Leukemia & Lymphoma
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Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria Hong Tian, Liming Liu, Jia Chen, Yang Xu, Zhengming Jin, Miao Miao, Zhengzheng Fu, Huiying Qiu, Aining Sun & Depei Wu To cite this article: Hong Tian, Liming Liu, Jia Chen, Yang Xu, Zhengming Jin, Miao Miao, Zhengzheng Fu, Huiying Qiu, Aining Sun & Depei Wu (2016): Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria, Leukemia & Lymphoma, DOI: 10.3109/10428194.2015.1068309 To link to this article: http://dx.doi.org/10.3109/10428194.2015.1068309
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Date: 26 February 2016, At: 10:03
LEUKEMIA & LYMPHOMA, 2016 http://dx.doi.org/10.3109/10428194.2015.1068309
ORIGINAL ARTICLE: CLINICAL
Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria Hong Tiana,b,c, Liming Liua,b,c, Jia Chena,b,c, Yang Xua,b,c, Zhengming Jina,b,c, Miao Miaoa,b,c, Zhengzheng Fua,b,c, Huiying Qiua,b,c, Aining Suna,b,c and Depei Wua,b,c
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a Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; bCollaborative Innovation Center of Hematology, Soochow University, Suzhou, China; cSuzhou Institute of Blood and Marrow Transplantation, Suzhou, China
ABSTRACT
ARTICLE HISTORY
Eighteen patients with paroxysmal nocturnal hemoglobinuria (PNH) receiving allogeneic hematopoietic stem cell transplant (allo-HSCT), either from HLA-haploidentical donors (HRD; n ¼ 10) or HLA-matched donors (n ¼ 5 from siblings and n ¼ 3 from unrelated donors), were retrospectively evaluated. One showed primary graft failure following unrelated-donor HSCT. He was given a second HRD-HSCT, but died from cytomegalovirus pneumonia after achieving hematopoietic recovery. The other 17 patients achieved sustained engraftment and full-donor chimerism. Four in the HRD-HSCT group experienced grade II/III acute graft-versus-host disease (aGVHD), and five in the HLA-matched HSCT group developed grade II aGVHD. Among all 18 patients, 10 developed chronic GVHD (cGVHD), only one patient receiving HRD-HSCT developed extensive cGVHD. Nine in the HRD-HSCT group and all those in the HLA-matched HSCT group were alive and transfusionindependent at last follow-up. Our findings suggest that allo-HSCT is a promising treatment for PNH, and HRD-HSCT is a viable option for patients with PNH who lack HLA-matched donors.
Received 30 March 2015 Revised 24 June 2015 Accepted 26 June 2015
Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder clinically characterized by the triad of chronic complement-mediated hemolysis anemia, thrombosis, and bone marrow failure. The disease originates from clonal expansion of hematopoietic stem cells with a mutant phosphatidylinositol glycan complementation class A (PIGA) gene (located on Xp22.1).[1] Consequently, stem cells affected by PNH and their progeny are deficient in glycosyl phosphatidylinositolanchored proteins (GPI-APs). CD55 and CD59 are the two relevant complement regulatory proteins, and their absence is fundamental to the pathophysiology of PNH.[2] The clinical features of PNH in Western and Asian populations are quite different. For example, Western patients are reported to experience more thrombotic events, whereas Asian patients are particularly predisposed to bone marrow failure.[3,4] The prognosis of PNH varies greatly, ranging from indolent to life-threatening, partly due to the risk of evolution to myelodysplastic syndrome or acute leukemia.[5] The management of PNH has entered the era of complement inhibitory therapy. However, complement inhibitory therapy has no effect on the bone marrow CONTACT D-P Wu, MD, Professor China ß 2016 Taylor & Francis
[email protected]
KEYWORDS
Haploidentical hematopoietic stem cell transplant; myeloablative conditioning; paroxysmal nocturnal hemoglobinuria
failure component of the disease.[6] Furthermore, allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative therapy for PNH.[7,8] Because of the known treatment-related toxicity, this approach to management is recommended only for patients with an underlying bone marrow abnormality, life-threatening complications, or refractory transfusion-dependent hemolytic anemia.[4,9] Haploidentical HSCT is now increasingly applied as a curative therapy for patients with hematologic diseases for whom a suitable unrelated or human leukocyte antigen (HLA)-matched sibling donor cannot be found. However, there are still few reports on the use of haploidentical HSCT for the treatment of PNH. In this study, we retrospectively evaluated long-term outcomes in PNH patients treated with HSCT, especially patients who underwent haploidentical HSCT in our center.
Methods Patients All 18 patients with PNH who underwent allogeneic HSCT at our center between July 2007 and June 2013 were enrolled in this study. Eligibility for HSCT included a diagnosis of classic PNH or clinical PNH (PNH clone 5%)
Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, Suzhou 215006,
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in the setting of another bone marrow failure condition with one or more of the following: (1) transfusion dependency; (2) recurrent hemolytic crises; and (3) a history of thrombotic events. None showed any evidence of dyshematopoiesis or chromosomal abnormalities. In all cases, the diagnosis of PNH was confirmed both by clinical manifestation and hematologic tests (Ham’s test and flow cytometric analysis of CD55 and CD59 expression). None of the patients received treatment with eculizumab, because the drug was unavailable before transplant. This study was approved by the ethics committee of The First Affiliated Hospital of Soochow University. All patients provided written informed consent before therapy.
Transplant procedure Stem cell mobilization was induced by subcutaneous delivery of 5 mg/kg/day granulocyte colony-stimulating factor (GCSF) for 5 consecutive days before stem cell harvesting. Bone marrow (BM) grafts from related donors were harvested by BM aspiration at day 0. If the count of CD34 + cells was 52 106/kg, peripheral blood stem cells (PBSCs) also were collected by apheresis using a COBE SPECTRA device (Gambro BCT, Lakewood, CO) from day 1 and if needed on the following day until a target number of 2 106/kg CD34 + cells was attained. PBSCs were used as the graft source when donors were unrelated or unable to undergo BM aspiration. Preconditioning consisted of cytarabine (10 to 9 days), busulfan (4 mg/kg per day, 8 to 6 days), cyclophosphamide (1.8 g/m2 per day, 5 to 4 days), and simustine (Me-CCNU, 250 mg/m2, 3 days). Furthermore, cytarabine was administered at 4 g/m2 per day along with anti-thymocyte globulin (ATG; 2.5 mg/kg, 5 to 2 days) in patients who received HLA-haploidentical allo-HSCT and at 2 g/m2 per day (not in combination with ATG) in patients who received HLA-matched alloHSCT.[10] Prophylaxis for graft-versus-host disease (GVHD) included cyclosporine (CSA), mycophenolate mofetil, and short-term administration of methotrexate, designed according to a previously described method.[11] Some patients were heavily transfused: the pretransplant serum ferritin level was markedly elevated at a median 1120 mg/L (range, 20–11,000 mg/L). Seven transfusion-dependent patients with high levels of iron overload (serum ferritin 1000 mg/L) received iron chelation therapy before transplant. Only when their serum ferritin level was below 1000 mg/L could blood transfusion be administered as indicated (hemoglobin 560 g/L and/or platelets 510 109/L) before HSCT.
