Defitelio (defibrotide)

She was successfully treated with the urgent insertion of a transjugular intrahepatic portosystemic shunt (TIPS), defibrotide, and high-dose corticosteroids. This case of successful treatment for very severe SOS supports a combination strategy involving the immediate mechanical reduction of portal hypertension through TIPS and drug-mediated inhibition of microvascular thrombosis. Furthermore, this case shows the need for an improved prevention strategy, including the identification of additional risk factors and biomarkers.

P2, N=0, Withdrawn, University of California, San Francisco | N=15 --> 0 | Not yet recruiting --> Withdrawn

P2, N=42, Recruiting, Brigham and Women's Hospital | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: May 2024 --> Sep 2024

The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and in SOS/VOD development, suggesting CECs as a valuable biomarker for its diagnosis and for the identification of patients at higher risk of this complication, especially in cases of late-onset SOS/VOD. Furthermore, CEC kinetics may assist in treatment strategies by providing insights into the optimal timing for discontinuing defibrotide treatment.

P2, N=20, Recruiting, New York Medical College | Initiation date: Dec 2023 --> Mar 2024 | Not yet recruiting --> Recruiting

P2, N=15, Not yet recruiting, University of California, San Francisco

P2, N=20, Not yet recruiting, New York Medical College | Initiation date: Aug 2023 --> Dec 2023

P2, N=20, Completed, New York Medical College | Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Nov 2023

One study reported outcomes for 206 children who received supportive care for VOD/SOS during 6-thioguanine therapy for ALL; only three pts had acute hepatic failure and all pts recovered from VOD/SOS. Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. A lack of consensus regarding VOD/SOS diagnosis in the non-HCT setting may lead to underdiagnosis; therefore, clinicians should be vigilant for VOD/SOS even in non-HCT pts. Though defibrotide is approved for post-HCT VOD/SOS, there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need.

Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9...After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively)...We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD.

Our data suggests that defibrotide is safe and well tolerated in SCD patients with ACS. sICAM-1, Ang2, IL-6, and PLA2G2A may serve as important biomarkers in SCD associated ACS. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate efficacy of defibrotide in patients with SCD-associated ACS.

Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through achievement of TI and normal or near-normal Hb. These data will inform real-world beti-cel treatment decisions for patients with TDT and providers.

P2, N=40, Recruiting, New York Medical College | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=2, Active, not recruiting, New York Medical College | Recruiting --> Active, not recruiting | N=20 --> 2 | Trial primary completion date: Mar 2024 --> Oct 2023

VAC (vincristine, dactinomycin, cyclophosphamide) therapy was initiated...She was successfully treated with defibrotide and transitioned to VIE (vincristine, ifosfamide, etoposide) given comparable response and toxicity to VAC in RMS... This is the first reported case of IRMS in association with NF1 and of the chest wall in an adolescent. Reported cases of RMS and NF1 are almost exclusively embryonal RMS, with coexistence of IRMS and NF1 not previously reported in the literature. Germline pathogenic variants in SBDS were only recently linked to RMS, but have not been reported in conjunction with NF1 variants, and their clinical significance is still uncertain.

This open-label, single-arm, phase 2 study evaluated safety and efficacy of defibrotide for prevention of CAR-T-associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T-associated neurotoxicity. Trial registration: ClinicalTrials.gov identifier: NCT03954106.

The highest incidences of non-HCT VOD/SOS were in patients with colorectal liver metastases (CLM) treated with oxaliplatin-based chemotherapy (median 41%) and in patients treated with vincristine plus actinomycin D for Wilms tumor (median 14%)...Management of VOD/SOS included defibrotide, supportive therapy (eg, fluid restriction, blood products), and switching/pausing chemotherapy... Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. Lack of consensus regarding diagnosis of non-HCT VOD/SOS may indicate underdiagnosis. Given the seriousness of VOD/SOS, clinicians should be vigilant for VOD/SOS even in patients who have not undergone HCT.

Of 35 pts with ALL who developed VOD/SOS, 15 cases were mild and 20 were severe, and 22 pts died within 18 mo post-HSCT; 8/35 pts received prophylactic defibrotide (22/244 of all pts). In this real-world population of adults with ALL who received InO before HSCT, including heavily pretreated pts, 18-mo OS was 54% and 18-mo NRM was 22%. Common AEs post-HSCT were bacterial infection, viral infection, and acute GVHD. VOD incidence was consistent with previous reports and dual alkylators should be avoided, when possible, in this subset of pts.

Of 26 adults with ALL who developed VOD/SOS, 10 were mild, 16 severe; 5/26 patients received prophylactic defibrotide; 12/26 received defibrotide alone or in combination. In this real-world population of ALL patients who received pre-HSCT InO, including heavily pretreated patients, the incidence of VOD/SOS post-HSCT was similar to that observed in INO-VATE (phase 3 study) and a pooled analysis of 2 clinical trials of InO-treated patients with R/R ALL. Although VOD/SOS mortality was higher (36% vs. 26%), 12-month NRM was lower (24% vs.

Four patients were diagnosed with GVHD before the onset of TA-TMA; in these patients the first intervention was to interrupt treatment with calcineurin inhibitors and administer mycophenolate mofetil and methylprednisolone 1-2 mg/kg/day...At a median follow up of 362 days from HSCT, 3/5 (60%) patients are alive; patient 1 died of leukemia relapse, patient 3 died of sepsis following multiple lines of treatment with concurrent remission of TA-TMA.Pt n°genderAge at HSCTDiagnosisConditioningDonor type, sourceGVHD prophylaxisaGVHD, organ and maximal gradecGVHDDays from HSCT to TA-TMADiagnosisHR featuresFirst line treatmentTime from Ta-TMA diagnosis (days)Second line treatmentTime from TA-TMA diagnosis(days)Third line treatmentTime from TA-TMA diagnosis(days)Fourth line treatmentTime from TA- TMA diagnosis(days)Fifth line treatmentTime from TA- TMA diagnosis(days)Sixth line of treatmentTime from TA- TMA diagnosis(days)OutcomeFollow up from HSCT(days)1F17.4Secondary MDS/AMLTBI, Melphalan, ATG, RituximabHaplo, CD19 and TCR αβ depletion PBSCnoneSkin, grade IIno95ClinicalElevated LDH, concurrent viral infection, concurrent GVHDEculizumab2NANANANANANANANANANADeath, AML relapse.No GVHD nor TMA at time of death2142F9.6ALL, HRTBI, TT; Cy, ATGMUD 11/12, PBSC (cryopreserved)CSA, MTXSkin, grade Ino111HistologicalNephrotic proteinuria,refractory hypertension, elevated LDH, polyserositisEculizumab, (Switch CSA to MMF)5Methylprednisolone 2 mg/kg/die39Defibrotide73Narsoplimab102Methylprednisolone, 20 mg/kg for 3 days and plasma exchange116Rituximab156Death, sepsis.Improvement of hypertension and hemolysis3073M8.4ALL, relapseTBI, TT; Cy, ATGMUD 11/12, PBSC (cryopreserved)CSA, MTXSkin and gut, grade IIIModerate, Skin, lung330HistologicalNephrotic proteinuria,refractory hypertension, elevated LDHEculizumab + Methylprednisolone 2 mg/kg/die (Switch CSA to MMF)5Rituximab and plasma exchange58Defibrotide89NANANANANANAAlive, off therapy, residual proteinuria with normal renal function, stable cGVHD7764M14.8XLP2Treo, TT, Flu, ATG, RituximabHaplo, CD19 and TCR αβ depletion PBSCnonenono328HistologicalAcute kidney injuryEculizumab2NANANANANANANANANANAAlive, off therapy, residual proteinuria and mild chronic renal disease6685F9.2ALL, HRTBI, TT; Cy, ATGMUD 11/12, BMCSA, MTXSkin, grade IIModerate, skin and lung182HistologicalRefractory hypertension, acute kidney injury,elevated LDH, concurrent viral infection, concurrent GVHDEculizumab (Switch Tacrolimus to MMF)2Plasma exchange8Defibrotide25Methylprednisolone 10 mg/kg (only 1 dose due to positive Adenovirus DNA)47Narsoplimab55NANAAlive, off therapy, severe chronic renal disease362 Following implementation of screening, 12% of our allogeneic HSCT patients could be diagnosed with TA-TMA with high risk features, even without sC5b9 assessment... Following implementation of screening, 12% of our allogeneic HSCT patients could be diagnosed with TA-TMA with high risk features, even without sC5b9 assessment. Despite the timely administration of Eculizumab, more than half of them did not respond and required multiple lines of treatment, including an experimental drug under compassionate program (Narsoplimab). This intense approach allowed resolution of TA-TMA in all the patients at the cost of important toxicity and morbidity, including a death of sepsis.

Of 26 adults with ALL who developed VOD/SOS, 10 cases were mild, 16 severe; 5/26 patients received prophylactic defibrotide; 12/26 patients received defibrotide treatment alone or in combination. In this real-world population of adults with ALL who received InO before HSCT, including heavily pretreated patients, the incidence of VOD/SOS after HSCT was similar to that observed in INO-VATE (phase 3 study) and a pooled analysis of 2 clinical trials of InO-treated patients with R/R ALL. Although the VOD/SOS mortality rate was higher (36% vs 26%), NRM at 12 months was lower (24% vs 38%) here vs the pooled clinical trial population.

After refractory disease at first relapse (one patient) or after second relapse (three patients), they all received anti-CD19 CAR T-cell therapy (tisagenlecleucel)...After two InO cycles, they all underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), after conditioning with total body irradiation and etoposide. One patient developed a sinusoidal obstruction syndrome (SOS) post-transplantation, but recovered after two weeks of treatment with defibrotide. InO can be successfully and safely used for the treatment of CD22+ relapse of BCP-ALL after anti-CD19 CAR T-cell therapy as a bridge to allo-HSCT in heavily pretreated pediatric patients.

The preliminary data suggests defibrotide is well tolerated in CAYA patients with high-risk SCD or beta thalassemia major following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. This study was supported by FDA R01FD004090 and Jazz Pharmaceuticals.

received prophylactic therapy with ursodiol and heparin was added to pts receiving myeloablative conditioning. To our knowledge, this is the largest single-center retrospective analysis of R/R ALL patients that received InO as salvage therapy pre-HCT. The incidence of SOS was high, and prompt initiation of defibrotide demonstrated efficacy in treating SOS. Despite the effectiveness of Ino as salvage therapy, the risk of SOS can potentially be mitigated by minimizing risk factors, especially the use of sirolimus-based GVHD prophylaxis.

Of 26 adults with ALL who developed VOD/SOS, 10 cases were mild and 16 severe; 5/26 patients received prophylactic defibrotide; and 12/26 patients received defibrotide treatment either alone or in combination with other treatment. In this real-world population of adults with ALL who received InO before HSCT, including heavily pretreated patients, the incidence of VOD/SOS after HSCT was similar to that observed in the phase 3 INO-VATE study (23%; Kantarjian et al, Cancer 2019; 125:2474-87) and a pooled analysis of 2 clinical trials of InO-treated patients with R/R ALL (19%; Marks et al, Biol Blood Marrow Transplant 2019; 25:1720-29). Although the VOD/SOS mortality rate was higher (36% vs 26%), NRM at 12 months was lower (24% vs 38%) here vs the pooled clinical trial population.

Defibrotide inhibits brain metastasis through activating the adenosine A2A receptors, which in turn inhibits the SDF-1/CXCR4 signaling axis. Our study hereby proposes defibrotide as a new and promising candidate drug against brain metastasis of multiple organ origins.

Our study provides evidence that defibrotide prophylaxis is feasible in pediatric patients undergoing HSCT at high risk for TA-TMA and preliminary data indicating that defibrotide may reduce the risk of TA-TMA.

