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

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.

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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 ◽

10.1182/blood.v128.22.3412.3412 ◽

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.

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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 ◽

10.1182/blood-2021-147834 ◽

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.

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Use of Pegylated Interferon in Six Pediatric Patients with Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-124023 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4194-4194 ◽

Cited By ~ 1

Author(s):

Nicole Kucine ◽

Shayla Bergmann ◽

Spencer Krichevsky ◽

Devin Jones ◽

Michael E. Rytting ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Myeloproliferative Neoplasms ◽

Adult Patients ◽

Specific Information ◽

Advisory Committees ◽

Oncology Research ◽

Increased Risk ◽

Future Fertility

Introduction: The classical BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are clonal disorders of marrow overproliferation. Clinical phenotypes include polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). In adults, both risk stratifications and treatment guidelines are available to physicians. Various agents, including clinical trial agents, are utilized for treatment in adults. Conversely, there are no management guidelines for children with MPNs, and therapeutic options are limited. Hydroxyurea (HU) is the most commonly used agent in children, likely because of physician experience using this medication for sickle cell anemia. Children with MPN have been treated with HU with effective cytoreduction, although its use is controversial because of the concern for leukemogenicity. While it is still considered as first-line therapy in adults with MPNs, some guidelines recommend avoiding hydroxyurea in younger adult patients. Interferon (IFN) has been utilized in adults with MPNs for many years, and pegylated forms (PEG) have made the medication more tolerable. Enthusiasm in IFN is increasing, due to reports in adult patients of hematologic remissions and significant molecular responses, including molecular remissions in rare cases. Given its improved tolerability and potential benefits, IFN may be an appropriate choice for treatment in many children with MPNs. Given the limited experience in this population and available literature, we sought to review a small cohort of pediatric MPNs treated with PEG. Methods: We reviewed the charts of pediatric patients with MPNs who have been treated with PEG and pooled de-identified data. Demographic, mutational, laboratory, and treatment-specific information was documented. This study was approved by institutional IRBs. Results: Six children were identified at four institutions who had been treated with IFN (Table 1). Age at diagnosis of MPN ranged from 2-14 years, and age at onset of PEG therapy ranged from 3-16 years. Two children are female, and four are male. Three children were diagnosed with PV and three with ET. One child with PV is positive for a JAK2 Exon 12 mutation, three children have JAK2V617F mutations (two with PV and one with ET), one child with ET has a CALR mutation, and one child has triple-negative ET. Cytoreductive therapy was started in this cohort for a variety of reasons, including worsening counts, concerning marrow findings, and symptoms (headache being the most common.) Three of the children in this cohort had been treated with HU prior to starting PEG. Reasons for switching cytoreduction to PEG included family concern for increased risk of malignancy and concern for negative effects on future fertility, interest in a disease-modifying agent, and poor side-effect profile of HU. PEG doses ranged from 45 to 90 mcg per dose (Table 2), with dosing frequency ranging from one dose every 1-4 weeks. Blood counts remained generally stable or improved in this cohort; no children required stopping and switching to another cytoreductive agent. One subject developed a pulmonary embolism while on PEG, but was able to remain on therapy; no other MPN-related complications occurred while on PEG. Some children experienced improvement in clinical disease-related symptoms. Mild side-effects reported by subjects included headache, flu-like symptoms, injection site reaction, and abdominal pain. One child had PEG dosed less frequently because of issues with depression and anxiety, and ultimately had therapy discontinued due to normalization of platelet counts. No other dose-limiting drug-related toxicity was reported. All other subjects remain on therapy with PEG, and the duration of therapy ranges from 3-168 months. Conclusion: This cohort of young MPN patients has been treated with PEG with no major dose-limiting toxicity, and with sustained tolerability. While further study is needed, it is clear that PEG can have a role to play in the management of children with MPNs. Having multiple options for cytoreduction available for families to discuss with their pediatric practitioners allows for greater family autonomy. Our results to date highlight the need for prospective study of a larger group of young patients with MPNs treated with PEG. Disclosures Bergmann: Novartis: Research Funding, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Shire/Takeda: Research Funding; NovoNordisk: Research Funding. Mascarenhas:Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding. Hoffman:Merus: Research Funding. OffLabel Disclosure: Use of interferon and hydroxyurea in children with MPNs is off-label

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

Blood ◽

10.1182/blood.v128.22.2213.2213 ◽

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.

