Biology of Blood and Marrow Transplantation
Volume 15, Issue 6 , Pages 656-661, June 2009

Current Status of Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria

  • Nelson A. Matos-Fernandez

      Affiliations

    • Department of Blood and Marrow Transplantation, Moffitt Cancer Center and Research Institute, Tampa, Florida
    • Department of Hematology and Medical Oncology, Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico
    • The first 2 authors contributed equally to the manuscript.
    • ,
  • Yasser R. Abou Mourad

      Affiliations

    • Leukemia and Bone Marrow Transplantation Program of British Columbia, University of British Columbia, British Columbia Cancer Agency, Vancouver General Hospital, Vancouver, BC, Canada
    • The first 2 authors contributed equally to the manuscript.
    • ,
  • William Caceres

      Affiliations

    • Department of Hematology and Medical Oncology, Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico
    • ,
  • Mohamed A. Kharfan-Dabaja

      Affiliations

    • Department of Blood and Marrow Transplantation, Moffitt Cancer Center and Research Institute, Tampa, Florida
    • Department of Oncological Sciences, Moffitt Cancer Center at the University of South Florida, Tampa, Florida
    • Corresponding Author InformationCorrespondence and reprint requests: Mohamed A. Kharfan-Dabaja, MD, FACP, Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 Magnolia Drive, BMT-WCB, Tampa, FL 33612.

Received 17 November 2008; accepted 22 December 2008. published online 13 February 2009.

Article Outline

Treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been traditionally empirical, primarily aiming at ameliorating symptoms or treating complications resulting from the disease. Novel therapies such as eculizumab result in stabilization of hemoglobin levels and improvement in quality of life, but does not cure PNH. Nonrandomized studies suggest that long-term remissions are achievable when using myeloablative or nonmyeloablative/reduced-intensity (NMT/RIC) allogeneic hematopoietic stem cell transplantation (HSCT) as treatment for PNH. Nevertheless, patients with previous life-threatening complications from PNH may be more appropriately treated with an NMT/RIC regimen, rather than a myeloablative approach, because of the increased transplant mortality associated with the latter. The decision to perform an allogeneic HSCT (allo-HSCT) should weigh disease prognosis, by incorporating known adverse prognostic factors such as previous history of thrombosis and/or evolution to pancytopenia, among others, against the risk of transplant-related complications. Selection of the appropriate candidate and, equally important, the right time to perform an allo-HCT are important questions that need to be answered in the context of large prospective randomized trials.

Key Words: Paroxysmal nocturnal hemoglobinuria, Allogeneic hematopoietic stem cell transplantation

 

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Introduction 

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disorder of the hematopoietic stem cells caused by a somatic mutation in the phosphatidylinositol glycan-class A (PIG-A) gene, located on the short arm of the X chromosome 1, 2, 3, 4, 5, 6. Identification of the resultant deficiency of GPI-linked proteins in patients with PNH led to the development of flow-cytometry analytic methods for diagnosing the disease with more accuracy [7]. Absence of CD55 (known as decay accelerating factor) and/or CD59 (known as the membrane inhibitor of reactive lysis) by flow-cytometric analysis of peripheral blood stem cells (PBSCs) is presently the most performed test when diagnosing PNH [7].

Treatment of patients with PNH had been traditionally empirical, primarily aiming at ameliorating symptoms or treating complications resulting from the disease. Better understanding of the pathogenesis of PNH is bringing more specific therapies into the clinical practice that aim at treating the disease rather than its complications. Eculizumab is a humanized monoclonal antibody (MAb) that targets the terminal complement protein C5 8, 9. Hillmen et al. [9] evaluated the efficacy of eculizumab in a randomized, double-blinded, placebo-controlled, multicenter international phase III clinical trial, showing stabilization of hemoglobin levels and, consequently, improvement in transfusion requirements. Eculizumab has also been shown to improve quality of life, but does not cure PNH [10].

The clinical course of PNH is variable. In some cases the disease can persist for many years with manageable symptoms, or even experience spontaneous recovery 3, 11, whereas in other cases the disease course may be more aggressive leading to bone marrow failure, or transforming into more aggressive entities such as acute myelogenous leukemia (AML) 6, 12. Nonrandomized studies suggest that long-term remissions are achievable in patients with PNH when using allogeneic hematopietic stem cell transplantation (allo-HSCT). However, the risk of treatmet-related mortality (TRM) with hematopoietic cell allografting is relatively high, particularly when using ablative doses of total body irradiation (TBI) [13]. This presents a particular challenge to treating hematologists in identifying patients who may benefit from allo-HCT. In this article we provide a comprehensive review of the role of allo-HSCT in patients with PNH published to date.