Evaluation of implantation and observations Myeloid engraftment was defined by the achievement of an absolute neutrophil count of 0.5 109/L for at least 3 consecutive days, and platelet engraftment was defined on the day the platelet count met or exceeded 20 109/L without transfusion for 1 week. Acute GVHD (aGVHD) was graded according to standard criteria, and chronic GVHD (cGVHD) was deEned as absent, limited, or extensive.[12] Hematopoietic chimerism was evaluated by DNA-based assays of short tandem repeat sequences using peripheral blood samples. Complete donor chimerism was defined as the first time more than 95% donor-type hematopoietic cells were found in the peripheral blood. All patients were screened for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) at twice per week for the first 3 months. HLA antibodies were measured routinely pretransplant in all patients using a microbead Fow cytometric assay with mean Fuorescence intensity readout for the serum antibody level. If screening for HLA antibodies returned positive results, donor-specific HLA antibodies (DSA) were further investigated with a Luminex Single Antigen assay. The results were analyzed as mean fluorescence intensity (MFI) versus donorspecific mismatch.
Results Patient characteristics Eighteen patients who were diagnosed with PNH and underwent HSCT were included in this study. Data for all patient characteristics at the time of transplant are shown in Table 1. The median age at the time of transplant was 25 years (range, 13–54 years), and the median disease duration was 15 months (range, 3–240 months). The major indication for transplant was bone marrow failure, including 11 patients with severe cytopenia, six with recurrent severe hemolysis and severe cytopenia, and one with recurrent hemolysis and thromboembolism. Five patients were anti-HLA antibody positive (Patients 1, 3, 6, 13, and 15), including two DSA-positive patients (Patients 6 and 13). The MFI (DSA level) was 17600 (target HLA loci of DSA was B13) and 5033 (target HLA loci of DSA was B60) in Patients 6 and 13, respectively. Both of these patients received a single dose of rituximab (375 mg/m2), but only Patient 13 experienced a reduction in the expression level of HLA antibodies (from 5033 to 1010). Of all 18 patients, 10 patients did not have a suitable HLA-matched donor and underwent HRD-HSCT (Patients 1–10). Among these patients, the median mononuclear cell and CD34 + counts were 9.7 108/kg and 3.7 106/kg, respectively. The other eight patients
54/M 29/M 25/M 13/M 21/M 42/M
40/M
20/F
17/M 21/M 28/M 24/M 23/M 23/F 47/M 41/M 40/F 21/M
1 2 3 4 5 6
7
8
9 10 11 12 13 14 15 16 17 18
PNH PNH PNH-AA PNH PNH-AA PNH PNH PNH-AA PNH PNH
PNH
PNH
PNH PNH PNH PNH-AA PNH PNH
Diagnosis
Hemolysis and cytopenia, TD Hemolysis and cytopenia, TD Hemolysis, TD Cytopenia, TD Cytopenia Hemolysis, TD Cytopenia Hemolysis, TD Cytopenia, TD Cytopenia, TD Hemolysis, TD Cytopenia
Hemolysis, TD Hemolysis, TD Cytopenia, TD Cytopenia Cytopenia, TD Hemolysis and thrombosis (cerebrovascular)
Clinical features
6 8 18 25 8 4 240 144 180 6
13
20
84 6 12 4 30 120
Duration of PNH (months)
99.0 98.9 20.0 25.1 60.0 99.1 99.0 89.0 80.0 85.0
42.6
60.6
56.9 41.6 99.9 99.0 99.3 20.0
Pretransplant %GPInegative neutrophils
Sep 2012 Jun 2013 Oct 2012 Mar 2013 Apr 2012 Aug 2009 Oct 2011 Dec 2007 Feb 2013 Nov 2012
Dec 2012
May 2011
Oct 2010
Jan 2013 Jun 2013 Jan 2011 Mar 2013 Aug 2012 Sep 2010
Date of transplant
3/6 3/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6
4/6
3/6 3/6 4/6 3/6 3/6 (first transplant) 6/6 (second transplant) 3/6 3/6
Compatibility of donor
A/A B/B B/A B/O O/A B/B AB/A AB/AB A/A A/A
A/A
AB/B
AB/B
A/B AB/AB A/A B/B A/A B/B
ABO pairs D/R
Father Brother Unrelated Unrelated Unrelated Sister Sister Brother Brother Brother
Brother
Sister
Daughter
Son Sister Mother Mother Father Unrelated
Donor
BM + PB BM + PB PB PB PB BM + PB PB BM BM + PB BM + PB
BM + PB
BM + PB
BM + PB
BM + PB BM + PB BM + PB BM + PB BM + PB PB
Stem cell source
11.57 11.3 8.68 7.83 3.85 12.07 5.57 4.43 8.90 12.19
8.27
5.70
8.20
5.77 10.42 9.07 13.76 12.81 10.20
MNC 108/kg
M: male; F: female; PNH: paroxysmal nocturnal hemoglobinuria; AA: aplastic anemia; TD: transfusion dependent on red cells and/or platelets; D: donor; R: recipient; MNC: mononuclear cells; BM: bone marrow; PB: peripheral blood.
Age (yr)/ Sex
Case
Table 1. Patient and transplant characteristics.
