1. Acute Promyelocytic Leukemia Ranjita Pallavi,MD Internal Medicine PGY-2

2. Acute Promyelocytic Leukemia FAB: AML M3 WHO 2008: AML with recurrent genetic abnormalities APL with t(15;17)(q22;q12);(PML-RARA) 10-15% of all AML cases (~1300/year in US) 80-90% cure rate, though morbidity and mortality is high before and during induction Disseminated intravascular coagulation relatively common at diagnosis Highly sensitive to anthracyclines t(15;17) and PML-RARa fusion gene required All-trans retinoic acid (ATRA) targets RARa Arsenic trioxide (ATO) targets PML Patients have high cure rates, once they survive induction 3. Molecular Features of APL PML/RARa gene product forms homodimer Homodimer represses target genes needed for differentiation Mechanisms act via aberrant histone modification and DNA methylation Mechanism of ATRA: ATRA causes a conformational change of the PML/RARa protein Downstream targets that had been repressed become activated, leading to normal differentiation Wang, Blood, 2008 4. Acute Promyelocytic Leukemia Without treatment, APL is the most malignant form of AML with a median survival of less than one month. Modern therapy has dramatically changed its prognosis and APL is now associated with the highest proportion of AML patients who are cured of their disease. APL represents a medical emergency with a high rate of early mortality, due mainly to hemorrhagic complications from a characteristic coagulopathy. The first golden rule that has to be followed as soon as the diagnosis of APL is suspected based upon cytologic criteria is: to immediately start treatment with all-trans retinoic acid (ATRA) without delay, even before definitive (cyto)genetic confirmation of the diagnosis has been made. If the diagnosis is not confirmed, ATRA can always be discontinued and treatment changed to that used for other types of AML. 5. A review of blasts 6. APL morphology: Hypergranular Tallman, Blood, 2009 7. APL Morphology: Microgranular Tallman, Blood, 2009 8. The Action of Differentiation Wang, Blood, 2008 9. Treatment Approaches Can the patient tolerate anthracyclines? What is the risk-stratification based on the Sanz criteria? (WBC and platelet count) Induction Consolidation Maintenance Relapse Several established treatment protocols Important not to mix and match induction from one trial with consolidation from another 10. Risk Stratification Low: WBC < 10,000 and platelets > 40,000 Intermediate: WBC < 10,000 and platelets < 40,000 High: WBC > 10,000 Sanz, Blood, 2000 11. Treatment Guidelines 12. Treatment Guidelines 13. Treatment Guidelines 14. Treatment Guidelines 15. Treatment Guidelines 16. APL and DIC APL associated with significant coagulopathy. Coagulation parameters (fibrinogen, FDP/XDP, PT, aPTT, and platelet counts) should be monitored closely. Transfusions of platelets or fresh frozen plasma are traditionally used to maintain the platelet count above 20,000 to 30,000/L and the plasma fibrinogen concentration above 150 mg/dL. Heparin must not be used for prophylaxis in this setting. In case of life-threatening bleeding, inhibitors of fibrinolysis should be considered. Invasive procedures such as central venous catheterization, lumbar puncture, and bronchoscopy should be avoided before and during induction remission. 17. ATRA and Coagulopathy 18. ATRA and Coagulopathy Principal pathways of APL cell interactions with the hemostatic system, which can be affected by ATRA. APL cell expresses: (a) cellular procoagulants (TF and CP) that activate the clotting cascade; ATRA decreases the expression of both TF and CP, thus reducing the procoagulant activity; (b) fibrinolysis proteins (u-PA, t- PA, PAI) and receptor (u-PAR); ATRA increases both plasminogen activators and inhibitors, resulting in unchanged or reduced fibrinolytic activity; (c) nonspecific proteases, including granule elastase, that proteolyze fibrinogen/fibrin and other coagulation factors; ATRA does not affect this cellular mechanism; and (d) cytokines, including IL-1 and TNF-, that induce the endothelium thrombogenicity; ATRA increases the production of cytokines. 19. Coagulation markers in newly diagnosed APL patients (n=9) receiving ATRA for induction therapy. Barbui T et al. Blood 1998;91:3093-3102 1998 by American Society of Hematology 20. Differentiation Syndrome Previously named Retinoid acid syndrome Occurs in 1025% of APL patients within 2 to 21 days after initiation of treatment. More frequently in patients with a high white blood cell count at diagnosis. Characterized by fever, peripheral edema, pulmonary infiltrates, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, and serositis resulting in pleural and pericardial effusions. Symptoms of fever, hypotension, dyspnea, and pulmonary infiltrates can mimic sepsis. Sometimes, the syndrome is accompanied by hyperleukocytosis Early recognition and aggressive management with dexamethasone therapy (10 mg IV every 12 hours for 3-5 days with a 2 week taper ) has been effective in most patients. Continue to hold ATRA till symptoms resolv.e ATRA or ATO can be restarted in most cases once the syndrome has resolved. 