Acute promyelocytic leukemia

What every physician needs to know:

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myeloid leukemia (AML) with unique molecular pathogenesis, clinical manifestations and treatment.

This is one of the few diseases where treatment must be started before the definitive diagnosis is established. This is the case because of the life-threatening and potentially fatal coagulopathy generated by the leukemic promyelocytes and perhaps by other cells. All-trans retinoic acid (ATRA), a derivative of vitamin A, differentiates the leukemic promyelocytes into mature granulocytes and corrects the coagulopathy in a median of four days. Aggressive and early blood product support with platelets and cryoprecipitate to replete fibrinogen are also mandatory.

The disease is highly curable and, in fact, is the most highly curable subtype of AML.

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Are you sure your patient has acute promyelocytic leukemia? What should you expect to find?

The majority of patients present with bleeding and pancytopenia. The physical examination usually demonstrates ecchymoses, often large and numerous on the trunk and extremities, but oropharyngeal bleeding may occur. There is rarely, if ever, adenopathy or organomegaly. Characteristically, most patients present with leukopenia, but approximately 15% of patients demonstrate leukocytosis. This has implications with regard to prognosis and treatment.

Other important findings characteristic of the disease are found in laboratory studies. Most patients have a coagulopathy manifested by a prolonged prothrombin time (PT) and partial thromboplastin times (PTT), a low fibrinogen and a very low platelet count. The pathogenesis of the coagulopathy is complex and includes disseminated intravascular coagulation (DIC), fibrinolysis and proteolysis (of fibrinogen and other proteins). Importantly, the absence of hypofibrinogenemia or any evidence of a coagulopathy does not exclude the diagnosis of APL.

Beware of other conditions that can mimic acute promyelocytic leukemia:

Few other diseases mimic APL.

Because of the often profound coagulopathy, patients with DIC due to other causes such as sepsis can mimic APL. In some cases there may even be an arrest in myeloid differentiation at the promyelocyte stage of development. Patients with acute myeloid leukemia of monocytic lineage may have an associated DIC which may also mimic APL. This is particularly true because the nuclear contours of both may have a so-called reniform, indented or bilobed appearance.

Most often, the combination of physical findings, review of the peripheral blood smear, and coagulation studies will strongly suggest the diagnosis.

Which individuals are most at risk for developing acute promyelocytic leukemia:

As is the case with most subtypes of AML, the factors that predispose to the development of APL are not well understood.

Interestingly enough, there are a number of reports of therapy-related APL following treatment with chemotherapy for other malignancies such as breast cancer as well as for nonmalignant diseases. For example, there appears to be an association with exposure to mitoxantrone for multiple sclerosis and the development of APL.

There is a suggestion that patients with a high body mass index may have a higher incidence of relapse and of the differentiation syndrome.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

In general, the diagnosis is easily established by the physical examination and laboratory findings. This includes review of the peripheral blood smear, complete blood count (CBC), coagulation studies, and bone marrow aspirate and biopsy.

Physical examination frequently demonstrates multiple ecchymoses. The peripheral blood smear usually reveals pancytopenia with an accumulation of promyelocytes. The leukemia cells show the characteristic reniform or bilobed nuclear contour and usually have abundant primary azurophilic granules. Cells often contain multiple Auer rods, termed faggot cells. However, the leukemia cells from patients with the microgranular variant (M3V) do not have these findings, and may be confused with nonpromyelocytic acute myeloid leukemia. The definitive diagnosis rests on the identification of either the t(15;17) translocation or the PML-RAR-alpha fusion transcript by molecular techniques.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of acute promyelocytic leukemia?

There are no imaging studies which are particularly useful in making or excluding the diagnosis. Chest imaging studies (a chest radiograph is usually sufficient) might be useful in making a diagnosis of the APL differentiation syndrome if symptoms or signs suggest this diagnosis.

If you decide the patient has acute promyelocytic leukemia, what therapies should you initiate immediately?

APL is a disease where emergent management is extremely important. At the very earliest suspicion of the disease treatment with all-trans retinoic acid (ATRA) should be started as well as intensive blood product support if there is any evidence of a coagulopathy. Such support should include platelet transfusions to maintain the platelet count of more than or equal to 30,000-50,000/uL. Fibrinogen should be repleted with cryoprecipitate to maintain the fibrinogen level of at least 150mg/dL.

It is important to emphasize that ATRA should be commenced well before confirmation of the diagnosis to prevent catastrophic bleeding. Hydration and attention to electrolytes is important, as is always the case in the treatment of patients with AML. Efforts to definitively establish the diagnosis by cytogenetic or molecular techniques are also emergently pursued, but after ATRA is initiated and blood product support is initiated.

More definitive therapies?

It is important to determine the risk (for relapse) for a given patient at diagnosis since therapies may change depending on the risk group. A simple risk classification is based on the presenting white blood cell count (WBC) at diagnosis and the presenting platelet count:

  • Low-risk is considered a WBC of less than 10,000/uL and a platelet count of more than 40,000/uL;

  • Intermediate-risk is considered when the WBC is less than 10,000/uL and a platelet count of less than 40,000/u;

  • High-risk is present when the WBC is more than or equal to 10,000/uL.

