22 oe VOL. 15, NO. 3, august 2016

Acute promyelocytic leukemia then and nowDr. Francesco Lo-Coco, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy

IntroductIon

Only a few thousand people worldwide are diagnosed each year with a rare tumour known as acute pro-myelocytic leukemia (APL), a subtype of acute

myelogenous leukemia (AML). However, progress in the treatment of APL, leading to dramatic improvements in patient outcomes, provides a unique paradigm in the field of oncology. Once considered one of the most malignant and rapidly fatal AML subtypes, APL has been transformed over the past 2 decades into the most frequently curable. This article provides a timeline of advances in both biologic and clinical research that have enabled more precise diagnosis and highly effective treatment (Figure 1).

unravellIng the cause of aPlIn 1957, the Norwegian hematologist Leif Hillestad first identi-fied APL as a distinct, highly aggressive subset of AML. The disease was described in more detail in 1959 by Jean Bernard, who reported on a series of 20 cases observed at St. Louis Hospital in Paris. However, it was only in 1977 that the unique translocation between chromosomes 15 and 17 (t[15;17]) that characterizes APL was described by Janet Rowley in Chicago.1

Then, in 1990, the altered genes involved (15;17) were identified. These were PML, a newly identified gene named after promyelocytic leukemia, and RARA (retinoic acid receptor alpha), which fuse as a consequence of the translo-cation to form the PML-RARA hybrid gene. Interestingly, the empirical use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) preceded by a few years the notion that these 2 agents actually target the RARA and PML moieties, respectively, of the hybrid protein.1

Progress in pinpointing the molecular features of APL also paved the way for more precise diagnosis at the genetic level. The gold standard for diagnosis today is reverse transcriptase-polymerase chain reaction (RT-PCR) from either bone marrow or peripheral blood (when infiltrated by high blast numbers), although fluorescence in situ hybridization (FISH) may also be used.2 White blood cell (WBC) counts are an important prognostic factor and help to determine the need for aggressive early treatment, as well as the risk of early death and relapse following initial treatment. The presence of PML/RARA fusion protein drives the disease and is predictive of favourable response to targeted treatment with ATRA and ATO.2,3

aPl treatment: Past, Present and futureThe first major breakthrough in the treatment of APL came in 1973, when the disease was found to be highly sensitive to daunorubicin. Clinical trials showed some durable responses with anthracycline chemotherapy, and this approach was adopt-ed in Italy and Spain, where specifically tailored clinical studies were designed for APL long before the advent of ATRA.4

Chinese scientists reported in 1988 that APL was highly sensitive to ATRA, which produced terminal differentiation of leukemic cells without inducing myelosuppression.5 This finding contradicted the dogma that malignant transformation was always an irreversible condition.

In 1997, a group from Shanghai reported that APL was also highly responsive to arsenic trioxide (ATO), an old remedy used for many centuries in the treatment of various conditions, including cancer.6 The efficacy of ATO as a single agent in APL was first established in patients who relapsed after ATRA + chemotherapy.7

Studies published in the early 2000s showed improved overall and relapse-free survival with ATO + ATRA in both relapsed and newly diagnosed low-risk patients.8,9 The randomized APL0406 trial found that ATO + ATRA was noninferior to ATRA + chemotherapy in low-intermediate risk patients, with higher event-free and overall survival after 2 years, less hematologic toxicity and fewer infections.10,11 In 2015, another randomized trial reported significantly better outcomes and less hematologic toxicity for ATRA + ATO vs ATRA + chemotherapy.12 A chemotherapy-free treatment regimen also reduces the risk of developing secondary malignancies.4,13

recognIzIng a medIcal emergencyAPL is a rare disease with early symptoms that may be attributed to other causes, increasing the risk of delayed or missed diagnosis. Comprising just 10% to 15% of all patients with newly diagnosed AML,14 only 399 cases of APL were diagnosed in Canada between 1993 and 2007.15 Clearly, many physicians will never see a case of APL. The most common symptoms include easy bleeding or bruising, pallor, dyspnea, fatigue, fever and infection. Compared to other AMLs, APL affects a younger patient population: the median age at diagnosis for APL is 44, versus 67 for AML. Men and women are affected in almost equal numbers.16,17

Prompt diagnosis is crucial, as APL frequently develops abruptly, and patients are at high risk of mortality from cerebral or pulmonary hemorrhage, which may occur in up

Figure 1. Timeline of advances in APL treatment

ATO=arsenic trioxide; ATRA=all-trans retinoic acid.

Responses with anthracycline chemotherapy

Responses to ATRA (vitamin A derivative)

High cure rates with ATRA + chemotherapy

Improved, risk-adapted ATRA + chemotherapy combination

First description

Specific chromosome lesion identified

Altered genes identified

Responses to ATO

Chemotherapy-free (ATO + ATRA) results

2004-10

1993

1988

19731957

1977

1990

1997

2006-15

AcuTe PromyeLocyTic LeukemiA:From highLy FATAL To highLy curAbLe

oe VOL. 15, NO. 3, august 2016 23

to 40% of untreated patients.18 Hence, the disease has to be considered and managed as a medical emergency.2

Initiating treatment quickly is essential in a patient sus-pected of having APL. Patients presenting with clinical symptoms suggestive of APL should have a blood and bone marrow smear done rapidly in conjunction with coagulation tests. Meanwhile, a sample should be sent to the reference laboratory for genetic analysis to identify the PML/RARA by RT-PCR or FISH. Simultaneously, and even before results of the RT-PCR are available, aggressive supportive care should be instituted with transfusion of platelets and fresh frozen plasma (or concentrates), and treatment with ATRA should be started.2,17,19

Risk stratification is important for determining appropri-ate treatment and assessing the risk of relapse: patients with WBC counts ≤10x109/L are considered as low-intermedi-ate risk for relapse, while those with WBC counts >10x109/L are considered at high risk and are generally subjected to more intensive consolidation regimens.17

current recommendatIonsUntil recently, ATRA + chemotherapy was the standard first-line therapy for APL, and it is still widely used in this setting.20 However, a chemotherapy-free approach has become the current standard of care for induction therapy in untreated low- to intermediate-risk APL patients.6,20

The U.S. National Comprehensive Cancer Network (NCCN) 2016 guidelines endorse the following options for newly diagnosed low-, intermediate- and high-risk patients: ATRA + ATO (+ idarubicin for high-risk patients); ATRA + daunorubicin + cytarabine; or ATRA + idarubicin.17 The panel advises using patient risk group, age and cardiovascu-lar risk to guide regimen selection, and following the chosen trial protocol consistently for both induction and consoli-dation. NCCN notes that all 3 combinations “will yield excellent results,” but lists ATRA + ATO as the first choice based on the APL0406 study results.17

Canadian consensus guidelines released in 2014 recom-mend ATRA + ATO for both induction and consolidation in untreated low- to intermediate-risk APL patients and, for high-risk patients, induction with ATRA + ATO + idarubicin, followed by consolidation with ATRA + ATO.19

ATO has been approved for induction of remission and consolidation in patients with APL that is refractory to or has relapsed from retinoid and anthracycline therapy, and whose APL is characterized by the presence of the t(15;17) trans-location or PML-RARA gene expression. Screening for cardiac arrhythmias is essential, along with monitoring for hemor-rhage, liver function alterations and QTc prolongation.21

Patients on ATRA or ATO need to be managed with vigilant monitoring for signs of potentially fatal differentiation syndrome (DS), which include: dyspnea, fever, weight gain, peripheral edema, hypotension, acute renal failure, congestive heart failure and, especially, pulmonary infiltrates or pleuro-pericardial effusion, with or without leukocytosis. At early signs of DS, high-dose dexamethasone should be used imme-

diately; in certain situations, such as patients with WBC counts >10x109/L, steroids may be provided prophylactically.17,21,22

real-world outcomesSurvival in APL has improved dramatically over the years: 5-year relative survival was only 18% in the 1975–1990 period, compared to 64% in 2000–2008.23 The early death rate (≤30 days after diagnosis) is low for patients enrolled in clinical trials (5%–10%) but remains high in the “real world” (17%–29% in registry studies).19 Older patients have still-poorer outcomes: population-based studies in Canada have shown an early death rate of 10.6% among <50-year-olds, but a significantly higher 35.5% in patients ≥50.15

contInuIng challenges Despite impressive progress, APL still represents a challenging disease, with many patients dying early of severe hemorrhage. It is likely that misdiagnosis, late recognition and delayed referral to secondary/tertiary care centres contribute to this situation. In addition to educational efforts, further laboratory and clinical investigation is needed to predict and prevent severe hemorrhagic and thrombotic events.

references1. Lo-Coco F, Cicconi L. History of acute promyelocytic leukemia: a tale of endless

revolution. Mediterr J Hematol Infect Dis. 2011;3(1):1-6. 2. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic

leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875-1891.

3. Testa U, Lo-Coco F. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Ann Hematol. February 2016:1-8.

4. Lo-Coco F, Cicconi L, Breccia M. Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol. 2016;172(6):841-854.

5. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72(2):567-572.

6. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (AFL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89(9):3354-3360.

7. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19(18): 3852-3860.

8. Shen Z-X, Shi Z-Z, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101(15):5328-

9. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107(9):3469-3473.

10. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N Engl J Med. 2013;369(2):111-121. doi:10.1056/NEJMoa1300874.

11. Platzbecker U, Avvisati G, Ehninger G, et al. Improved outcome with ATRA-arsenic trioxide compared to ATRA-chemotherapy in non-high risk acute promyelocytic leukemia – updated results of the Italian-German APL0406 trial on the extended final series. Blood. 2014;124:12.

12. Burnett AK, Russell NH, Hills RK, 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.

13. Eghtedar A, Rodriguez I, Kantarjian H, et al. Incidence of secondary neoplasms in patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus chemotherapy or with all-trans retinoic acid plus arsenic trioxide. Leuk Lymphoma. 2015;56(5):1342-1345.

14. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Leukemia. 2009;114(25):5126-5135.

24 oe VOL. 15, NO. 3, august 2016

15. Paulson K, Serebrin A, Lambert P, et al. Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: A pan-Canadian epidemiological study. Br J Haematol. 2014;166(5):660-666.

16. Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all- trans retinoic acid. Blood. 2011;118(5):1248-1255.

17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Acute Myeloid Leukemia, Version 1.2016. Fort Washington, PA; 2016.

18. Kotiah SD, Besa EC. Acute Promyelocytic Leukemia Clinical Presentation. Medscape Drugs & Diseases. 2015. http://emedicine.medscape.com/article/1495306-clinical.

19. Seftel MD, Schuh AC, Barnett MJ, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21(5):234-250.

20. Cicconi L, Lo-Coco F. Current management of newly diagnosed acute promyelocytic leukemia. Ann Oncol. 2016;27(8):1474-1481.

21. Lundbeck Canada Inc. PrTRISENOX® (arsenic trioxide) Product Monograph. 2013.

22. CHEPLAPHARM Arzneimittel GmbH. VESANOID® (all-trans retinoic acid/tretinoin) Product Monograph. 2013.

23. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. Cancer. 2012;118(23):5811-5818.