Diagnosing PNH 

The wide array of clinical manifestations in patients with PNH poses a significant challenge to treating physicians, not only in establishing the diagnosis, but managing the complications of the disease as well. Acute exacerbations of intravascular hemolysis and subsequent hemoglobinuria results in anemia from urinary loss of iron. Also, thrombosis is seen in over one-third of patients, and is one of the most serious clinical complications from the disease [3].

The Ham's test, which relies on the abnormal sensitivity of PNH cells to complement mediated intravascular hemolysis, was the gold standard for diagnosing PNH in the past [14]. The Ham test and the sucrose lysis test [15] have been largely replaced by flow-cytometry, which measures absence of CD55 and/or CD59. Flow-cytometry can identify a small-size PNH clones, of <5%, not otherwise possible in complement-dependent methodology [16]. Flow-cytometry targeting both CD55 and CD59 is the preferred approach to establish the diagnosis of PNH. Granulocytes and monocytes clones, rather than the red cell clones, are used for flow cytometric analysis of PNH [16]. This is because red blood cells of patients with PNH have a shortened life span because of intravascular hemolysis [16].

Clinical Course of PNH 

Recently, de Latour et al. [5] compared clinical outcomes in 460 patients with various subcategories of PNH where the disease manifests either as intravascular hemolysis without overt marrow failure (classic PNH), or with predominant marrow failure (aplastic PNH), or those cases whose clinical presentation(s) do not fit within previous categories (intermediate) [5]. Thrombosis remains a major complication adversely affecting outcomes in each of the subgroups [5]. Risk factors associated with increased thrombogenesis included older age, thrombosis at presentation, previous transfusions, and lack of immunosuppressive therapy. Also, development of pancytopenia resulted in worse outcomes in patients presenting with classic PNH, whereas malignant transformation adversely affected survival in patients with aplastic and intermediate PNH [5]. The authors conclude that outcomes among the various subcategories of PNH are similar, despite differing clinical presentations [5]. These findings support previous reported by Socie et al. [2] showing that occurrence of thrombosis, evolution to pancytopenia, myelodysplastic syndrome (MDS) or AML, among others, are independent factors associated with worse outcome in patients with PNH.

Nontransplant Therapies for PNH 

Treatment of PNH, besides allo-HSCT, is generally supportive including measures such as red cell transfusions, anticoagulants, or therapies such as glucocorticoids or eculizumab aiming at controlling hemolysis. Transfusion of packed red blood cells has been found to be safe in patients with PNH, circumventing the need of washed red cells [7]. The iron deficiency resulting from hemoglobinuria can be treated with iron supplementation.

Androgen therapy with danazol has been used with mixed results 8, 17, 18, 19. Administration of glucocorticoids has also been reported to be useful for ameliorating the severity of hemolysis. Anticoagulants are indicated for cases presenting with thrombosis, such as the Budd-Chiari syndrome, among others. Prophylactic use of anticoagulants has been advocated for patients with large clones of PNH (>50% granulocytes) [20]. Eculizumab is a C5-blocking mAb that has been recently approved for the treatment of PNH 9, 10. Treatment with eculizumab is relatively well tolerated, and results in reduction of intravascular hemolysis, hemoglobinuria, and, consequently less need for transfusion, and overall improvement in the quality of life in patients with PNH.

Allogeneic HCT as Treatment of PNH 

Using a matched-related donor 

In 1984, Szer et al. [21] reported a series of 4 male patients treated with allogeneic bone marrow transplantation (allo-BMT) for PNH in aplastic phase. Three patients received allogeneic BM from a matched-related donor (MRD), and one from a syngeneic donor. Conditioning regimen consisted of cyclophosphamide (Cy; N = 2) or Cy plus procarbazine (N = 1), or none (N = 1). All patients engrafted and remained alive and asymptomatic from their disease at 51 to 144 months from allograft. Acute graft-versus-host disease (aGVHD) (≥grade II) was reported in 1 (25%) patient.

