Feasibility and Optimal Schedule Of Using Eculizumab In Patients With Hemolytic Paroxysmal Nocturnal Hemoglobinuria (hPNH) With Severe Aplastic Anemia (SAA) Prior To Haemopoietic Stem Cell Transplant (HSCT)

Eculizumab, humanized monoclonal antibody directed against complement component C5, has changed the treatment paradigm of patients with haemolytic paroxysmal nocturnal haemoglobinuria (hPNH). It stabilizes the hemoglobin by inhibiting complement mediated intravascular haemolysis, prevents thrombotic complications and significantly improves the quality of life. The data for hematopoietic stem cell transplant (HSCT) in eculizumab era is lacking, although patients with large PNH clone and severe aplastic anaemia (SAA) should be treated as dictated by their predominant clinical manifestation. HSCT should be the preferred option for PNH patients on eculizumab who develop overt bone marrow failure (BMF) during their clinical course or presenting concomitantly with SAA and PNH. The optimal use of eculizumab in the peri-transplant setting to prevent haemolytic/thrombotic complications and also the ideal conditioning regimen to eradicate the PNH clone is yet undetermined.

We analyzed 7 patients with PNH and SAA who underwent HSCT at our Centre for their BMF. Of these 5 patients were on eculizumab for a median of 8 months (range 4-12) for PNH prior to worsening of their aplasia necessitating regular blood product (red cells and platelet) support. Two patients were initiated eculizumab during the pre-transplant period for their coexisting haemolytic PNH and SAA, whilst donor search was undertaken.

The median age 32 years (range 18-56 yrs) and M/F was 4;3. The median disease duration was 48 months (range 4-252 months). All patients had evidence of haemolysis, elevated LDH and a large granulocyte clone (median 95%, range 57-100). The red cell clone was <5% in all the patients due to ongoing haemolysis and dilutional effect of transfusions. CD52 (GPI anchor protein) expression on CD3+ & CD19+ cells was done to help decide use of alemtuzumab in conditioning.

The conditioning received was a fludarabine/BU-based RIC HSCT, of these 4 received T-cell depletion using ATG (anti-thymocyte globulin) and 1 with alemtuzumab (100% CD3+ cells co-expressed CD52). Two patients received a haploidentical transplant using the Seattle protocol with post-transplantation cyclophosphamide. The source of stem cells in all 7 was GCSF mobilized peripheral blood stem cells.

Eculizumab was continued until the transplant and the last dose was given on the start of the conditioning protocol, i.e 7 days prior to cell infusion.

Pre-transplant 3 patients successfully underwent embryo (n=1) and ova (n=2) cryopreservation with ovarian hyper stimulation protocol (supraphysiological doses of estrogen) with eculizumab used prophylactically to cover thrombotic complication, as they were severely thrombocytopenic and were unable to receive low molecular weight heparin.

Eculizumab given during the immediate pre-transplant period did not increase the infectious complications. Neutrophil and platelet engraftment occurred at 16 and 21 days respectively. The PNH clone was undetectable on D+14 and none was seen after engraftment with normalization of LDH. No clinical evidence of venoocclusive disease (VOD) was seen. Acute GVHD (grade 2) and Chronic GvHD (skin and gut) were observed in one patient each. Two patients failed to engraft, of which one was successfully rescued with a haploidentical HSCT although the PNH clone disappeared following the conditioning used in the first transplant for both patients. Full donor chimerism in unfractionated, CD3 and CD15 lineages was achieved at D100 post HSCT.

This data demonstrated the feasibility of using eculizumab in patients with PNH and SAA, during the peri-transplant setting. The use of myeloablation in conditioning facilitates the eradication of the PNH clone. The successful use of eculizumab in preventing the thrombotic risks associated with ovarian hyper stimulation protocol is also evident. It is theoretically possible that VOD post HSCT could be exaggerated in the presence of another thrombotic condition (PNH), but we did not observe VOD to warrant eculizumab in the immediate post-transplant period. Larger studies and uniform strategies are needed to evaluate the optimal use of anti-complement therapy for SAA/PNH patients undergoing HSCT.

Kulasekararaj:Alexion: Consultancy, Honoraria, Speakers Bureau. Large:Alexion: Speakers Bureau. Marsh:Alexion: Honoraria, Speakers Bureau.