Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) with HLA geno-identical sibling donor is the treatment of choice for children and young adults with constitutional or acquired (SAA) bone marrow failure (BMF). However, results of unrelated HSCT for BMF have been poorer due to high transplant related mortality mainly related to rejection and GVHD. Generally, a myeloablative regimen HSCT is used for acquired and some constitutional BMF but not for Fanconi anemia (FA) patients for whom a low dose conditioning regimen is employed. We have driven the hypothesis that immunosuppressive reduced intensity conditioning regimen should decrease TRM, decreasing GVHD and allowing engraftment. In a Phase I-II trial, 20 patients (pts) with BMF were enrolled and transplanted between 2002 and 2004. Thirteen pts had a constitutional aplasia: FA n=11, congenital megakaryocytopenia (CMK) n=1, Rothmund-Thomson syndrome n=1 and 7 pts had SAA among those two had paroxystic nocturnal hemoglobinuria (PNH). There were 12 male and 8 female. Median age was 8 years for constitutional BMF and 26 years for SAA. The HSC source was bone marrow for 11 pts, PBSC for 1 pt and cord blood for 8 pts. Ten of the twelve BM or PBSC donors were HLA matched for 10 loci (A, B, C, DRB1, and DQB1) and eight cord blood donors were HLA mismatched with 2 generic differences and were used for FA. All pts received the same conditioning regimen consisting of Busulfan (3mg/kg x 2), cyclophosphamide (10mg/kg x 4), fludarabine (30mg/m2 x3) and ATG (2.5mg/kg x4). The mean of nucleated stem cells infused and CD34 + cells was 2.8x108/kg and 5.9x106/kg respectively for the 12 pts who received BM stem cells and PBSC and 6.4x107/kg and 4.6x106/kg respectively for the eight pts who received CB cells. Acute GVH disease prophylaxis consisted of ciclosporine A (CsA) for pts with constitutional BMF and CsA and short course methotrexate for 6 of the 7 pts with acquired BMF, (one received tacrolimus instead of CsA due to thrombotic pre-existing co-morbidity). One pt (with CMK) died on day 0 from cerebral haemorrhage. Eighteen pts out of 19 had WBC recovery with a median time of 23 days (11–42); one FA pt did never reach sustained engraftment and died at D+291 from adenovirus infection. Three others had late graft rejection: in a context of acute GvHD and EBV infection and pulmonary aspergillosis for two pts with SAA who received BM graft and with acute GvHD and adenovirus infection for one FA pt who received CB graft. The conditioning was well tolerated without severe mucositis even in FA patients, sixteen patients experienced transient liver abnormalities. Nine patients developed reversible haemorrhagic cystitis at a median of 47 days post-transplant. There were 3 bacterial, 10 viral and 5 fungal infections with a cumulative incidence of TRM at one year of 45 ±24%. The cumulative incidence of acute GVH (II–IV) was 50 ±23%. Overall survival (OS) at one year was 55±11 %. It was 86%± 13 for SAA and 38% ± 13 for constitutional BMF. In spite of the short follow-up and few patients included, reduced intensity conditioning regimen provides encouraging results for patients with SAA. For constitutional BMF, low toxicity was observed, however the overall results seem similar to those reported in the literature using other RIC regimen and are probably related to other factors than the conditioning regimen.
Efficacy and Safety of Hematopoietic Stem Cell Transplantation for Pediatric Bone Marrow Failure Syndromes Using a Reduced Intensity Conditioning Regimen with Fludarabine, Thiotepa, Melphalan, and ATG
