Acute Promyelocytic Leukemia (APL) with PML-RARα

Lead: Signy Chow
Date of last revision: Aug 14, 2020

Terms of use: These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

Diagnosis and Pathologic Classification

The diagnosis of APL is made by the detection of the PML-RARα fusion gene and/or the associated chromosomal translocation. The majority (90%) of cases result from a t(15;17)(q24.1;q21.2) fusion, however complex cytogenetic rearrangements may also result in this fusion gene. The WHO 2016 revised the classification of APL under Acute Myeloid Leukemia with recurrent genetic abnormalities to “APL with a PML-RARα” so as to include such cases.¹

Pathophysiology

RARα with physiologic levels of retinoic acid ligand functions as a transcription activator in normal myeloid differentiation. PML is a growth suppressor on PML nuclear bodies. The aberrant PML-RARα fusion protein homo-dimerizes via the PML domain and binds to DNA via the RARα domain. PML complexes with other transcriptional co-repressors and the complex acts as a transcriptional repressor, resulting in differentiation block and inhibition of apoptosis.

At pharmacologic doses of retinoic acid (ATRA), binding to the RARα domain of PML-RARα results in a conformation change of the complex and reactivates gene transcription and differentiation. ATRA initiates degradation of fusion protein via normal feedback mechanism of retinoic acid. Arsenic trioxide (ATO) binds PML-RARα via the PML domain and triggers conjugation by SUMO, resulting in fusion degradation.^2,3

Baseline Evaluation & Testing

History with particular attention to:

• bleeding history, leukostasis and neurologic symptoms

Physical exam with particular attention to:

• bleeding, DIC - petechiae, purpura, bleeding from peripheral and central lines

Laboratory Testing

• CBCd, peripheral blood film, reticulocyte count
• electrolytes, creatinine, Ca profile, Mg, liver enzymes (ALT, bilirubin, ALP), uric acid, LDH
• INR, PTT, Fibrinogen
• Hep B & C screening, HIV serology, TBST
• Bone marrow aspiration and biopsy for:
  • Morphologic diagnosis
    • Typical (75%) – hypergranular promyelocytes with high nucleus: cytoplasmic ratio, creased/folded nuclei, prominent violet granules, clusters of Auer rods
    • hypogranular variant (25%) –bilobed/folded nucleus but no apparent granules
  • Flow cytometry - bright cMPO, CD13+CD33+, CD34weak/neg, HLA-DR-
  • Cytogenetics (t(15;17 or additional cryptic genetic rearrangement)
  • Molecular (RT-PCR for PML-RARα)
  • Next-Generation Sequencing for Myeloid Leukemias

Additional Testing & Considerations

• ECG, MUGA scan (if at risk for cardiac disease)
• low dose CT chest
• CT head - if any neurologic symptoms, use a high index of suspicion given risk of bleeding in APL patients

Staging and Prognostic Factors

APL is classified as low, intermediate and high risk based on wbc and platelet count.⁴

• Low risk: wbc ≤10 and plts > 40
• Intermediate risk: wbc ≤10 and plts <40
• High risk: wbc >10

Treatment

APL is a medical emergency with a high rate of early mortality, primarily due to hemorrhage from associated coagulopathy. In the clinical trial population including the early use of ATRA, the rate of hemorrhagic death was 3.7%, however population estimates indicate much higher early death rates. It is critical to start treatment with ATRA and correct coagulopathy as soon as the diagnosis is suspected based on clinical or morphologic features. If APL is not confirmed, therapy can then be switched to AML treatment as appropriate.

Patients with low and intermediate risk APL are treated with ATRA and ATO on the Lo-Coco protocol.⁵ Patients with high risk APL are treated on the APML4 protocol.⁶ The two protocols differ in both induction and post-remission phases, with high risk patients receiving an anthracycline for greater cytoreduction as well as a prolonged maintenance phase.

The role of maintenance therapy has been questioned since ATO has become routinely incorporated in induction. One study has demonstrated similar outcomes for high and low risk patients treated with ATO during induction, with no benefit to maintenance therapy.^7,8 More recent APL trials omit maintenance therapy altogether with similar results to the APML4 and APL0406 studies.⁹ The ongoing APML5 study comparing IV and oral ATO provides 4 cycles of consolidation as in the Lo-Coco protocol and omits maintenance treatment in all risk groups.