Another series by Antin et al. [22] reported outcome of PNH, also in the aplastic phase, after allo-BMT from MRD in 4 patients (female = 3, male = 1) using a preparative regimen of Cy, procarbazine plus antithymocyte globulin (ATG) (N = 3) or busulfan (Bu), Cy, procarbazine plus ATG (N = 1). Complete trilineage engraftment occurred in all patients. There was no evidence of recurrence of PNH up to 5 years after allografting. The authors note that eradication of PNH was possible despite using a nonmyeloablative preparative regimen (Cy, procarbazine plus ATG). This would suggest that PNH is sensitive to adoptive T cell-mediated immunity derived through a graft-versus-PNH effect as later demonstrated by Takahashi and colleagues [23].

Bemba et al. [24] reported the largest single institution series of 16 patients (female = 6, male = 10), with a median age of 28 (9-46) years, with PNH treated with allo-HCT from MRD over a period of 20 years. Six of 16 patients were in aplastic phase and the rest were transfusion dependent. Conditioning regimens included Cy plus thoracoabdominal irradiation (N = 8) or Cy plus TBI (N = 1), or Cy plus other (N = 7). All patients engrafted. aGVHD (≥grade II) occurred in 8 (50%) patients. Three (21%) of 14 patient who were alive beyond 100 days, from allograft, developed chronic GVHD (cGVHD). Nine patients were alive at a median follow-up of 53 (3-169) months. The 5-year survival rate was 58%. None of the patients had previous history of thrombosis, suggesting a possible enrollment bias because thrombosis is known to be associated with poor outcomes in patients with PNH. An absolute neutrophil count (ANC) >1.0 × 109/L and a hemoglobin level (Hgb) >9.0 g/dL at time of transplant were associated with a better outcomes (5-year survival >90%).

A registry study by the International Bone Marrow Transplant Registry (IBMTR) reported outcome of 57 patients, median age 28 (10-47) years, who received an allo-BMT for PNH at 31 transplant centers between 1978 and 1995 [25]. Source of hematopoietic cells consisted of MRD (N = 48), syngeneic (N = 2), or alternative donors (MUD = 6, haploidentical = 1) (N = 7). The majority of patients received a myeloablative preparative regimen (Bu plus Cy [Bu/Cy] = 53%; TBI plus Cy [TBI/Cy] = 21%). The 2-year probability of survival for the matched sibling group was 56%. Survival was significantly better for those patients with sustained engraftment after allo-BMT (70% versus 10%, P = .0003). Two recipients of syngeneic transplants were well and alive at 8 and 12 years posttransplantation. Only 1 (14%) of 7 alternative donor allograft recipients was alive at the 5-year follow-up. This suggests that TRM may be more pronounced in recipients of alternative donor allografts. Nonetheless, the study is limited by its retrospective nature and the relative small sample size. The most common causes of adverse outcomes were graft failure and infections.

These aforementioned studies suggest that allo-HSCT is capable of inducing prolonged remissions in over 50% patients with PNH. The risk of mortality from allograft appears more pronounced in recipients of unrelated donor allografts. Several questions remain unaddressed. (1) What is the most effective preparative regimen for PNH? (2) What is the preferred regimen for GVHD prophylaxis? (3) When is the right time to consider allo-HSCT? (4) What risks factors should be considered when selecting patients for allograft? These and other similar studies 26, 27, 28 are summarized in Table 1.

Table 1. Allogeneic MRD Transplants for PNH
Author (Ref)Year PublishedNMedian (Range) Age YearsGender M/FTTT Median (Range) monthsPeriod of allo-HCTPreparative RegimenOutcome
Szer et al. [21]19844†17 (14-23)4/028.5 (5-60)1971–1979Cy-based††
TRM = 0%

Median survival 13 (51-144) months

Antin et al. [22]1985425 (22-27)1/3NA1980–1985Cy-based
TRM = 0%

Median survival 30 (1-60) months

Kahawara et al. [27]19929§22 (14-38)5/424 (6-180)1971–1990
Bu/Cy = 2

Cy-only = 3

Cy-TBI = 1

Cy-based = 1

None = 2


TRM = 11%

8 of 9 long-term survivors with long-term follow-up from 2.2 to 19.2 years§§

Bemba et al. [24]19991628 (9-46)10/623 (1-97)1978–1997
Cy/TAI = 8

Cy/TBI = 1

CY-based = 7

5-year OS = 58%
Sašo et al. [25]199957∗28 (10-47)26/3126 (2-240)1978–1995
Bu/Cy = 30

