Summary:A 15-year-old female received an unrelated three of six HLA antigen matched umbilical cord blood (UCB) transplant for refractory, relapsed T-cell ALL. Conditioning consisted of TBI, melphalan, and anti-thymocyte globulin (ATG), with cyclosporin A (CsA) and solumedrol for GVHD prophylaxis. She engrafted and a day 34 bone marrow aspirate showed 100% donor cells and no evidence of leukemia. The post-transplant course was complicated by mild grade I acute GVHD involving skin, and limited chronic GVHD of the gut which resolved with the addition of 1 mg/kg/day of steroids to her CsA prophylaxis. One hundred and ninety days after transplantation the patient developed pancytopenia and was subsequently found to have a leukemic relapse. Immunosuppression was discontinued and she was started on G-CSF and erythropoietin. Moderate skin and gut GVHD developed which was treated with both topical and low-dose oral steroids. Over the next few weeks she became transfusion independent and a follow-up bone marrow aspirate showed complete remission. She continued in complete remission for 4 months, at which time localized leukemic relapse was found in a soft tissue breast mass in spite of continued bone marrow remission. from BMT but lack a suitably matched conventional transplant donor.1-4 Preliminary results have suggested that UCB transplantation may be associated with a lower incidence of acute GVHD than unrelated bone marrow, and require less stringent HLA matching.2-4 While less GVHD is a potential benefit of UCB transplantation, there is concern that UCB may not be able to generate a sufficient GVL effect in patients with hematologic malignancies, resulting in increased relapse rates and limiting its practical utility. In this report we describe a patient who relapsed after undergoing UCB transplantation from a partially mismatched (3/6) unrelated donor for refractory relapsed T cell ALL. A complete remission was achieved following discontinuation of immunosuppression and institution of cytokine support. Whether UCB cells generate a GVL effect in all patients is unknown, but this case report clearly demonstrates that UCB has the potential to generate a GVL effect and this effect can be powerful enough to induce a complete remission. As the biology and mechanisms of GVHD and GVL are more completely understood, it may become possible to uncouple these two immune responses and maximize the benefits of hematopoietic stem cell transplantation without compromising anti-leukemic effects. Case reportA 15-year-old white female had been diagnosed with CD7 +
Introduction: Severe VOD is an important regimen-related toxicity of hematopoietic SCT characterized by MOF and high mortality (>80% at d+100 post SCT). DF is a novel polydisperse oliogonucleotide with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. DF appears to modulate endothelial cell (EC) injury in sVOD, with encouraging complete response (CR) rates, survival at d+100 post SCT and minimal toxicity reported. Methods: A multi-center, phase II trial was conducted in which patients (pts) stratified for age (<18y) and cyclophosphamide-based conditioning were randomized to 25 mg/kg/d or 40 mg/kg/d of DF. VOD diagnosis was made by Baltimore criteria, with severity determined by MOF or Bearman model (>30% risk). Study endpoints included CR, d+100 survival post SCT and toxicity. CR was defined as bilirubin <2 mg/dL and resolution of VOD-related MOF, with pts having ≥3d of DF evaluable for response. Abdominal ultrasound (US) with Doppler was required at study entry, d14 of DF, and completion of therapy, with blood collected serially to examine markers of EC stress. Results: 150 pts were treated with DF, with 75 pts on each treatment arm: 129 pts underwent allo- and 21 auto- SCT. Median age was 36y (6m–63y). At DF start, median bilirubin was 5.0 mg/dL; median weight gain 12%; ascites was present in 77%; RUQ pain in 71%; hepatomegaly in 69%; abnormal portal flow in 44%; and MOF in 99% (at study entry, 7% were dialysis-dependent (DD), 7% ventilator-dependent (VD); 28% developed DD and 23% VD during treatment). Median duration of DF therapy was 19d (1–82d). Of 150 pts treated, 141 were evaluable for response: 65 pts achieved CR (46%) and 62 survived to d+100 (41%), including pts with prior DD and VD. Results for CR and d+100 survival have been analyzed by dose level according to age, prior SCT and Mylotarg use. No significant difference in CR and d+100 survival was found between the 2 doses, although in pediatric pts receiving 25 mg/kg/d, CR and d+100 survival was 67% (p=0.06). Toxicity was limited, but more attributable G3/4 events, including bleeding and hypotension, were recorded in pts on 40 mg/kg/d, although the difference was not significant (p=0.11). Preliminary US review demonstrated improvement in portal flow abnormalities with DF therapy. EC stress markers showed reduction in median levels of PAI-1 and nitric oxide with increase in Protein C in pts achieving CR (p<0.05): median serum thrombomodulin, TFPI and soluble tissue factor increased in pts without response (p<0.05). Correlation with additional markers is ongoing. Similarly, multivariate analysis of factors predicting CR and d+100 survival is in process. Conclusion: DF treatment of sVOD/MOF results in a 46% CR rate and 41% d+100 survival post SCT: 25 mg/kg/d is the preferred dose. A phase 3 pivotal trial to confirm safety and efficacy is underway, comparing a prospective cohort of 80 DF-treated pts with sVOD/MOF to a matched historical group at 30 SCT centers across North America.
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 (<18y) and cyclophosphamide-based conditioning. Treatment was planned for ≥14d. Pts receiving ≤3d of therapy were inevaluable for response. CR was defined as a bilirubin <2 mg/dl and resolution of VOD-related MOF. Results: 102 pts have been treated; 51 pts on arm A and 51 pts on arm B: 87 pts underwent allo- and 15 auto-SCT. Median age was 33y (6 mos - 63y). At DF initiation, median bilirubin was 7.1 mg/dl; median wt gain 12%; ascites in 78%; RUQ pain in 65%; hepatomegaly in 71%; abnormal portal flow in 42%, and MOF in 97%. Median duration of therapy was 20d. There were no unexpected side effects and no treatment related deaths. In a subset of pts (n=14), central review of US was performed. Portal flow improved by wk 3 in pts with CR (n=8). Improvement was not seen in nonresponders (NR) (n=6), suggesting changes in portal flow may help predict outcome. Median values of markers of endothelial stress with DF treatment are summarized below. In pts with CR, median PAI-1 levels decreased and Protein C increased. Median NO declined regardless of response. Median thrombomodulin, tissue factor and TFPI increased in NR. CR was achieved in 50/93 pts (54%; 95% CI (43%,64%)), with survival to d+100 in 43/91 pts (47%; 95% CI (37%,58%)). No difference in outcome between the 2 dose arms was seen. An analysis using 38 controls matched for VOD severity confirmed a survival advantage (p=0.0004). Conclusion: US findings and trends in endothelial stress markers may help predict successful DF treatment. The CR rate (54%) and d+100 survival (47%) in this first prospective, randomized trial of DF in pts with severe VOD and MOF confirm the encouraging results of prior studies, and a case control analysis shows a highly significant survival benefit with DF treatment. *p<0.05 Arm A Arm B **p<0.001 CR NR CR NR Pre/Post Pre/Post Pre/Post Pre/Post PAI-1 (nl<40) 109/53** 84/92 87/64* 99/102 Protein C (nl>70) 35/50** 33/31 29/43* 26/31 NO (nl<58) 98/68* 119/91 84/67 108/57 Thrombomodulin (nl<40) 144/135 149/178* 149/140 139/283** TFPI (nl<111) 116/124 154/213* 132/138 150/196* Tissue Factor (nl<162) 195/164 176/278* 197/202 179/298**
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