Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) involves the proliferation of an abnormal and possibly premalignant hematopoietic stem cell. Successful treatment of PNH by marrow grafting requires that the PNH clone be eradicated by the pretransplant conditioning regimen. Four patients with PNH-associated marrow aplasia were transplanted with marrow from their HLA-matched, MLR-nonreactive siblings. Three patients were conditioned with cyclophosphamide, procarbazine, and antithymocyte serum (CTX/PCZ/ATS), and one was conditioned with busulfan/CTX/PCZ/ATS. Persistent complete engraftment of myeloid, lymphoid, and erythroid cell lines was demonstrated in all four patients by DNA sequence polymorphism analysis or cytogenetics, and RBC typing. There was no recurrence of the abnormal clone of cells for up to five years after transplantation despite the use of a conditioning regimen in three of them, which is not usually associated with permanent marrow aplasia. Bone marrow transplantation is a curative therapy in patients whose illness is severe enough to warrant the risk.

Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view

“…The clinical results of BMT with human leucocyte antigen (HLA)-identical sibling donors in PNH have been similar, but somewhat inferior to those seen in AA (Saso et al, 1999;Lee et al, 2003;Santarone et al, 2010); some successful procedures with unrelated and with haploidentical related donors have been also reported (Woodard et al, 2001;Hegenbart et al, 2003;Santarone et al, 2010), but they are too few to assess how they compare. Not surprisingly, in view of (a)-(c) above, a myeloablative conditioning regime is not needed (Brodsky et al, 2008b), as had been already shown by Antin et al (1985) before the reduced conditioning transplant had been introduced.…”

Stem cell transplantation for paroxysmal nocturnal haemoglobinuria in childhood

“…There is a long-standing discussion of whether a myeloablative conditioning regimen is necessary for SCT in PNH without myelodysplasia or leukaemia (Antin et al, 1985;Raiola et al, 2000). A number of PNH patients have successfully been transplanted after conditioning with cyclophosphamide only (Antin et al, 1985;Kawahara et al, 1992;Saso et al, 1999) or after reduced-intensity conditioning with cladribine, busulphan and anti-thymocyte globulin (Suenaga et al, 2001). It is not fully understood by what mechanisms non-ablative SCT eliminates the abnormal PNH clone, but many authors advocate that intense immunosuppression is the key process.…”

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria

“…(The fact that the latter responded suggests they too have an autoimmune pathophysiology, as in AA.) (iii) Unlike in MDS (Appelbaum et al, 1984), in PNH a non-myeloablative conditioning regimen for allo-BMT may be preferable (see Discussion in because it has been shown to be curative (Antin et al, 1985;Kawahara et al, 1992) yet it is less toxic, with a lower chance of permanent infertility (Sanders et al, 1996). (iv) Finally, it is important not to miss PNH in a patient thought to have MDS, given the high risk in PNH of life-threatening thromboses, which are potentially reversible with prompt administration of fibrinolytic therapy (McMullin et al, 1994).…”