Practically, the outcomes of patients with low- and intermediate-risk are excellent and quite similar. Therefore, many combine low- and intermediate-risk and consider those patients with a WBC of less than 10,000/uL as low-risk for relapse.

Standard therapy for newly diagnosed patients with APL includes ATRA and anthracycline-based chemotherapy. There have been several regimens published which are very effective approaches. It may well be important to follow one regimen or another rather than selecting parts of one regimen and parts of another.

One popular regimen has been promoted by the PETHEMA Spanish group and includes ATRA at standard doses of 45mg/m2 in divided doses daily until complete remission (CR) and idarubicin 12mg/m2 given for 4 doses on days 2, 4, 6 and 8. This provides 1-2 days for the ATRA to begin to correct the coagulopathy, together with aggressive blood product support. There is no primary resistance in APL and if the patient survives induction, essentially every patient will achieve CR.

There is no need for a nadir marrow to document aplasia since aplasia may not be present and does not appear necessary for the achievement of CR. Patients then receive 3 cycles of consolidation followed by maintenance therapy for approximately 2 years.

The consolidation regimen for low-risk patients (WBC <10,000/uL) is as follows:

  • cycle 1: idarubicin 5mg/m2/day for 4 days with ATRA 45mg/m2/day for 15 days;

  • cycle 2: mitoxantrone 10mg/m2/day for 3 days and ATRA 45mg/m2/day for 15 days;

  • cycle 3: idarubicin 12mg/m2/day for 1 day and ATRA 45mg/m2/day for 15 days.

Maintenance therapy includes ATRA 45mg/m2/day for 15 days out of every three months plus methotrexate 15mg/m2/week, and 6-mercaptopurine 50mg/m2/day, all administered for 2 years.

For patients categorized as high-risk (WBC>/= 10,000/uL) the induction is the same as for low-risk. The consolidation is as follows:

  • cycle 1: idarubicin 5mg/m2/day for 4 days and ATRA 45mg/m2/day for 15 days and ara-C 1,000mg/m2/day for 4 days;

  • cycle 2: mitoxantrone 10 mg/m2/day for 5 days and ATRA 45mg/m2/day for 15 days;

  • cycle 3: idarubicin 5mg/m2/day for 1 day and ATRA 45mg/m2/day for 15 days and ara-C 150mg/m2/8 hours for 4 days.

Pediatric hematologists-oncologists usually reduce the dose of ATRA to 25mg/m2/day for patient ages less than 20 years due to an apparent increase in retinoid toxicity in children and young adults.

High-risk patients should receive either intermediate-dose ara-C in consolidation as above or in induction as administered in regimens promoted by the German AML Cooperative Group, or arsenic trioxide as an early consolidation. For older adults or patients who cannot receive anthracyclines, an attractive approach has been the combination of ATRA and arsenic trioxide. These agents can be administered concomitantly watching the WBC carefully. Minimal amounts of anthracyclines may be needed to control the WBC.

What other therapies are helpful for reducing complications?

A potential toxicity unique to the treatment of patients with APL with ATRA or arsenic trioxide is the APL differentiation syndrome. This is a cardiorespiratory distress syndrome manifested by pleural and pericardial effusions, dyspnea, pulmonary infiltrates, episodic hypotension, and renal failure. At the very first sign of any respiratory distress, even in the absence of pulmonary infiltrates, the institution of dexamethasone should be considered at a dose of 10mg/m2 twice daily until all symptoms have resolved.

ATRA can be continued if the symptoms and signs are mild, but if it is more severe, ATRA should be held and can be resumed under the coverage of steroids when all symptoms have resolved. While there are no randomized clinical trial data to support the prophylactic use of steroids to prevent the APL differentiation syndrome, many investigators now administer it prophylactically for high-risk patients (WBC >/= 10,000/uL) and some even consider it for all patients.

What should you tell the patient and the family about prognosis?

APL is the most highly curable among the subtypes of AML in adults. There is no primary resistance and therefore if a patient survives induction, virtually every patient will achieve CR, provided that PML-RAR-alpha fusion transcript is present.

The cure rate is excellent and overall approximately 80% of patients are cured of their disease. The cure rate among those patients who present with low- and intermediate-risk disease is higher and those with high-risk disease somewhat lower.

The prognosis is excellent regardless of additional cytogenetic abnormalities at diagnosis (trisomy 8 is the most common), immunophenotype, specific subtype of PML isoform, identification of therapy-related APL, or the presence of the microgranular variant. Therefore, there appears to be no indication to change conventional therapy based on any of these factors.

Patients who present with high-risk disease or those who develop a WBC >10,000/UL during the course of therapy can be considered for intrathecal chemotherapy once in CR and the coagulopathy has resolved completely, since such patients appear to have a higher risk of central nervous system relapse.

What if scenarios.

