ALBERT

Description: Introduction: DF, a polydisperse oligonucleotide, has anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Studies have suggested that DF modulates endothelial injury in VOD. Methods: A phase II randomized study of two doses, 25 mg/kg/d [arm A] or 40 mg/kg/d [arm B], was carried out in pts with severe VOD. Correlation with markers of vascular injury was undertaken. Endpoints included CR rate, toxicity and mortality at d+100 post SCT. VOD diagnosis was by Baltimore criteria and severity by ≥30% risk on the Bearman model or MOF. Abdominal ultrasound (US) was required prior to enrollment, repeated during therapy and at completion of treatment.Pts with ≥ grade II GVHD were excluded. Treatment arms were stratified for age (

Description: Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T- cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD 〉 or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.

Description: Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T- cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical- related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow- up.

Description: Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T- cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical- related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow- up.

Description: Introduction: Veno-Occlusive Disease (VOD) is a significant regimen-related toxicity of hematopoietic stem cell transplant (SCT), which when complicated by multi-system organ failure (MOF) has a case fatality rate 〉90%. We have treated 139 patients (pts) with VOD/MOF in a randomized, multicenter Phase II dose-finding study of Defibrotide (DF), a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and d+100 survival post SCT. Methods: We reviewed pts to define status of renal, pulmonary, and CNS dysfunction at entry and on DF therapy. We also determined dialysis dependence (DD) and/or ventilator dependence (VD) at study entry or when newly acquired while on study. These subgroups were examined for response to treatment (CR vs no CR) and d+100 survival. Results: Of 139 pts treated, 97 had creatinine (creat) ≥ 2x admission value at study entry, of whom 42 pts had creat ≥ 3x admission value, and 12 were DD. 35 pts developed new DD on DF therapy. At entry, 69 pts had room air O2 saturation ≤ 90%, 10 were VD and 34 developed new VD on DF therapy. 33 pts were encephalopathic at study entry and 23 became encephalopathic during treatment. CR was achieved in 59/124 (48%) evaluable pts. By Kaplan Meier and on intent to treat, d+100 survival was 51/133 (38%). Pts were analyzed according to MOF (Table 1). In those with both renal and pulmonary dysfunction at study entry, 44% achieved CR and 39% d+100 survival. Pts with renal or pulmonary dysfunction at study entry, combined with encephalopathy, had a CR rate of 55% and d+100 survival of 45%. Those with MOF in all 3 systems achieved a CR rate of 50%, although d+100 survival was lower at 33%. The presence of DD at study entry or newly acquired on DF therapy reduced CR rates to 33 and 20% respectively, with a similar reduction in CR rates for VD at 20 and 25%. D+100 survival in both categories was also reduced. Conclusion: DF therapy achieved encouraging CR rates and d+100 survival in pts with MOF in up to three systems complicating VOD post SCT, and clinical benefit was seen even if pts were DD and/or VD. However, CR rates and d+100 survival were lower with DD and/or VD both at study entry and when newly acquired on DF therapy, which suggests that earlier intervention with DF may further improve outcome. Degree and Type of MOF CR D+100 survival *p