Summary:This retrospective cohort study of 462 consecutive adult allogeneic and autologous blood or marrow transplantation (BMT) patients compared the incidence of hepatic veno-occlusive disease (VOD) after BMT with three prophylactic regimens. Patients receiving heparin (Hep), heparin + prostaglandin E1 (Hep + PGE1) or low molecular weight heparin (LMWH) as a prophylactic VOD regimen were compared to a historical cohort receiving no VOD prophylaxis. Of 462 BMT patients, VOD was diagnosed in 22% (31 of 142) of the no prophylaxis group, 11% (11 of 104) of the Hep, 12% (13 of 110) in the Hep + PGE1 and 4% (four of 106) of the LMWH group (P = 0.0002). VOD was the primary cause of death in 20% (12 of 59). By multivariate logistic regression, independent risk factors for developing VOD were: no VOD prophylactic regimen, unrelated allogeneic BMT, Karnofsky performance score (KPS) Ͻ80 and aspartate aminotransferase (AST) у50 U/l. There was no increase in the rate of death due to hemorrhagic events or VOD in any prophylaxis group compared to the control group. Prospective randomized trials of Hep vs LMWH vs placebo are warranted to assess the efficacy of heparin compounds in the prevention of VOD. Bone Marrow Transplantation (2001) 27, 627-633. Keywords: veno-occlusive disease; prophylaxis; heparin; blood and marrow transplantation Veno-occlusive disease (VOD) of the liver is a clinical syndrome, characterized by hyperbilirubinemia, painful hepatomegaly and fluid retention. 1 It occurs in up to 54% of patients and is a leading cause of blood or marrow transplantation (BMT)-related death with a mortality rate up to 3 The etiology of VOD is not clearly defined, however, drug-induced hepatocellular damage occurs in the centrilobular zones of the liver. The coagulation cascade may have a role in VOD pathophysiology due to clotting factor activation leading to fibrin deposition in the central veins. It has been postulated that anticoagulant therapy could prevent fibrin deposition and subsequent hepatic damage. 5,6 Several clinical trials of prophylactic heparin (Hep) during BMT have shown contradictory results. [7][8][9][10][11][12] Nevertheless, these studies demonstrated that low doses of Hep could be safely administered to BMT patients. Prostaglandin E1 (PGE1) was used as a VOD prophylactic regimen by Gluckman et al, 13 who found a decreased incidence of VOD in patients treated with PGE1, whereas Bearman et al, 14 concluded that PGE1 was too toxic. Previous work has demonstrated the efficacy and safety of low molecular weight heparin (LMWH) for deep venous thrombosis prophylaxis and treatment. 15,16 A small prospective study comparing LMWH to placebo revealed a shorter duration of VOD-related symptoms after BMT in the LMWH treated patients. 17 In our retrospective study, we analyzed three VOD prophylactic regimens in 462 patients undergoing allogeneic or autologous BMT. The VOD preventive effects of Hep, Hep + PGE1 and LMWH were compared to each other and to a historical control group. This is the first retrospective mul...

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.

Eight patients with refractory Hodgkin's disease received intensive combination chemotherapy conditioning with cyclophosphamide, carmustine (BCNU), and etoposide (VP 16-213), and allogeneic marrow transplants. All patients achieved complete responses. Three patients relapsed; two died of Hodgkin's disease and one of chronic graft-v-host disease (GVHD) and infection. In all, four patients died due to transplant-related toxicity. One patient developed a fatal B-cell lymphoproliferative disorder soon after transplantation, and died without evidence of Hodgkin's disease. One patient is alive and free of progression 29 months after transplantation. These data indicate that allogeneic marrow transplantation may be considered as therapy for selected patients with advanced Hodgkin's disease and, despite substantial toxicity, will occasionally result in long-term responses. Better patient selection would likely improve results.

