A Dose Intensified Pediatric-Like Regimen Using Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2823-2823 ◽  
Author(s):  
Dan Douer ◽  
Kristy Watkins ◽  
Lisa Mark ◽  
Ann Mohrbacher ◽  
Allen S. Yang ◽  
...  
Keyword(s):  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Neutropenic Sepsis ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Pediatric All ◽  
Remission Phase ◽  
Grade 3

Abstract Introduction: Recent studies have suggested that more intensive pediatric regimens may improve the outcome of adults with ALL. In particular, higher dose of asparaginase (ASP) are often used in pediatric ALL protocols than in adults. Large randomized pediatric ALL trials have shown that multiple doses of E.Coli ASP given throughout the post remission phase are associated with improved outcome. PEG-asparaginase (PEG-ASP) is a modified formulation of E.coli ASP, with lower risk of hypersensitivity reactions and prolonged half life. Data on PEG-ASP in adults is limited. In a previous study we showed in adult ALL patients that a single IV dose of PEG-ASP given during induction produces a long duration of asparagine depletion (up to 3-4 weeks) with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood19:2744, 2007). We currently report in adults the use of multiple doses of PEG-ASP given throughout the treatment course of patients with newly diagnosed previously untreated ALL as part of an intensive pediatric regimen. Methods: The therapeutic backbone of this protocol is based on an augmented BFM pediatric ALL protocol consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Results: 34 patients aged 19–57 (median 33) years with newly diagnosed ALL (precursor B cell - 29, T cell-5, Ph+ 7) were studied. Median WBC at diagnosis was 21,000/cumm (range 1,900–512,000). Thirty three patients (97%) achieved a CR after induction phase I. Eight (26%) patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. Other reasons for not completing all PEG-ASP doses are: relapse -3 pts., death in CR from neutropenic sepsis-2 pts., pancreatitis -4 pts. To date six patients received all 6 doses of PEG-ASP havingcompleted all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6-6pts, 5-1 pt., 4-3 pts., 3-5 pts., 2-7 pts., 1-12 pts. Total number of doses was 94. Grade 3/4 toxicities during cycles after PEG-ASP was given were: elevated liver enzymes - 18/34 (53%) pts (25 doses), hyperbilrubinema - 7/34 (21%) pts (7 doses), hyperglycemia - 11/34 (32%) pts (13 doses), pancreatitis 4/34 (12%) pts, fatigue 3/34 (9%) pts, hypertriglyceridemia-2/34 (6%) pts, neuropathy, catheter thrombosis-1/34 pt each; no allergic reactions. All toxicities were reversible. In 20 patients anti-asparaginase antibodies were assayed and none were found. With a median follow up of 15 months event free survival at 3 yrs is 61%. Conclusion: Administration of multiple doses of PEG-ASP IV to adults (ages19–57 years) in an intensified BFM-based pediatric-like strategy is feasible and provides long term asparagine depletion. Such approach may benefit adults with ALL.

The Pharmacokinetics, Safety and Lack of Antibody Production from Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1873-1873
Author(s):  
Dan Douer ◽  
Kristy Watkins ◽  
Niyati Nathwani ◽  
Alexandra M. Levine ◽  
Prakash N. Tiwari ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Phase I ◽  
Antibody Production ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Multiple Doses ◽  
Long Duration ◽  
Elevated Liver Enzymes

Abstract Introduction: Large randomized trials in pediatric ALL show that multiple doses of E.Coli asparaginase (ASP) given throughout post remission phase are associated with improved outcome. ASP is routinely incorporated into most front line adult ALL protocols. PEG-asparaginase (PEG-ASP) is E.coli ASP, which is linked to polyethylene glycol reducing the risk of hypersensitivity reactions and prolonging the half life compared to the native forms. In children multiple doses of PEG-ASP produce less neutralizing antibodies than equivalent doses of native E. coli ASP with similar toxicity (Avramis Blood 99:1986Avramis Blood 99:2002). Information on PEG-ASP in adults is very limited. In a previous study we showed that in adult ALL, a single IV dose of PEG-ASP given at induction produces a long duration of serum ASP enzymatic activity and concomitant asparagine depletion with similar toxicity to equivalent multiple doses of E.coli ASP. We currently report in adults the pharmacokinetics (PK), antibody production and toxicity of multiple doses of PEG-ASP given throughout the treatment of patients with newly diagnosed previously untreated ALL. Methods: We used a modified augmented BFM ALL protocol consisting of 8 cycles of multi-agent chemotherapy followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Serum samples were taken weekly for three weeks for ASP enzymatic activity after PEG-ASP dosing in induction phase 1 (dose 1) and in delayed re-inductions I and II (doses 4 and 6, respectively). Results: 18 patients aged 19–57 (median 28) years with newly diagnosed ALL (precursor B cell - 14, T -4) were studied. All 18 patients (100%) achieved a CR after induction phase I. Six patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. The number of doses of PEG-ASP was: all 6 doses- 4 pts, 4-3 pts., 2–5 pts., 1– 6 pts. Total number of doses was 52. T ½ was 7±4.7 days (n=18) after the fist dose increasing to 11.9±5.9 days (n=11) after dose 4 and 6. In the first cycle the AUC and MRT were lower while the Vd, Vdss and total clearance (Clt) were higher compared to the subsequent cycles. The change in PK parameters over time is most likely due to Michaelis-Menten (M-M) rate-limiting step on the elimination of the drug. Peak serum levels did not change significantly between the cycles. Anti-ASP antibodies were not detected in any patient-cycles. Grade 3/4 toxicities were hyperbilirubinemia - 3 pts (3 doses), elevated liver enzymes - 10 pts (13 doses), hyperglycemia - 7 pts (10 doses), allergy, pancreatitis, neuropathy, and fatigue - 1 pt (1 dose) each. All toxicities were reversible. We saw no pattern of increasing toxicity in subsequent doses of PEG-ASP. Only two patients had relapsed (median follow up of 15 months). Conclusion: multiple doses of PEG-ASP can be given IV to adults (age<57 years) and provide a very long duration of post remission ASP enzymatic activity. The M-M kinetics suggest that multiple doses of PEG-ASP lead to gradually increasing trough levels resulting in longer depletion of asparagine and glutamine levels and possibly better clinical activity, without being associated with increased toxicity or neutralizing antibody production.

Sustained and Prolonged Asparagine Depletion by Multiple Doses of Intravenous Pegylated Asparaginase in the Treatment of Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1928-1928
Author(s):  
Dan Douer ◽  
Kristy Watkins ◽  
Lisa Mark ◽  
Mohrbacher Ann ◽  
Allen S Yang ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Liver Enzymes ◽  
Induction Phase ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Pediatric All ◽  
Multi Agent ◽  
Asparaginase Activity ◽  
Grade 3

Abstract The better outcome in pediatric ALL may not be solely related to the biology of the disease. Adult regimens are less intensive than used in children and include less, shorter or no use of asparaginase; the drug is often considered more toxic than in children. However, adequate serum asparagine depletion was shown to be associated with improved overall outcome. Further in several, multi-agent, large pediatric randomized trials, longer administration of asparaginase in the post remission phase and more sustained asparagine depletion resulted in better outcome. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP, with less hypersensitivity reactions and longer half-life. In adults a single IV dose of PEG-ASP during induction produces long duration of asparagine depletion of up to 4 weeks, t½ = 7 days, with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood 19:2744,2007). We now report the use of multiple doses of PEGASP, given during induction and throughout the post-remission phases in order to produce prolonged and sustained asparagine depletion in the context of an intensified pediatric protocol, in newly diagnosed, treatment naïve, adult ALL. Sustained asparaginase activity after the short acting E.coli ASP, can be impaired by development of neutralizing anti – asparaginase antibodies. We therefore measured the asparaginase enzymatic activity in a cohort of our patients who received PEG-ASP which in children was shown to be associated with less antibody formation (Avramis et al Blood2002;99:1986). Methods: The backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Since December 2006, Ph+ patients receive imatinib 600mg/daily. Asparaginase enzymatic activity was measured in samples obtained before and after PEG-ASP doses in cycles 1, 5 and 8. Results: 41 patients, aged 19–57 (median 33) years, with precursor B cell – 36, T cell-5, Ph+ 9, were studied. Median WBC at diagnosis - 15,900/cumm (range 1,900–512,000). CR rate: 37 (95%) pts. all after induction phase I. To date 15 patients received all 6 doses of PEG-ASP, having completed all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6(15pts), 3(6 pts), 2(7 pts), 1(13 pts) Fifteen patients could not continue the protocol for: allogeneic stem-cell transplantation (8), refusal (1), pancreatitis (5), grade 3 DVT(1). Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, or hyperglycemia continued on the study. Total number of PEG-ASP doses was 135. No pt had an allergic reaction. The number of pts with grade 3/4 toxicities during PEG-ASP cycles were: elevated liver enzymes 24 (59%), hyperbilrubinema 8 (20%), hyperglycemia 12 (29 %), pancreatitis 6(15%), fatigue 4(10%), hypertriglyceridemia 3 (7%), catheter thrombosis- 4 (10%), neuropathy-1. All toxicities were reversible. With a median follow up of 18 months, EFS at 3 and 4 yrs is 68 % (Ph- patients 74%) and CIR is 23%. Asparaginase enzymatic activity after each dose was very long in a cohort of 19 pts with a population average of t½ = 10.99 days (peak concentration 0.88 IU/ml). All 74 specimens analyzed from this cohort of patients had significant asparaginase activity after each PEG-ASP dose, highly suggesting that none of the patients analyzed had developed neutralizing anti asparaginase antibodies. Additional patients with enzymatic measurements will be presented Conclusions: Multiple doses of PEG-ASP IV in adults (ages 19–57 years) provide prolonged and sustained asparagine depletion and no apparent drug inactivating by antibody formation. In combination with an intensified BFM-based protocol this pediatriclike strategy is feasible, without allergic reactions, and with acceptable toxicity. Although the follow up is relatively short the EFS appears to be high. Such approach may benefit adults with ALL