21. Differentiation Syndrome 22. Differentiation Syndrome 23. Hyperleucocytosis Marked increase in WBC count due to the rapid maturation induced by ATRA of a large mass of leukemic cells, may result in leukostasis. Most current remission induction regimens now combine ATRA with cytotoxic chemotherapy, the frequency of hyperleukocytosis has decreased. 24. Pseudotumour Cerebri Idiopathic intracranial hypertension (IIH), commonly called pseudotumor cerebri, can complicate the treatment of APL with ATRA. More common in children and adolescents treated with ATRA and the incidence in this population decreased with the use of lower dose ATRA (25 mg/m2/day). Diagnosis of IIH is suspected in patients with headache, papilledema, and/or vision loss. Evaluation includes a physical examination including lumbar puncture, cerebral imaging studies (computed tomography or magnetic resonance) and fundus oculi. diagnosis is confirmed in patients with increased intracranial pressure, normal cerebrospinal fluid, and negative cerebral imaging studies. If symptoms persist, therapeutic options include the temporary discontinuation or dose reduction of ATRA, analgesics, and/or the administration of steroids and acetozolamide. 25. Management of special situations: Pregnant Women Treatment approach depends largely upon the trimester of pregnancy during which APL is diagnosed. First Trimester: Both ATRA and ATO are considered to be highly teratogenic and are contraindicated during the first trimester of pregnancy. if elective termination of the pregnancy is unacceptable to the patient, the only available treatment option is the administration of chemotherapy alone. If treatment with chemotherapy alone is chosen, daunorubicin may be the preferred anthracycline for pregnant women because there is greater experience with this drug during pregnancy. If a remission is achieved and the pregnancy continues normally, ATRA may be added during the second or third trimester. 26. Management of special situations: Pregnant Women Second or Third Trimester: Two main options are available: 1.Remission induction with ATRA alone and chemotherapy postponed until after delivery. 2.Simultaneous administration of ATRA plus chemotherapy. Simultaneous administration of ATRA plus chemotherapy offers the best chance of cure. Vaginal delivery is generally preferred since it is associated with a reduced risk of bleeding. After delivery, breastfeeding is contraindicated while on chemotherapy or ATO. 27. Management of special situations: Therapy related APL Develops usually less than 3 years after a primary neoplasm (especially breast carcinoma). Particularly with topoisomerase IItargeted drugs (anthracyclines or mitoxantrone and less often etoposide). t-APL appear to have a similar prognosis as de novo APL and benefit from standard APL therapy. In patients with a history of anthracycline exposure or cardiac impairment that limits their ability to receive further treatment with anthracyclines, alternative regimens, such as ATRA plus ATO may be used. 28. Management of special situations: Genetic variants of APL More than 90% of patients with APL have t(15;17)(q22;q12) translocation resulting in the PML/RARA fusion gene. Very rarely have been described alternative fusion genes resulting in leukemias classified as "AML with a variant RARA translocation" Some of these conditions are sensitive to ATRA therapy while others are not. In general, patients with alternative fusion genes ATRA-sensitive are treated with standard ATRA-based therapy. Patients with variants known to be resistant to ATRA are treated with standard AML induction therapy. 29. Management of special situations: Genetic variants of APL The following are the alternative fusion genes identified as ATRA- sensitive: NuMA/RARA and t(11;17) NPM1/RARA and t(5;17) FIP1L1/RARA The following are ATRA-resistant variants: STAT5b/RARA and interstitial chromosome 17 deletion PLZF/RARA and t(11;17) In case APL patients have additional cytogenetic abnormalities, as trisomy 8, or particular molecular abnormalities (gene mutations in FLT3) the prognosis is not worsened and they are considered to have the same prognosis as standard APL.