Diagnostic workup and supportive care
| Recommendation . | Level of evidence–grade of recommendation . | Changes compared with the 2009 recommendations . |
|---|---|---|
| 1.1. Once a diagnosis of APL is suspected, the disease should be managed as a medical emergency | IV–C | Unchanged |
| 1.2. Patients should be managed by an experienced and multidisciplinary team in centers with rapid access to genetic diagnosis, blood products, and specific drugs, such as ATRA, ATO, and chemotherapy | IV–C | Unchanged |
| 1.3. Diagnosis should be confirmed by molecular detection of PML-RARA fusion (or rare molecular variants) | IIa–B | Unchanged |
| 1.4. In addition to FISH, RT-PCR, RQ-PCR, RT-QLAMP, and immunostaining with anti-PML antibody can be used for rapid diagnosis of APL | IIa–B | Updated |
| Management of coagulopathy | ||
| 1.5. Treatment with ATRA should be started immediately when a diagnosis of APL is suspected | Ib–A | Unchanged |
| 1.6. Transfusions of fibrinogen and/or cryoprecipitate, platelets, and fresh-frozen plasma should be given immediately upon suspicion of the diagnosis, and then daily or more than once a day if needed, to maintain the fibrinogen concentration above 100-150 mg/dL, the platelet count above 30 × 109/L to 50 × 109/L, and the INR below 1.5 | IIb–B | Slightly modified |
| 1.7. Platelet counts and routine coagulation parameters, prothrombin time, activated partial thromboplastin time, and thrombin time, as well as levels of fibrinogen and fibrinogen-fibrin degradation products, should be monitored at least daily and more frequently if required, until disappearance of all clinical and laboratory signs of the coagulopathy | IIb–B | New recommendation |
| 1.8. The benefit of heparin, tranexamic acid, or other anticoagulant or antifibrinolytic therapy remains questionable and should not be used routinely outside of the context of clinical trials | IV–C | Unchanged |
| 1.9. Central venous catheterization, lumbar puncture, and other invasive procedures (eg, bronchoscopy) should be avoided before and during remission induction therapy due to high risk of hemorrhagic complications | IV–C | Unchanged |
| Management of hyperleukocytosis (WBC count >10 × 109/L) at presentation | ||
| 1.10. Cytoreductive chemotherapy should be started without delay, even if the molecular results are still pending: | IV–C | Updated |
| • For patients to be treated with ATRA + chemotherapy, idarubicin or daunorubicin alone or combined with cytarabine should be given | ||
| • For patients to be treated with ATRA + ATO, cytoreduction can be done with idarubicin (12 mg/m2) or GO (6-9 mg/m2) | ||
| 1.11. Leukapheresis should be avoided due to risk of precipitating fatal hemorrhage | III–B | Unchanged |
| 1.12. Prophylactic corticosteroids can be given, which may reduce the risk of APL differentiation syndrome | IV–C | Unchanged |
| Management of APL differentiation syndrome | ||
| 1.13. Corticosteroids (10 mg of dexamethasone IV twice daily) should be started immediately at the earliest clinical suspicion of incipient APL differentiation syndrome; once the syndrome has resolved, steroids can be discontinued and ATO/ATRA recommenced | IIa–B | Unchanged |
| 1.14. Temporary discontinuation of differentiation therapy (ATRA or ATO) is indicated only in case of severe APL differentiation syndrome | IIa–B | Unchanged |
| Management of treatment with ATO | ||
| 1.15. An increase of WBC levels above 10 × 109/L after treatment initiation with ATRA and/or ATO should be interpreted as a sign of ATRA/ATO-induced differentiation and should not lead to reclassification of the patient as having high-risk disease | IV–C | New recommendation |
| 1.16. For patients who develop a significant increase of WBC counts after treatment initiation with ATRA and/or ATO, the addition of hydroxyurea (2 g/d) or, in case of extreme hyperleukocytosis, idarubicin (12 mg/m2) or GO (6-9 mg/ m2) can be considered | IV–C | New recommendation |
| 1.17. Treatment with ATO should be restricted to cases confirmed to be PML/RARA+ | IIb–B | Unchanged |
| 1.18. Treatment with ATO requires careful monitoring to maintain electrolytes in the normal range, keeping the serum potassium above 4.0 mEq/L and serum magnesium above 1.8 mg/dL | IV–C | Unchanged |
| 1.19. Treatment with ATO requires monitoring of the QT/QTc interval at least twice weekly: | IV–C | New recommendation |
| • For routine ECG surveillance of QT interval prolongation, alternative rate adjustment formulas other than the classical Bazett correction (eg, Fridericia, Hodges, or Sagie/Framingham) should be used | ||
| • Patients with episodes of significant QT prolongation or torsades de pointes, with clinical symptoms, such as dizziness and syncope, or with other risk factors should be closely monitored; telemetered ECG monitoring can be strongly considered in some patients at very high risk | ||
| • If the QT (or QTc for patients with heart rate >60 beats per minute) interval is prolonged longer than 500 ms, ATO should be withheld, the electrolytes repleted (potassium and magnesium), and other medications that may cause prolonged QTc interval sought and possibly discontinued | ||
| • Once the QT/QTc returns to ∼460 ms, and the electrolytes are repleted, ATO may be resumed |