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3.97 4.13 3.80 5.02 5.00 3.47 3.02 3.07 6.57 8.42
2.97
3.01
3.45
4.30 4.62 2.55 2.86 4.86 3.10
CD34+ 106/kg
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Table 2. Outcomes of PNH patients after allo-HSCT. Engraftment (days) Case
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
ANC 40.5 109/L
PLT 420 109/L
15 33 11 13 12 20 13 28 12 18 First transplant: graft failure 14 23 12 18 12 15 12 14 11 13 11 17 11 13 12 18 11 12 11 12 9 18 11 13 10 16
GVHD Full-donor chimerism (days)
Acute
Chronic
34 28 30 36 32 – 42 32 40 34 34 30 34 32 32 30 28 28 32
Grade I Absent Grade I Absent Absent – Grade II Grade III Absent Grade II Grade II Grade II Absent Grade I Absent Grade II Grade II Absent Grade II
Limited Absent Limited Limited Limited – Absent Limited Absent Extensive Absent Limited Limited Absent Absent Limited Absent Absent Limited
Follow-up (months)/ Outcome 21/Alive 19/Alive 14/Alive 15/Alive 29/Alive 6/Dead (infection) 15/Alive 17/Alive 20/Alive 17/Alive 22/Alive 15/Alive 33/Alive 24/Alive 39/Alive 85/Alive 22/Alive 15/Alive
ANC: absolute neutrophil count; PLT: platelet
received HLA-matched transplants, including three cases of MUD-HSCT (Patients 11–13) and five cases of MRD-HSCT (Patients 14–18). Among these patients, the median mononuclear cell and CD34 + counts were 8.3 108/kg and 4.4 106/kg, respectively. The median percentage of PNH granulocytes at the time of transplant was 79.8% in the HRD-HSCT group (range, 20.0–99.9%) and 82.5% in the HLA-matched group (range, 20.0–99.1%; p40.05). Additionally, no significant differences were observed between the two groups in the median number of peripheral counts at transplant (p40.05). In the HRD-HSCT group, the neutrophil count was 1.03 109/L (range, 0.02–3.22 109/L), the hemoglobin level was 60 g/L (range, 51–82 g/L), and the platelet count was 17 109/L (range, 12–40 109/L). In the HLA-matched group, the neutrophil count was 1.03 109/L (range, 0.2–3.59 109/L), the hemoglobin level was 61 g/L (range, 36–69 g/L), and the platelet count was 18 109/L (range, 4–82 109/L). The distributions of characteristics such as age, gender, and CD34 + counts in grafts were similar in both groups of patients.
Hematopoietic recovery and donor engraftment As shown in Table 2, one case (Patient 6) in the HRD-HSCT group experienced graft failure after the first transplant (URD-HSCT), whereas the other 17 patients achieved primary sustained engraftment within a median time of 11.5 days (range, 9–15 days) to reach a neutrophil count of 0.5 109/L and 16.5 days (range, 12–33 days) to reach a platelet count of 20 109/L.
The engraftment time did not differ significantly between patients who received transplants from haplo-identical donors and those who received transplants from HLA-matched donors. Patient 6 showed primary graft failure with no sign of engraftment at day 30 following URD-HSCT. The patient was then given a second transplant from his daughter following conditioning with total body irradiation, cyclophosphamide, and ATG. He achieved hematopoietic recovery but died from CMV pneumonia on day 181 post-transplant. Fulldonor chimerism occurred in all 17 evaluable patients at a median of 32 days (range, 28–36 days) post-HSCT. The distribution of the time of chimerism was similar in both groups of patients.
Transplant-related complications Of the 17 evaluable patients, two patients developed grade I intestinal aGVHD, three patients developed grade II intestinal/skin aGVHD, and one patient developed grade III intestinal aGVHD following HRD-HSCT. Five patients developed grade II skin/intestinal aGVHD following HLA-matched HSCT. In all cases, aGVHD was controlled with steroid/cyclosporine A therapy. Among all 18 patients who survived for more than 100 days after transplant, 10 patients developed cGVHD. Of these patients, 9 showed limited cGVHD and one patient who underwent HRD-HSCT developed extensive cGVHD that responded well to oral administration of prednisone and cyclosporine A (Table 2). CMV infection occurred in three patients (two in the HRD-HSCT group and one in the URD-HSCT group).
TRANSPLANTATION IN PNH
Two of these patients (Patients 5 and 11) did not develop CMV disease, whereas Patient 6 did. Epstein-Barr virus infection occurred in four patients (two patients in each group), and no case of Epstein-Barr virus post-transplant lymphoproliferative disorder occurred.
Survival outcomes One patient who underwent HRD-HSCT died from complications related to CMV disease on day 181 post-transplant. As of 31 January 2015, at a median follow-up period of 20 months (range, 14–85 months), all of the other 17 patients remained alive and transfusion-independent without relapse.
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Discussion Here we report the characteristics and outcomes of a small cohort of patients with PNH who underwent HSCT in our center. Remarkably, this small cohort of 18 patients included 10 recipients of transplants from HLA-haploidentical related donors. The present study showed that allo-HSCT resulted in favorable outcomes in PNH patients, and substantial survival was achieved by PNH patients who underwent either HRD-HSCT or HLA-matched HSCT. Moreover, one patient received a salvage HRD-HSCT after graft failure following MUD-HSCT and then achieved hematopoietic recovery. Although he died from a transplant-related complication, his case still suggests the feasibility of HRD-HSCT as a salvage treatment. A limited number of single-center studies of HSCT for PNH have been published,[13,14] and these studies included small numbers of patients. Furthermore, reports investigating outcomes in PNH patients who receive HRD-HSCT are rare. The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in 48 recipients of HLA-identical sibling transplants between 1978 and 1995.[7] Recently, the largest cohort of 211 PNH patients was reported by the European Group for Blood and Marrow Transplantation (EBMT), and 65% of these patients received grafts from HLA-identical siblings with the rest receiving grafts from HLA-matched unrelated donors.[15] They found that the indication for HSCT, such as aplastic anemia (AA), recurrent hemolytic crises, or thrombotic events (TE), was the only significant predictor of survival, with patients receiving a transplant as therapy for TE having the worst outcome. The 5-year overall survival (OS) rates were 54% among patients with TE, 69% for patients with AA and no TE, and 86% for patients with recurrent hemolytic anemia without TE or AA. However, the clinical features of PNH in white and
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Asian patients have been shown to be quite different, e.g. white patients were reported to experience more TE, whereas Asian patients were particularly predisposed to BM failure.[4] With cytopenia and hemolysis being the main indications for transplant in our study, only one patient experienced TE and died after the second transplant. Good results were achieved in patients who received HSCT for the other two indications. Moreover, we also found that the incidence of grade II–III aGVHD was 40% (4/10) and that of cGVHD was 60% (6/10). These frequencies are consistent with the findings of a previous study on the use of HRD-HSCT to treat nonmalignant hematologic disease.[16] Although the incidence of GVHD in the HRD-HSCT group seemed to be slightly higher in the present study, compared with the results of other reports on HLA-matched transplant on PNH,[7,13,14] the severity and controllability of GVHD were favorable. In a considerable percentage of PNH patients, a suitable matched donor is not available or cannot be identiEed within a reasonable time frame. Indeed, it is more difficult to find a suitable HLA-identical sibling donor for Chinese patients due to the population policy. Furthermore, the often long period of time required to find a matched unrelated donor or a matched cord blood unit can permit disease progression prior to treatment. Haploidentical HSCT virtually ensures the opportunity for nearly all patients to benefit from HSCT and offers the advantage of immediate accessibility to transplant therapy. Although provided only by small retrospective case series, evidence from the medical literature supports the use of haploidentical donors as a viable option in PNH patients. The first report of successful HLA-haploidentical HSCT in three PNH patients was published in 2008 by Brodsky et al. [17]. Two of their patients achieved long-term survival, and one died from graft failure. In the present study, we report the outcomes of 10 consecutive PNH patients treated with HSCT from an HLA-haploidentical related donor. Nine of them survived without major complications. Moreover, we observed no significant differences in transplant-related complications and outcomes between the HRD-HSCT group and the HLA-matched HSCT group in our study. It remains unclear whether a nonmyeloablative conditioning regimen or myeloablative regimen is more suitable for PNH patients. A previous study found no differences in treatment-related mortality or overall survival between 42 HLA-matched patients who received reduced intensity conditioning and 169 HLA-matched patients who received a myeloablative conditioning regimen.[15] Recently, however, Pantin et al. reported that among 17 PNH patients who
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received cyclophosphamide/fludarabine with or without ATG followed by HSCT from an HLA-matched relative, 15 achieved long-term survival without evidence of PNH.[18] Further studies are needed to establish the role of the conditioning regimen for transplant and its ability to reduce early treatment-related mortality and thereby improve the outcome of allo-HSCT in the treatment of PNH. The role of HLA antibodies in HSCT has drawn increasing attention because of the risk of graft failure in patients who receive HLA-mismatched HSCT, including cord blood transplantation,[19,20] haploidentical SCT,[21,22] and unrelated SCT.[23] Rituximab, bortezomib, plasma exchange (PE), and high dose intravenous immunoglobulin (IVIG) have been used for the reduction of HLA antibody levels before SCT, but the efficiency of each treatment option remains unclear due to the small number of reported cases.[24] Gladstone et al. proved that PE/IVIG treatment can reduce DSA to negative or weak levels and achieve full donor engraftment in eight patients who underwent mismatched allo-HSCT.[25] Recently, it has been reported that desensitization treatment with PE/Rituximab/IVIG plus the addition of buffy coat infused might be more effective,[26] suggesting that strong DSA levels should not be an absolute barrier to HSCT. In this study, a high level of HLA antibodies is the most likely explanation for the nonengraftment experienced by Patient 6. Fortunately, Patient 13 received rituximab before transplant for a high level of HLA antibodies, and she achieved fast engraftment after an infusion of stem cells. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH [27] and has been shown to not only signiEcantly reduce hemolysis, but also to improve anemia and patients’ quality of life.[16,28] Nonetheless, eculizumab has no effect on either the underlying stem cell abnormality or the associated bone marrow failure. Furthermore, not all patients have a favorable response to eculizumab. Nishimura et al. found that genetic variants in C5 (Arg885) cause failure to undergo blockade by eculizumab, which accounts for the poor response to this agent.[29] In addition, eculizumab is prohibitively expensive (about $400,000/year in the United States) for patients without medical insurance. Transplant is the only curative therapy for PNH; however, the risks associated with this option are not insignificant. In the era of complement inhibitory therapy, the most challenging problem is to identify those patients who are most likely to benefit from transplant. Several transplant-related issues could not be addressed in this study because of the small number of patients and the retrospective nature of the study.
More prospective trials are needed to develop strategies for identifying such patients. In conclusion, our data demonstrate that patients with recurring PNH can benefit from HSCT. Our results also show that HRD-HSCT is a viable alternative option for patients who have no suitable HLA-matched donor who might be able to use it as a salvage treatment after failure of the first transplant. However, definitive conclusions cannot be drawn based on the small number of patients included in our study, but it will be interesting to see if similar results are obtained in a larger cohort of PNH patients with longer follow-up. Finally, it is essential that patients who have a transfusion history are screened for HLA antibody levels prior to HSCT to avoid related complications.
Acknowledgements This work was supported by the Jiangsu Provincial Special Program of Medical Science (BL2012005), the Jiangsu Province’s Key Medical Center (ZX201102), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the National Public Health Grand Research Foundation (No. 201202017). Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at http:// dx.doi.org/10.3109/10428194.2015.1068309.
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[9] Young NS, Meyers G, Schrezenmeier H, et al. The management of paroxysmal nocturnal hemoglobinuria: recent advances in diagnosis and treatment and new hope for patients. Semin Hematol. 2009;46(1 Suppl 1): S1–S16. [10] Mo XD, Xu LP, Liu DH, et al. Patients receiving HLAhaploidentical/partially matched related allo-HSCT can achieve desirable health-related QoL that is comparable to that of patients receiving HLA-identical sibling alloHSCT. Bone Marrow Transplant. 2012;47:1201–1205. [11] Wu Y, Cao Y, Li X, et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Res. 2014;12:132–138. [12] Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828. [13] Hegenbart U, Niederwieser D, Forman S, et al. Hematopoietic cell transplantation from related and unrelated donors after minimal conditioning as a curative treatment modality for severe paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant. 2003;9:689–697. [14] Lee JL, Lee JH, Lee JH, et al. Allogeneic hematopoietic cell transplantation for paroxysmal nocturnal hemoglobinuria. Eur J Haematol. 2003;71:114–118. [15] Peffault de Latour R, Schrezenmeier H, Bacigalupo A, et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica. 2012;97:1666–1673. [16] Xu LP, Liu KY, Liu DH, et al. A novel protocol for haploidentical hematopoietic SCT without in vitro T-cell depletion in the treatment of severe acquired aplastic anemia. Bone Marrow Transplant. 2012;47:1507–1512. [17] Brodsky RA, Luznik L, Bolan˜os-Meade J, et al. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42:523–527. [18] Pantin J, Tian X, Geller N, et al. Long-term outcome of fludarabine-based reduced-intensity allogeneic hematopoietic cell transplantation for debilitating paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant. 2014;20:1435–1439.
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[19] Takanashi M, Fujiwara K, Tanaka H, et al. The impact of HLA antibodies on engraftment of unrelated cord blood transplants. Transfusion. 2008;48:791–793. [20] Takanashi M, Atsuta Y, Fujiwara K, et al. The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood. 2010;116:2839–2846. [21] Ciurea SO, de Lima M, Cano P, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88:1019–1024. [22] Yoshihara S, Maruya E, Taniguchi K, et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant. 2012;47:508–515. [23] Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA-speciEc alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010;115:2704–2708. [24] Yoshihara S, Taniguchi K, Ogawa H, et al. The role of HLA antibodies in allogeneic SCT: is the ‘type-andscreen’ strategy necessary not only for blood type but also for HLA? Bone Marrow Transplant. 2012;47:1499– 506. [25] Gladstone DE, Zachary AA, Fuchs EJ, et al. Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies. Biol Blood Marrow Transplant. 2013;19:647–652. [26] Ciurea SO, Thall PF, Milton DR, et al. Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:1392–1398. doi: 10.1016/j.bbmt.2015.05.001. [27] Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009;373:759–767. [28] Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117:6786–6792. [29] Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–639.
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria Hong Tian, Liming Liu, Jia Chen, Yang Xu, Zhengming Jin, Miao Miao, Zhengzheng Fu, Huiying Qiu, Aining Sun & Depei Wu To cite this article: Hong Tian, Liming Liu, Jia Chen, Yang Xu, Zhengming Jin, Miao Miao, Zhengzheng Fu, Huiying Qiu, Aining Sun & Depei Wu (2016): Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria, Leukemia & Lymphoma, DOI: 10.3109/10428194.2015.1068309 To link to this article: http://dx.doi.org/10.3109/10428194.2015.1068309
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Date: 26 February 2016, At: 10:03
LEUKEMIA & LYMPHOMA, 2016 http://dx.doi.org/10.3109/10428194.2015.1068309
ORIGINAL ARTICLE: CLINICAL
Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria Hong Tiana,b,c, Liming Liua,b,c, Jia Chena,b,c, Yang Xua,b,c, Zhengming Jina,b,c, Miao Miaoa,b,c, Zhengzheng Fua,b,c, Huiying Qiua,b,c, Aining Suna,b,c and Depei Wua,b,c
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a Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; bCollaborative Innovation Center of Hematology, Soochow University, Suzhou, China; cSuzhou Institute of Blood and Marrow Transplantation, Suzhou, China
ABSTRACT
ARTICLE HISTORY
Eighteen patients with paroxysmal nocturnal hemoglobinuria (PNH) receiving allogeneic hematopoietic stem cell transplant (allo-HSCT), either from HLA-haploidentical donors (HRD; n ¼ 10) or HLA-matched donors (n ¼ 5 from siblings and n ¼ 3 from unrelated donors), were retrospectively evaluated. One showed primary graft failure following unrelated-donor HSCT. He was given a second HRD-HSCT, but died from cytomegalovirus pneumonia after achieving hematopoietic recovery. The other 17 patients achieved sustained engraftment and full-donor chimerism. Four in the HRD-HSCT group experienced grade II/III acute graft-versus-host disease (aGVHD), and five in the HLA-matched HSCT group developed grade II aGVHD. Among all 18 patients, 10 developed chronic GVHD (cGVHD), only one patient receiving HRD-HSCT developed extensive cGVHD. Nine in the HRD-HSCT group and all those in the HLA-matched HSCT group were alive and transfusionindependent at last follow-up. Our findings suggest that allo-HSCT is a promising treatment for PNH, and HRD-HSCT is a viable option for patients with PNH who lack HLA-matched donors.
Received 30 March 2015 Revised 24 June 2015 Accepted 26 June 2015
Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder clinically characterized by the triad of chronic complement-mediated hemolysis anemia, thrombosis, and bone marrow failure. The disease originates from clonal expansion of hematopoietic stem cells with a mutant phosphatidylinositol glycan complementation class A (PIGA) gene (located on Xp22.1).[1] Consequently, stem cells affected by PNH and their progeny are deficient in glycosyl phosphatidylinositolanchored proteins (GPI-APs). CD55 and CD59 are the two relevant complement regulatory proteins, and their absence is fundamental to the pathophysiology of PNH.[2] The clinical features of PNH in Western and Asian populations are quite different. For example, Western patients are reported to experience more thrombotic events, whereas Asian patients are particularly predisposed to bone marrow failure.[3,4] The prognosis of PNH varies greatly, ranging from indolent to life-threatening, partly due to the risk of evolution to myelodysplastic syndrome or acute leukemia.[5] The management of PNH has entered the era of complement inhibitory therapy. However, complement inhibitory therapy has no effect on the bone marrow CONTACT D-P Wu, MD, Professor China ß 2016 Taylor & Francis
[email protected]
KEYWORDS
Haploidentical hematopoietic stem cell transplant; myeloablative conditioning; paroxysmal nocturnal hemoglobinuria
failure component of the disease.[6] Furthermore, allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative therapy for PNH.[7,8] Because of the known treatment-related toxicity, this approach to management is recommended only for patients with an underlying bone marrow abnormality, life-threatening complications, or refractory transfusion-dependent hemolytic anemia.[4,9] Haploidentical HSCT is now increasingly applied as a curative therapy for patients with hematologic diseases for whom a suitable unrelated or human leukocyte antigen (HLA)-matched sibling donor cannot be found. However, there are still few reports on the use of haploidentical HSCT for the treatment of PNH. In this study, we retrospectively evaluated long-term outcomes in PNH patients treated with HSCT, especially patients who underwent haploidentical HSCT in our center.
Methods Patients All 18 patients with PNH who underwent allogeneic HSCT at our center between July 2007 and June 2013 were enrolled in this study. Eligibility for HSCT included a diagnosis of classic PNH or clinical PNH (PNH clone 5%)
Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, Suzhou 215006,
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in the setting of another bone marrow failure condition with one or more of the following: (1) transfusion dependency; (2) recurrent hemolytic crises; and (3) a history of thrombotic events. None showed any evidence of dyshematopoiesis or chromosomal abnormalities. In all cases, the diagnosis of PNH was confirmed both by clinical manifestation and hematologic tests (Ham’s test and flow cytometric analysis of CD55 and CD59 expression). None of the patients received treatment with eculizumab, because the drug was unavailable before transplant. This study was approved by the ethics committee of The First Affiliated Hospital of Soochow University. All patients provided written informed consent before therapy.
Transplant procedure Stem cell mobilization was induced by subcutaneous delivery of 5 mg/kg/day granulocyte colony-stimulating factor (GCSF) for 5 consecutive days before stem cell harvesting. Bone marrow (BM) grafts from related donors were harvested by BM aspiration at day 0. If the count of CD34 + cells was 52 106/kg, peripheral blood stem cells (PBSCs) also were collected by apheresis using a COBE SPECTRA device (Gambro BCT, Lakewood, CO) from day 1 and if needed on the following day until a target number of 2 106/kg CD34 + cells was attained. PBSCs were used as the graft source when donors were unrelated or unable to undergo BM aspiration. Preconditioning consisted of cytarabine (10 to 9 days), busulfan (4 mg/kg per day, 8 to 6 days), cyclophosphamide (1.8 g/m2 per day, 5 to 4 days), and simustine (Me-CCNU, 250 mg/m2, 3 days). Furthermore, cytarabine was administered at 4 g/m2 per day along with anti-thymocyte globulin (ATG; 2.5 mg/kg, 5 to 2 days) in patients who received HLA-haploidentical allo-HSCT and at 2 g/m2 per day (not in combination with ATG) in patients who received HLA-matched alloHSCT.[10] Prophylaxis for graft-versus-host disease (GVHD) included cyclosporine (CSA), mycophenolate mofetil, and short-term administration of methotrexate, designed according to a previously described method.[11] Some patients were heavily transfused: the pretransplant serum ferritin level was markedly elevated at a median 1120 mg/L (range, 20–11,000 mg/L). Seven transfusion-dependent patients with high levels of iron overload (serum ferritin 1000 mg/L) received iron chelation therapy before transplant. Only when their serum ferritin level was below 1000 mg/L could blood transfusion be administered as indicated (hemoglobin 560 g/L and/or platelets 510 109/L) before HSCT.
Evaluation of implantation and observations Myeloid engraftment was defined by the achievement of an absolute neutrophil count of 0.5 109/L for at least 3 consecutive days, and platelet engraftment was defined on the day the platelet count met or exceeded 20 109/L without transfusion for 1 week. Acute GVHD (aGVHD) was graded according to standard criteria, and chronic GVHD (cGVHD) was deEned as absent, limited, or extensive.[12] Hematopoietic chimerism was evaluated by DNA-based assays of short tandem repeat sequences using peripheral blood samples. Complete donor chimerism was defined as the first time more than 95% donor-type hematopoietic cells were found in the peripheral blood. All patients were screened for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) at twice per week for the first 3 months. HLA antibodies were measured routinely pretransplant in all patients using a microbead Fow cytometric assay with mean Fuorescence intensity readout for the serum antibody level. If screening for HLA antibodies returned positive results, donor-specific HLA antibodies (DSA) were further investigated with a Luminex Single Antigen assay. The results were analyzed as mean fluorescence intensity (MFI) versus donorspecific mismatch.
Results Patient characteristics Eighteen patients who were diagnosed with PNH and underwent HSCT were included in this study. Data for all patient characteristics at the time of transplant are shown in Table 1. The median age at the time of transplant was 25 years (range, 13–54 years), and the median disease duration was 15 months (range, 3–240 months). The major indication for transplant was bone marrow failure, including 11 patients with severe cytopenia, six with recurrent severe hemolysis and severe cytopenia, and one with recurrent hemolysis and thromboembolism. Five patients were anti-HLA antibody positive (Patients 1, 3, 6, 13, and 15), including two DSA-positive patients (Patients 6 and 13). The MFI (DSA level) was 17600 (target HLA loci of DSA was B13) and 5033 (target HLA loci of DSA was B60) in Patients 6 and 13, respectively. Both of these patients received a single dose of rituximab (375 mg/m2), but only Patient 13 experienced a reduction in the expression level of HLA antibodies (from 5033 to 1010). Of all 18 patients, 10 patients did not have a suitable HLA-matched donor and underwent HRD-HSCT (Patients 1–10). Among these patients, the median mononuclear cell and CD34 + counts were 9.7 108/kg and 3.7 106/kg, respectively. The other eight patients
54/M 29/M 25/M 13/M 21/M 42/M
40/M
20/F
17/M 21/M 28/M 24/M 23/M 23/F 47/M 41/M 40/F 21/M
1 2 3 4 5 6
7
8
9 10 11 12 13 14 15 16 17 18
PNH PNH PNH-AA PNH PNH-AA PNH PNH PNH-AA PNH PNH
PNH
PNH
PNH PNH PNH PNH-AA PNH PNH
Diagnosis
Hemolysis and cytopenia, TD Hemolysis and cytopenia, TD Hemolysis, TD Cytopenia, TD Cytopenia Hemolysis, TD Cytopenia Hemolysis, TD Cytopenia, TD Cytopenia, TD Hemolysis, TD Cytopenia
Hemolysis, TD Hemolysis, TD Cytopenia, TD Cytopenia Cytopenia, TD Hemolysis and thrombosis (cerebrovascular)
Clinical features
6 8 18 25 8 4 240 144 180 6
13
20
84 6 12 4 30 120
Duration of PNH (months)
99.0 98.9 20.0 25.1 60.0 99.1 99.0 89.0 80.0 85.0
42.6
60.6
56.9 41.6 99.9 99.0 99.3 20.0
Pretransplant %GPInegative neutrophils
Sep 2012 Jun 2013 Oct 2012 Mar 2013 Apr 2012 Aug 2009 Oct 2011 Dec 2007 Feb 2013 Nov 2012
Dec 2012
May 2011
Oct 2010
Jan 2013 Jun 2013 Jan 2011 Mar 2013 Aug 2012 Sep 2010
Date of transplant
3/6 3/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6 6/6
4/6
3/6 3/6 4/6 3/6 3/6 (first transplant) 6/6 (second transplant) 3/6 3/6
Compatibility of donor
A/A B/B B/A B/O O/A B/B AB/A AB/AB A/A A/A
A/A
AB/B
AB/B
A/B AB/AB A/A B/B A/A B/B
ABO pairs D/R
Father Brother Unrelated Unrelated Unrelated Sister Sister Brother Brother Brother
Brother
Sister
Daughter
Son Sister Mother Mother Father Unrelated
Donor
BM + PB BM + PB PB PB PB BM + PB PB BM BM + PB BM + PB
BM + PB
BM + PB
BM + PB
BM + PB BM + PB BM + PB BM + PB BM + PB PB
Stem cell source
11.57 11.3 8.68 7.83 3.85 12.07 5.57 4.43 8.90 12.19
8.27
5.70
8.20
5.77 10.42 9.07 13.76 12.81 10.20
MNC 108/kg
M: male; F: female; PNH: paroxysmal nocturnal hemoglobinuria; AA: aplastic anemia; TD: transfusion dependent on red cells and/or platelets; D: donor; R: recipient; MNC: mononuclear cells; BM: bone marrow; PB: peripheral blood.
Age (yr)/ Sex
Case
Table 1. Patient and transplant characteristics.
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3.97 4.13 3.80 5.02 5.00 3.47 3.02 3.07 6.57 8.42
2.97
3.01
3.45
4.30 4.62 2.55 2.86 4.86 3.10
CD34+ 106/kg
TRANSPLANTATION IN PNH 3
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Table 2. Outcomes of PNH patients after allo-HSCT. Engraftment (days) Case
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
ANC 40.5 109/L
PLT 420 109/L
15 33 11 13 12 20 13 28 12 18 First transplant: graft failure 14 23 12 18 12 15 12 14 11 13 11 17 11 13 12 18 11 12 11 12 9 18 11 13 10 16
GVHD Full-donor chimerism (days)
Acute
Chronic
34 28 30 36 32 – 42 32 40 34 34 30 34 32 32 30 28 28 32
Grade I Absent Grade I Absent Absent – Grade II Grade III Absent Grade II Grade II Grade II Absent Grade I Absent Grade II Grade II Absent Grade II
Limited Absent Limited Limited Limited – Absent Limited Absent Extensive Absent Limited Limited Absent Absent Limited Absent Absent Limited
Follow-up (months)/ Outcome 21/Alive 19/Alive 14/Alive 15/Alive 29/Alive 6/Dead (infection) 15/Alive 17/Alive 20/Alive 17/Alive 22/Alive 15/Alive 33/Alive 24/Alive 39/Alive 85/Alive 22/Alive 15/Alive
ANC: absolute neutrophil count; PLT: platelet
received HLA-matched transplants, including three cases of MUD-HSCT (Patients 11–13) and five cases of MRD-HSCT (Patients 14–18). Among these patients, the median mononuclear cell and CD34 + counts were 8.3 108/kg and 4.4 106/kg, respectively. The median percentage of PNH granulocytes at the time of transplant was 79.8% in the HRD-HSCT group (range, 20.0–99.9%) and 82.5% in the HLA-matched group (range, 20.0–99.1%; p40.05). Additionally, no significant differences were observed between the two groups in the median number of peripheral counts at transplant (p40.05). In the HRD-HSCT group, the neutrophil count was 1.03 109/L (range, 0.02–3.22 109/L), the hemoglobin level was 60 g/L (range, 51–82 g/L), and the platelet count was 17 109/L (range, 12–40 109/L). In the HLA-matched group, the neutrophil count was 1.03 109/L (range, 0.2–3.59 109/L), the hemoglobin level was 61 g/L (range, 36–69 g/L), and the platelet count was 18 109/L (range, 4–82 109/L). The distributions of characteristics such as age, gender, and CD34 + counts in grafts were similar in both groups of patients.
Hematopoietic recovery and donor engraftment As shown in Table 2, one case (Patient 6) in the HRD-HSCT group experienced graft failure after the first transplant (URD-HSCT), whereas the other 17 patients achieved primary sustained engraftment within a median time of 11.5 days (range, 9–15 days) to reach a neutrophil count of 0.5 109/L and 16.5 days (range, 12–33 days) to reach a platelet count of 20 109/L.
The engraftment time did not differ significantly between patients who received transplants from haplo-identical donors and those who received transplants from HLA-matched donors. Patient 6 showed primary graft failure with no sign of engraftment at day 30 following URD-HSCT. The patient was then given a second transplant from his daughter following conditioning with total body irradiation, cyclophosphamide, and ATG. He achieved hematopoietic recovery but died from CMV pneumonia on day 181 post-transplant. Fulldonor chimerism occurred in all 17 evaluable patients at a median of 32 days (range, 28–36 days) post-HSCT. The distribution of the time of chimerism was similar in both groups of patients.
Transplant-related complications Of the 17 evaluable patients, two patients developed grade I intestinal aGVHD, three patients developed grade II intestinal/skin aGVHD, and one patient developed grade III intestinal aGVHD following HRD-HSCT. Five patients developed grade II skin/intestinal aGVHD following HLA-matched HSCT. In all cases, aGVHD was controlled with steroid/cyclosporine A therapy. Among all 18 patients who survived for more than 100 days after transplant, 10 patients developed cGVHD. Of these patients, 9 showed limited cGVHD and one patient who underwent HRD-HSCT developed extensive cGVHD that responded well to oral administration of prednisone and cyclosporine A (Table 2). CMV infection occurred in three patients (two in the HRD-HSCT group and one in the URD-HSCT group).
TRANSPLANTATION IN PNH
Two of these patients (Patients 5 and 11) did not develop CMV disease, whereas Patient 6 did. Epstein-Barr virus infection occurred in four patients (two patients in each group), and no case of Epstein-Barr virus post-transplant lymphoproliferative disorder occurred.
Survival outcomes One patient who underwent HRD-HSCT died from complications related to CMV disease on day 181 post-transplant. As of 31 January 2015, at a median follow-up period of 20 months (range, 14–85 months), all of the other 17 patients remained alive and transfusion-independent without relapse.