Summary:The treatment of established veno-occlusive disease (VOD) of the liver with tissue plasminogen activator (tPA) has been disappointing. In attempts to improve upon these results we identified a subgroup of patients with consistently elevated bilirubin levels who did not meet conventional criteria for VOD (Susp VOD) but who had a significant risk of later developing clinical VOD. In January 1994 we began to treat patients who developed Susp VOD with tPA rather than waiting until they developed clinical VOD. We now report on the results of the first 37 patients who ultimately developed clinical VOD and received tPA therapy prior to Susp VOD, or at the time they had established VOD. Significant bleeding complications occurred in 13 (35%) patients but resolved with discontinuation of therapy in all but one. We found that patients treated early in the course of hepatotoxicity prior to the development of overt VOD had a significantly higher response rate and 100 day survival than patients treated at the time of established VOD. Given the poor results seen in treating late VOD, we suggest that early treatment with tPA may improve the outcome in patients who develop signs of hepatotoxicity following marrow transplantation. Keywords: tissue plasminogen activator; hepatotoxicity; bone marrow transplant Hepatic veno-occlusive disease (VOD) is a frequent and serious complication of bone marrow transplantation (BMT). Published reports indicate an incidence of 5-50%, and a mortality as high as 15% depending on the clinical series and the definition used.1-4 Clinically, VOD has been defined as hyperbilirubinemia within the first 4 weeks following BMT, with associated findings of ascites, unexplained weight gain, hepatomegaly or right upper quadrant pain. VOD is characterized histologically, by necrosis of zone 3 hepatocytes and deposition of fibrin and factor VIII in hepatic venules. These findings suggest a role of the coagulation system in the pathophysiology of VOD. sparse, and treatment options are limited. Despite the paucity of data, early experience with tissue plasminogen activator (tPA) is encouraging. Presently, tPA represents the most promising therapy for the treatment of hepatotoxicity following BMT. [6][7][8][9] Based on the promising initial reports of Bearman et al, 9 we began to treat patients with established VOD with tPA in April 1993. Our early experience in treating patients with advanced VOD using tPA was unfavorable, as in the larger trial recently reported by Bearman and colleagues.10 Others had suggested that successful treatment required early therapy.11 Thus in January 1994 we began to treat patients when they developed persistent unexplained hyperbilirubinemia (suspected VOD) without additional clinical evidence of VOD. To investigate whether earlier treatment may influence the course of hepatotoxicity, we examined only those patients who developed clinical VOD, and compared the results for those who received tPA prior to or after developing clinical VOD. Methods Patient selection and hepato...

Summary:Two patients with CsA-associated neurotoxicity developed severe cerebellar swelling and thrombotic thrombocytopenic purpura after switching to FK506 and high-dose corticosteroids. The prodrome of CsAassociated neurotoxicity, TTP and hypertension while receiving FK506, and high-dose corticosteroids could all be implicated in the development of this syndrome. Close monitoring of patients receiving FK506 and highdose corticosteroids, for the development of TTP is warranted. Early radiological examination should also be considered in such patients to allow early surgical intervention. Keywords: cerebellar swelling; TTP; FK506; cyclosporine neurotoxicity; steroids Common side-effects of cyclosporin A (CsA) include renal dysfunction, hypertension and tremors.1,2 Rare severe neurotoxicity including ataxia and occipital blindness is also reported. [3][4][5][6] This syndrome resembles thrombotic thrombocytopenic purpura (TTP). There are numerous case reports of TTP following BMT. [7][8][9][10][11][12][13] Clinical manifestations include: hypertension, edema, renal failure, neurologic changes and microangiopathic hemolytic anemia. Although the syndromes are both associated with CsA use, the presence or absence of microangiopathic hemolytic anemia can distinguish them. 14 Treatment of CsA neurotoxicity consists of discontinuing the drug, correcting electrolyte abnormalities and controlling hypertension. 3,13,15 Neurologic changes typically resolve within 48 h of discontinuing CsA. In contrast, patients with TTP have a much poorer outcome despite discontinuing CsA, often requiring intensive support.14 Although ideal management is unclear, it appears that plasma exchange alone 16 or combined with protein immunoadsorption may be effective modes of therapy. and to alter the ratio of thromboxane to prostacyclin production resulting in procoagulant activity. [18][19][20][21][22][23][24] Since patients who develop neurologic symptoms attributable to CsA without microangiopathic changes and those who develop TTP are frequently early post-transplant, discontinuing CsA may be associated with development of severe GVHD. The introduction of FK506 into clinical use has allowed substitution of FK506 for CsA in patients developing TTP following BMT and solid organ transplantation. 25 However, the safety of this approach is not well established as there are now reports of FK506-induced TTP following BMT and solid organ transplantation. 26-28 Case 1A 28-year-old male with Hodgkin's disease received an HLA-matched unrelated donor BMT 2 years after relapsing following an autologous BMT. Conditioning was with thiotepa and carboplatin. He received low-dose intravenous heparin as hepatic veno-occlusive disease (VOD) prophylaxis. GVHD prophylaxis consisted of cyclosporine, methotrexate and methylprednisolone. On day +8, he developed hyperbilirubinemia (primarily direct), associated with an elevated CsA level of 514 (normal range, 250-450). CsA was held and restarted at one-third the previous dose on day +10. On day +11, he developed cort...