Acute Promyelocytic Leukemia

Etiology

The RAR-alpha (Retinoic acid-alpha) gene which encodes nuclear hormone receptor transcription factors is present on the long arm of chromosome 17 and is invariably involved in APL. It promotes the expression of various genes after binding to retinoic acid. In majority (90% to 95%) of the cases, APL results from a t (15;17) (q22;q21) translocation resulting in the head to tail fusion of the promyelocytic leukemia (PML) gene, to RAR-alpha to generate two fusion genes, PML-RARalpha and a reciprocal RAR-alpha-PML (80%) that encode a protein, which functions as an aberrant retinoid receptor. The other cytogenetic abnormalities associated with APL include t(5;17)(q35;q21), t(11;17)(q23;q21), t(11;17)(q13;q21), and t(17;17)(q11;q21) fuse RAR-alpha to the Nucleophosmin (NPM), Promyelocytic Leukemia Zinc Finger (PLZF), Nuclear Mitotic Apparatus (NuMA), and STAT5b genes, respectively, leading to expression of their fusion proteins. These translocations also have clinical significance due to their responsiveness (NPM/RAR-alpha, NuMA/RAR-alpha) or partial/complete refractoriness to retinoids (STAT5B/RAR-alpha, PLZF/RAR-alpha).[4][5]

The mechanisms of formation of the above chromosomal rearrangements and initiation of the leukemia are unknown. Chemotherapy, ionizing radiation, industrial solvents, and other toxic agents are some of the known risk factors. 

Epidemiology

Acute promyelocytic leukemia is a relatively rare and comprises about 7% to 8% of adult AML cases. Acute promyelocytic leukemia is usually seen in middle-aged people with a median age of 47 years. Acute promyelocytic leukemia occurs very rarely before the age of 20. The incidence is slightly higher in males than in females.

Pathophysiology

The PML/RARa protein heterodimerizes with the retinoid X receptor (RXR), the resulting PML/RARa-RXR complex binds to retinoic acid-responsive elements in target genes, resulting in cessation of myeloid differentiation at the promyelocytic stage. The excessive promyelocytes express tissue factor (TF) which forms a complex with factor VII and activates factor X and IX and result in a pro-coagulant state. The immature promyelocytes also cannot build defenses against infections, rendering patients immunosuppressed.[6][7]

There are also certain fusions that make this leukemia insensitive to retinoic acid and chemotherapy.

Histopathology

Acute promyelocytic leukemia is characterized by the presence of the large atypical promyelocytes and other myeloid precursors in various stages of development in the peripheral blood. The bone marrow is hypercellular, and APL promyelocytes account for about 30% of the myeloid cells in the classic variant. The typical acute promyelocytic leukemia promyelocyte has a creased, folded, bilobed, kidney-shaped, or dumb-bell shaped nuclei with a high nucleus-cytoplasmic ratio, fine chromatin, and prominent nucleoli, in addition to many violet granules (which coalesce to form Auer rods) in the cytoplasm and intense myeloperoxidase activity. In the microgranular variant (20% to 30%), pellets and Auer rods are less prominent, and the nucleus has a characteristic bilobed, folded appearance. Other less common variants, hyperbasophilic variant, M3r (associated with the PLZF) have also been described in the literature.

On immunophenotyping, the premature malignant promyelocytes express bright cytoplasmic myeloperoxidase, early myeloid markers, CD13 and CD33 but do not express HLA-DR, CD11b and are weakly positive/negative for CD15, CD117 (expressed in mature myelocytes) and CD34 (early myeloid progenitor cells). CD9 is expressed in acute promyelocytic leukemia but not in other AML subtypes. Co-expression of CD 2 is commonly seen in the hypogranular variant of acute promyelocytic leukemia.

History and Physical

Patients usually present with generalized weakness and fatigue, gingival bleeding, petechiae or ecchymoses, visual changes secondary to retinal hemorrhages, epistaxis, or menorrhagia or infections. Patients may also present with thrombotic complications such as deep venous thrombosis, pulmonary embolism, cerebrovascular accident, etc. Some patients with advanced disease may present with overt disseminated intravascular coagulation and frank bleeding.

Pancytopenia is common at presentation. The key difference between APL and AML is that many patients with the former ae at risk for disseminated intravascular coagulation and associated hyperfibrinolysis. The coagulopathy has to be managed as a medical emergency otherwise it often leads to CNS and pulmonary hemorrhage.

Evaluation

When acute promyelocytic leukemia is suspected, evaluation of peripheral blood smear and FISH for the fusion of PML/RARA should be expedited for rapid diagnosis of this time-sensitive disease. A prompt coagulopathy workup including a platelet count, prothrombin time (PT), activated partial thromboplastin time (PTT), d-dimer or fibrin split products, and fibrinogen should also be performed. Bone marrow biopsy and immunophenotyping should also be performed. Conventional karyotyping should also be performed as a part of initial workup as it detects rare molecular subtypes of acute promyelocytic leukemia and other additional coexistent cytogenetic abnormalities- t(15:17). Reverse transcriptase-polymerase chain reaction (RT-PCR) for PML-RARA RNA is also used for confirming the diagnosis of acute promyelocytic leukemia and can also be used can for monitoring minimal residual disease.

