scholarly journals Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Acute Leukemias: A Subgroup Analysis from the Defibrotide Expanded-Access Program

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3412-3412
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Kaplan Meier ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Reported mean incidence of VOD/SOS following HSCT is an estimated 13.7% (range 0%-62.3%). VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Endothelial cell (EC) damage, triggered by cytotoxic chemotherapeutic conditioning regimens and a prothrombotic-hypofibrinolytic state, is a critical factor in the pathophysiology of VOD/SOS. In the United States, defibrotide is approved for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT, and in the European Union, defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT. Prior to its approval, defibrotide had been available in the United States through an expanded-access program. Here, Day +100 post-HSCT survival and safety are analyzed for the 2 largest primary-disease subgroups in that study: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Methods Patients in the expanded-access program had VOD/SOS diagnosed by Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy, and this study included patients with or without MOD (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Results A total of 867 patients were enrolled in the safety population of the expanded-access program through April 18, 2015, including 476 patients with MOD. The primary diseases affecting 5% or more of the safety population at baseline were AML, 25.7% (222/867); ALL, 23.4% (202/867); neuroblastoma, 8.5% (73/867); and myelodysplastic syndrome, 5.7% (27/867). Data were available for 756 post-HSCT patients who received ≥1 dose of defibrotide. Of those patients, 207 (27.4%) patients had AML and 152 (20.1%) patients had ALL as their primary disease. Of the AML patients, 49.8% (103/207) were male, and 50.2% (104/207) were female; median age at HSCT was 23 years (range: 0.5, 74.0 years); and all had allogeneic HSCT. Among the ALL patients, 62.5% (95/152) were male, and 37.5% (57/152) were female; median age at HSCT was 16 years (range: 0.3, 68.0 years); and all had allogeneic HSCT. At Day +100 post-HSCT, observed survival was 45.4% (94/207) among AML patients and 42.8% (65/152) among ALL patients; 50.7% (105/207) and 52.0% (79/152), respectively, had died; and status was not available (ie, no HSCT date recorded, did not have sufficient follow-up, or their data were not available) for 3.9% (8/207) and 5.3% (8/152), respectively. For AML patients, Kaplan-Meier estimated survival rate was 47.8% (95% confidence interval [CI], 40.7%-54.5%; Figure 1); among ALL patients, Kaplan-Meier estimated survival rate was 46.0% (95% CI, 37.7%-53.9%; Figure 2). Adverse events (AEs) occurred in 76.8% (159/207) of AML patients and 64.5% (98/152) of ALL patients, with serious AEs in 57.5% (119/207) and 52.6% (80/152), respectively. Treatment-related AEs, as assessed by investigators, occurred in 21.7% (45/207) of AML patients and 17.1% (26/152) of ALL patients (>2% in either group [all <4%]: pulmonary hemorrhage, epistaxis, gastrointestinal hemorrhage, hypotension). Treatment-related AEs leading to discontinuation developed in 14.5% (30/207) of AML patients and 8.6% (13/152) of ALL patients (>2% in either group [all <3%]: pulmonary hemorrhage, gastrointestinal hemorrhage); treatment-related deaths occurred in 3.4% (7/207) of AML patients and 2.6% (4/152) of ALL patients, respectively, with none occurring in >1 patient in either subgroup. Conclusions The Day +100 survival rates and safety profile for the AML and ALL subgroups in the expanded-access program were consistent with prior defibrotide studies and analyses of the overall HSCT population in this study. Kaplan-Meier estimates of survival at Day +100 were similar between the AML (47.8%) and ALL (46.0%) subgroups. Taken together, these subgroup results affirm the overall efficacy and safety profile of defibrotide in post-HSCT patients with VOD/SOS and underlying acute leukemia. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:The National Cancer Institute of the National Institutes of Health: Research Funding; Gentium: Research Funding. Grupp:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Impact on Outcomes of Baseline Bilirubin in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Receiving Defibrotide Treatment: A Post-Hoc Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2213-2213
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Weight Gain ◽  
Board Of Directors ◽  
Bilirubin Level ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Advisory Committees ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a difficult to predict, and potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). VOD/SOS develops via a pathophysiologic cascade, and VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with >80% mortality. Defibrotide was recently approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and is approved in the European Union to treat severe hepatic VOD/SOS post-HSCT. In the United States, defibrotide had been available through an expanded-access program. Methods Patients in the expanded-access program were diagnosed with VOD/SOS by investigators using Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of the following: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of the following: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy; elevated bilirubin was not required for patients with biopsy or who met modified Seattle criteria by presence of hepatomegaly with ascites/weight gain. This program included patients with or without MOD/MOF (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT is explored post hoc based on 4 bilirubin-level categories at time of study entry; together these categories have been defined as 1 of the criteria in the proposed VOD/SOS grading scale for adults from the European Society for Blood and Marrow Transplantation (EBMT; ≥2 mg/dL to <3 mg/dL, ≥3 mg/dL to <5 mg/dL, ≥5 mg/dL to <8 mg/dL, and ≥8 mg/dL [Mohty M et al. Bone Marrow Transplant. 2016;51:906-912]). It is important to note that bilirubin <2 mg/dL is not part of the proposed EBMT criteria for VOD/SOS in adults. Results Among 756 post-HSCT patients enrolled through April 18, 2015, who received ≥1 dose of defibrotide, 427 also had MOD/MOF. Median age was lowest in patients with bilirubin <2 mg/dL (5 years). By comparison, median age in patients with bilirubin ≥2 to <3 mg/dL (56% of all patients) was 16 years; for bilirubin ≥3 to <5 mg/dL, median age was 13 years; and for the 2 small groups with bilirubin ≥5 to <8 or ≥8 mg/dL, median ages were 15 and 16.5 years, respectively. Day +100 survival in the overall HSCT population of the expanded-access program was 55.4% by Kaplan-Meier estimate. The survival rate was 81.4% in patients with bilirubin <2 mg/dL; for patients with bilirubin levels ≥2 mg/dL, who tended to be older, survival estimates decreased (Table). Day +100 survival patterns by bilirubin level were generally similar in the subgroups of patients with and without MOD/MOF (Table). Overall, 515 post-HSCT patients (67%) reported ≥1 adverse event (AE). Serious AEs were reported by 386 patients (50%), and AEs leading to death occurred in 250 patients (33%). Among all AEs, 158 patients (21%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Conclusions Overall, higher bilirubin levels were associated with worse Day +100 outcomes (with the exception of the ≥5 to <8 mg/dL group, which represented only 5% of patients, and so has limited validity). However, interpretation of these results has to be treated with caution because only a single criterion from the EBMT guidelines was analyzed and because potentially confounding interactions (eg, age) were not assessed. Across all bilirubin-level categories, VOD/SOS with MOD/MOF was consistently associated with worse outcomes than VOD/SOS without MOD/MOF. These results further support the importance of identifying VOD/SOS earlier and suggest that diagnosis and treatment of VOD/SOS, before bilirubin becomes markedly elevated, may be associated with improved outcomes. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Expanded Access Program: Evaluating Safety of Erythrocytes Encapsulating L-Asparaginase in Combination with Polychemotherapy in Patients Under 55 Years Old with Acute Lymphoblastic Leukaemia (ALL) at Risk to Receive Other Formulations of Asparaginase

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1214-1214
Author(s):  
Yves Bertrand ◽  
Nicolas Boissel ◽  
Claudine Schmitt ◽  
Alban Villate ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
At Risk ◽  
Board Of Directors ◽  
Whole Blood ◽  
Research Funding ◽  
Advisory Committees ◽  
E Coli ◽  
Expanded Access ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Introduction Asparaginase is an important part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity is found in 16.8% of patients treated with pegylated asparaginase (PEG-asp). Hypersensitivity is the most common cause of truncated asparaginase therapy which has been associated with decreased event free survival. Asparaginase (ASNase) encapsulated in erythrocytes (eryaspase) is an alternative formulation of ASNase aiming to prolong the half-life of ASNase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane protects asparaginase against elimination and prevents activation of the immune system. In the NOR-GRASPALL 2016 trial eryaspase consistently demonstrated prolonged ASNase activity in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated when combined with multiagent chemotherapy. The objective of this expanded access program was to explore the tolerability of eryaspase (150 U/Kg) combined with polychemotherapy in patients under 55 years of age with ALL, unable or at risk to receive any other available ASNase formulation. Patients in this study had developed hypersensitivities to prior E-Coli- and Erwinia-derived asparaginase therapies. Methods This was a non-randomized, multicentre, open label, Phase 1 study to assess the limiting toxicities, global safety and biological efficacy of eryaspase in combination with chemotherapy regimens. Patients were under 55 years of age with ALL de novo or in relapse or refractory; eligible for a chemotherapy treatment including ASNase; known contraindication and/or at risk of toxicity from other ASNase formulations. Eryaspase (150 U/Kg) was given as a replacement therapy for the remaining intended courses of asparaginase therapy. The number of courses was not defined and depended on therapeutic treatment chosen by the Investigator and the patient's response and tolerance. The primary endpoint was the exploration of the toxicity of eryaspase defined as the number and percent of patients presenting at least one limiting toxicity (LT) of eryaspase in combination with chemotherapy. Major secondary endpoints included: adverse events (AEs), pharmacokinetics (PK), pharmacodynamics (PD) and complete remission (CR) status at end of induction and survival status up to 12 months after inclusion. Results Eighteen patients enrolled of which seven (38.8%) patients experienced a total of 24 AE limiting toxicities, which were primarily bone marrow failure, and were indicative of the underlying ALL disease process and of the concomitant chemotherapy-related myelosuppression. All patients experienced at least one AE and Treatment Emergent (TEAE) and most (11 [61.1%] patients) experienced at least one SAE. A total of 17 (94.4%) patients experienced a TEAE of Grade 3 or above. No TEAEs led to withdrawal or dose reduction of eryaspase. Sparse whole blood ASNase concentrations following 150 U/Kg were within the range of concentrations expected for this dose level. At 14 days following the first infusion, the range of whole blood ASNase was 111 to 1160 U/Kg, which would be equivalent to the trough (nadir) for infusions every 2 weeks. Mean and median plasma asparagine (ASN) concentrations over time demonstrated a reduction by approximately 50% at 3 days post eryaspase infusion, followed by a slow return toward baseline before the next infusion of eryaspase. Seventeen (94.4%) patients achieved CR at least once overall. Fourteen (77.8%) patients were alive at the end of the study. Survival rate was 88.9% at 6 months and 77.8% at 12 and 18 months. Conclusion The AE profile of eryaspase was consistent with other studies and was as expected for this cohort of patients. Serious AEs were generally consistent with those that would be expected in this study population. A total of 17 patients in the study achieved a CR at least once overall and 14 were still alive at the end of the study. This study evaluated additional asparaginase therapy in double (and even triple) allergic patient population, who have received prior E-Coli- or Erwinia-derived asparaginase therapy. All patients achieved target asparaginase activity. Therefore, eryaspase provides an additional option for patients for whom further ASNase treatment is contraindicated due to toxicity and/or immunization. Disclosures Boissel: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; CELGENE: Honoraria. Recher: Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Incyte: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. El-Hariry: Erytech: Current Employment, Current holder of stock options in a privately-held company.

scholarly journals Incidence of Post-Hematopoietic Stem Cell Transplantation (HSCT) Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) without Hyperbilirubinemia at Diagnosis and Efficacy of Defibrotide in an Expanded-Access Program

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2080-2080 ◽  
Author(s):  
Selim Corbacioglu ◽  
Nancy A. Kernan ◽  
Antonio Pagliuca ◽  
Robert Ryan ◽  
William Tappe ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Late Onset ◽  
Adult Patients ◽  
Advisory Committees ◽  
Expanded Access Program ◽  
Kaplan Meier ◽  
Elevated Bilirubin ◽  
Access Program

Abstract Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication early post-HSCT, or of nontransplant chemotherapy. VOD/SOS diagnosis has been based on Baltimore (≤21 days post-HSCT and bilirubin ≥2 mg/dL plus ≥2 of: hepatomegaly, ascites, weight gain ≥5%) or modified Seattle (≤20 days post-HSCT and ≥2 of: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, weight gain [>5% in defibrotide studies]) criteria. Recent European Society of Blood and Marrow Transplantation (EBMT) VOD/SOS guidelines require elevated bilirubin only for adults diagnosed ≤21 days post-HSCT (the literature suggests bilirubin <2 mg/dL before Day +21 is uncommon) but not for adults with late-onset (diagnosis >21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin <2 mg/dL]). EBMT notes that hyperbilirubinemia may be a late finding in the progression of VOD/SOS. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in defibrotide-treated, post-HSCT patients in the T-IND program (2007-2016). Methods Prior to US approval, defibrotide was available through the T-IND expanded-access program. The original protocol required VOD/SOS post-HSCT diagnosed per Baltimore criteria (which require hyperbilirubinemia) or biopsy, and multi-organ dysfunction (MOD). The protocol was amended to include patients without MOD (2009) and with VOD/SOS per modified Seattle criteria (which do not require hyperbilirubinemia; 2012). Patients received defibrotide 25 mg/kg/day (6.25 mg/kg q6h) recommended for ≥21 days. Results Of 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin <2 mg/dL (breakdown by subgroups in the Table), and 801 (81%) had bilirubin ≥2 mg/dL. Of those with bilirubin <2 mg/dL, 133 were pediatric patients aged ≤16 years (24% of all post-HSCT pediatric patients with recorded bilirubin [n=564]), and 57 were adult patients aged >16 years (13% of all post-HSCT adult patients with recorded bilirubin [n=427]). Diagnosis by Day +21 post HSCT (ie, not late onset) was recorded for 135/190 (71%) patients with bilirubin <2 mg/dL (107/133 [80%] pediatric patients; 28/57 [49%] adults). In the overall post-HSCT group treated with defibrotide in the T-IND (n=1000; with and without elevated bilirubin at diagnosis, including 9 patients without bilirubin measurement at diagnosis), Kaplan-Meier estimated Day +100 survival was 58.9% (95% confidence interval [CI], 55.7%-61.9%). Kaplan-Meier estimated Day +100 survival was 85.6% (95% CI, 79.7%-89.9%) for the 190 patients with bilirubin <2 mg/dL at diagnosis and 52.3% (95% CI, 48.7%-55.7%) for the 801 patients with bilirubin ≥2 mg/dL (survival by age subgroups in the Figure). In the overall population of patients with bilirubin <2 mg/dL, 61.1% and 18.4% of patients had ≥1 treatment emergent adverse event (TEAE) and ≥1 treatment related adverse event (TRAE), respectively, and 21.1% had ≥1 hemorrhage event; for patients with bilirubin ≥2 mg/dL: 73.8% had ≥1 TEAE, 21.7% had ≥1 TRAEs, and 31.1% had ≥1 hemorrhage event. Conclusions: In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin <2 mg/dL at diagnosis, including 24% of children. Accordingly, 190 patients would not have been diagnosed if hyperbilirubinemia was a required criterion. Moreover, enrollment prior to 2012 required hyperbilirubinemia (or biopsy), so this percentage may understate the incidence of anicteric VOD/SOS. Of patients with bilirubin <2 mg/dL, 80% of pediatric patients and 49% of adults were diagnosed with VOD/SOS by Day +21 post-HSCT, suggesting that anicteric VOD/SOS may develop in this timeframe not only in pediatric patients but also in a sizeable number of adult patients. Defibrotide showed higher survival in patients with bilirubin <2 mg/dL compared to those with levels ≥2 mg/dL. These results compare favorably with the overall study findings, suggesting that treatment before the onset of hyperbilirubinemia may lead to better outcomes. The safety profile of the T-IND was similar to that of previous studies of defibrotide for the treatment of VOD/SOS. Support: Jazz Pharmaceuticals. Disclosures Corbacioglu: Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Targeted FGFR Inhibition Results in Hematologic and Cytogenetic Remission in a Myeloid Neoplasm Driven By a Novel PCM1-FGFR1 Fusion: Data from an Expanded Access Program

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5371-5371
Author(s):  
Monica Kasbekar ◽  
Valentina Nardi ◽  
Paola Dal Cin ◽  
Andrew M. Brunner ◽  
Yi-Bin Chen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Fusion Transcript ◽  
Advisory Committees ◽  
Expanded Access ◽  
Myeloid Neoplasm ◽  
Expanded Access Program ◽  
Lymphoid Neoplasms ◽  
Cytogenetic Remission ◽  
Access Program

Introduction In 2008, the World Health Organization defined a new classification of myeloid and lymphoid neoplasms with eosinophilia that result from gene rearrangements of PDGFRA, PDGFRB, and FGFR1. While rearrangements involving PDGFRA and PDGFRB generally respond well to imatinib, those associated with FGFR1 are typically aggressive and require treatment with allogeneic hematopoietic stem cell transplantation (SCT). Here we present the case of a patient with a previously unreported fusion of PCM1-FGFR1. The patient was treated with an Oral, potent, selective, and irreversible small-molecule inhibitor of FGFR 1- 4 (futibatinib (TAS-120)) under an expanded access program, resulting in the first reported instance of complete hematologic and cytogenetic remission using futibatinib in an FGFR-driven myeloid neoplasm. Results A 55-year-old male presented with dyspnea and fatigue and was found to have peripheral eosinophilia (3,660/microliter) and thrombocytopenia (46,000/microliter). Diagnostic bone marrow biopsy was notable for a hypercellular (cellularity >95%), erythroid dominant marrow with increased eosinophilic forms and increased pronormoblasts. Break-apart fluorescence in situ hybridization (FISH) studies revealed an FGFR1 gene rearrangement in 11.3% of nuclei (normal < 5.7%). The nature of the rearrangement was shown to be a paracentric inversion of chromosome 8p based on the distinct gap between the 5'FGFR1 and 3'FGFR1 probes in metaphase FISH (Figure 1). A validated, targeted next generation sequencing assay for fusion transcript detection (heme fusion assay) revealed a previously unreported PCM1-FGFR1 fusion transcript (40 unique fusion reads), with an in-frame fusion of PCM1 (exons 1-36) to FGFR1 (exons 11-18). No additional clonal markers were identified. The patient was not considered an SCT candidate due to medical comorbidities and was enrolled on a single-patient protocol expanded access program for futibatinib. He was initially treated with prednisone for control of his eosinophilia, and then started on oral therapy with futibatinib (20 mg daily). Within 1 month of initiation of futibatinib, prednisone was tapered without recurrence of eosinophilia and with improvement in platelet count (169,000/microliter). After 6 months, repeat bone marrow biopsy showed a moderately hypocellular marrow with maturing trilineage hematopoiesis. Additionally, the paracentric inversion of chromosome 8p was no longer observed in metaphase FISH, consistent with cytogenetic remission. Furthermore, the PCM1-FGFR1 fusion transcript was no longer detectable by heme fusion assay. The patient has experienced grade 2 skin rash requiring brief dose interruption (7 days) followed by dose reduction to 16 mg daily, on which he remains. He has also experienced grade 2 hyperphosphatemia, a known side effect of futibatinib, which is adequately controlled with sevelamer. The patient continues on futibatinib, with ongoing evidence of hematologic and cytogenetic remission after 11 months of therapy. Conclusions To our knowledge, this case represents the first report of a PCM1-FGFR1 fusion driving a myeloid neoplasm with eosinophilia. Treatment with futibatinib has resulted in hematologic and cytogenetic remission, with treatment successfully ongoing after 11 months. Our findings support further exploration of FGFR inhibitors as a therapeutic strategy for myeloid/lymphoid neoplasms driven by FGFR1 rearrangement, particularly in individuals who are not candidates for SCT. A phase 2 study of futibatinib in patients with FGFR1 driven myeloid/lymphoid neoplasms is planned. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Chen:Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Incyte: Consultancy; Abbvie: Consultancy. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Narayan:Genentech: Other: Equity ownership (spouse); Merck: Other: Equity ownership (spouse); Takeda: Other: Employment (spouse). Benhadji:Taiho Oncology: Employment. Hobbs:Incyte: Consultancy, Research Funding; Merck: Research Funding; Jazz pharmaceuticals: Consultancy; Celgene: Consultancy; Bayer: Research Funding; Agios: Consultancy.

Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3121-3121
Author(s):  
Nancy A. Kernan ◽  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
The United States ◽  
Occlusive Disease ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Equity Ownership ◽  
Chemotherapy Patients

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS. Methods In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy. Results Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month-58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2-11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively. The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively. Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported. Conclusions Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Expanded Access Program of Graspa for Treatment of Patients with Acute Lymphoblastic Leukemia Unable to Receive Other Form of L-Asparaginase - a Status Update (NCT02197650)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4877-4877 ◽  
Author(s):  
Yves Bertrand ◽  
Hervé Dombret ◽  
Bruno Quesnel ◽  
Jean-Louis Stephan ◽  
Claudine Schmitt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Allergic Reactions ◽  
Advisory Committees ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Background L-asparaginase (L-ASP) is a key drug in the treatment of acute lymphoblastic leukemia (ALL). However the toxicity profile, especially hypersensitivities up to acute allergic reactions is a major drawback. GRASPA (eryaspase (proposed INN) or E-Coli L-Asparaginase encapsulated into red blood cells) is a new product under development with the aim of improving the tolerance of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as "bioreactors". The RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Recently, a Phase III pivotal study of GRASPA in combination with COOPRALL chemotherapy protocols in patients with relapsed ALL demonstrated highly significant safety profile and clinical activity compared to control. However, there is an unmet medical need for patients who cannot receive current formulations of L-ASP. An expanded access program has recently been initiated in France to provide access for treatment with GRASPA in patients who are unable to receive other forms of L-ASP. Methods: This is a non randomized multicenter open label study, currently initiated in France. The primary objective of the EAP is to evaluate the tolerability of GRASPA. Patients under 55y of age presenting with de novo, relapsed or refractory ALL who are at risk to receive any other available L-ASP formulation are enrolled into this program. Patients with known allergic reactions to E.Coli L-ASP are also eligible. GRASPA is administrated every 2 to 3 weeks at a dose equivalent to 150 IU/kg of L-ASP during all chemotherapy courses intended to contain an asparaginase. Chemotherapy protocols are given according to the Investigator's choice. Patients are assessed regularly for safety and tolerability. The primary endpoint is tolerability; Key secondary endpoints include asparaginase activity, asparagine depletion, and clinical remission rates. An independent Safety Monitoring Board (DSMB) is set up, which will assess toxicities on yearly basis. Results As of time of June 2015, 13 patients were enrolled into the program. The first DSMB meeting reviewed the outcome of the first 7 patients enrolled into the program. Of the 7 pts (range 3 - 49 years), 5 males and 2 females were enrolled. Four pts presented with refractory disease and 3 with relapse, with all patients had evidence of allergies to 2 prior asparaginases (double allergies). There were 2 pts presenting with limiting toxicities, in the form of myelosupression, and streptococcal infection. There was no modification to the protocol recommended by the first DSMB An updated safety and clinical activity information on all patients will be provided. Conclusion: The EAP provides a potential treatment alternative for ALL patients, who are unable, or at risk of developing hypersensitivity reactions to prior asparaginases. The initial results from this program suggests that GRASPA is well tolerated, and may have a potential benefit in patients with double allergies. The program will be expanded to other European countries Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salako:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

scholarly journals A Pooled Analysis of Survival By Defibrotide Timing of Initiation in Adults with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Following Hematopoietic Stem Cell Transplant (HSCT)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 815-815
Author(s):  
Paul Richardson ◽  
Enric Carreras ◽  
Antonio Pagliuca ◽  
Robert Ryan ◽  
William Tappe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Survival Rates ◽  
The United States ◽  
Adult Patients ◽  
Pulmonary Dysfunction ◽  
Advisory Committees ◽  
Cut Points

Abstract Introduction Hepatic VOD/SOS is a potentially life-threatening complication of HSCT or of nontransplant-associated high-dose chemotherapy. VOD/SOS associated with multi-organ dysfunction (MOD; eg, renal or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. Prior to US approval, defibrotide was available through an international compassionate-use program (CUP; 1998-2009) and an expanded-access protocol (T-IND; 2007-2016). Data for adults with VOD/SOS post-HSCT from the CUP and the T-IND were pooled to investigate whether the time to initiate defibrotide therapy after VOD/SOS diagnosis had an impact on Day +100 survival. Methods In both the CUP (N=710) and the T-IND (N=1137), defibrotide was used to treat hepatic VOD/SOS following HSCT or nontransplant-associated chemotherapy in pediatric and adult patients with or without MOD. Diagnosis of VOD/SOS was made using the Baltimore or modified Seattle criteria or was proven by biopsy (the CUP also allowed patients with hemodynamic, ultrasound, or histologic evidence of VOD/SOS to enroll). In the CUP cohort, the defibrotide median daily dose was 25 mg/kg/day administered for a median of 15 days; only patients who received 25 mg/kg/day were included in the analysis. In the T-IND, the defibrotide dose was 25 mg/kg/day for a recommended administration ≥21 days. In this analysis, adult patients (aged >18 years) from the CUP and the T-IND with VOD/SOS post-HSCT were pooled to examine Day +100 survival rates by time to start of defibrotide post-diagnosis. The first analysis examined patients who initiated defibrotide before/after Days 1, 2, 3, 4, 7, and 14 after VOD/SOS diagnosis, using Fisher's exact test, and the second examined starting defibrotide on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15 (Cochran-Armitage test for trend across days). Results Of 534 pooled adult patients with VOD/SOS following HSCT who were treated with defibrotide 25 mg/kg/day and had reported time to dosing, 300 (56%) patients had MOD. Defibrotide treatment was initiated by Day 1 in 273 (51%) patients. In the analysis of treatment initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide showed numerically higher survival rates for all cut points (Day +100 survival before and after all cut points is provided in Table 1). Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation following diagnosis (nominal P=0.011; for patients with MOD, P=0.048; Table 2). Safety information for the CUP and T-IND were not pooled, as adverse events in the CUP were reported only if those events caused death in a consistent fashion. In all adult patients with post-HSCT VOD/SOS in the T-IND, treatment-related adverse events that occurred in ≥2% of adults were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each). Conclusion: These results from the pooled post hoc analysis of adult patients with VOD/SOS post-HSCT from the CUP and T-IND studies suggest that earlier defibrotide initiation post-VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome, suggesting that later intervention still retains value if therapy is not initiated sooner. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other defibrotide studies in VOD/SOS. Support: Jazz Pharmaceuticals. Disclosures Richardson: Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carreras:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Mohty:Molmed: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau.

scholarly journals Timing of Initiation of Defibrotide Post-Diagnosis of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Post-Hematopoietic Stem Cell Transplantation: Exploratory Age-Group Analysis from an Expanded Access Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 66-66 ◽  
Author(s):  
Stephan A. Grupp ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Joseph H. Antin ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Treatment Initiation ◽  
Adult Patients ◽  
Sinusoidal Obstruction Syndrome ◽  
Age Group ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Post Hoc

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT), and its severity can be variable in its course over time. VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with >80% mortality. In the European Union, defibrotide is approved for the treatment of severe hepatic VOD/SOS post-HSCT. Defibrotide recently was approved for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States (US). In the US, defibrotide had been available through an expanded-access program to generate the largest experience of its kind (n >750). The optimal time to initiate VOD/SOS treatment with defibrotide is an area of active investigation, with previous studies suggesting that earlier intervention is associated with better outcome. Methods Patients with VOD/SOS (by Baltimore or modified Seattle criteria, or biopsy), with or without MOD/MOF (renal and/or pulmonary dysfunction) were eligible for the expanded-access program. Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT in pediatric (age ≤16 years) and adult patients were explored post hoc based on time from VOD/SOS diagnosis to initiation of defibrotide. There were 2 analyses: (1) survival rate analyzed by treatment initiation day for all post-HSCT patients in each age group before or after days 1, 2, 3, 4, 7, and 14, using Fisher's exact test; (2) survival rate by age group for only those patients with treatment initiated on a particular day (0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15), with a Cochran-Armitage test for trend across days. Results Treatment initiation data were available for 755 post-HSCT patients enrolled through April 18, 2015, including 423 pediatric patients (232 with MOD) and 332 adults (194 with MOD). In the pediatric and adult groups, defibrotide was started on the day of diagnosis in 33% of pediatric and 30% of adult patients respectively, and 94% and 92%, received defibrotide within 7 days post-diagnosis. In the analysis of treatment initiation before or after days 1, 2, 3, 4, 7, and 14 across each age group, earlier initiation of defibrotide was associated with higher survival rates for all cut-points except Day 14, with only 2% of pediatric and 4% of adult patients beginning treatment post-day 14 (Table). In the analysis of the relationship between Day +100 survival and treatment initiation day, there was a statistically significant trend over time for higher Day +100 survival with earlier initiation both in pediatric patients (P<.001) and adults (P=.028; Figure). In pediatric and adult patients with MOD/MOF, survival was lower than in the overall cohorts, but patterns of better outcomes with earlier treatment were generally similar to those in the overall VOD/SOS age groups. Conclusions In this post-hoc analysis, decreased Day +100 survival in pediatric and adult groups was associated with longer treatment delays post-VOD/SOS diagnosis, confirmed by Cochran-Armitage testing. These results suggest that irrespective of age, early defibrotide initiation post-VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome, suggesting that later intervention still retains value if therapy is not initiated sooner. Support: Jazz Pharmaceuticals. Disclosures Grupp: Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Kernan:The National Cancer Institute of the National Institutes of Health: Research Funding; Gentium: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Treatment of Adults with Minimal Residual Disease (MRD) Positive Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2624-2624
Author(s):  
Nicolas Boissel ◽  
Renato Bassan ◽  
Josep-Maria Ribera ◽  
Sabina Chiaretti ◽  
Robin Foà ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Equity Ownership ◽  
Access Program

Introduction: In November 2015, conditional approval of blinatumomab was granted for adults with relapsed and/or refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (R/R Ph- BCP-ALL). Prior to country-specific reimbursement, blinatumomab was made available to patients (pts) who met pre-specified criteria via an expanded access program in specific countries: this included both adults and pediatric pts with diagnosis of R/R Ph- BCP-ALL, R/R Ph+ BCP-ALL, or minimal residual disease (MRD)-positive Ph-/Ph+ ALL. Here, we report on adults with MRD+ BCP-ALL enrolled in this expanded access program with reference to their characteristics and both blinatumomab usage and effectiveness. Methods: The retrospective observational study (NEUF) recruited pts who initiated blinatumomab in the available expanded access setting between 2014 and 2016. Pts were followed from blinatumomab initiation until death, entry into a clinical trial, end of follow-up, or the end of the study period (30 June 2017), whichever occurred first. Efficacy analyses were undertaken on a MRD intention-to-treat basis. MRD response was defined as MRD level <10-4 within first cycle and within the first 2 cycles. MRD assessment was undertaken as per local clinical practice, including flow cytometry and polymerase chain reaction (PCR): MRD status was then extracted from the patient medical record. Median disease-free survival (DFS) was defined as time from initiation of blinatumomab until date of relapse (blasts in bone marrow >5% or extramedullary relapse after documented response) or death, whichever occurred first. Adverse events were reported separately, according to local regulations. Results: Out of 373 enrolled pts, 109 MRD positive adult ALLs (83 Ph-; 26 Ph+) were included in Italy (53), France (23), Spain (20), Russia (11), and the UK (2). Most patients (76%, n=83) were Ph-. Forty-one percent (n=45) were female and median age was 43 years (interquartile range [IQR]: 27, 55). In their medical history, 16% (n=17 out of 109 MRD positive patients) had a prior allogeneic hematopoietic stem cell transplant (HSCT). The median number of prior salvage therapies was 0 (IQR: 0.0, 1.0). Among blinatumomab co-medications, almost 90% were treated with dexamethasone, 35% (n=36) as pre-phase and 87% (n=92) as pre-medication. Of the 82 pts with evaluable MRD within two cycles of blinatumomab, 83% (n=66) had a MRD response (Table), including 48 with non-detectable MRD and 18 with MRD <10-4. Following blinatumomab initiation, 68% (n=74 out of 109) of pts proceeded to HSCT: 65 (88%) of these patients had documented complete remission with full/partial/incomplete recovery of peripheral blood counts before transplant. The median time from complete response (CR) to HSCT was 2.4 months (range: 1.6, 5.3), with median follow-up time being 18.5 months (IQR: 14.0, 27.7). The median DFS was 27.6 months (IQR: 7.4, not estimable [NE]). Censoring for HSCT increased DFS to 33.0 months (IQR: 8.9, NE). At 24 months following blinatumomab initiation, overall survival ((OS) was 65% (95% confidence interval [CI]: 52.8, 74.2): when censoring for HSCT, OS was 77.6% (95% CI: 52.8, 88.9); median follow-up time was 4.0 months (IQR: 2.6, 13.7). The Kaplan-Meier estimate of the non-relapse mortality following HSCT post-blinatumomab was 6% (95% CI: 1.9, 16.4) at 3 months and 10% (95% CI: 4.6, 22.3) at 12 months. Conclusions: In this large multi-country, multi-site study, blinatumomab was shown to induce molecular response within two cycles in the majority of patients with evaluable MRD. Furthermore, the median DFS was over two years, while two-thirds of pts were still alive 24 months after initiation. This study demonstrates the real-world effectiveness of blinatumomab and is consistent with results from clinical studies (BLAST). Disclosures Boissel: NOVARTIS: Consultancy. Bassan:Shire: Honoraria; Incyte: Honoraria; Amgen Inc.: Honoraria; Pfizer: Honoraria. Chiaretti:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Papayannidis:Novartis: Honoraria; Incyte: Honoraria; Teva: Honoraria; Shire: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Alam:Amgen: Employment, Equity Ownership. Brescianini:Amgen: Employment, Equity Ownership. Pezzani:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership. Rambaldi:Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