Toxicities in Adults with Acute Lymphoblastic Leukemia (ALL) Treated with Regimens Using Pegasparaginase.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1924-1924 ◽  
Author(s):  
Michael Rytting ◽  
Marc Earl ◽  
Dan Douer ◽  
Brenda Muriera ◽  
Anjali Advani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cleveland Clinic ◽  
Adult Patients ◽  
Close Monitoring ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Long Acting ◽  
Age Range

Abstract Background: The current therapeutic strategy of applying pediatric-based regimens for acute lymphoblastic leukemia (ALL) to adults with ALL exposes these patients to multiple doses of asparaginase (ASP). Exposure to long-acting or pegylated ASP is particularly prominent due to dosing convenience, since pegylated ASP can be administered intravenously and requires fewer doses than shorter-acting forms. Previously, adult patients were much less likely to be treated with ASP-containing regimens due to reports from the 1970s of increased toxicity from ASP in adults compared with children. We report on the toxicities encountered in 3 protocols that include multiple doses of pegylated ASP as part of therapy for ALL in adult patients. Methods: Thus far, the 3 protocols have enrolled 92 patients between the ages of 14 and 71 years. The pegylated ASP dose ranges from 2000–2500 IU/m2. Approximately 330 doses of pegylated ASP have been given. Results: Grade 3–4 hepatic toxicity is the most prominent; grade 3–4 transaminase elevation occurred in 47 (51%) patients, and grade 3–4 hyperbilirubinemia was seen in 22 (24%) patients (Table). Hyperglycemia was grade 3–4 toxicity in 30 (33%) patients. Grade 3–4 allergic reactions to pegylated ASP occurred in 5 (5%) patients. Twelve (13%) patients developed thromboses. Of note, 3 (3%) patients have had leukoencephalopathy on magnetic resonance imaging scans with reversible stroke-like symptoms. The majority of hepatic toxicities resolve spontaneously, allowing patients to continue chemotherapy. All of the patients with stroke-like symptoms have fully recovered. Conclusions: Considerable hepatotoxicity and hyperglycemia occur in adult ALL patients treated with polychemotherapy that includes long-acting ASP. Other toxicities occur with a frequency similar to that seen in pediatric patients treated with a long-acting ASP. This toxicity profile warrants close monitoring and continued data collection from clinical trials that use pegylated ASP in adults with ALL. USC Cleveland Clinic M.D. Anderson Total *No. of patients with grade 3–4 toxicities. Median age (years) 33 46 20 33 Age range (years) 18–57 20–71 14–34 14–71 No. doses/patients 127/39 56/25 147/28 330/92 Toxicity* Elevated liver enzymes 23 7 17 47 Hyperbilirubinemia 7 6 9 22 Hyperglycemia 12 5 13 30 Clinical pancreatitis 5 N/A 3 8 Fatigue 3 1 7 11 Thrombosis 3 (SVC only) 2 7 12 Hypofibrinogenemia N/A 8 N/A 8 Elevated PT / INR N/A 1 N/A 1 Bleeding 0 N/A 0 0 Nausea / vomiting 1 4 2 7 Allergy / hypersensitivity 0 2 3 5 Neuropathy 1 1 N/A 2 CNS stroke-like syndrome 0 0 3 3