Acute promyelocytic leukemia is classified into low-risk (white blood cell count (WBC) 10,000/microL or less and platelets 40,000/microL or more), intermediate (WBC 10,000/microL or less and platelets 40,000/microL or less), and high-risk (WBC more than 10,000/microL) to guide treatment.[8][9][10][11]

Lumbar puncture is done in high-risk patients with elevated WBC count if intrathecal therapy is contemplated. Further, a cardiac evaluation is necessary before administering anthracyclines.

Treatment / Management

Chemotherapy

Acute promyelocytic leukemia is a medical emergency with a very high pre-treatment mortality. All-Trans Retinoic Acid (ATRA) is the mainstay in the treatment of acute promyelocytic leukemia and used in all modern regimens. ATRA should be initiated without any delay even before cytogenetic confirmation is obtained. Before the introduction of ATRA in the 1980s, the prognosis of this disease was poor with chemotherapy alone. ATRA was then used in combination with anthracycline-based regimens with increased survival and cure rate. ATO (arsenic trioxide) also induces differentiation of the malignant myeloid clone by dissociating the PML/RAR-alpha-RXR complex from the target genes and found to have a synergistic action with ATRA. ATRA-ATO was also shown to have comparatively lesser toxicities than ATRA-chemo. Hence, ATRA-ATO for induction and consolidation has emerged as the new standard of care for patients with low-(to-intermediate) risk acute promyelocytic leukemia. ATRA- Idarubicin or ATRA - ATO plus gemtuzumab ozogamicin (antibody-drug conjugate) are preferred in patients with high risk without cardiac dysfunction. ATRA-ATO therapy with or without gemtuzumab ozogamicin is also a reasonable choice for patients with severe comorbidities, older adults, patients with cardiac dysfunction who cannot tolerate anthracycline-based regimens or overall poor functional status. Maintenance therapy after the initial consolidation is widely debated. Maintenance may not be necessary for patients receiving intensive induction/consolidation including ATO. Treatment and post-treatment monitoring up to 2 years with PCR are recommended. Treatment of relapsed APL is beyond the scope of this article.

Supportive Therapy 

Supportive therapy plays a very important role in the survival of patients with acute leukemia. Bleeding diathesis is a known complication, especially in patients receiving treatment and platelets, should be maintained above 30 to 50 × 10/l and fibrinogen above 100 mg/dl to 150 mg/dl, with aggressive blood product support. High suspicion should be maintained for systemic infections as the patients are routinely immunosuppressed. In granulocytopenic patients with fever, an empiric antibiotic regimen to treat gram-negative bacteria should be instituted. Vancomycin should be started, if there is suspicion of catheter-related infection or based on blood cultures or if there is a suspicion of severe unknown infection. Antifungal should be considered if fever persists 5 days after the initiation of empiric antibiotics with appropriate testing.

Because cure rates for APL are high, bone marrow transplantation is not the first option. It is only offered to patients who relapse or are resistant to therapy.

Intrathecal therapy is done in high-risk patients.

Differential Diagnosis

• Acute lymphoblastic leukemia (ALL)
• Acute myeloid leukemia (AML)
• Aplastic anemia
• Folic acid deficiency
• Myelodysplastic syndrome

Toxicity and Adverse Effect Management

Arsenic trioxide can cause prolonged QT and hepatotoxicity. Chemotherapy containing regimens cause cytopenias, increased risk of infections, mucositis. Idiopathic intracranial hypertension or pseudotumor cerebri is a known complication of retinoic acid derivatives. It is characterized by headaches, papilledema, increased intracranial pressure and improvement with a lumbar puncture. Steroids, acetazolamide, and analgesics can be used in patients with persistent symptoms.

Medical Oncology

Guidelines

1. Immediately admit patient, initiate ATRA and manage the coagulopathy
2. Confirm the diagnosis
3. Monitor coagulation parameters
4. Start transfusions until coagulation parameters are normalized
5. Start therapy with ATRA
6. Perform bone marrow assessment to determine the response
7. Continue ATRA therapy until there is clinical benefit
8. Combine ATRA with chemotherapy in patients who relapse

Prognosis

The prognosis of APL is very poor without treatment (median survival~1 month). However, with modern treatment, survival has improved greatly and most patients achieve complete remission and remain so. In the Lo-coco[12] study, the 2-year disease-free survival rate was 97% (95% CI, 94 to 100) in the ATRA–arsenic trioxide group and 90% (95% CI, 84 to 97) in the ATRA–chemotherapy group (P=0.11). 

Without treatment, death is inevitable due to infection and hemorrhagic differentiation syndrome. The WBC count is an indicator of prognosis; high counts are associated with high risk. Other factors that affect prognosis include advanced age, male gender, elevated serum creatinine, and fibrinogen levels.

Complications

Differentiation Syndrome is a cytokine release syndrome seen after initiation of differentiating agents characterized by fever, peripheral edema, pulmonary edema, multiorgan dysfunction which can be fatal, if not promptly recognized. High dose systemic steroids are helpful in these cases.

Hyper Leukocytosis can occur as a complication of differentiation agents due to rapid differentiation of immature promyelocytes. Systemic steroids and chemotherapy are used in severe cases.