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Table 1 Statements and results of the Delphi consensus process

From: National Italian Delphi panel consensus: which measures are indicated to minimize pegylated-asparaginase associated toxicity during treatment of adult acute lymphoblastic leukemia?

No Statement Consensus degree (%)
1. Clinical usefulness of E.coli Peg-ASP for the treatment of adult patients with Ph negative ALL
 1.1 Peg-ASP is a pivotal medication in the treatment of ALL, indispensable if the treatment aim is curative 100% affirmative
 1.2 There are patients for whom there is an absolute contraindication to the use of Peg-ASP (age, comorbidity) Consensus not reached
 1.3 The study of patient-associated risk factors may significantly limit the incidence of adverse events related to the use of Peg-ASP 100% affirmative
 1.4 The toxicities associated with the administration of Peg-ASP are manageable in the majority of adult patients 100% affirmative
2. Peg-asparaginase toxicity profile
 2.1 It is difficult to predict and characterize by significant variability from patient to patient (individual predisposition Consensus not reached
 2.2 Appropriate knowledge is needed of the mechanisms underlying the development of toxicities in order to establish adequate preventive measures and early intervention at the onset of toxicity 100% affirmative
 2.3 It may potentially be influenced by concomitant therapies (chemotherapy, antibiotics, antifungals, steroids) 95% affirmative
 2.4 Fatal outcome on rare occasions 100% affirmative
3. Hypersensitivity reactions
 3.1 It is advisable to pre-medicate every administration of Peg-ASP to reduce its incidence and/or severity 74% affirmative
 3.2 In case of known grade 3–4 allergic reaction, further administrations of Peg-ASP are contraindicated 95% affirmative
 3.3 In case of established grade 3–4 allergic reaction to Peg-ASP, substitution with the Erwinia chrysanthemi formulation is indicated 95% affirmative
 3.4 In case of a clinically manifested hypersensitivity reaction, ASP activity should be measured to promptly identify any possible inactivation of the medication 74% affirmative
4. Hepatic toxicity
 4.1 It is the most frequent toxicity and therefore requires close monitoring (pre-during-post-therapy) 95% affirmative
 4.2 In addition to abdominal ultrasound, other instrumental examinations are recommended prior to initiating Peg-ASP therapy Consensus not reached
 4.3 BMI > 30 and pre-existing hepatic steatosis contraindicate the use of Peg-ASP 89% negative
 4.4 BMI > 30 and pre-existing hepatic steatosis require a reduction in the dosage of Peg-ASP 89% affirmative
 4.5 Regardless of severity and degree of compensation, a diagnosis of chronic liver disease is an absolute contraindication of Peg-ASP treatment 74% negative
 4.6 Development of grade 3–4 toxicity does not contraindicate subsequent administrations of Peg-ASP 68% affirmative
5. Treatment of hepatic and/or metabolic toxicity
 5.1 Concomitant therapy (chemotherapy, antibiotics, antifungals, steroids, other) plays a decisive role in increasing the risk of hepatotoxicity during Peg-ASP therapy 95% affirmative
 5.2 L-carnitine is recommended in the event of hyperbilirubinemia 89% affirmative
 5.3 Hyperglycaemia should only be corrected with insulin therapy 84% affirmative
 5.4 Hypoalbuminemia should be corrected 95% affirmative
6. Hemorrhagic/thrombotic toxicity
 6.1 Laboratory alterations of the hemocoagulative parameters in the absence of clinical signs of thrombosis or bleeding do not necessitate discontinuation of Peg-ASP 100% affirmative
 6.2 The use of fresh plasma to correct hypofibrinogenemia is not recommended in the absence of haemorrhagic symptoms 89% affirmative
 6.3 Prophylaxis with LMWH is always recommended consensus not reached
 6.4 Any concomitant oral contraceptives or hormone replacement therapy should be discontinued 95% affirmative
 6.5 It is advisable to correct hypofibrinogenemia with cryoprecipitate 79% affirmative
 6.6 Replenishment of AT is advisable to maintain levels consistently above 60% 100% affirmative
7. Peg asparaginase-associated pancreatitis
 7.1 Therapy should be discontinued if asymptomatic pancreatitis develops (CTCAE grade 2, i.e. enzymes > 3 times normal or radiological evidence) Consensus not reached
 7.2 The dosage should be reduced if asymptomatic pancreatitis develops (CTCAE grade 2, i.e. enzymes > 3 times normal or radiological evidence) Consensus not reached
 7.3 CTCAE grade 2 pancreatitis, once resolved, does not contraindicate subsequent administration of Peg-ASP 95% affirmative
 7.4 Development of CTCAE grade 2 pancreatitis contraindicates subsequent administrations even with a different ASP formulation (Erwinia chrysanthemi) 79% negative
 7.5 Development of CTCAE grade 3–4 pancreatitis contraindicates subsequent administrations even with a different ASP formulation (Erwinia chrysanthemi) 95% affirmative
8. Metabolic toxicity management and prevention
 8.1 In the event of hyperglycemia with Peg-ASP and steroid therapy, it may be appropriate to reduce the steroid dose and enhance the insulin therapy rather than delay subsequent administrations of Peg-ASP 100% affirmative
 8.2 Patients being treated should be monitored for triglycerides 100% affirmative
 8.3 In case of severe (> 500 mg/dl), persistent, isolated hypertriglyceridemia, it is advisable to delay subsequent administrations of ASP Consensus not reached
 8.4 There is insufficient evidence that reducing the Peg-ASP dose reduces development of hepatopancreatic, thrombotic and metabolic toxicity Consensus not reached
 8.5 A preventive reduction in the dosage is always advisable if factors predisposing the development of toxicity are identified (e.g. BMI > 30, hepatosteatosis) 84% affirmative consensus
9. Monitoring of asparaginase plasmatic activity
 9.1 Monitoring of asparaginase plasmatic activity is essential in clinical practice in order to optimize the therapeutic activity of asparaginase (e.g. change of formulation in case of drug inactivation) 74% affirmative
 9.2 In clinical practice, routine monitoring of ASP plasmatic activity is useful in all patients with ALL Consensus not reached
 9.3 Searching for anti-asparaginase antibodies is of questionable value and should not therefore be routinely performed outside research studies in adult ALL 74% affirmative