ALBERT

Description: Background : Although considerable progress has been made in treating acute lymphoblastic leukemia (ALL) in the pediatric population, with long-term survival exceeding 80%, the prognosis for adolescents, young adult, and adult patients with ALL remains poor, with only 30%-45% of patients achieving long-term survival. Several studies suggest that young adult patients have superior overall survival when treated with intensive "pediatric-inspired" regimens that include the use of asparaginase [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Despite these results, many young adult patients with ALL continue to be treated with chemotherapy regimens that include little or no asparaginase. The goal of this study was to assess the views and practices of hematologists and oncologists with respect to asparaginase use in young adult patients with ALL. Methods : This study was conducted between May 14 and June 22, 2015, and consisted of a 10-minute online quantitative survey, with a 10-minute per-patient chart audit component for up to 4 charts provided by participating physicians. The survey targeted physicians treating young adult patients (aged 18-40 years) with ALL. To be included in the final analysis, physicians were required to be board certified with 2-30 years in practice, with ≥75% of their time spent in direct patient care and ≥20% of their time spent in an academic setting (NCCN/NCI or academic/teaching hospital). Inclusion criteria also required that physicians' total ALL patient volume (young adults and adults aged 〉40 years) was greater than 5 over the past 2 years, that the physician primarily treats adult patients, and has personally managed and treated at least 1 young adult ALL patient in the past 2 years. Results: The study included results reported by a total of 63 practicing physicians for 189 young adult patients with ALL (62% were aged 25-40 years). Sixty percent (114/189) of young adult patients were treated with a protocol that included asparaginase, and only 29% (55/189) on a pediatric-inspired protocol. The most common protocols reported for patients receiving asparaginase included the pediatric-inspired CALGB 10403 (18%, 21/114), as well as regimens with more limited asparaginase use, including augmented hyper-CVAD (29%, 33/114) and CALGB 8811 (12%, 14/114). Overall 40% (75/189) of young adult patients were treated with protocols that did not include asparaginase, most commonly hyper-CVAD (77%, 58/75). Fifty percent (18/36) of responding physicians using hyper-CVAD reported the perception of similar outcomes with nonasparaginase regimens as with asparaginase-intensive regimens. When questioned about the greatest barrier to the use of intensive asparaginase-containing regimens, 88% (7/8) of responding physicians reported safety and tolerability concerns. Conclusion: Only 6 out of 10 patients in the study were treated with an asparaginase-containing regimen; of all patients, less than 1 out of 3 received a pediatric-inspired regimen. Fifty-three percent (60/114) of asparaginase-receiving patients were treated on a regimen that structures asparaginase dosing intermittently between alternating courses. Pediatric-inspired regimens include intensive asparaginase therapy and have consistently shown improvements in overall survival when compared with traditional adult protocols in clinical trials [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Support: This study was funded by Jazz Pharmaceuticals. Disclosures Sender: Jazz Pharmaceuticals: Research Funding, Speakers Bureau. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership. Hall:Jazz Pharmaceuticals: Employment, Equity Ownership. Bernard:Jazz Pharmaceuticals: Employment, Equity Ownership.

Description: Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin 〉2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin 〉2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain 〉2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with 〉80% mortality. To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists. Methods Participating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete. Results Surveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU. The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL. Conclusions The survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update. Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation. Table. VOD/SOS Assessment Measures Used by Physicians Baltimore/Seattle Item US(n=95), % EU(n=152), % Weight increase Y 50 78* Bilirubin increase Y 46 62* Hepatomegaly Y 36 57* Ascites Y 36 49* Ultrasound 27 47* Liver Doppler 23 29 Pain Y 16 29* Jaundice Y 25 28 Liver function Y 25 26 Distention/Swelling Y 22 18 *P

