Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among its multiple toxic effects, L-asparaginase induces allergic reactions that may reduce its biological effect. The impact of hypersensitivity reactions on the duration of leukemia-free survival (LFS) was assessed in adults with newly diagnosed acute lymphoblastic leukemia (ALL) receiving intensive multi-agent chemotherapy. In CALGB study 8811 (Blood 1995; 85: 2025-2037), 197 adults were scheduled to receive 14 doses of Escherichia coil L-asparaginase (6000 U/m2 SC) during 7 of the first 12 weeks of chemotherapy. No further L-asparaginase was given. Chemotherapy was given for 24 months. The median follow-up time has been 5.7 years. Of the 141 patients who remained on study after 12 weeks, 82 (58%) had received all 14 planned doses; 38 (27%) had 12-13 L-asparaginase doses documented in their treatment record; 21 (15%) patients had received < or =11 doses due to a variety of toxic effects. The mean number of doses received prior to experiencing any hypersensitivity reaction was seven (range 1-11). Seven patients had mild hypersensitivity reactions, but all seven eventually received 12-14 doses of E. coil L-asparaginase. Twenty-one other patients had severe hypersensitivity reactions that required discontinuation of E. coil L-asparaginase; 20 of these patients were switched to Erwinia L-asparaginase to complete their treatment. Ultimately, 12 of these 20 patients received 14 doses of L-asparaginase in total, and six received 12-13 doses. Thus, only three of the 21 patients who had severe hypersensitivity reactions received < or =11 total L-asparaginase doses. Other L-asparaginase-related complications included pancreatitis (15 patients), hypofibrinogenemia <100mg/dl (29 patients), and deep venous thrombosis or pulmonary embolism (eight patients); some of these patients had L-asparaginase discontinued after these complications. The estimates for LFS at 3 years were 55% (95% confidence interval, 44-65%) for the patients who received all 14 L-asparaginase doses (median LFS, 5.1 years), 47% (95% CI, 33-62%) for those who received 12-13 doses, and 48% (95% CI, 29-67%) for those who received < or =11 doses. There were no significant differences between these three groups in the length of LFS (P=0.68). LFS did not correlate with a history of severe hypersensitivity reaction (P=0.67). In general, E. coil L-asparaginase was well tolerated in these adult patients, and most patients received all of the planned therapy. Patients who had mild L-asparaginase hypersensitivity reactions and patients who switched to Erwinia L-asparaginase because of more severe allergic reactions did not have significantly shorter LFS than the remaining adults treated on this ALL protocol. The possibility that E. coli L-asparaginase is inactivated or destroyed in those individuals who have become hypersensitive to it becomes less important when allergic patients are secondarily treated with Erwinia L-asparaginase.
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PMID:Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia. 959 62

We attempted to administer PEG-L-asparaginase (PEG-L-A) following hematologic recovery to 38 patients undergoing autologous or allogeneic marrow transplantation for acute lymphoblastic leukemia (ALL). Twenty-four patients (12 of 22 receiving allogeneic and 12 of 16 receiving autologous transplants) received between one and 12 doses of PEG-L-A, including nine who completed the planned 12 doses of therapy. The toxicities encountered were similar to those observed in non-transplanted patients undergoing therapy with PEG-L-A and included allergic reactions, pancreatitis, weight loss, hypoalbuminemia, and low levels of anti-thrombin III. Of the 24 who received the drug, eight remain in remission. Of 12 patients in second remission at the time of transplantation who received PEG-L-A, five of seven who received allogeneic and two of five who received autologous transplants remain in remission, 16+ to 46+ months from transplant. While PEG-L-A could be administered to most of the patients undergoing marrow transplantation for ALL, most patients either relapsed while receiving the drug or developed toxicities which resulted in abbreviated courses. At this time, we cannot recommend PEG-L-A as single agent, post-BMT chemotherapy.
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PMID:Toxicity, pharmacology and feasibility of administration of PEG-L-asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia. 961 79

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)
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PMID:Use of L-asparaginase in childhood ALL. 976 45

A major complication of L-asparaginase therapy in acute lymphoblastic leukemia (ALL) is pancreatitis. Among the 915 cases of ALL seen over last 10 years, 19 (2%) developed pancreatitis. Median age was 5.5 years with a median duration of symptoms of 4 weeks. All cases had raised serum amylase and lipase. Pancreatitis was not related to the dose/duration of L-asparaginase therapy. Ultrasonography can be used as a corroborative investigation for diagnosis along with serum chemistries. Close clinical monitoring of children for early diagnosis of this complication is recommended.
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PMID:L-asparaginase (Leunase) induced pancreatitis in childhood acute lymphoblastic leukemia. 984 47

From January 1994 until May 1997, 54 children with leukemia and non Hodgkin lymphoma were analyzed. The enzymatic function and ultrasound examination of pancreas were estimated. In 17 of 54 patients the clinical symptoms suggesting pancreatitis or toxic lesion of pancreas were observed. In 13 cases L-asparaginase was administered. The main symptom of the pancreas disease was severe abdominal pain with vomiting. The typical ultrasound view of pancreatitis was observed in 4 cases, pancreas oedema was seen in 6 patients. The most serious course of pancreatitis was diagnosed in 3 children. Diabetes mellitus coexisted in two cases, in the third case osteoporosis was seen. Because of the toxic pancreas lesion in one patient the administration of L-asparaginase and cortical hormones was discontinued, in the remaining 2 children the therapeutic scheme was modified. In all 17 cases this side effect was completely reversible, as well as in 3 children with the most serious clinical course of pancreas lesions.
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PMID:[Clinical manifestation of toxic pancreas lesion in children with hematopoietic malignancies]. 1073 49

Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children. It has minimal bone marrow toxicity. Its major side effects are anaphylaxis, pancreatitis, diabetes, coagulation abnormalities, and thrombosis, especially intracranial. It is derived from 2 different sources: Escherichia coli and Erwinia chrysanthemi. Nonrandomized clinical studies have suggested a similar efficacy of these 2 types of asparaginases and a lower toxicity for Erwinia-asparaginase. The European Organisation for Research and Treatment of Cancer-Children's Leukemia Group (EORTC-CLG) 58881 trial randomized 700 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to either E coli- or Erwinia-asparaginase at the same dosage of 10 000 IU/m(2) twice weekly to compare toxicity and efficacy. Coagulation abnormalities were more frequent in the E coli-asparaginase than in the Erwinia-asparaginase arm of the study (30.2% versus 11.9%, P <.0001). The incidence of other toxicity was not significantly different. In the Erwinia-asparaginase arm, more patients failed to achieve complete remission (4.9% versus 2.0%; P =.038) and the relapse rate was higher, leading to shorter event-free survival (hazard ratio,1.59; 95% CI, 1.23-2.06; P =.0004). The estimate of event-free survival rate (SE) at 6 years was 59.8% (2.6%) versus 73.4% (2.4%). Overall survival rate at 6 years was also lower in the Erwinia-asparaginase arm at 75.1% (2.3%) versus 83.9% (2.0%), P =.002. With the dose scheduling used in this protocol, E coli-asparaginase induced more coagulation abnormalities but was superior to Erwinia-asparaginase for the treatment of childhood lymphoid malignancies.
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PMID:Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. 1192 60

Diabetic ketoacidosis (DKA) and pancreatic pseudocysts are rare complications following treatment of hematological malignancies with L-asparaginase (L-asp). Persistent hyperglycemia with recurrent DKA presenting as a long-term complication of L-asp-induced pancreatitis is even rarer. A 21-year-old man with pre-B-type acute lymphoblastic leukemia (ALL) developed pancreatic pseudocysts, DKA and persistent hyperglycemia after L-asp therapy. The patient was treated with oral hypoglycemic agents (OHA) for sugar control thereafter. Ten months later, another episode of DKA developed during relapsed ALL without having obvious precipitating factors. Insulin was then instituted for control of his blood sugar until death. The leukemic process may play some role in glucose homeostasis and may be considered as a precipitating factor for DKA. The patient finally died of disease progression of ALL and sepsis 2 years after the initial diagnosis of ALL.
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PMID:Diabetic ketoacidosis and persistent hyperglycemia as long-term complications of L-asparaginase-induced pancreatitis. 1243 31

To identify risk factors associated with the development of diabetes mellitus and to describe the prevalence of diabetes in pediatric hematopoietic cell transplant (HCT) survivors. The follow-up records of 748 patients who survived for at least 2 years after pediatric HCT were retrospectively reviewed for diagnosis of diabetes. Risk factors for type 2 diabetes were analyzed using multivariate statistics. Among 748 patients with a median of 11 years of follow-up, 38 developed diabetes after HCT. Four patients (three leukemia and one neuroblastoma) developed type 1 diabetes 8 to 14 years after HCT, at between 10 and 19 years of age. Thirty-four patients (32 leukemia and 2 aplastic anemia) developed type 2 diabetes 1 to 24 years after HCT, at between 11 and 41 years of age. Of the 34 patients with type 2 diabetes, 23 were non-Hispanic white, 3 had experienced asparaginase toxicity (hyperglycemia and/or pancreatitis), and 26 had a family history of diabetes. Risk factors associated with type 2 diabetes were diagnosis of acute or chronic leukemia, race/ethnicity other than non-Hispanic white, family history of diabetes, and asparaginase toxicity. The prevalence of type 1 diabetes among all surviving patients was 0.52%, or three times higher than the general U.S. population. The prevalence of type 2 diabetes was 9% among leukemia survivors and 2% among aplastic anemia survivors, both higher than expected. Pediatric HCT survivors are more likely to develop diabetes than the general population.
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PMID:Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. 1476 93

L-asparaginase is a key component of the antileukemic therapy in children with acute lymphoblastic leukemia (ALL). Pancreatitis has been noted to be a complication in 2-16% of patients undergoing treatment with L-asparaginase for a variety of pediatric neoplasms. Most cases of pancreatitis associated with L-asparaginase toxicity are self-limiting and respond favorably to nasogastric decompression and intravenous hyperalimentation. However, in rare instances, hemorrhagic pancreatitis or necrosis may occur. L-asparaginase-induced pancreatitis is an uncommon but potential lethal complication of the treatment of leukemia. We present a pediatric patient with leukemia and a severe, L-asparaginase-induced necrotizing pancreatitis, treated successfully with percutaneous drainage used to flush the infected necrotic parts.
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PMID:L-asparaginase-induced severe necrotizing pancreatitis successfully treated with percutaneous drainage. 1536 48

A major complication of L-asparaginase used in the treatment of paediatric malignancies in children is pancreatitis (2%-16%). However, only seven paediatric cases of pancreatic pseudocyst caused by the utilization of the agent have been reported in literature. We present the case of a 5-year old girl who had abdominal pain and epigastric dullness after the third course of BMF-95 protocol with a diagnosis of ALL. A pancreatic pseudocyst of 10 x 10 cm size was found by abdominal tomography. The cyst was treated by percutaneous external drainage, total parenteral nutrition (TPN), administration of octreotide and antibiotherapy for one month. Percutaneous external drainage has proven to be an effective, noninvasive method in this special case with a systemic disorder and the high risk of mortality should a surgical intervention have been performed.
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PMID:Pancreas pseudocyst associated with L-asparaginase treatment: a case report. 1643 84


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