Hematopoietic Stem Cell Transplantation for Treatment of paroxysmal nocturnal hemoglobinuria (PNH)


 

Hematopoietic Stem Cell Transplantation

Prior to the availability of eculizumab, the primary indications for transplantation were marrow failure, recurrent, life-threatening thrombosis, and uncontrollable hemolysis (Table 40–4).27 The latter process can be eliminated by treatment with eculizumab and the thrombophilia of paroxysmal nocturnal hemoglobinuria (PNH) may also respond to inhibition of intravascular hemolysis by eculizumab.49 Nonetheless, transplant is the only curative therapy for paroxysmal nocturnal hemoglobinuria (PNH), and the availability of molecularly defined, matched, unrelated donors, less-toxic conditioning regimens, reduction in transplantation-related morbidity and mortality, and improvements in posttransplantation supportive care make this option a viable alternative to medical management. The decision to transplant is complex, however, and requires an understanding of the unique pathobiology of paroxysmal nocturnal hemoglobinuria (PNH) and the input of physicians experienced in transplantation and medical management of paroxysmal nocturnal hemoglobinuria (PNH).

Table 40–4. Hematopoietic Stem Cell Transplantation for paroxysmal nocturnal hemoglobinuria (PNH)
Indications for transplantation
  • Marrow failure—approach to management depends primarily on the underlying marrow abnormality (e.g., aplastic anemia) but the treatment regimen must be sufficient to eradicate the paroxysmal nocturnal hemoglobinuria (PNH) clone
  • Major complications of paroxysmal nocturnal hemoglobinuria (PNH)
Refractory, transfusion-dependent hemolytic anemia*
Recurrent, life-threatening thromboembolic complications
Conditioning regimens and donors
  • Ablative and reduced intensity conditioning regimens have been successful
  • For transplantations involving syngeneic twins, an ablative regimen is recommended
  • Matched unrelated donor transplantations have been successful but experience is limited
Outcomes
  • There are no paroxysmal nocturnal hemoglobinuria (PNH)-specific adverse events. Severe, acute graft-versus-host disease occurs in approximately 33% of patients and the incidence of chronic graft-versus-host disease is roughly 35%
  • Overall survival for unselected paroxysmal nocturnal hemoglobinuria (PNH) patients who undergo transplantation using an HLA-matched sibling donor is in the range of 50–60%
*Treatment with eculizumab controls the intravascular hemolysis of paroxysmal nocturnal hemoglobinuria (PNH). Mild to moderate extravascular hemolytic anemia persists in most patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab, likely as a consequence of opsonization of erythrocytes by activation and degradation products of complement C3.Eculizumab may ameliorate the thrombophilia of paroxysmal nocturnal hemoglobinuria (PNH).

Absence of graft-versus-host effect may render nonablative approaches inadequate.

For patients who are receiving transplantation for marrow failure, the focus of management is on the etiology of the marrow failure (see Table 40–4). For patients with aplastic anemia and a small paroxysmal nocturnal hemoglobinuria (PNH) clone who undergo matched sibling donor allotransplantation, the conditioning regimen of antithymocyte globulin and cyclophosphamide coupled with graft-versus-host effects appear sufficient to eradicate the paroxysmal nocturnal hemoglobinuria (PNH) clone.27 However, in the unusual situation in which the patient has a syngeneic twin, a more intense conditioning regimen is required, as graft-versus-tumor effect does not contribute to clonal eradication in this circumstance.55 In the event that a patient with low-risk MDS with a paroxysmal nocturnal hemoglobinuria (PNH) clone requires allotransplantation, the conditioning regimen (marrow ablative or reduced intensity) in combination with graft-versus-tumor effects is sufficient to eradicate the paroxysmal nocturnal hemoglobinuria (PNH) clone.

Transplantation for classic paroxysmal nocturnal hemoglobinuria (PNH) is aimed at eradicating the paroxysmal nocturnal hemoglobinuria (PNH) clone, and both marrow ablative56–58 and reduced intensity59,60 conditioning regimens appear to be effective, although experience with the latter is more limited. Successful outcomes have been reported using matched unrelated donors, as well as matched sibling donors.59,61

There are no paroxysmal nocturnal hemoglobinuria (PNH)-specific adverse events associated with transplantation; severe, acute graft-versus-host disease (GVHD) occurs in more than one-third of the patients and the incidence of chronic GVHD is roughly 35 percent. Overall survival for unselected paroxysmal nocturnal hemoglobinuria (PNH) patients who undergo transplantation using an human leukocyte antigen (HLA)-matched sibling donor is in the range of 50 to 60 percent.27