Long-term safety of pegloticase in chronic gout refractory to conventional treatment.

OBJECTIVE: To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout. METHODS: This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy. RESULTS: Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence. CONCLUSIONS: The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.

A Phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma.

BACKGROUND: Multiple myeloma remains an incurable disease. New agents are needed to improve therapy for patients with this disease. Previous investigators evaluated in vitro sensitivity of myeloma cells to polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) using the human tumor clonogenic assay. Of the 19 myeloma samples evaluated, 63% were inhibited at 0.075 IU/mL, and 74% were inhibited at 0.75 IU/mL. PEG-L-asparaginase is a form of Escherichia coli-derived L-asparaginase that is bound covalently to polyethylene glycol. Compared with the native form, it has a longer half-life and is less likely to cause allergic reactions. METHODS: The authors conducted a Phase I-II trial using PEG-L-asparaginase as a single agent in patients with recurrent and/or refractory multiple myeloma. RESULTS: Twenty-two patients received a median of two doses of PEG-L-asparaginase. In the 17 patients who are evaluable for response, a complete response was observed in one patient after four doses, and stable disease was observed in eight patients. Progression of disease was the reason for termination from study in the remaining eight patients. The median survival was 31.7 months, with four patients who were alive at 72 months after the start of therapy. Grade 3-4 toxicity was noted by the PEG-L-asparaginase 2000 mg/m(2) level. Severe allergic reactions were noted only at the highest dose level. CONCLUSIONS: Current data suggest that the maximal tolerated dose for single agent PEG-L-asparaginase in relapse/refractory multiple myeloma patients is 1000 mg/m(2) every 4 weeks. We could not identify any correlation between dose, plasma level and response. In this advanced group of patients we noted stable disease and/or response in 52% of evaluable patients. PEG-L-asparaginase has lower tolerance when used in the standard dosage as a single agent in this group of patients. We therefore recommend further studying of PEG-L-asparaginase dose of 1000 mg/m(2) on alternate weeks with steroids and/or other immune modulators.

Pegaspargase-induced pancreatitis.

BACKGROUND: The purpose of this study is to report the incidence of pancreatitis in patients treated with pegaspargase in our hospital during a 2-year period. PROCEDURE: We identified episodes of pancreatitis related to the intramuscular administration of pegaspargase 2,500 IU/m(2) for the treatment of childhood hematological malignancies during a 2-year period (May 1996-April 1998). Patients were evaluated clinically and by sequential serum amylase and lipase determinations and radiographic examinations. For comparison, episodes of pancreatitis in patients who only received native Escherichia coli L-asparaginase were examined during the same time period. RESULTS: Nine children with acute lymphoblastic leukemia (ALL) of 50 (18%) patients who received pegaspargase were diagnosed to have pancreatitis. All had prior therapy with native L-asparaginase. These children developed symptoms consisting of abdominal pain, nausea, vomiting, and decreased appetite within a median of 15 days from the onset of pegaspargase administration. Six patients became symptomatic after their initial dose. Seven patients developed severe or unacceptable toxicity (grades 3 and 4), measured by increased amylase (>2 times normal) and lipase levels or radiographic evidence of pancreatic inflammation or pseudocyst. One patient also developed hyperammonemia and encephalopathy. In contrast, only one out of 52 (1.9%) ALL patients who received native E. coli L-asparaginase during the same time period developed pancreatitis (P= 0.007). CONCLUSION: Clinicians should be aware of a possible higher incidence of pancreatitis associated with pegaspargase.

Evaluation of L-asparaginase: polyethylene glycol conjugate versus native L-asparaginase combined with chemotherapy. A randomized double-blind study in canine lymphoma.

L-asparaginase is an enzyme that inhibits protein synthesis by the depletion of sources of L-asparagine, which is necessary for transformed lymphoid cells to proliferate. L-asparaginase is used in the treatment of childhood acute lymphoblastic leukemia. A problem with L-asparaginase therapy is the immunogenicity of the enzyme and the development of anaphylactic reactions. Canine lymphoma is a predominantly B-cell tumor with widespread disease; without treatment, dogs with lymphoma usually survive 1-2 months. Canine lymphoma will respond to L-asparaginase therapy. A randomized double-blind study evaluated a polyethylene glycol (PEG) conjugate L-asparaginase combined with chemotherapy (vincristine, cyclophosphamide, doxorubicin, and prednisone). Thirty-five dogs were randomized to the PEG L-asparaginase group, and 34 dogs were randomized to the native L-asparaginase group. Thirty dogs (85.7%) achieved a complete remission (CR) with a median time to relapse of 217 days, and 32 (94.1%) dogs in the native L-asparaginase group achieved a CR with a median time to relapse of 214 days (P greater than 0.05). The asparaginase was well tolerated in both groups. Two dogs in the native L-asparaginase group had severe allergic reactions, and one dog in the PEG asparaginase group had a generalized urticarial reaction after repeated injections. This study indicates that PEG L-asparaginase has equal therapeutic efficacy to native L-asparaginase.

Polyethylene glycol-L-asparaginase versus native L-asparaginase in canine non-Hodgkin's lymphoma.

42 dogs with non-Hodgkin's lymphoma (NHL) were randomized for treatment with either PEG-L-asparaginase 10 IU/kg intramuscularly (n = 22) or L-asparaginase 400 IU/kg intraperitoneally (n = 20). Another 20 dogs were treated with either PEG-L-asparaginase 30 IU/kg (n = 10) or L-asparaginase 400 IU/kg (n = 10). Each treatment protocol consisted of two asparaginase treatments followed by a 10-week period of induction chemotherapy and then maintenance on asparaginase until progression occurred. No significant differences were found between treatments in the response rates after 2 weeks of asparaginase therapy or in the time to relapse, the time to treatment failure or the remission period. The reaction to asparaginase after the initial 2 weeks was a prognostic factor for the total duration of remission under asparaginase maintenance therapy. No side-effects were noted in the dogs treated with PEG-L-asparaginase, whereas 14 (48%) of the L-asparaginase treated dogs had side-effects related to this drug, including anaphylactic shock (9), anorexia or vomiting (4), hypersensitivity-related oedema (3), seizures (1) and acute pancreatitis (1). No abnormalities in clotting times, fibrinogen levels or antithrombin-III levels were found in any of the 62 dogs. PEG-L-asparaginase has the same anti-tumour activity as native L-asparaginase in dogs with NHL, but lacks side-effects.