 A 9-month-old girl with leukemia (KMT2A-MLL) underwent a 10/10 unrelated bone marrow transplant conditioned with busulfan and cyclophosphamide, complicated by anicteric veno-occlusive disease (day+16). Despite treatment with defibrotide, she required a peritoneal drain, ventilator support, and renal replacement therapy (CRRT)...She was started on inhaled tranexamic acid, and CRRT again...She was treated with meropenem and vancomycin though her infectious work up was unrevealing... We describe an infant who developed severe TA-TMA that progressed on adequate blockade of terminal pathway using eculizumab, who had an excellent response to narsoplimab, emphasizing the role of lectin pathway activation in the pathophysiology of TA-TMA. Additional clinical trials of narsoplimab to treat pediatric TA-TMA are warranted.

All patients received intravenous Busulfan and prophylactic Ursodeoxycholic acid... Of a total of 44 patients 19 (43%) fulfilled the diagnostic criteria for VOD and received Defibrotide... Compared to previous studies, we report a higher incidence of VOD in our patient cohort. We report a clinical association of early drop in platelet count within 8 days post autologous transplant and VOD development. If proven significant in larger studies, this might be beneficial for early diagnosis of VOD.Further, we identified for the first time a weight < 25th percentile as a potential factor contributing to VOD.

The preliminary data suggests defibrotide is well tolerated in CAYA patients with high-risk SCD or beta thalassemia major following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. This study was supported by FDA R01FD004090 and Jazz Pharmaceuticals.

In this respect, MIDO is a more powerful KIT inhibitor as compared to dasatinib which has been applied in previous studies...Standard 7+3 IC using cytarabine 200 mg/m 2 continuous infusion over 7 days plus daunorubicin 60 mg/m 2 on 3 days was combined with increasing doses of MIDO and GO in three dose levels: 1 st dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 25 mg MIDO p.o. BID days 8-21); 2 nd dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 50 mg MIDO p.o. BID days 8-21); 3 rd dose level (GO 3 mg/m 2 i.v. QD on day 1+4+7 plus 50 mg MIDO p.o. BID days 8-21)...The patient was treated with defibrotide and supportive care until recovery on day 28...In the phase-I cohort of the MOSAIC trial, CR/CRi/CRp rates of 91% were reached. Based on the results of this dose finding trial the MTD of combined MIDO and GO will be defined as phase-II dose for the randomized phase-II studies in CBF and FLT-mut AML.

Conclusion : Treatment with DF in pts with grade 5 WHO COVID 19 ARDS does not induce bleeding, and is associated with rapid restoration of respiratory function (73% of pts). Notably, no oxygen support was needed at discharge and a 1-month OS rate of 89% was observed, which is higher than historical controls (77%) treated in the same setting.

She received a cycle of induction chemotherapy with daunorubicin and cytarabine (DA 3+7), achieving complete remission. In cases of suspected VOD, early diagnosis, swift initiation of treatment and close monitoring of supportive care are crucial to most effectively resolve this condition. Niche Science and Technology provided medical writing support, funded by Jazz Pharmaceuticals.

Methods : We retrospectively analyzed 105 children who underwent allogeneic HSCT for the first time and did not receive a defibrotide prophylaxis...We analyzed the transplantation-related factors graft source, donor-recipient human leukocyte antigen match, donor age, donor sex and conditioning regimen based on busulfan or total body irradiation...Conclusions : Our data confirm the risk factors of young patient age (2400 ng/mL) in the pediatric population. Moreover, we report for the first time that there is a significant association between high INR (≥1.3) before HSCT and the occurrence of SOS. Especially this new finding could improve the risk stratification of SOS and should be evaluated in further trails.

ASCT ASCT should be potentially considered in pts with high-risk disease (KMT2A rearrangement, low-hypodiploidy / near triploidy, CD22 expression <70%). Further improvement of outcome might be achieved with the administration of more courses of inotuzumab and blinatumomab, optimal selection of the transplant preparative regimen to minimize further hepatotoxicity, and the use of VOD-preventive measures (e.g. ursodiol, defibrotide).

There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen...Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals.