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.

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 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 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 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 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 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 Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Monika M Kutyna ◽  
Li Yan A Wee ◽  
Sharon Paton ◽  
Dimitrios Cakouros ◽  
Agnieszka Arthur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Cytotoxic Therapy ◽  
Advisory Committees ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Damage Repair

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

scholarly journals Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 218-218
Author(s):  
Jil Rotterdam ◽  
Margot Thiaucourt ◽  
Juliana Schwaab ◽  
Andreas Reiter ◽  
Sebastian Kreil ◽  
...  
Keyword(s):  
Antibody Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Grade ◽  
Hematological Disease ◽  
Advisory Committees ◽  
Hematological Diseases ◽  
Myeloid Neoplasms ◽  
Lymphoid Neoplasms ◽  
Treatment Naïve

Abstract Background: In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited. Aim: To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders. Patients and methods: In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim. Results: Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented. In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative (&lt;0.8 U/mL) in 27/175 (15.4%) patients. The distribution of the negative cohort regarding the disease subgroups were as followed: myeloid neoplasms 7/27 (25.9%), lymphoid neoplasms 16/27 (59.3%), non-malignant hematological disease 4/27 (14.8%). Within the negative cohort, 21/27 (77.8%) were treated on active therapy, 6/27 (22.2%) were previously treated or treatment naïve. In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response. In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL). In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result. Conclusion: A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients. Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials. Disclosures Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Pooled Treatment Analysis of Pediatric Patients with Defibrotide for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Multi-Organ Dysfunction Following Hematopoietic Stem Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4330-4330
Author(s):  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
Kamalika Banerjee ◽  
Alison L. Hannah ◽  
Robin L. Hume ◽  
...  
Keyword(s):  
Research Funding ◽  
Pediatric Patients ◽  
Occlusive Disease ◽  
Dose Finding ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Equity Ownership ◽  
Access Program

Abstract Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Defibrotide (DF) is approved for treatment of severe hepatic VOD/SOS in the European Union. In the United States, DF is available through an ongoing expanded-access protocol. Methods DF treatment for hepatic VOD/SOS with MOD is being assessed in a clinical program in pediatric and adult patients, including a phase 2 dose-finding trial, a pivotal phase 3 study of DF compared to historical controls (HC), and a single-arm expanded-access program. In the phase 2 dose-finding study, patients were randomized to receive 25 or 40 mg/kg/day. In the other 2 studies, treated patients received DF 25 mg/kg/d. DF was given in 4 divided doses for a recommended ≥14 days (dose-finding trial) or ≥21 days (pivotal and expanded-access studies). VOD/SOS was defined in each study by Baltimore and/or modified Seattle criteria. Here, we report results for treatment with DF 25 mg/kg/day in pediatric patients (aged ≤16y) with VOD/SOS plus MOD post-HSCT across these 3 studies. Results A pooled efficacy analysis included 255 pediatric patients with VOD/SOS and MOD post-HSCT who received DF 25 mg/kg/d in the dose-finding trial (n=22), pivotal trial (n=44), and expanded-access program (n=189). Among patients, 29.8% (n=76) were aged 0-23 mo, 48.6% (n=124) aged 2-11y, and 21.6% (n=55) aged 12-16y. 83.9% received allogeneic transplants (98.7% of patients aged 0-23 mo; 66.7% of patients aged 2-11y; 100% of patients aged 12-16y) and 16.1% received autologous transplants (1.3%, 0-23 mo; 32.3%, 2-11y; none, 12-16y). Acute leukemia (41.2%) was the most common primary disease (23.7%, 0-23 mo; 40.3%, 2-11y; 67.3%, 12-16y). At day +100 following HSCT, the survival rate in the overall pediatric population was 51.4% (95% CI, 45.2%-57.5%; n=131/255). Day +100 survival by age subgroup was 52.6% (95% CI, 41.4%-63.9%; n=40/76) in patients aged 0-23 mo, 53.2% (95% CI, 44.4%-62.0%; n=66/124) in those aged 2-11y, and 45.5% (95% CI, 32.3%-58.6%; n=25/55) in patients aged 12-16y. A safety analysis pooled data from the dose-finding and the pivotal trials, which incorporated on-site data monitoring, included 65 children who received DF at a dose of 25 mg/kg/day and 14 children in the HC group. At least 1 AE was reported for 93.8% (61/65) of DF-treated patients from these trials (95.5%, 0-23 mo; 89.7%, 2-11y; 100%, 12-16y), and for all HC patients. Overall AE profiles were generally similar between treated and HC patients. In these 2 trials, 67.7% of pediatric patients receiving 25 mg/kg/day DF had ≥1 serious AE (77.3%, 0-23 mo; 58.6%, 2-11y; 71.4%, 12-16y). Treatment-related AEs (TR-AEs) were reported in 44.6% of patients (31.8%, 0-23 mo; 44.8%, 2-11y; 64.3%, 12-16y). The most common TR-AE overall was pulmonary alveolar hemorrhage (2 patients per age group: 9.1%, 0-23 mo; 6.9%, 2-11y; 14.3%, 12-16y). AEs leading to death were reported for 49.2% (32/65) of patients from these 2 trials (72.7%, 0-23 mo; 31.0%, 2-11y; 50.0%, 12-16y) and 57.1% of HC patients (8/14; 40.0%, 0-23 mo; 85.7%, 2-11y; none, 12-16y). In the expanded-access program, ≥1 serious AE occurred in 98 (51.9%) patients ≤16y old; TR-AEs occurred in 41 (21.7%) of patients ≤16y old, most commonly pulmonary hemorrhage (6.9%), gastrointestinal hemorrhage (3.7%), and hypotension (3.7%). Conclusions In this pooled analysis of data from pediatric patients with VOD/SOS and MOD enrolled in 3 DF studies, day +100 survival was generally consistent across pediatric age subgroups. The safety profile in pediatric patients with VOD/SOS and MOD was generally consistent with what would be expected for this critically ill population. 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.. Grupp:Novartis: Consultancy, Research Funding. Banerjee:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Non-Interventional Retrospective Multicenter Study Evaluating Real Word Idelalisib Use in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin Lymphoma Patients Enrolled in the French Early Access Program

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5924-5924 ◽  
Author(s):  
Loic Ysebaert ◽  
Pierre Feugier ◽  
Gilles Andre Salles ◽  
Eric Durot ◽  
Alexis Talbot ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Real Word ◽  
First Line ◽  
Advisory Committees ◽  
Early Access ◽  
Access Program ◽  
Retrospective Multicenter Study

Abstract INTRODUCTION Idelalisib (IDELA), the first-in-class PI3K-delta inhibitor, is indicated in Europe in combination with rituximab (R) or ofatumumab for the treatment (tt) of adult patients (pts) with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, or as first-line tt of pts with 17p deletion (del(17p)) or TP53 mutation (TP53m), not eligibles for any other therapies and as monotherapy for pts with follicular lymphoma (FL) refractory to two prior lines of tt. IDELA has significant clinical activity with a manageable safety profile. However, there is a paucity of real word data regarding its effectiveness and safety. The REALIST study was initiated to better describe pts who started IDELA treatment during the French Early Access Program (EAP). AIMS The aim of this retrospective multicenter study was to describe efficacy, adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESIs, defined as diarrhea/colitis, pneumonitis, liver enzyme elevation, neutropenia, infection, and rash) and IDELA use in adult pts previously enrolled in the French EAP for CLL or iNHL. METHODS All Investigators who enrolled at least one pt in the EAP were contacted by email inviting them to participate in this study. Only pts who initiated IDELA tt between June and October 2014 have been included in this study. For each pt, 12 months (m) follow up data were collected via an electronic Case Report Form and monitored by the Lymphoma Academic Research Organization (LYSARC). The Primary endpoint was the overall response rate (ORR) at 6 m and its 95% confidence interval (95% CI). Statistical analysis was descriptive. RESULTS Seventy-five pts were included, 41 in CLL group (39 in third-line or late and 2 in first-line with del(17p)/TP53m unsuitable for chemo-immunotherapy (CIT)) and 34 in iNHL group, all refractory after two prior lines of tt. Table 1 lists key pt characteristics at the time of initiation of IDELA. In CLL/iNHL groups respectively, median IDELA tt duration was 25.1 weeks/18.9 weeks, ORR, was 82.8%/56.5% at 6 m (data reported in 29 pts/23 pts) and 100%/57.1% at 12 m (data reported in 12 pts/14 pts), median PFS was not reached (NR)/ 6.7 m, median time to next tt (TTNT) defined as the time between the date of the last IDELA intake and the start of next tt after progression of disease (PD) was NR/11.6 m, median OS was NR in both groups and OS estimate at M12 was 69.9%/67.6%. Additional efficacy data are presented in Table 2, Fig 1 and Fig 2. In CLL/iNHL groups respectively, at least one AE was reported during the study in 35 pts (85.4%)/26 pts (76.5%), most frequently reported AEs by SOC/PT were: infections and infestations 61.0%/50.0% (pneumocystis jirovecii pneumonia (PJP) 2.4%/5.9%), gastrointestinal disorders 56.1%/35.3% (diarrhea 41.5%/29.4%), blood and lymphatic system disorders 41.5%/41.2% (neutropenia 17.1%/23.5%) and investigation 43.9%/47.1% (hepatic enzyme increase 19.5%/14.7%). 24 pts (58.5%)/15 pts (44.1%) discontinued temporary IDELA, 6 pts (14.6%)/8 pts (23.5%) discontinued permanently for AE, 38 pts (92.7%)/25 pts (73.5%) had at least one AESI, 10 pts (24.4%)/11 pts (32.4%) had at least one serious AESI, 3 pts (7.3%)/6 pts (17.6%) permanently discontinued IDELA for AESI and deaths were reported during the study in 13 pts (31.7%)/11 pts (32.4%), mainly due to PD (46.2%/72.7%). CONCLUSION The results of this non-Interventional study of heavily pretreated CLL and iNHL population treated by IDELA monotherapy or in combination with rituximab indicate that IDELA is an effective treatment in routine clinical practice with an acceptable safety profile. ORR at 6 months was 83% in CLL full analysis set and 79% in del(17p)/TP53m sub-group and 55% in FL sub group. These results mirror those of clinical trials. No unexpected IDELA safety information was identified in this study and the pattern of AEs corresponds to that reported in previous clinical studies and might be improved by specific management of AESI including PJP prophylaxis to be administered to all patients throughout IDELA treatment. Disclosures Ysebaert: Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Sylvain:Gilead: Other: scientific advisor board. Glorian Kergaravat:Gilead Sciences: Employment. Simpson:Gilead Sciences: Employment. Ramroth:Gilead Sciences: Employment. Abdelhadi:Gilead Sciences: Employment. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Troussard:Gilead: Other: scientific advisory board.

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