defibrotide and Neoplasms

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.

Topics: Adolescent; Adult; Bilirubin; Child; Child, Preschool; Drug Evaluation; Feasibility Studies; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hemorrhage; Heparin; Hepatic Veno-Occlusive Disease; Humans; Male; Multiple Organ Failure; Neoplasms; Palliative Care; Polydeoxyribonucleotides; Receptors, Purinergic P1; Retrospective Studies; Risk; Thalassemia; Tissue Plasminogen Activator; Treatment Outcome

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication of autologous stem cell transplant (ASCT) in children with historically high mortality rates. Defibrotide has shown proven benefit in its treatment and may have a modest role in prevention. We report our experience with SOS in children undergoing autologous transplant.. Case records of 82 consecutive patients undergoing ASCT following high-dose chemotherapy between 2010 and 2017 were reviewed. Defibrotide was used for treatment of all with SOS and prophylactically in patients receiving busulfan-based conditioning until 2014.. Fourteen of the 82 children (17%) were diagnosed with SOS. The incidence was higher in those receiving busulfan-based conditioning (13/42 vs 1/40, P = 0.008). Mean (±SD) time to diagnosis of SOS was 19 (±5.6) days following stem cell rescue. Bilirubin levels and ultrasound were normal in 7/14 and 3/14 patients. Coagulopathy was noted in 10/14; one child developed multiorgan involvement. Nine children had mild SOS, whereas two and three had moderate and severe SOS, respectively. Intensive care was required for four of five non-mild cases. Patients with SOS had significantly delayed platelet recovery, higher transfusion requirement, and longer hospital stay. Unavailability of defibrotide prophylaxis for 17/42 receiving busulfan did not change the incidence of SOS (7/25 with defibrotide vs 6 /17 without defibrotide, P = 0.74). There was no significant difference in the severity of SOS between these groups.. Hepatic SOS was more commonly seen in children receiving busulfan-based conditioning. Stopping the use of prophylactic defibrotide did not increase incidence or severity of SOS. Overall outcome was excellent with supportive care and timely treatment with defibrotide.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Female; Fibrinolytic Agents; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Neoplasms; Polydeoxyribonucleotides; Prognosis; Retrospective Studies; Survival Rate; Transplantation, Autologous

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.. Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).. Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%.. In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Female; Fibrinolytic Agents; Hepatic Veno-Occlusive Disease; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Polydeoxyribonucleotides; Young Adult

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.

Topics: Adolescent; Adult; Ascites; Bilirubin; Biopsy; Child; Child, Preschool; Female; Fibrinolytic Agents; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Infant; Infusions, Intravenous; Liver; Male; Middle Aged; Multiple Organ Failure; Neoplasms; Peripheral Blood Stem Cell Transplantation; Polydeoxyribonucleotides; Prospective Studies; Transplantation Conditioning; Treatment Outcome

The efficacy of postoperative DVT prophylaxis of defibrotide and heparin calcium was evaluated in a group of 47 patients undergoing general surgery for oncological pathologies. A sub-group (24 patients) received defibrotide treatment, 400 mg b.i.d. i.m.; the second subgroup (23 patients) was treated with heparin calcium, 5000 IU b.i.d. s.c., from the day before operation until the 7th postoperative day. No postoperative thrombotic symptoms were observed in either group of patients.

Topics: Fibrinolytic Agents; Heparin; Humans; Neoplasms; Polydeoxyribonucleotides; Postoperative Complications; Premedication; Thrombophlebitis

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication generally occurring after hematopoietic stem cell transplantation. SOS after standard dose chemotherapy in malignancies is rare. Between the year 1995 and 2016, 414 patients were diagnosed with acute lymphoblastic leukemia and 113 patients were diagnosed with Wilms tumor in our institution. Among these patients, 4 patients with acute lymphoblastic leukemia (0.96%) and 2 patients with Wilms tumor (1.7%) developed SOS during treatment. SOS behaves like a local disseminated intravascular coagulation. Defibrotide has proved to be effective in SOS. In this article, we report our experience with defibrotide in SOS.

Topics: Antineoplastic Agents; Child; Hepatic Veno-Occlusive Disease; Humans; Neoplasms; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Wilms Tumor

The novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.. This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).. This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients.

Topics: Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Dogs; Female; HSP90 Heat-Shock Proteins; Indoles; Male; Neoplasms; Prodrugs; Tandem Mass Spectrometry; Triazoles