Multiple Doses of Intravenous Pegylated Asparaginase with a “Pediatric-like” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): Toxicity, Clinical Outcome and Low Rate of Anti Asparaginase Antibody Formation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3082-3082 ◽  
Author(s):  
Dan Douer ◽  
Kristy Watkins ◽  
Lisa Mark ◽  
Janice Vrona ◽  
Ann Mohrbacher ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antibody Formation ◽  
Neutralizing Antibody ◽  
Induction Phase ◽  
E Coli ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Pediatric All ◽  
Multi Agent ◽  
Low Rate

Abstract Abstract 3082 Poster Board III-19 Several, large randomized multi-agent trials, in pediatric ALL have shown that prolonged use of asparaginase (ASP) during remission resulted in better outcomes. Adequate serum asparagine depletion from ASP administration has been suggested to have a therapeutic impact. Historically, adult ALL regimens use less, shorter or no ASP compared to pediatrics, as the drug is considered more toxic. However, a recent Adult ALL study (Huguet et al, JCO 27:911, 2009), suggested an improved outcome (EFS 55%, OS 60%) using a “pediatric-inspired” protocol, which included longer duration and higher cumulative doses of E-coli ASP. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP with a longer half life, resulting in sustained asparagine depletion. PEG-ASP is also considered to be less allergogenic, and in children causes fewer clinical hypersensitivity reactions and lower rate of anti-ASP neutralizing antibodies (“silent” hypersensitivity i.e. antibodies without clinical hypersensitivity) than the native E. coli ASP. We report, the use of multiple doses (up to 6) of PEG-ASP, given throughout the induction and the post-remission phases in a “pediatric-like” protocol, to newly diagnosed adult ALL. We also determined the rate of anti-ASP neutralizing antibody formation throughout our study; currently these rates are unknown in adults. Methods The backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by two year maintenance. PEG-ASP (2000 U/m2/dose) is given intravenously (IV) once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Steroids are always given before and for at least 7 (dexamethasone) or 14 (prednisone) days after the PEG-ASP dose depending on the treatment cycle. Since December 2006 Ph+ patients receive imatinib 600mg/daily. Results 46 patients, aged 18-57 (median 33) years, precursor B cell - 41, T cell-5, Ph+ 11, were studied. Median WBC at diagnosis - 14,500/cumm (range 1,900-512,000). CR rate: 44(96%) pts (43 after induction phase I). So far the total number of PEG-ASP doses given was 160: 6-16 pts, 5- 3pts 3- 6 pts., 2-10 pts., 1-11 pts. Eighteen patients could not complete all doses of PEG-ASP: allogeneic SCT -8, refusal -1, pancreatitis -5 (one pt. had pancreatitis and SCT), anaphylaxis -2, DVT-1. Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, DVT (except for one pt.) or hyperglycemia continued on the study. Number of pts. with PEG-ASP related grade 3/4 toxicities (at least once of each): anaphylaxis -2 (4%) (one additional patient a had grade 2 rash); pancreatitis 6 (13%) (one pt. after last dose); thrombosis- 5 (11%) with 4 of the 5 catheter-related in upper extremity; elevated liver enzymes -30 (64%); hyperbilrubinema - 11 (24%); hyperglycemia - 12 (26 %); hypertriglyceridemia -3 (7%); fatigue-5 (11%). All toxicities were reversible. Neutralizing antibodies were measured in 247 serum samples from 34 patients (33, 11 and 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively). An antibody was detected in only ONE patient (after dose #1); he had PEG-ASP related rash. We confirmed the very long half life of PEG-ASP: 7 ±4.7 days after the fist dose increasing to 11.9±5.9 days after dose 4 and 6. Peak serum levels did not change significantly between the cycles. Four year EFS, OS and CIR were 59%, 64% and 32%, respectively. The 16 patients who received all 6 doses of PEG-ASP (no BMT) had a 4 year EFS of 85% (only 3 relapsed at 19, 28, 55 months). Conclusion This study suggests that multiple IV dosing with the long acting PEG-ASP is feasible in replacing the native E.coli asparaginase in the context of “pediatric-inspired” ALL protocols in adults (age <57 years), maintaining their reported favorable outcomes, adding convenience with less frequent dosing, and acceptable toxicity. Multiple doses of PEG-ASP given IV (in conjunction with steroids) to adults, is associated with a low rate of clinical hypersensitivity reactions and neutralizing antibody formation. The very low rate, so far, of “silent” hypersensitivity in adults, suggests that PEG-ASP can be continued IV, with less concern for drug inactivation. Such approach may benefit adults with ALL. Disclosures Douer: Enzon Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.

High-Grade Pegylated Asparaginase-Related Hepatotoxicity Occurrence In a Pediatric-Inspired Adult Acute Lymphoblastic Leukemia Regimen Does Not Necessarily Predict Recurrent Hepatotoxicity In Subsequent Cycles

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2671-2671 ◽  
Author(s):  
Patrick W. Burke ◽  
Ibrahim Aldoss ◽  
Matthew A. Lunning ◽  
Vassilios I. Avramis ◽  
Ann M. Mohrbacher ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Common Adverse Effect ◽  
High Rate ◽  
High Grade ◽  
Post Induction ◽  
Multiple Doses ◽  
Pediatric All ◽  
Grade 3

Abstract Introduction Cure rates of pediatric acute lymphoblastic leukemia (ALL) have markedly improved to approximately 80%, while in adult ALL the rates remain 40-50%. Pediatric ALL regimens contain higher doses of non-myelosuppressive chemotherapy, e.g., vincristine, corticosteroids, and, particularly, higher cumulative doses of asparaginase. Asparaginase use in adults was previously limited due to toxicity concerns. However, several recent studies, using pediatric regimens in adults, contain higher cumulative doses of asparaginase and are showing promising preliminary results. In these studies it was also noted that the long-acting pegaspargase (PEG-ASN) was much more commonly associated with hepatotoxicity in adults than in children. Although hepatotoxicity appears to be the commonest adverse effect of PEG-ASN in adults, it has not been well defined. We report the frequency and characteristics of PEG-ASN-related high-grade hepatotoxicity after multiple doses in adults treated by a pediatric regimen. Methods Between July 2004 and July 2009, 51 adults aged 18 to 57 years were enrolled on a phase II trial with a pediatric ALL regimen that included six planned PEG-ASN doses. PEG-ASN-related toxicities were carefully monitored on a weekly basis after each dose and reported using NCI CTCAE v3.0 for 185 doses delivered. The PEG-ASN dosing schedule was: two doses in induction phases I and II, and four during post-induction cycles (ASH Abstract 1495, 2012). Each PEG-ASN dose was 2000 IU/m2/dose IV, given at intervals of four weeks or greater. Pegaspargase was not discontinued and subsequent doses were not reduced after hepatotoxicity. Results A total of 192 pegaspargase doses were delivered (3.8 doses/patient), with 23 patients receiving all six doses. Of the 28 patients who received fewer than six doses, only 10 (20%) discontinued due non-hepatic toxicity (pancreatitis, allergy, and DVT). Eight (16%) patients discontinued due to allogeneic HSCT while in CR1, while nine (18%) discontinued for other reasons (death post-induction, induction failure, and relapse). Grade 3/4 hyperbilirubinemia occurred in 16 patients (31%) and in 23 doses (12%); grade 3/4 transaminitis occurred in 33 patients (65%) and in 62 doses (34%). Patients with grade 3/4 hyperbilirubinemia tended to be older than those without hepatotoxicity (median age 39 vs 31 years), but all other baseline characteristics were similar. Results of different parameters related to high-grade liver toxicity are detailed in Table 1. Patients with grade 3/4 hyperbilirubinemia and transaminitis received a mean of 4.0 and 4.3 PEG-ASN doses, while the mean number of PEG-ASN doses causing hyperbilirubinemia and transaminitis was only 1.4 and 1.9 doses per patient, respectively. Those without hepatotoxicity received 2.8 PEG-ASN doses per patient. Induction I had the highest incidence (20% of doses delivered) of grade 3/4 hyperbilirubinemia. High-grade transaminitis was spread more evenly among cycles. Grade 3/4 hepatotoxicity was long, with a median duration of 34 days to return to grade 1 for bilirubin and 38 days to return to grade 2 for transaminitis. Of the 16 patients with grade 3/4 hyperbilirubinemia, five did not receive a subsequent PEG-ASN dose for other reasons; of the 11 other patients who received subsequent doses, five (45%) did not re-experience the same toxicity. Of the 33 patients with grade 3/4 transaminitis, eight did not receive a subsequent PEG-ASN dose due to other reasons; of the 25 other patients who received subsequent doses, 10 (40%) did not have this toxicity recur. Summary Our study shows in adults with ALL treated with multiple doses of PEG-ASN that: (1) high-grade hepatoxicity (grade 3/4 hyperbilirubinemia and transaminitis) is a common adverse effect of PEG-ASN; (2) recovery from hepatotoxicity is often long and can delay subsequent chemotherapy; (3) high-grade hepatotoxicity did not necessarily recur after subsequent doses and did not lead to PEG-ASN discontinuation; (4) the dose and schedule of other hepatically cleared or hepatotoxic drugs should be adjusted during periods of PEG-ASN-related hepatotoxicity. In conclusion, although PEG-ASN at this dose and interval is associated in adults with a high rate of hepatotoxicity, it is tolerable and can be given again despite earlier PEG-ASN-related hepatotoxicity. Disclosures: Douer: Sigma Tau Pharmaceuticals : Research Funding.

Phase I/II Study of Clofarabine Plus Cyclophosphamide in Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4335-4335
Author(s):  
Stefan Faderl ◽  
Deborah A. Thomas ◽  
Varsha Gandhi ◽  
Gautam Borthakur ◽  
Xuelin Huang ◽  
...  
Keyword(s):  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Nyha Class ◽  
Median Number ◽  
Infectious Complications ◽  
Acute Leukemias ◽  
Fda Approval ◽  
Pediatric All ◽  
Grade 3 ◽  
Dose Levels

Abstract Clofarabine (CLO) is a nucleoside analog with activity in pediatric ALL salvage where it has received FDA approval. Less experience with CLO exists in adult ALL. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I/II study of the combination of CLO with cyclophosphamide (CY) for therapy of adult patients (pts) with primary refractory or relapsed ALL. Pts with NYHA class ≥ 3 and a cardiac ejection fraction < 45% were excluded. The continual reassessment method (CRM) was applied to determine MTD from 4 dose levels. The starting dose level was CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. For cohort 2, the dose of CY was increased to 300 mg/m2. Cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Additional samples for clinical pharmacology were obtained from consenting pts prior to and following CY on d1 and d2 and prior to CLO on d2.Thirteen pts have been enrolled. Median age was 34 yrs (range 21–72 yrs). Eight pts had pre-B ALL, 2 pts T ALL/LL, 1 pt mature B ALL, and 2 pts biphenotypic acute leukemias. Karyotype was abnormal in 9 pts (no Ph). Median number of prior regimens was 2 (1–6). Two (15%) pts were primary refractory. Median remission duration to initial induction was 11 mos (0–29.8 mos). Three patients were treated in cohort 1 and 10 in cohort 2. Four pts in cohort 2 experienced DLTs (≥ grade 3): elevation of creatinine/renal failure (1), diarrhea (1), transaminase elevations (2), and hyperbilirubinemia (2). Twelve patients were evaluable for response. One pt (70 yrs, prim. refr. pre-B ALL, complex karyotype) of cohort 1 achieved CR after 2 courses, which lasted for 10.3 months. Four pts died on study from infectious complications (days 2, 15, 34, and 41, respectively). Although no MTD has been defined yet and accrual continues in cohort 2, it appears unlikely that the MTD will exceed the dose levels of cohort 2. More information on efficacy will be obtained in the phase II extension part of the study.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

MRD-Detection by Multiparametric Flow Cytometry in Childhood Precursor B-Cell All:Predictive Impact of Early Blast Reduction Kinetics in Peripheral Blood (PB) on MRD-Level in Bone Marrow (BM) at Day 33 of the All-BFM2000 Potocol.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 987-987
Author(s):  
Richard Ratei ◽  
Mathilde Martin ◽  
Guiseppe Basso ◽  
Guiseppe Gaipa ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Correlation Coefficient ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Spearman Correlation ◽  
Multiparametric Flow Cytometry ◽  
Cell Counts ◽  
The Impact

Abstract Detection of minimal residual disease in childhood acute lymphoblastic leukemia (ALL) has been proven to be of crucial importance for relapse prediction. However, MRD assessment, usually performed at postinduction time points, does not allow early stratification of induction therapy. Here, we address the predictive impact of early blast reduction in pB on BM MRD-levels at the end of induction therapy phase I (d33), quantified by multiparametric flow cytometry (MFC-MRD). Absolute blast cell counts (BCC, blasts/μl) in pB at diagnosis and day 8 as well as MRD-levels in BM and pB at day 15 and 33 were determined in a series of 77 consecutive patients (pts.) enrolled in the AIEOP-BFM-FCM-MRD pilot study (BM d33:MRD+ n=29, MRD- n=48). Blast cells were detected using a two platform method and a 4-color antibody panel with three follow-up tubes:1) CD20-FITC/CD10-PE/CD34-PC5/CD19-PC7, 2) CD58-FITC/CD10-PE/ CD34-PC5/CD19-PC7, 3) CD10-FITC/CD11a-PE/CD45-PC5/CD19-PC7. Additionally, staining with the cell permeant live-cell nucleic acid fluorochrome SYTO 16 combined with CD19 or CD3 and CD45 were used to exclude residual non-nucleated erythroid cells, platelets or debris from absolute blast calculations. We found that BCC in BM and pB at d15 but not at diagnosis and after prednisone prephase at day 8 correlated with MRD-levels in BM at d33 (Spearman correlation coefficient rs=0.41, p<0.001 and rs=0,30, p<0,01). In order to further investigate the impact of early blast reduction between day 0 and day 8 we calculated the relative blast reduction rate on day 8 (BRRd8 = 1-BCCd8/BCCd0). In the group of MRD-negative patients the mean values of BRRd8 were found to be significantly higher than in the group of MRD-positive pts. (98,9% vs. 88,0%, p< 0,05). Moreover, the BRRd8 correlated with MRD-levels in BM at day 33 (Spearman correlation coefficient rs=−0.25, p<0.05). In the current series of pts. maximally selected log-rank statistics were performed for the BRRd8 and the MRD-level in BM at d33 and provided a cut-off value of 97% separating MRD-positive and MRD-negative pts. In conclusion, the assessment of the dynamics of early blast reduction with the parameter of BRRd8 is highly predictive for the outcome of induction phase I of the ALL-BFM2000 protocol.

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