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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 ◽

10.1182/blood.v126.23.4877.4877 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4877-4877 ◽

Cited By ~ 1

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.

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Clinical Characteristics of Classic Paroxysmal Nocturnal Hemoglobinuria (PNH) in Pediatric Patients: A Comparison with Classic PNH in Adults. An International PNH Registry Study

Blood ◽

10.1182/blood.v118.21.2102.2102 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2102-2102 ◽

Cited By ~ 1

Author(s):

Alvaro Urbano-Ispizua ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jaroslaw P Maciejewski ◽

Gérard Socié ◽

...

Keyword(s):

Kidney Disease ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Event Rate ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

Equity Ownership

Abstract Abstract 2102 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, life-threatening hematopoietic stem cell disorder characterized by deficiency of the GPI-anchored complement inhibitory proteins CD55 and CD59. Uncontrolled complement activation is responsible for chronic hemolysis that leads to the serious clinical morbidities including thromboembolism (TE) and chronic kidney disease, which increase risk of mortality. PNH is infrequent in children and as such, there is a paucity of data in the literature examining their burden of disease. This is the largest series of pediatric patients with PNH, and the first comparison with adult PNH patients. AIM: To assess the clinical differences between pediatric and adult PNH patients with classic/hemolytic PNH. Methods: Data from 1143 PNH patients from 204 clinical sites in 21 countries on 5 continents (as of 6/30/11) were analyzed to evaluate clinical characteristics of PNH. Patients registered as having classic/hemolytic PNH were initially included (n=559). Of these, 62 additional patients were excluded due to either a <30% granulocyte clone size, or missing data on enrollment date, date of birth, sex, date of disease start and history of TE. The final population for this study was 497 patients, classified into two groups, those first diagnosed at age <18 years (pediatric patients N=49) and at age ≥18 years (adult patients N=448). Baseline demographics, laboratory values, PNH-related medical history, and physician-reported PNH symptoms were compared for pediatric and adult patients. Patients/guardians gave informed consent prior to enrollment. Results: The median age at disease start for pediatric patients was 15 years (5–17), and for adults was 33 years (18–87). Hemoglobin, leucocytes, neutrophils, reticulocytes, LDH, and number of transfusions were similar between both pediatric and adult patients. There were no differences in GPI-deficient granulocyte or RBC clone sizes between pediatric and adult patients. Follow-up was longer for children (mean + SD, in years: 14.5 + 13.6 vs 9.6 + 9.1, P<0.001, respectively). The number of pediatric and adult patients receiving concomitant medications such as anticoagulants (peds 49% vs adults 54.9%; P=0.43) and eculizumab (peds 40.8% vs adults 45.5%; P=0.53) prior to enrollment were similar. No differences between pediatric and adult patients were observed in bone marrow disorders, renal impairment, hemoglobinuria, abdominal pain, dysphagia, headache and shortness of breath. In contrast, pediatric patients reported less fatigue (57.1% vs. 76.8%; P=0.001). TE incidence was 12.2% for pediatric and 23.9% for adults, which was statistically significant when the length of the time of exposure to this complication was taken into account; TE event rate was significantly lower in pediatric patients compared to adults (1.0/100 pt-yrs vs 4.4/100 pt-yrs; P<0.001 by Poisson regression). Patients with TE had a mean granulocyte clone size of 85.7% vs 81.0% for patients without TE (P=0.026). Both in children and adults the risk of TE was much higher than expected for the general population (general pediatric population: TE incidence is 0.07 per 10,000 or 0.0007%, vs 12.2% in this study). TE events at venous sites (hepatic/portal, mesenteric/visceral, renal, and cerebral veins) and arterial sites were less frequent in pediatric patients compared to adults. The most striking difference in TE type was thrombophlebitis/deep vein thrombosis, which occurred significantly less frequently in pediatric than adult patients (2.0% vs 11.8%; p=0.037). In multivariate analysis, age >18 years at disease onset and kidney disease were predictors of TE (odds ratio [OR] 3.01, 95% CI 1.15–7.72; P=0.02, and OR 1.87, 95% CI 1.03–3.4; P=0.04, respectively), while clone size was not a significant predictor of TE (OR 1.010, 95% CI 0.995–1.025; P=0.18). Conclusions: Pediatric PNH patients experience a significant burden of disease similar to adult PNH patients. There were no differences in LDH levels, GPI-deficient clone size, or in the incidence of bone marrow disorders, renal impairment, hemoglobinuria, abdominal pain, shortness of breath and dysphagia between pediatric and adult patients. TE event rate was lower in pediatric PNH patients when compared to adults, especially for those with concomitant kidney disease However, TE still remains an issue in this population and pediatric PNH patients are at significant risk for TE. Disclosures: Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novarts: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Brodsky:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion Pharmaceuticals, Inc.: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Rosse:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kanakura:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion: Employment, Equity Ownership. Bedrosian:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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 ◽