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Discussion Here we report the characteristics and outcomes of a small cohort of patients with PNH who underwent HSCT in our center. Remarkably, this small cohort of 18 patients included 10 recipients of transplants from HLA-haploidentical related donors. The present study showed that allo-HSCT resulted in favorable outcomes in PNH patients, and substantial survival was achieved by PNH patients who underwent either HRD-HSCT or HLA-matched HSCT. Moreover, one patient received a salvage HRD-HSCT after graft failure following MUD-HSCT and then achieved hematopoietic recovery. Although he died from a transplant-related complication, his case still suggests the feasibility of HRD-HSCT as a salvage treatment. A limited number of single-center studies of HSCT for PNH have been published,[13,14] and these studies included small numbers of patients. Furthermore, reports investigating outcomes in PNH patients who receive HRD-HSCT are rare. The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in 48 recipients of HLA-identical sibling transplants between 1978 and 1995.[7] Recently, the largest cohort of 211 PNH patients was reported by the European Group for Blood and Marrow Transplantation (EBMT), and 65% of these patients received grafts from HLA-identical siblings with the rest receiving grafts from HLA-matched unrelated donors.[15] They found that the indication for HSCT, such as aplastic anemia (AA), recurrent hemolytic crises, or thrombotic events (TE), was the only significant predictor of survival, with patients receiving a transplant as therapy for TE having the worst outcome. The 5-year overall survival (OS) rates were 54% among patients with TE, 69% for patients with AA and no TE, and 86% for patients with recurrent hemolytic anemia without TE or AA. However, the clinical features of PNH in white and
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Asian patients have been shown to be quite different, e.g. white patients were reported to experience more TE, whereas Asian patients were particularly predisposed to BM failure.[4] With cytopenia and hemolysis being the main indications for transplant in our study, only one patient experienced TE and died after the second transplant. Good results were achieved in patients who received HSCT for the other two indications. Moreover, we also found that the incidence of grade II–III aGVHD was 40% (4/10) and that of cGVHD was 60% (6/10). These frequencies are consistent with the findings of a previous study on the use of HRD-HSCT to treat nonmalignant hematologic disease.[16] Although the incidence of GVHD in the HRD-HSCT group seemed to be slightly higher in the present study, compared with the results of other reports on HLA-matched transplant on PNH,[7,13,14] the severity and controllability of GVHD were favorable. In a considerable percentage of PNH patients, a suitable matched donor is not available or cannot be identiEed within a reasonable time frame. Indeed, it is more difficult to find a suitable HLA-identical sibling donor for Chinese patients due to the population policy. Furthermore, the often long period of time required to find a matched unrelated donor or a matched cord blood unit can permit disease progression prior to treatment. Haploidentical HSCT virtually ensures the opportunity for nearly all patients to benefit from HSCT and offers the advantage of immediate accessibility to transplant therapy. Although provided only by small retrospective case series, evidence from the medical literature supports the use of haploidentical donors as a viable option in PNH patients. The first report of successful HLA-haploidentical HSCT in three PNH patients was published in 2008 by Brodsky et al. [17]. Two of their patients achieved long-term survival, and one died from graft failure. In the present study, we report the outcomes of 10 consecutive PNH patients treated with HSCT from an HLA-haploidentical related donor. Nine of them survived without major complications. Moreover, we observed no significant differences in transplant-related complications and outcomes between the HRD-HSCT group and the HLA-matched HSCT group in our study. It remains unclear whether a nonmyeloablative conditioning regimen or myeloablative regimen is more suitable for PNH patients. A previous study found no differences in treatment-related mortality or overall survival between 42 HLA-matched patients who received reduced intensity conditioning and 169 HLA-matched patients who received a myeloablative conditioning regimen.[15] Recently, however, Pantin et al. reported that among 17 PNH patients who
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H. TIAN ET AL.
received cyclophosphamide/fludarabine with or without ATG followed by HSCT from an HLA-matched relative, 15 achieved long-term survival without evidence of PNH.[18] Further studies are needed to establish the role of the conditioning regimen for transplant and its ability to reduce early treatment-related mortality and thereby improve the outcome of allo-HSCT in the treatment of PNH. The role of HLA antibodies in HSCT has drawn increasing attention because of the risk of graft failure in patients who receive HLA-mismatched HSCT, including cord blood transplantation,[19,20] haploidentical SCT,[21,22] and unrelated SCT.[23] Rituximab, bortezomib, plasma exchange (PE), and high dose intravenous immunoglobulin (IVIG) have been used for the reduction of HLA antibody levels before SCT, but the efficiency of each treatment option remains unclear due to the small number of reported cases.[24] Gladstone et al. proved that PE/IVIG treatment can reduce DSA to negative or weak levels and achieve full donor engraftment in eight patients who underwent mismatched allo-HSCT.[25] Recently, it has been reported that desensitization treatment with PE/Rituximab/IVIG plus the addition of buffy coat infused might be more effective,[26] suggesting that strong DSA levels should not be an absolute barrier to HSCT. In this study, a high level of HLA antibodies is the most likely explanation for the nonengraftment experienced by Patient 6. Fortunately, Patient 13 received rituximab before transplant for a high level of HLA antibodies, and she achieved fast engraftment after an infusion of stem cells. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH [27] and has been shown to not only signiEcantly reduce hemolysis, but also to improve anemia and patients’ quality of life.[16,28] Nonetheless, eculizumab has no effect on either the underlying stem cell abnormality or the associated bone marrow failure. Furthermore, not all patients have a favorable response to eculizumab. Nishimura et al. found that genetic variants in C5 (Arg885) cause failure to undergo blockade by eculizumab, which accounts for the poor response to this agent.[29] In addition, eculizumab is prohibitively expensive (about $400,000/year in the United States) for patients without medical insurance. Transplant is the only curative therapy for PNH; however, the risks associated with this option are not insignificant. In the era of complement inhibitory therapy, the most challenging problem is to identify those patients who are most likely to benefit from transplant. Several transplant-related issues could not be addressed in this study because of the small number of patients and the retrospective nature of the study.
More prospective trials are needed to develop strategies for identifying such patients. In conclusion, our data demonstrate that patients with recurring PNH can benefit from HSCT. Our results also show that HRD-HSCT is a viable alternative option for patients who have no suitable HLA-matched donor who might be able to use it as a salvage treatment after failure of the first transplant. However, definitive conclusions cannot be drawn based on the small number of patients included in our study, but it will be interesting to see if similar results are obtained in a larger cohort of PNH patients with longer follow-up. Finally, it is essential that patients who have a transfusion history are screened for HLA antibody levels prior to HSCT to avoid related complications.
Acknowledgements This work was supported by the Jiangsu Provincial Special Program of Medical Science (BL2012005), the Jiangsu Province’s Key Medical Center (ZX201102), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the National Public Health Grand Research Foundation (No. 201202017). Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at http:// dx.doi.org/10.3109/10428194.2015.1068309.
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