If a patient presents with high-risk disease, concurrent ATRA and chemotherapy is generally administered. If the coagulopathy is severe and the WBC is not much higher than 10,000/uL, ATRA may be started alone for 12-24 hours before chemotherapy in an effort to stabilize the coagulopathy with aggressive blood product support. However, if the coagulopathy is more modest and the WBC significantly higher than 10,000/uL, concurrent ATRA and chemotherapy may be commenced and aggressive blood product instituted.

If a patient presents with an intracerebral hemorrhage or for any other reason cannot tolerate ATRA (only available in an oral formulation) then arsenic trioxide can be considered (only available an intravenous formulation). If a patient develops leukocytosis (above 10,000/uL) during the course of therapy, one can consider the patient as having high-risk disease and can be treated in a similar way as a patient who presents with high-risk disease.

Pathophysiology

APL is believed to be caused by the formation of the PML-RAR-alpha fusion transcript which results from the t(15;17) translocation. The PML-RAR-alpha fusion transcript attracts histone deacetylase and the complex inhibits transcription. When the ligand such as retinoic acid is present in sufficient levels, dissociation of the nuclear corepressor complex takes place, a conformational change occurs and normal transcription resumes.

The coagulopathy is believed to be induced by procoagulants, antifibrinolytic substances and elastases released from the leukemic promyelocytes. However, it is possible that other cells contribute to the pathogenesis.

What other clinical manifestations may help me to diagnose acute promyelocytic leukemia?

When a young patient presents with pancytopenia perhaps, but not always in association with peripheral blasts, particularly with a predominance of promyelocytes, with bleeding and ecchymoses, one should consider the diagnosis of APL. It is characteristic to find multiple ecchymoses on the trunk and extremities. Often oropharyngeal, conjunctival or retinal bleeding are present.

What other additional laboratory studies may be ordered?

Review of the peripheral blood smear for leukemic promyelocytes and the coagulation profile (PT, PTT, fibrinogen and D-dimer) are important. The rapid anti-PML antibody test is widely used in Europe and elsewhere. Confirmation of the diagnosis is established by cytogenetic or molecular studies to identify the t(15;17) or the PML-RAR-alpha fusion transcript.

What’s the evidence?

Melnick, A, Licht, JD. “Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia”. Blood. vol. 93. 1999. pp. 3167-215. [This manuscript describes in detail the molecular pathogenesis of APL.]

Park, JH, Qiao, B, Panageas, KS. “Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid”. Blood. vol. 118. 2011. pp. 1248-54. [This manuscript provides evidence that the early death rate in APL is higher than commonly reported in multicenter clinical trials and has not changed substantially in the last two decades despite the routine use of ATRA.]

Tallman, MS, Kim, HT, Montesinos, P. “Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group”. Blood. vol. 116. 2010. pp. 5650-9. [This manuscript describes a large cohort of patients with the microgranular variant of APL and suggests that the morphology of the microgranular variant itself is not an independent prognostic factor and the outcome is excellent with ATRA and anthracycline-based chemotherapy strategies.]

Sanz, MA, Montesinos, P, Rayon, C. “Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracyclines with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome”. Blood. vol. 115. 2010. pp. 5137-46. [This manuscript provides evidence that cytarabine confers a benefit for patients with high-risk APL.]

Tallman, MS, Andersen, JW, Schiffer, CA. “Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome”. Blood. vol. 95. 2000. pp. 90-5. [This is one of the manuscripts characterizing the APL differentiation syndrome and describes the outcome with contemporary therapy.]

Breccia, M, Mazzarella, L, Bagnardi, V. “Increased body mass index correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols”. Blood. vol. 119. 2012. pp. 49-54. [This manuscript reports that a high body mass index appears to be associated with the development of the APL differentiation syndrome and a high relapse rate.]

Lo-Coco, F, Avvisati, G, Vignetti, M. “Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group”. Blood. vol. 116. 2010. pp. 3171-9. [This manuscript provides recent outcome data for patients treated with contemporary therapeutic strategies and provides evidence that intermediate-dose cytarabine is beneficial in high-risk patients.]

Estey, E, Garcia-Manero, G, Ferrajoli, A. “Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia”. Blood. vol. 107. 2006. pp. 3469-73. [This is one of the first manuscripts to provide strong evidence that patients with APL cvan be successfully treated with the combination of ATRA and arsenic trioxide.]

Powell, BL, Moser, B, Stock, W. “Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710”. Blood. vol. 116. 2010. pp. 3751-7. [This report of the North American Intergroup trial indicates that arsenic trioxide as an early consolidation confers a significant benefit for all risk groups of APL.]

Avvisati, G, Lo-Coco, F, Paoloni, FP. “AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance”. Blood. vol. 117. 2011. pp. 4716-25. [This randomized clinical trial suggests that for patients with APL in complete molecular remission after intensive consolidation chemotherapy, there appears to be no benefit for any maintenance therapy.]

Lengfelder, E, Haferlach, C, Saussele, S. “High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG”. Leukemia.. vol. 23. 2009. pp. 2248-2258. [Study demonstrating improved outcomes in high rixk patients treated with high-dose Ara-C.]

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