Cy/TBI = 12

Cy/LI = 11

Cy-based = 3

None = 1

2-year survival = 56% ∗∗
Raiola et al. [26]2000729 (23-37)4/330 (12-192)1991–1999Bu/Cy
TRM = 0%

all alive at median F/U of 51 (6-103) months post-allo-HSCT

Lee et al. [28]2003328 (21-31)0/346 (15-188)1999–2001Bu/Flu/ATG
TRM = 33%

2 patients alive at 31 and 37 months post-allo-HSCT

N indicates number of patients; TTT, time from diagnosis to transplantation; Cy-based, cyclophosphamide or Cy-PAPAPA, procarbazine, rabbit antithymocyte globulin plus cyclophosphamide; TRM, transplant-related mortality; OS, overall survival; NA, not available; Bu/Cy, busulfan plus cyclophosphamide; Cy/TBI, cyclophosphamide and total body irradiation; Cy/TAI, cyclophosphamide and thoraco abdominal irradiation; Cy/ALG, cyclophosphamide plus antilymphocyte globulin; LI, limited irradiation; Bu/Flu/ATG: busulfan, fludarabine, and antithymocyte globulin.

†One of 4 patients had syngeneic transplant with †† no conditioning chemotherapy.

§Six had HLA-MRD, 2 syngeneic and 1 haploidentical.

§§Only 1 patient who had haplo-identical transplant died at day +35 of first transplant.

∗HLA-MRD (N = 48), syngeneic (N = 2) and alternative donor (N = 7).

∗∗For only 48 patients who had HLA-matched transplants.

Allo-HCT using an unrelated donor 

Most experience using unrelated donor allograft for PNH is limited to nonrandomized small series from single institutions or registry data. A previously mentioned IBMTR registry study included 6 patients with PNH who received a MUD allograft [25]. Only 1 (16%) was alive after 5 years of follow-up. Causes of death included graft-failure, organ failure, interstitial pneumonitis, and cGVHD, among others.

Woodward et al. reported a series of 3 cases of unrelated donor allografts (MUD = 2, mismatched unrelated donor (MMUD) = 1) [29] with ages ranging from 13 to 20 years of age. All patients had aplastic phase of disease at time of allografting. Patients received T cell-depleted grafts after conditioning with TBI-based regimens. All patients experienced transplant-related complications, but were alive and disease free at 30 to 62 months after allo-HSCT. Interestingly, this study suggests a potentially beneficial role for myeloablation per se, independent of the graft-versus-PNH effect, as these patients received allografts devoid of T cells. Other series have also shown adequate engraftment and prolonged disease-free survival (DFS) after allografting [30].

These suggest that use of alternate donor allografts is feasible. A selection bias for younger age at time of allograft appears to be a favorable factor that may have contributed to the difference in outcomes amongst the various studies using unrelated donors.

NMT/RIC allo-HSCT in PNH 

Reducing the intensity of the preparative regimens could potentially allow broader applicability of allo-HSCT in patients with PNH, especially those with more advance age or with associated comorbidities.

Hegenbart et al. [31] reported outcome of 7 adult patients, median age 34 (25-49) years, who underwent allo-HSCT from peripheral mobilized stem cells (MUD = 5; MRD = 2) using a regimen of Flu plus 2 Gy TBI and immunosuppresion with cyclosporine (CsA) and mycophenolate mofetil (MMF). All patients engrafted, with a median T cell chimerism of 77% by 28 days. All patients achieved complete remission of the disease, but 3 (43%) patients died from transplant-related complications. Four patients remained alive at 13 to 38 months from allo-HCT. This study shows that using peripheral mobilized stem cells is also feasible when performing allografts for PNH; and that PNH is sensitive to adoptive immunotherapy after minimal conditioning. The TRM of 43% is particularly high. One should note that two of the transplant-related deaths occurred in patients with previous history of thrombosis, emphasizing the importance of patient selection.

Takahashi et al [23] reported a series of 5 patients, median age 30 (25-35) years, with PNH who were transplanted with a nonmyeloablative regimen of Flu/Cy plus ATG using MRD as cell source. All patients had high-risk features such as transfusion dependency or thrombosis. PHN cells were detected in all patients at time of engraftment but became undetectable by 4 months. All patients were alive and disease free at 5 to 39 months after transplantation. This study also shows that PNH can be immunologically eradicated, both in vitro and in vivo, following a non-myeloablative transplant. These and other studies 28, 32 are summarized on Table 2.