Thus, in select high risk patients achieving remission after induction, the ‘low/int’ post-induction approach of four consolidation phases and no maintenance may be considered. As there is no published evidence comparing the two approaches, this must be undertaken with appropriate informed consent and discussion of the risks vs. potential benefits of maintenance.

Special treatment considerations

1. Coagulopathy

   APL blasts over-express tissue factor, annexin 2 and urokinase. Tissue factor expression triggers coagulation, which leads to a consumptive coagulopathy. Annexin A2 and urokinase leads to hyperfibrinolysis. Recent studies also hypothesize that aberrant expression of Podoplanin on APL cells leads to platelet activation and aggregation.¹⁰ Patients with APL often present with thrombocytopenia, low fibrinogen and may have a prolonged PT and PTT/INR.¹¹

   In patients with suspected or confirmed APL without active bleeding:

   • transfuse cryoprecipitate or fibrinogen concentrates to keep fibrinogen > 1.5g/L
   • transfuse platelets to keep platelet 30-50 x 10⁹/mL until coagulopathy has resolved.^12,13

   In patients with established bleeding, fibrinogen and platelet targets should be established on a case-by-case basis.

2. Differentiation Syndrome

   The pathogenesis of differentiation syndrome (DS) is not entirely defined, but it is thought to arise from ATRA activation of systemic inflammatory response mediated by cytokine release from differentiating myeloid cells. ATRA may also induce changes in APL cells that promote endothelial damage and tissue infiltration.¹⁴ In clinical trials, the incidence was 35% in patients treated with ATRA+chemotherapy without prophylaxis,¹⁵ and 12-19% of patients treated with steroid prophylaxis in ATRA+ATO, ATRA+ATO+chemotherapy protocols,^5,6 though estimates vary. In multivariate analysis, only wbc > 10 at presentation was predictive of differentiation syndrome overall, though baseline elevated creatinine and wbc > 5 were also found to predict severe DS. ¹⁵

   Symptoms of Differentiation Syndrome

   fever weight gain reripheral edema dyspnea with pulmonary infiltrates pleuro/pericardial effusion hypotension renal failure

   There is variation in practice with regard to the use of steroid treatment to prevent differentiation syndrome, ranging from steroid prophylaxis throughout the duration of induction to no prophylaxis and initiation of therapy with symptoms of DS. At Sunnybrook, we use the following risk-stratified measures for prophylaxis:

   In low/intermediate patients:

   • no prophylactic steroids
   • daily weights and assessments for differentiation syndrome
   • dexamethasone 10mg BID at first indication of differentiation syndrome, continue until clinical resolution. A steroid taper may be used.
     
     

   In high risk patients

   • prophylactic prednisone 0.5mg/kg from d1-10 or until wbc <1 or resolution of differentiation syndrome, whichever occurs last (as in APML4 study)

   Supportive care for differentiation syndrome includes diuretic therapy, dialysis/ultrafiltration and respiratory support as needed. ATRA is held in severe in cases not responding to steroid and supportive care treatment

3. Arsenic Toxicity

   ATO causes QT prolongation in 33% of patients and may lead to serious cardiac arrthymias including torsade de points. Monitoring with ECGs, Magnesium levels and potassium should be monitored at the initiation of therapy and at least twice weekly. Potassium levels should be kept above 4.0mmol/L and Magnesium ideally above 0.9mmol/L. If QTc is increased or electrolytes are out of the desirable range, daily monitoring may be indicated during the period of abnormality. ATO should be held for QTc above 500ms. Concurrent medications that prolong QTc should be held or alternatives considered.

   Calculation of the QTc

   Normal QT intervals shorten with increased heart rate (HR) and should be corrected to arrive at an accurate estimation (QTc). Several correction formulas are available to calculate QTc, the commonly used Bazett correction may overestimate the QTc when HR exceeds 80bpm.¹⁶ The Framingham formula was used in recent clinical trials.⁵ In cases of uncertainty or persistently elevated QTc, cardiology consultation is recommended in order to avoid treatment delays.