Description: Background : Asparaginase is an important component of therapy for acute lymphoblastic leukemia (ALL). In the United States, asparaginase may be administered as a course of intramuscular (IM) injections. These injections can be painful and may cause anxiety in children undergoing chemotherapy treatment for ALL [August KJ, et al. J Pediatr Hematol Oncol. 2013;35(7):e283-e286]. Intravenous (IV) administration of asparaginase may offer a less painful therapeutic option for patients; however, there exist concerns over an increased incidence of infusion-related reactions associated with this administration method compared with IM delivery. The goal of this study was to assess the practices and attitudes of physicians regarding their treatment of pediatric patients with ALL, including the route of administration of asparaginase. Method : This study consisted of a 30-minute, online, quantitative survey targeting board-certified physicians with 2-30 years in practice. Inclusion criteria required that physicians have spent ≥75% of their time in direct patient care, treat ≥5 pediatric patients with ALL (aged ≤21 years) in a typical month, and have treated at least 80% of patients with ALL with a Children's Oncology Group, Dana Farber, or St Jude protocol in the past year. Results: Data regarding route of administration were available from 67 of 74 participating physicians; 63 reported this information for PEG-asparaginase and 67 for asparaginase Erwinia chrysanthemi. Responses included some data not aligned with the product label. IV administration was the standard route of administration for 86% (54/63) of physicians using PEG-asparaginase and for 37% (25/67) of physicians using asparaginase Erwinia chrysanthemi. Five percent (3/63) of PEG-asparaginase users and 15% (10/67) of those using asparaginase Erwinia chrysanthemi reported that the route of administration was determined by patient characteristics and situation. Among physicians who preferred IM administration of asparaginase Erwinia chrysanthemi, the most commonly cited reason was standard of practice or protocol (38%, 12/32). Ease of administration (68%, 17/25) was the most commonly reported reason for physicians using IV administration of asparaginase Erwinia chrysanthemi. Of 15 physician responders who have used IV administration of asparaginase Erwinia chrysanthemi for 6 or more months, 67% (10/15) adhered to a 60-minute infusion duration, whereas 27% (4/15) reported using an infusion duration of ≥90 minutes, which is not aligned with the product label. Of those who administered asparaginase for ≥90 minutes, 1 physician reported that this practice reduced the risk of an infusion reaction, 1 reported that it was due to patient preference, and 1 reported that it was the standard infusion time at their institution. Additionally, 1 physician erroneously reported that the infusion time of ≥90 minutes was in line with the product label for asparaginase Erwinia chrysanthemi. Regarding the rate of infusion, 40% (6/15) of physicians reported that they typically start the infusion gradually (at a lower drug delivery rate) before ramping up the infusion speed for the remaining dose; 1 respondent stated that this infusion method was hospital policy, while the other 5 physicians stated that this method improved patient tolerance/less reactions or the ability to better monitor the patients for side effects. Conclusion: The majority of physicians using asparaginase Erwinia chrysanthemi preferred using IM administration to treat pediatric patients with ALL. Institutional preferences and standard of practice were the most common responses given for using IM administration. Infusion reactions that may occur with IV administration may be attenuated by prolonging the duration of the infusion, which was reported by a number of physicians experienced with IV asparaginase Erwinia chrysanthemi administration. Support: This study was funded by Jazz Pharmaceuticals. Disclosures Bernard: Jazz Pharmaceuticals: Employment, Equity Ownership. Off Label Use: Asparaginase Erwinia chrysanthemi is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with ALL who have developed hypersensitivity to E. coli-derived asparaginase. It can be administered by intramuscular injection or by intravenous infusion. For intramuscular use, limit the volume of reconstituted asparaginase Erwinia chrysanthemi at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites. For intravenous use, infuse asparaginase Erwinia chrysanthemi in 100 mL of normal saline over 1 hour.. Hall:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.

Description: Background: VOD/SOS, a potentially life-threatening complication of HSCT conditioning, has historically been diagnosed using modified Seattle criteria (≥2 of: bilirubin 〉2 mg/dL, hepatomegaly, or 〉2% weight gain [sometimes 〉5%]) or Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain); the European Society for Blood and Marrow Transplantation proposed new adult criteria in 2016. VOD/SOS with multi-organ dysfunction (MOD) may be associated with 〉80% mortality. This chart review characterizes VOD/SOS diagnosis patterns. Methods: Physicians performed ≥5 transplants/year in accredited centers listed by the Center for International Blood and Marrow Transplant Research, and provided data from the most recent 1-3 patients with VOD/SOS (with or without MOD) post-HSCT diagnosed in the past 3 years. MOD was defined by renal failure (creatinine clearance 3´ baseline), pulmonary failure (mechanical ventilation, oxygen requirement, or saturation 2 mg/dL bilirubin components (Figure). Adults had higher laboratory values at diagnosis, while pediatric patients generally had more clinical symptoms (Table). MOD was identified in 54% of adult and 69% of pediatric VOD/SOS patients, and these patients generally had greater clinical and laboratory burden than patients without MOD. MOD was more common among patients receiving RIC (65%) than MAC (57%). Bilirubin and weight gain at diagnosis and at peak were higher in patients with vs without MOD (Table). The increase in bilirubin level between the day before diagnosis and day of diagnosis was generally higher in patients with MOD, although rate of weight gain was similar between adult MOD and non-MOD groups. Conclusion: In this study, many patients' signs at diagnosis had progressed beyond VOD/SOS diagnostic criteria. Overall, adults were diagnosed later in disease progression than pediatric patients. Patients with MOD generally had earlier occurrence and higher, more rapidly rising levels of markers at diagnosis: an observation that may aid early identification of MOD. Interestingly, patients with VOD/SOS who received RIC vs MAC had higher rates of MOD. Together, these findings may help in prompt diagnosis of VOD/SOS, which may improve patient outcomes. Support: Jazz Pharmaceuticals Disclosures Doede: Jazz Pharmaceuticals: Employment, Equity Ownership. Viddam:Jazz Pharmaceuticals: Employment, Equity Ownership. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Weaver:Jazz Pharmaceuticals: Consultancy. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc.