than other SAA haploidentical HSCT studies without timely IVIG.30 Although systematic review and meta-analysis show there is no advantage in terms of CMV infection prevention of IVIG,31 we still believe that IVIG has an important role in the prevention of infection for SAA patients after HLA-haploidentical HSCT. After all, this meta-analysis just included hematologic malignancies, SAA is not within the scope of this systematic review. Furthermore, we are pleased to find that only one patient diagnosed IFI with clinical manifestations and chest computed tomography. That is to say micafungin can be effective in preventing IFI during agranulocytosis. A multicenter, randomized, open-label study in China compared the efficacy and safety of micafungin versus itraconazole for prophylaxis of IFI in patients undergoing HSCT. The results of the study indicate micafungin has the same effect and shows better tolerance than itraconazole.32
In summary, this multicenter, retrospective clinical study provides encouraging results and suggests that HLA-haploidentical HSCT without in vitro T-cell depletion might be feasible for SAA/VSAA patients without HLA-identical sibling or unrelated donors, as a salvage therapy. An effective and safe conditioning regimen that combines Flu with CY/ATG had the ability to promote engraftment and inhibit the GVHD activity of allogeneic lymphocytes. Early administration of rhTPO will do good to recover platelets and reduce the possibility of lethal intracranial hemorrhage. Intensive infection prophylaxis using IVIG and micafungin will also be an important component of the protocol. At last, the OS rate was 84.6% (22/26). All of the 22 surviving patients achieved stable myeloid recovery and were transfusion independent. Our future trial will use a uniform protocol and widespread adoption of upfront or salvage treatment for SAA/VSAA patients. A randomized study with more patients is warranted.
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This research was supported in part by the Research Fund from the Natural Science Foundation of Chongqing (no. 2009BA5056), Clinical Foundation of TMMU and ‘1130’ Foundation of Xinqiao Hospital.
The authors declare no conflict of interest.
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