10.1182/blood-2019-124100 ◽

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.

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Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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Correlation of Hemophagocytosis with Clinical Criteria of Hemophagocytic Lymphohistiocytosis and Recommendations for Screening Bone Marrow Samples in Adult Patients

Blood ◽

10.1182/blood-2020-139246 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Caroline Wilson ◽

Wei-i Lee ◽

Matthew Cook ◽

Lillian Smyth ◽

Dipti Talaulikar

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Hemophagocytic Lymphohistiocytosis ◽

Research Funding ◽

Interobserver Variability ◽

Laboratory Data ◽

Adult Patients ◽

Advisory Committees ◽

Bone Marrow Biopsies ◽

Immunohistochemical Stain

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. It can prove difficult to diagnose and portends a poor prognosis. Bone marrow (BM) biopsy is an easily accessible test that is often used to identify the presence of hemophagocytosis and assess for underlying malignancy. Currently there are no evidence-based guidelines on the reporting of hemophagocytosis on BM biopsy and no reports of a correlation between hemophagocytosis with the clinical diagnostic criteria for HLH. We therefore aimed to assess if the amount of hemophagocytosis identified in the BM biopsy correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting hemophagocytosis, and to formulate recommendations for screening in BM specimens. Method A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by 2 hematopathologists who were blinded to the original biopsy report. Relevant clinical and laboratory data was extracted from medical records. The average number of actively hemophagocytic cells in each slide prepared from BM aspirates were quantified into 0, 1, 2-4 and ≥5. On trephine samples, hemophagocytosis was reported as either 'present' or 'absent', with the assistance of the CD68 immunohistochemical stain. Cases with discordance pertaining to the degree of hemophagocytosis were reviewed by both assessors to reach a consensus. Results Sixty-two specimens from 59 patients were available for assessment. An underlying hematological condition was identified in 34 cases (58%). The most common underlying hematological condition was lymphoma, found in 15 cases (25%). There was a significant association between the amount of hemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.05). In patients where hemophagocytosis was present (n=31), there was a significant correlation between the amount of hemophagocytosis and ferritin levels (p<0.05). Interobserver variability was present in 63% of cases. Based on our review, we make the following recommendations for reporting of hemophagocytosis in the BM samples:> 1. Count only macrophages ingesting intact hemopoietic cells. W2. Quantify the average number of active histiocytes per aspirate slide. W3. Count histiocytes away from particles where the cellular outline is clear. W4. Avoid counting conglomerates of histiocytes where the cellular margins are indistinct W5. On the aspirate specimen, assess for hemophagocytosis on both the trail and squash preparations. W6. Delineating hemophagocytosis on trephine samples is difficult without the use of a CD68 immunohistochemical stain. Interestingly, a study by Ho et al found no association between the BM histologic findings and the probability of hemophagocytosis (Ho et al, American Journal of Clinical Pathology, 2014). This difference highlights the need for standardised reporting of BM specimens. Conclusion Our findings indicate that the amount of hemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria met. We found marked interobserver variability which we anticipate can be rectified with our recommendations on the reporting of hemophagocytosis. Disclosures Talaulikar: Takeda: Research Funding; Amgen: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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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 ◽

10.1182/blood.v126.23.4330.4330 ◽

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.

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