   Assessment of Remission and Post remission monitoring

   APL has an excellent long-term prognosis, with a 97% event free survival (EFS) and 99% overall survival (OS) at 2 years in low and intermediate risk patients treated on ATRA+ATO (compared to 85% EFS and 91% OS in the ATRA-chemo arm).⁵ High-risk patients treated with ATRA+ATO+idarubicin in the APML4 study had an OS of 90%, failure free survival 88.1% and freedom from relapse of 97.5% at 2 years.⁶

   Low/Intermediate risk APL treated with ATRA/ATO

   ATRA and ATO are given until hematologic complete remission (CR/CRi). In clinical trials, median time to hematologic remission was 32 days (range 22-68d) and ATRA/ATO was given for a maximum of 60days.⁵ Generally, a bone marrow to assess for morphologic response may be performed when counts recover or after day 30-40 of induction, whichever is sooner, to assess for response, as ATRA/ATO may have continued myelosuppressive effects extending beyond remission.

   High risk APL

   A remission assessment is done at the completion of 36 days of induction at the time of hematologic recovery.

   For both low and high risk patients, morphologic CR is required to continue proceed to consolidation therapy. Molecular positivity for PML-RARα transcripts at the end of induction treatment is common (>60% of patients), and is not predictive of recurrence.¹⁷ However, persistent positivity for PML-RARα transcripts by RT-PCR post consolidation has been shown to predict impending relapse, thus another bone marrow following consolidation is required to assess for clearance of PML-RARα transcripts.¹⁷

   At Sunnybrook, for low risk patients, no further bone marrow monitoring is required following the establishment of molecular negativity post consolidation and patients are transitioned to regular clinical follow up. High-risk patients are at increased risk of relapse and should be assessed with a bone marrow for PML-RARα transcripts every 3 months for 2 years during maintenance, then q6 monthly for 2 years.

References:

1. Arber DA, Orazi A, Hasserjian R, Borowitz MJ, Beau MM Le, Bloomfield CD, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2406.
2. de Thé H, Pandolfi PP, Chen Z. Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. Cancer Cell. 2017;32(5):552-560.
3. Ablain J, de The H. Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood. 2011;117(22):5795-5802.
4. Sanz MA, Coco F Lo, Martı́n G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groupsPresented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999. Blood. 2000;96(4):1247-1253.
5. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N Engl J Med. 2013;369(2):111-121.
6. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120(8):1570-1580.
7. Powell BL, Moser BK, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Adding Mercaptopurine and Methotrexate to Alternate Week ATRA Maintenance Therapy Does Not Improve the Outcome for Adults with Acute Promyelocytic Leukemia (APL) in First Remission: Results From North American Leukemia Intergroup Trial C9710. Blood. 2011;118(21):258-258.
8. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116(19):3751-3757.
9. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16(13):1295-1305.
10. Lavallée V-P, Chagraoui J, MacRae T, Marquis M, Bonnefoy A, Krosl J, et al. Transcriptomic landscape of acute promyelocytic leukemia reveals aberrant surface expression of the platelet aggregation agonist Podoplanin. Leukemia. 2018;32(6):1349-1357.
11. Shahmarvand N, Oak JS, Cascio MJ, Alcasid M, Goodman E, Medeiros BC, et al. A study of disseminated intravascular coagulation in acute leukemia reveals markedly elevated D-dimer levels are a sensitive indicator of acute promyelocytic leukemia. Int J Lab Hematol. 2017;39(4):375-383.
12. Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. GU I DELI N E A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-250.
13. Sanz M a., Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875-1891.
14. Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777-2782.
15. Montesinos P, Bergua JM, Vellenga E, Rayón C, Parody R, de la Serna J, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775-783.
16. Roboz GJ, Ritchie EK, Carlin RF, Samuel M, Gale L, Provenzano-Gober JL, et al. Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide. J Clin Oncol. 2014;32(33):3723-3728.
17. Cicconi L, Fenaux P, Kantarjian H, Tallman M, Sanz MA, Lo-Coco F. Molecular remission as a therapeutic objective in acute promyelocytic leukemia. Leukemia. 2018;32(8):1671-1678.