Overcoming graft rejection in heavily transfused and allo‐immunised patients with bone marrow failure syndromes using fludarabine‐based haematopoietic cell transplantation

Abstract

Summary Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non‐malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo‐immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine‐based non‐myeloablative conditioning regimen in patients with transfusion‐dependent non‐malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty‐six patients with transfusion dependent/anti‐thymocyte globulin (ATG)‐refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)‐compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft‐versus‐host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion‐independence. Twenty‐four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II–IV, 54% grades III–IV) and chronic GVHD (56%) was observed, only one patient died from transplant‐related causes (cumulative incidence 7%). These data show that HCT following fludarabine‐based non‐myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

“…11,14 These studies demonstrate that a similar approach may be successful to cure the disease and interestingly suggest that an important "graft-versus-PNH" effect with reduced intensity conditioning transplant could be hypothesized. 19 The use of hematopoietic stem cell transplantation to treat paroxysmal nocturnal hemoglobinuria has become less frequent now that there is an effective drug therapy such as eculizumab.…”

“…Thus, reduced intensity conditioning regimen should be restricted to prospective clinical trials; perhaps some specific reduced intensity conditioning regimens which seem to be as effective as myeloablative conditioning in a single center experience. 14 In conclusion, our survey shows that hematopoietic stem cell transplantation may lead to a long-term cure rate as high as 60% in a heterogeneous cohort of seriously ill paroxysmal nocturnal hemoglobinuria patients but improvements in hematopoietic stem cell transplantation procedure are still desirable. While the recent availability of targeted therapy has certainly reduced the indication for hematopoietic stem cell transplantation, its potentially curative use remains a valid therapeutic option for patients candidate to a low-risk transplant procedure.…”

“…Eradication of the PNH clone has been achieved with both myeloablative and reduced-intensity conditioning regimens. [10][11][12][13][14] Younger patients with severe manifestations of the disease (high transfusion requirement, severe pancytopenia, life-threatening thrombosis) and availability of an HLAidentical sibling donor are the best candidates for hematopoietic stem cell transplantation. There are few reports on the use of allogeneic transplantation for paroxysmal nocturnal hemoglobinuria, and nearly all of them include small numbers of patients with only one large survey (57 consecutive patients) reported by the International Bone Marrow Transplant Registry.…”

Allogeneic hematopoietic SCT in patients with non-malignant diseases, and importance of chimerism

“…2 Graft failure and graft rejection are known to be high in patients with non-malignant diseases. 6,7 This may be because of the fact that there has been no earlier chemotherapy to the risk of immunization from repeated transfusions in hemoglobinopathies, and to the use of less myeloablative-conditioning regimens. In recent years, an increasing number of patients with non-malignant diseases have been treated with reduced intensity conditioning (RIC) to reduce acute toxicity and late side effects.…”

Management of adult patients older than 40 years refractory to at least one immunosuppressive course: HLA-identical sibling HSCT using fludarabine-based conditioning

“…8 In patients with SAA specifically, several noncomparative studies have reported encouraging results in the setting of HLA-matched related HSCT. [9][10][11][12][13] A recent report from the EBMT SAA working party retrospectively analyzed 30 patients older than 30 years receiving reduced-intensity conditioning HSCT (using fludarabine 30 mg/m 2 Â 4, CY 300 mg/m 2 Â 4 and most with ATG, namely a FCA regimen) and compared their outcome with a control group receiving the standard regimen (CY þ / À ATG) over the same study period (1998-2007). 14 Recipients of fludarabine-based conditioning had a higher probability of ageadjusted overall survival than the control group (P ¼ 0.04).…”