| Recommendation . | Level of evidence–grade of recommendation . | Changes compared with the 2009 recommendations . |
|---|---|---|
| 1.1. Once a diagnosis of APL is suspected, the disease should be managed as a medical emergency | IV–C | Unchanged |
| 1.2. Patients should be managed by an experienced and multidisciplinary team in centers with rapid access to genetic diagnosis, blood products, and specific drugs, such as ATRA, ATO, and chemotherapy | IV–C | Unchanged |
| 1.3. Diagnosis should be confirmed by molecular detection of PML-RARA fusion (or rare molecular variants) | IIa–B | Unchanged |
| 1.4. In addition to FISH, RT-PCR, RQ-PCR, RT-QLAMP, and immunostaining with anti-PML antibody can be used for rapid diagnosis of APL | IIa–B | Updated |
| Management of coagulopathy | ||
| 1.5. Treatment with ATRA should be started immediately when a diagnosis of APL is suspected | Ib–A | Unchanged |
| 1.6. Transfusions of fibrinogen and/or cryoprecipitate, platelets, and fresh-frozen plasma should be given immediately upon suspicion of the diagnosis, and then daily or more than once a day if needed, to maintain the fibrinogen concentration above 100-150 mg/dL, the platelet count above 30 × 109/L to 50 × 109/L, and the INR below 1.5 | IIb–B | Slightly modified |
| 1.7. Platelet counts and routine coagulation parameters, prothrombin time, activated partial thromboplastin time, and thrombin time, as well as levels of fibrinogen and fibrinogen-fibrin degradation products, should be monitored at least daily and more frequently if required, until disappearance of all clinical and laboratory signs of the coagulopathy | IIb–B | New recommendation |
| 1.8. The benefit of heparin, tranexamic acid, or other anticoagulant or antifibrinolytic therapy remains questionable and should not be used routinely outside of the context of clinical trials | IV–C | Unchanged |
| 1.9. Central venous catheterization, lumbar puncture, and other invasive procedures (eg, bronchoscopy) should be avoided before and during remission induction therapy due to high risk of hemorrhagic complications | IV–C | Unchanged |
| Management of hyperleukocytosis (WBC count >10 × 109/L) at presentation | ||
| 1.10. Cytoreductive chemotherapy should be started without delay, even if the molecular results are still pending: | IV–C | Updated |
| • For patients to be treated with ATRA + chemotherapy, idarubicin or daunorubicin alone or combined with cytarabine should be given | ||
| • For patients to be treated with ATRA + ATO, cytoreduction can be done with idarubicin (12 mg/m2) or GO (6-9 mg/m2) | ||
| 1.11. Leukapheresis should be avoided due to risk of precipitating fatal hemorrhage | III–B | Unchanged |
| 1.12. Prophylactic corticosteroids can be given, which may reduce the risk of APL differentiation syndrome | IV–C | Unchanged |
| Management of APL differentiation syndrome | ||
| 1.13. Corticosteroids (10 mg of dexamethasone IV twice daily) should be started immediately at the earliest clinical suspicion of incipient APL differentiation syndrome; once the syndrome has resolved, steroids can be discontinued and ATO/ATRA recommenced | IIa–B | Unchanged |
| 1.14. Temporary discontinuation of differentiation therapy (ATRA or ATO) is indicated only in case of severe APL differentiation syndrome | IIa–B | Unchanged |
| Management of treatment with ATO | ||
| 1.15. An increase of WBC levels above 10 × 109/L after treatment initiation with ATRA and/or ATO should be interpreted as a sign of ATRA/ATO-induced differentiation and should not lead to reclassification of the patient as having high-risk disease | IV–C | New recommendation |
| 1.16. For patients who develop a significant increase of WBC counts after treatment initiation with ATRA and/or ATO, the addition of hydroxyurea (2 g/d) or, in case of extreme hyperleukocytosis, idarubicin (12 mg/m2) or GO (6-9 mg/ m2) can be considered | IV–C | New recommendation |
| 1.17. Treatment with ATO should be restricted to cases confirmed to be PML/RARA+ | IIb–B | Unchanged |
| 1.18. Treatment with ATO requires careful monitoring to maintain electrolytes in the normal range, keeping the serum potassium above 4.0 mEq/L and serum magnesium above 1.8 mg/dL | IV–C | Unchanged |
| 1.19. Treatment with ATO requires monitoring of the QT/QTc interval at least twice weekly: | IV–C | New recommendation |
| • For routine ECG surveillance of QT interval prolongation, alternative rate adjustment formulas other than the classical Bazett correction (eg, Fridericia, Hodges, or Sagie/Framingham) should be used | ||
| • Patients with episodes of significant QT prolongation or torsades de pointes, with clinical symptoms, such as dizziness and syncope, or with other risk factors should be closely monitored; telemetered ECG monitoring can be strongly considered in some patients at very high risk | ||
| • If the QT (or QTc for patients with heart rate >60 beats per minute) interval is prolonged longer than 500 ms, ATO should be withheld, the electrolytes repleted (potassium and magnesium), and other medications that may cause prolonged QTc interval sought and possibly discontinued | ||
| • Once the QT/QTc returns to ∼460 ms, and the electrolytes are repleted, ATO may be resumed |
GO, gemtuzumab ozogamicin.