Table 2. Nonmyeloablative allo-HCT for PNH
Author (Ref)Year PublishedNMedian (Range) Age YearsGender M/FTTT Median (Range) MonthsPeriod of allo-HCTPreparative RegimenOutcome
Hegenbart et al. [31]2003
MUD = 5

MRD = 2

34 (25-49)3/424 (12-59)1999-2001Flu/TBI
TRM = 43%

CR = 100%

4 (57%) patients alive at 13-38 months after allograft

Takahashi et al. [23]2004MRD = 530 (25-35)3/223 (15-49)NRFly/Cy/ATG
TRM = 0%

100% survival at 5-39 months after allograft

Lee et al. [28]2003MMUD = 229, 432/04 and 1161999-2001Bu/Flu/ATG or Cy/ATG
TRM = 0%

Both alive at 17 and 30 months after allograft

Brodsky et al. [32]2008HLA- Haploidentical = 327, 33, and 372/112, 84, and 180NRCy/Flu/TBI
TRM = 33%

One death on day +8.

2 patients alive at 1 and 4 years after allograft.

N indicates number of patients; TTT, time from diagnosis to transplantation; MUD, matched-unrelated donor; MRD, matched-related donor; Flu/TBI, fludarabine and 2 Gy of TBI on day 0; TRM, treatment-related mortality; CR, complete remission; NR, not reported; Flu/Cy, cyclophosphamide,fludarabine, and antithymocyte globulin; MMUD, mismatched-unrelated donor; Bu/Flu/ATG, Busulfan, fludarabine, and antithymocyte globulin; Cy/ATG, cyclophosphamide and antithymocyte globulin; CyFlu/TBI, cyclophosphamide, fludarabine and 2 Gy of TBI on day 1.

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Conclusions and Recommendations 

Understanding the natural history of PNH is of paramount importance when deciding about therapeutic interventions for individual patients. A small number of patients with PNH may experience spontaneous remissions and long-term survival from the disease; this is particularly important to take into account when considering allo-HSCT for PNH.

Allo-HSCT is a feasible therapeutic intervention that can result in eradication of PNH. Decision to perform an allo-HSCT has been usually reserved until evidence of disease progression, such as development of life-threatening hemolysis, increased transfusion requirements, or development of cytopenias despite immunosuppressive therapies. In vitro and/in vivo data suggests that PNH is susceptible to the bona fide graft-versus-PNH effect [24]. Both myeloablative and nonmyeloablative regimens appear to yield durable engraftment and sustained remissions with eradication of the PNH clone. However, most of the studies reported herein have limited allo-HCT to relatively younger patients.

RIC regimens have been generally associated with lesser transplant-associated morbidity and mortality in various hematologic malignancies such as chronic lymphocytic leukemia (CLL) [33] or AML [34], with reasonable preservation of efficacy. Available data, albeit nonrandomized, shows that using an NMT/RIC regimen is feasible in patients with PNH, especially those of more advanced age and/or PNH related morbidities who would not be otherwise eligible for a myeloablative approach. Younger patients without serious morbidities could be treated with a myeloablative or RIC regimens.

Previous history of thrombosis confers worse outcomes in patients undergoing allo-HCT for PNH [30]; conversely, other series suggest that patients with preserved hematopoietic function at transplantation (ANC >1.0 × 109/L and Hgb >9.0 g/dL) have better outcomes postallografting [24]. This is not particularly surprising because a large series of 220 patients with PNH has shown that occurrence of thrombosis, evolution to pancytopenia, MDS or AML, age >55 years at diagnosis, requirement of additional therapy, and thrombocytopenia at diagnosis are independent adverse prognostic factors associated with PNH [2]. Patients with previous life-threatening complications from PNH may be more appropriately treated with an NMT/RIC regimen rather than a myeloablative approach because of increased TRM from the latter [31].

The decision to perform an allo-HSCT should weigh disease prognosis, by incorporating known adverse prognostic factors 2, 5, against the risk of transplant complications. Selection of the appropriate candidate and, equally important, the right time to consider an allo-HSCT are important questions that could only be answered in the context of large prospective collaborative trials.

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Acknowledgments 

Financial disclosure: The authors have nothing to disclose.

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References 

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 Financial disclosure: See Acknowledgments on page 660.

PII: S1083-8791(08)01231-7

doi:10.1016/j.bbmt.2008.12.507

Biology of Blood and Marrow Transplantation
Volume 15, Issue 6 , Pages 656-661, June 2009

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