scholarly journals Survival after Hematopoietic Stem Cell Transplantation in an Older, Fit Cohort of Patients with Advanced Myelodysplastic Syndromes: The MDS-TAO Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 972-972
Author(s):  
Gregory A. Abel ◽  
Haesook T. Kim ◽  
David P. Steensma ◽  
Richard M. Stone ◽  
Angel M. Cronin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Time Dependent ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Kaplan Meier ◽  
Baseline Characteristics

Abstract Background: The utility of reduced-intensity conditioning hematopoietic stem cell transplantation (RIC HSCT) for fit elderly patients with advanced myelodysplastic syndromes (MDS) is unclear. Methods: The MDS Transplant-Associated Outcomes Study, or "MDS-TAO," was a prospective longitudinal observational study at the Dana-Farber/Harvard Cancer Center designed to examine survival, quality of life, and other outcomes for RIC HSCT versus non-HSCT approaches for HSCT-eligible patients with advanced MDS ages 60 to 75. All patients who met eligibility criteria were approached in the leukemia or HSCT clinics; 96% agreed to enroll. Inclusion criteria included histologically-confirmed diagnosis of MDS or CMML, and (1) therapy-related disease or (2) Int-2/high IPSS (Greenberg, Blood, 1997), or (3) non-IPSS poor-risk cytogenetics (Haase, Blood, 2007), or (4) severe cytopenia/platelet or red cell transfusion-dependence. Exclusions were (1) comorbidities that in the judgment of the treating physician precluded HSCT eligibility (2) prior donor search and (3) patient unwillingness to consider HSCT. Considering time to transplant as a time-dependent variable, hazard ratio for ultimate HSCT was estimated using Cox regression analysis controlling for age, gender, ECOG performance status, IPSS, IPSS cytogenetic risk group, and year of consent. Landmark analyses at 5 months were conducted to present estimates of overall survival for patients who were alive for at least 5 months and received HSCT versus patients who did not (landmark cohort). Subgroup analyses (e.g., molecular characteristics) are also ongoing. Results: 290 patients were enrolled between May 2011 and May 2018; 24 had less than 1.5 months of follow up after consent and were excluded from this analysis. Of the remaining 266 patients, 143 were deceased at last follow up. Baseline characteristics are presented in the table. The median follow-up time among survivors was 31 months (range 1.9, 84). 102 patients received HSCT, of whom 45 subsequently died; of the 164 patients who have not undergone HSCT, 98 have died. The median time to HSCT among those transplanted (n=102) was 4.6 months. The median follow-up for patients alive and not yet transplanted (n=66) was 24 months (range 1.9, 82). Considering time to HSCT as a time-dependent variable (n=266), the hazard ratio for death in multivariable analysis was 0.63 (95% CI 0.42-0.96, p=0.03). Poor risk IPSS cytogenetic group was the only other factor associated with mortality, HR=1.86 (95% CI 1.15-3.00, p=0.006); age, gender, ECOG performance status, IPSS, and consent year were not. Five months was chosen for the landmark analysis given it was closest to the median time to HSCT. In the landmark cohort (N=229), HSCT patients were more likely to have Int-2/high IPSS at baseline (65% vs 35% for none, p=0.0003). No other baseline characteristics were different. Figure A shows Kaplan-Meier plots for the landmark cohort, comparing 54 who received HSCT ≤ 5 months versus 175 patients who did not receive a transplant within 5 months (log rank p=0.04). Figure B shows Kaplan-Meier plots for HSCT comparing 99 patients who received HSCT at any time during follow-up versus 130 patients who did not (log rank p=0.005). Conclusion: In this large cohort of fit elderly patients with advanced MDS, a treatment strategy that included HSCT was associated with better overall survival. Table Table. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. DeAngelo:Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Amgen: Consultancy; Shire: Honoraria; Takeda: Honoraria; BMS: Consultancy; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Pfizer Inc: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; BMS: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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