Current management of newly diagnosed acute promyelocytic leukemia

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1 reviews Annals of Oncology 73. Harada N, Hiramatsu N, Oze T et al. Efficacy of pegylated interferon and ribavirin combination therapy for patients with hepatitis C virus infection after curative resection or ablation for hepatocellular carcinoma a retrospective multicenter study. J Med Virol 2015; 87: Shirabe K, Sugimachi K, Harada N et al. Favorable prognosis in patients with sustained virological response to antiviral therapy, including interferon, for chronic hepatitis C before hepatic resection for hepatocellular carcinoma. Anticancer Res 2015; 35: Saito T, Chiba T, Suzuki E et al. Effect of previous interferon-based therapy on recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. Int J Med Sci 2014; 11: Jimenez-Perez M, Gonzalez-Grande R, Rando-Munoz FJ. Management of recurrent hepatitis C virus after liver transplantation. World J Gastroenterol 2014; 20: Berenguer M, Schuppan D. 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Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution. J Hepatol 2016, pii: S (16) Current management of newly diagnosed acute promyelocytic leukemia L. Cicconi & F. Lo-Coco* Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy Received 8 February 2016; revised 29 March 2016; accepted 4 April 2016 The management of acute promyelocytic leukemia (APL) has considerably evolved during the past two decades. The advent of all-trans retinoic acid (ATRA) and its inclusion in combinatorial regimens with anthracycline chemotherapy has provided cure rates exceeding 80%; however, this widely adopted approach also conveys significant toxicity including severe myelosuppression and rare occurrence of secondary leukemias. More recently, the advent of arsenic trioxide (ATO) and its use in association with ATRA with or without chemotherapy has further improved patient outcome by allowing to minimize the intensity of chemotherapy, thus reducing serious toxicity while maintaining high anti-leukemic efficacy. The advantage of ATRA ATO over ATRA chemotherapy has been recently demonstrated in two large randomized trials Annals of Oncology 27: , 2016 doi: /annonc/mdw171 Published online 15 April 2016 *Correspondence to: Dr Francesco Lo-Coco, Department of Biomedicine and Prevention, University of Tor Vergata, Via Montpellier 1, Rome 00133, Italy. Tel: ; Fax: ; francesco.lo.coco@uniroma2.it The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

2 Annals of Oncology reviews and this option has now become the new standard of care in low-risk (i.e. non-hyperleukocytic) patients. In light of its rarity, abrupt onset and high risk of early death and due to specific treatment requirements, APL remains a challenging condition that needs to be managed in highly experienced centers. We review here the results of large clinical studies conducted in newly diagnosed APL as well as the recommendations for appropriate diagnosis, prevention and management of the main complications associated with modern treatment of the disease. Key words: acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, PML-RARA introduction Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with specific clinical and biologic features. The genetic hallmark of the disease is the balanced reciprocal translocation t(15;17)(q22;q11-12), leading to the fusion of promyelocytic (PML) gene with the retinoic acid receptor α (RARA) gene. The resulting PML RARA hybrid oncoprotein is responsible for the block of differentiation of leukemic promyelocytes and is able to induce leukemia in animal models [1, 2]. The identification and characterization of PML RARA in the early 1990s also proved relevant in clinical practice, especially for refinement of APL diagnosis at genetic level, and for sensitive assessment of treatment response and early identification of relapse through minimal residual disease monitoring [3]. Interestingly, biologic studies that were carried out after the empirical use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) showed that either RARA or PML moieties of the hybrid protein contained binding sites for these agents and that both ATRA and ATO were able to induce disease remission through degradation of the oncoprotein, thus acting as complementary targeted agents [4]. APL is a rare disease, accounting for 5% 10% of AMLs of the adult, with an estimated incidence of 0.1/ [5] in Western countries. The disease presentation is frequently accompanied by a consumptive coagulopathy that can cause lifethreatening hemorrhages (most severe ones occurring in the brain and lungs) and more rarely thrombosis. A rapid diagnosis of APL and the institution of adequate anti-leukemic and supportive therapy are of paramount importance to prevent early death, which is currently considered the most important obstacle to the final cure of this disease. With the introduction of differentiation therapy with ATRA combined with conventional chemotherapy and the subsequent advent of ATO, APL has been transformed from the most rapidly fatal to the most frequently curable form of acute leukemia with long-term survival rates up to 90%. These remarkable advances have been the results of combined biologic and clinical research and provided a paradigm of targeted therapy in the entire oncology field. historical overview of advances in APL therapy APL was initially recognized as a distinct clinical entity by the Norwegian hematologist Hillestad in 1957 [6] and was fully characterized for its peculiar clinical presentation by Bernard few years later [7]. Bernard et al. working at Saint Louis Hospital in Paris also reported in 1973 the exquisite sensitivity of APL to anthracyclines, describing in a seminal study high complete remission (CR) rates obtained with daunorubicin as monochemotherapy [8]. This approach was to be followed soon in Italy and Spain, where specifically tailored clinical studies were designed for APL long before the advent of ATRA [9, 10]. The first reports on ATRA in APL therapy and subsequent studies conducted with ATRA in France and the United States represented the first example of successful differentiation therapy in oncology and revolutionized the treatment of the disease [11 13]. In fact, ATRA as a single-agent induced terminal differentiation of APL blasts into mature granulocytes and produced CR rates in up to 80% of cases without inducing myelosuppression; however, these results were not paralleled by satisfactory outcomes in the long-term because of high relapse rates [11 13]. These observations led several cooperative groups to design combinatorial approaches in which ATRA was given in association with chemotherapy [14]. ATRA and chemotherapy as induction and consolidation therapy resulted in long-term survival rates approaching 90%, especially after the introduction of risk-adapted approaches de-escalating chemotherapy intensity for the lower risk categories [14 17]. More recently, ATO (an old remedy used for centuries for the cure of various diseases) was shown to be the most potent single agent in APL therapy [18]. First employed in relapsed patients and subsequently approved by FDA and EMA for salvage therapy in patients relapsing after ATRA, ATO has been recently used either in front-line therapy of APL as a single agent or in combination with ATRA ± chemotherapy. After a pilot study conducted in the United States [19], the results of two randomized trials established this approach as the new standard of care at least for low- to intermediate-risk patients, allowing the cure of APL with targeted agents alone without chemotherapy [20, 21]. management of suspected APL APL can be diagnosed in patients of all ages, but median age is typically lower compared with other AML subsets (i.e. 40, versus 70 in other AMLs). APL manifests as a second malignancy following the treatment of a primary cancer or following the treatment of non-malignant conditions such as multiple sclerosis after treatment with topoisomerase II inhibitors ( particularly mitoxantrone) [22, 23]. A consumptive coagulopathy is present at diagnosis in 80% of patients and consists of hypofibrinogenemia, thrombocytopenia and increased PT, PTT and D-dimers; clinically, this may manifest in a variety of signs from mild muco-cutaneous hemorrhages (petechiae, bruising and ecchymosis) to severe internal intracranial or pulmonary bleeding. Less frequently, signs and symptoms related to thrombosis are Volume 27 No. 8 August 2016 doi: /annonc/mdw

3 reviews Annals of Oncology the initial manifestations of the disease [24]. Recent data from population-based studies describing the real-world situation (with many patients not even being entered into clinical trials) reported an early mortality rate ranging from 17% to 29%. These figures are in sharp contrast to those described in clinical trials employing ATRA and anthracycline-based chemotherapy ( 5%) [25 27]. Given the frequent abrupt onset and the risk of severe hemorrhagic events, immediate institution of ATRA and/ or ATO treatment and supportive therapy are critical for the correct management of APL and especially to avoid fatal outcomes. Current recommendations strongly suggest that these measures are started upon clinical suspicion of APL, without the need for waiting for genetic confirmation of correct diagnosis [28, 29]. The suspicion of APL generally arises from morphologic examination of the bone marrow, showing the characteristic infiltrate of abnormal hypergranular promyelocytes. A morphologic hypogranular variant defined as M3v by the French American British (FAB) classification can be identified in 20% of cases, and this is more challenging as it can resemble other AML subsets such as M5 or M1 types. Flow cytometry shows a distinctive pattern of antigen expression including strong positivity for CD33, expression of CD13 and CD117, infrequent expression of HLA-DR and CD34, and lack of CD11a, CD11b and CD14. Although not conclusive for APL diagnosis, this antigenic profile may help generating alert on a possible diagnosis of APL [30 32]. The sole morphologic suspicion of APL should always be followed by immediate institution of ATRA and/or ATO therapy and lead to aggressive replacement of platelets, fresh-frozen plasma and cryoprecipitates to counteract the ongoing coagulopathy without waiting for genetic confirmation. The search for the PML RARA gene rearrangement is, however, essential as the response to specific therapy depends on the presence of this genetic lesion. It is advised that wellexperienced, reference laboratories should be involved in this step. Current guidelines recommend transfusion support to maintain the fibrinogen concentration and platelet count above mg/dl and /l, respectively [28, 29]. Invasive procedures routinely done at presentation in other acute leukemias like placement of a central venous catheter (CVC) or lumbar puncture should be avoided during induction to avoid thrombo-hemorrhagic complications. For the same reason, leukapheresis in hyperleukocytic patients, even in cases showing signs of leukostasis, should be avoided [28, 33]. Current methods for genetic confirmation of APL diagnosis include assays able to identify PML RARA lesion at the DNA, RNA and chromosome level using FISH and RT-PCR, and indirect immunofluorescence tests to assess the nuclear distribution pattern of the PML protein. FISH analysis is preferred over karyotyping on G-banded metaphases because it does not require good quality metaphases and overcomes the false-negative results, possibly occurring with conventional karyotype analysis in case of cryptic or complex rearrangements [34]. RT-PCR is a well-standardized technique and the only assay allowing the identification at diagnosis of the precise PML RARA transcript isoform (long, short or variant) [35]. Such information is essential for subsequent molecular monitoring of minimal residual disease. Immunofluorescence analyzing nuclear distribution of PML protein allows a rapid diagnosis within 2 h using bone marrow smears [36]. The test identifies the typical staining pattern associated with PML-RARA referred to as microspeckled, as opposite to the so-called nuclear bodies pattern characteristic of other leukemias and normal hematopoietic cells. This type of assay is rapid and cheap, and is highly recommended in small laboratories not equipped and/or experienced for molecular testing [37]. Current recommendations for the management of suspected APL are summarized in Table 1. first-line therapy ATRA combined with chemotherapy Table 1. Recommendations for initial management of APL Management measures Recommendations Open issues Transfusional supportive care Initiation of therapy with ATRA and/or ATO Genetic diagnosis Lumbar puncture, placement of CVC line, leukapheresis and other invasive procedures Prophylaxis of differentiation syndrome Intensive transfusion support with plasma and platelet concentrates to maintain platelets /l and fibrinogen >1.5 g/l. Strict monitoring of blood count and coagulation profile (every 6 h in high-risk patients) Upon morphologic or clinical suspect of APL, therapy with ATRA and/or ATO should be started without waiting for genetic confirmation of diagnosis Diagnostic confirmation at genetic level is mandatory. FISH and/or RT-PCR are preferred tests to rapidly identify PML-RARA. To be avoided in light of the augmented risk of bleeding and/or thrombosis Prophylaxis with steroids is commonly recommended, particularly in patients with elevated WBC (> /l). ATRA in combination with simultaneous chemotherapy has represented the standard of care until very recently and still remains a widely used option in front-line therapy of APL. Long-term updates of studies using ATRA plus anthracyclinebased approaches confirm outstanding rates of cure exceeding 80% [14 16]. French investigators were the first to show that the simultaneous administration of ATRA and chemotherapy Benefit of antifibrinolytic, anticoagulant (heparins) and procoagulant (e.g. recombinant activated Factor VII) agents is controversial Type of steroid (methylprednisolone or dexamethasone) and duration of prophylaxis 1476 Cicconi and Lo-Coco Volume 27 No. 8 August 2016

4 Annals of Oncology provided better outcomes when compared with the sequential schedule [38]. In line with this approach, the Gruppo Italiano per le Malattie EMatologiche dell Adulto (GIMEMA) and the Programa Espanol para el Tratamiento de las HEmopatias Malignas del Adulto (PETHEMA) used only an anthracycline (idarubicin) as chemotherapy in addition to simultaneous ATRA for remission induction, followed by three cycles of consolidation and maintenance therapy [39 41]. This approach called all-trans retinoic acid and idarubicin (AIDA) was adopted worldwide, and it has become one of the most widely used protocols. In 2000, the definition of relapse-risk categories by the collaborative efforts of the Spanish PETHEMA and Italian GIMEMA cooperative groups refined the original ATRA plus chemotherapy protocols, allowing the use of less intense chemotherapy schedules for low and intermediate risk patients [15 17]. Risk-adapted protocols were conducted by multicenter groups in Europe, Japan, United States and Australia. These consistently showed improved outcomes and the benefit of riskadapted approaches [14]. Several issues in the setting of ATRA and chemotherapy have remained controversial. These include the role of cytarabine in induction and/or consolidation therapy, the role of maintenance and the need for central nervous system (CNS) prophylaxis. Two prospectively randomized trials conducted in Europe compared ATRA plus anthracycline-based induction with or without cytarabine [42, 43]. CR rates were comparable in both studies; however, the French Swiss Belgian study showed an increase in relapse rate with the omission of cytarabine from induction and consolidation courses, whereas the British Medical Research Council study (MRC AML15 trial) reported an increase in deaths in remission when cytarabine was administered, without differences in survival rates [42, 43]. Current recommendations suggest that cytarabine is potentially useful as part of consolidation therapy to decrease relapse rate in the setting of high-risk disease, whereas the use of anthracycline-based chemotherapy is indicated in low-risk disease [28, 29]. The incidence of CNS involvement in first relapse has been estimated to be 2% in PETHEMA LPA96 and LPA99 trials, with higher prevalence in high-risk patients (5.5%) [44]. Intrathecal prophylaxis with methotrexate and steroids is adopted by some cooperative groups including the GIMEMA for high-risk patients only. As for low intermediate patients, there is a general consensus, indicating that CNS prophylaxis is not needed due to the extremely low incidence of this event in such category [28, 29, 44]. Finally, the benefit of maintenance therapy, especially in the low-risk category, is still a matter of debate. French investigators initially reported superior overall survival (OS) for patients receiving maintenance therapy with low-dose chemotherapy, ATRA or combined ATRA and chemotherapy [38]. This survival benefit was confirmed by a large US North Intergroup randomized trial for patients receiving ATRA maintenance after obtaining CR with ATRA plus chemotherapy regimens [45]. On the contrary, a GIMEMA study randomizing patients in molecular CR (mcr) to maintenance therapy with ATRA alone, ATRA plus low-dose chemotherapy or no maintenance, reported no significant differences in outcomes among the four groups [46]. Similarly, Japanese investigators by the JALSG reported no improvement in diseasefree survival (DFS) for patients in mcr receiving intensified maintenance chemotherapy after induction and three intensive reviews consolidation courses [47]. Despite the high cure rates, the toxicity profile of ATRA plus chemotherapy regimens includes severe hematologic toxicity with deaths in remission together with occurrence of secondary myeloid neoplasms in 2% 3% of cases [48]. ATO and ATRA combined with chemotherapy In 2004, Chinese investigators from Shanghai reported a randomized trial with 61 newly diagnosed APL patients treated with ATO or ATRA or the combination of the two drugs for induction therapy [49]. CR rates were similar in the three arms ranging from 90% to 95.2%, but the median time to achieve CR was shorter in the combination arm (25.5 days) compared with the single-agent arm (40.5 days in the ATRA group and 31 days in the ATO group). After induction, all patients received chemotherapy. None of the patients treated with the ATRA ATO combination relapsed, whereas 26% and 11% patients relapsed in the ATRA and ATO groups, respectively, with a median DFS of 13, 16 and 20 months for ATRA, ATO and combination groups, respectively. In a long-term update of the study, the estimated 5- year event-free survival (EFS) and OS rates for patients treated with ATRA ATO were 89.2% and 91.7%, respectively [49]. The role of ATO as a consolidation therapy added to conventional ATRA plus chemotherapy was investigated in a randomized trial conducted by United States and Canadian investigators [50]. In this study, 481 newly diagnosed patients were randomly assigned to receive induction with ATRA, cytarabine and daunorubicin followed by two consolidation courses with ATRA and daunorubicin or to the same induction and consolidation and two 25- day cycles of ATO administered after induction therapy. Patients receiving ATO showed significantly better 3-year EFS compared with those receiving ATRA plus chemotherapy (80% versus 63%) as well as superior 3-year OS (86% versus 81%) and 3-year DFS (90% versus 70%) [50]. More recently, the Australasian group reported the results of the APML4 trial, combining anthracycline chemotherapy, ATO and ATRA for remission induction therapy, followed by two consolidation cycles with ATO ATRA without further chemotherapy [51]. Compared with a previous study from the same group (APML3), this regimen resulted in improved survival outcomes, with 2-year freedom from relapse (FFR), failure-free survival and OS of 97.5%, 88% and 93%, respectively. A recent update of this study with a follow-up of 4.2 years showed 5-year FFR of 95% (95% CI 89 98), DFS of 95% as well as EFS of 90% and OS of 94% [51]. ATO alone and ATO ATRA (chemotherapy-free approach) The first prospective, non-randomized trials using a chemotherapy-free approach were conducted in India and Iran after ATO was administered as a single agent for both induction and consolidation therapy [52, 53]. The Indian study reported, at a median follow-up of 25 months, 3-year EFS, DFS and OS of 74.8%, 87.2% and 86%, respectively [52]. Similar results were reported by investigators from Iran with 2-year DFS and 3-year OS of 63.7% and 87.6%, respectively [53]. Both studies showed significantly better outcomes for patients with low-risk disease. A pilot study with combined ATRA and ATO was conducted by Estey et al. [19] at the MD Anderson Cancer Center (MDACC). Forty-four patients (25 low-risk and 19 high-risk) received Volume 27 No. 8 August 2016 doi: /annonc/mdw

5 reviews induction therapy with ATRA and ATO (0.15 mg/kg daily, 10 days after the beginning of ATRA) until the achievement of CR, followed by four 28-day consolidation cycles with the same induction schedule. In addition, high-risk patients received a single dose of gemtuzumab ozogamicin (GO) 9 mg/m 2, administered on day 1. Overall CR rate was 89% (96% in low-risk and 79% in high-risk patients) and relapses were detected in three high-risk patients (after 9, 9 and 15 months, respectively) and none of the low-risk patients. An update of this trial on an extended series of 82 patients treated with the same schedule with 17 patients receiving both ATRA and ATO on day 1 was reported in 2009 [54]. At a median follow-up of 99 weeks, the study confirmed high CR rates (92%) and an estimated 3-year OS of 86%. Also using this schedule, the results were significantly better in the category of patients with low-risk disease. Given the lack of randomized studies directly comparing the standard ATRA plus chemotherapy and the novel chemotherapy-free regimens, the Italian cooperative group GIMEMA designed in 2006 the APL0406 randomized study that was conducted in collaboration with the German AMLSG and SAL cooperative groups [20]. ATO ATRA therapy was given concomitantly during induction therapy, followed by four consolidation cycles with intermittent ATO and ATRA, as in the updated MDACC study mentioned above. With a median follow-up of 34 months for eligible patients, this combination therapy was superior in terms of either EFS or OS to the standard AIDA (2-year EFS: 97% versus 86%, P = 0.02; 2-year OS: 99% versus 91%; P = 0.02) and was associated with significantly less myelosuppression and infections. With respect to other toxicities, more frequent increase in liver enzymes and episodes of QTc prolongation were observed in patients receiving ATRA ATO; however, these sideeffects were reversible and managed with temporary drug discontinuation as per protocol recommendations [20]. On the basis of the results of this randomized trial, the updated NCCN guidelines included ATO ATRA combination as the favorite option for front-line therapy of low- and intermediate-risk APL patients [55]. A recent update of this trial on an extended series of 276 patients with a median follow-up of 40 months showed that the advantage of ATRA ATO over ATRA chemotherapy significantly increases over time in terms of both EFS (2-year EFS 98% versus 84.9%, P = ) and OS (2-year OS 99.1% versus 94.4%, P = 0.01). In addition, while no significant differences in cumulative incidence of relapse (CIR) rates were observed between the two treatment arms in the initial series, a significantly lower CIR was detectable in the updated series in the ATRA ATO group compared with the AIDA cohort (1.1% and 9.4%, respectively; P = 0.005) [56]. The AML17 trial independently conducted in the UK by the NCRI cooperative group recently confirmed the benefit of the ATRA ATO chemo-free approach over the standard ATRA chemotherapy [21]. In this study, NCRI investigators compared a widely used ATRA and chemotherapy (AIDA protocol) approach and an ATO ATRA combination with a different schedule for ATO. In fact, ATO was given at 0.3 mg/kg on days 1 5 of each course and then in weeks 2 8 of course 1 and weeks 2 4 of courses 2 5 at 0.25 mg/ kg twice weekly. Fifty-seven patients with high-risk disease were included in the study with the provision to receive one or two infusions of GO (6 mg/m 2 ) during the first 4 days of induction therapy. At a median follow-up of 32.5 months, the results showed a significant benefit for ATRA ATO compared with AIDA in terms of 4-year EFS (91% versus 70%; P = 0.002), 4- year molecular recurrence-free survival (98% versus 70%; P = <0.0001) and 4-year cumulative incidence of molecular relapse (1% versus 18%; P = ). OS was comparable between the ATRA ATO and AIDA groups (93% versus 89%) [21]. In summary, the results of the two randomized studies conducted by large cooperative groups strongly support ATRA ATO as the new standard of care at least in low-risk patients with APL. With respect to high-risk disease, the patients in low number included in the NCRI probably leave open the issue of the most appropriate regimen. In this context, a randomized study comparing AIDA and ATRA ATO plus minimal chemotherapy in high-risk APL will be started soon. monitoring of minimal residual disease Molecular remission after third consolidation cycle is considered a therapeutic objective in APL. Moreover, salvage treatment of molecular relapse as accurately tracked by quantitative reversetranscriptase PCR (RT-PCR) monitoring has been shown to provide a survival advantage compared with the treatment of overt relapse [57 59]. On the basis of this evidence, longitudinal RT-PCR monitoring and pre-emptive therapy of early relapse are currently adopted by most cooperative groups. However, given the extremely low risk of relapse reported for patients receiving ATO-based regimens [20, 21], the cost benefit of prolonged molecular monitoring has been recently questioned. management of most common treatment-related complications Annals of Oncology differentiation syndrome Differentiation syndrome (DS, previously referred to as retinoic acid syndrome ) is a relatively common and potentially lifethreatening complication that can occur during the first days or weeks after the start of ATRA and/or ATO. The complex of clinical signs and symptoms of this complication includes dyspnea, interstitial pulmonary infiltrates, unexplained fever, weight gain >5 kg, pleuro-pericardial effusion, hypotension, acute renal failure and peripheral edema. No single sign or symptom is per se sufficient to diagnose DS as they may be associated with other conditions such as infection, septic shock or hemorrhage [60]. The PETHEMA group recently revised the DS grading and classified patients into those with severe DS (>3 signs or symptoms) or moderate DS (2 3 signs or symptoms) [61]. The incidence of DS was, as described by the same PETHEMA investigators, higher during the first week of treatment, with a second lower peak in the third week of induction therapy. Most ATRA chemotherapy and ATRA ATO regimens adopted nowadays include steroid prophylaxis. Preventive treatment is particularly important in high-risk patients (WBC > /l), given their increased risk of DS. For the treatment of overt or suspected DS, expert panels recommend the prompt use of intravenous dexamethasone 10 mg BID until resolution of signs and symptoms or for a minimum of 3 days [62]. ATRA and/or ATO treatment should be discontinued only in case of severe DS. The main recommendations for the management 1478 Cicconi and Lo-Coco Volume 27 No. 8 August 2016

6 Annals of Oncology reviews of DS and other common complications associated with the use of ATRA and ATO in APL are summarized in Table 2. pseudotumor cerebri Pseudotumor cerebri (PTC) is a rare but peculiar complication of ATRA therapy, with a reported incidence of 3% in the largest international trials [28]. PTC is mostly observed in children and adolescents, and is characterized by headache as the main presenting symptom with clinical signs of papilledema, provided the exclusion by cerebral imaging of intracranial spaceoccupying lesions and alteration of the cerebrospinal fluid. Recommended measures to treat PTC are reported in Table 2. QTc prolongation and hepatic toxicity QTc prolongation is a common and well-documented sideeffect of ATO, while it is not observed with ATRA treatment. QT prolongation can lead to torsade de pointes-type ventricular arrhythmia, which can be potentially fatal. The GIMEMA-SAL- AMLSG APL0406 trial reported prolonged QTc interval in 15 patients in the ATRA ATO group (16%) [20]. Clinically significant arrhythmias are very rare and none has been reported in the most recent trials employing ATO as first-line therapy. Patients with a prolonged QTc interval above 500 ms, according to international guidelines, are recommended to maintain potassium and magnesium concentrations above 4.0 meq/l and 1.8 mg/dl, ATO should be withheld, electrolytes repleted and other drugs that may cause prolonged QTc interval potentially discontinued until normalization of the QTc [29]. A recent analysis from US investigators assessed QT intervals in 113 non- APL patients treated with ATO using four different correction formulas of the QT interval [63]. With a commonly used Bazett rate correction formula, 90% of patients had QTc greater than 470 ms, including 65% above 500 ms. Using other rate correction formulas (i.e. Framingham and Fredericia), only 24% 32% of patients had rate-corrected QT intervals above 500 ms. It is, therefore, conceivable that 500 ms QTc calculated with formulas other than Bazett should be an acceptable threshold to withhold ATO treatment [63]. Hepatic toxicity has frequently been reported in studies employing ATO with or without ATRA, especially in terms of increase in liver enzymes (mostly AST and ALT and less frequently alkaline phosphatase and bilirubin). This complication may occur in up to 60% of cases [20]; however, it is generally reversible and successfully managed with a decrement or temporary discontinuation of ATO and/or ATRA. No cases of hepatic failure have been reported in recent trials [20, 21]. hyperleukocytosis The development of hyperleukocytosis is a well-known and frequent side-effect occurring in APL patients receiving ATO and/ or ATRA. In the APL0406 study including low- and intermediate-risk patients, leukocytosis defined as WBC > /l was reported in 47% of patients in the ATRA ATO combination group and was managed using hydroxyurea as per protocol recommendation [20]. In the NCRI Study AML17, patients with a peripheral WBC count of > /l at baseline (high risk) had a provision to receive GO 3 mg/m 2 on day 1 of treatment and on day 4 if the white count had not fallen below /l. In addition, a fraction of low-risk patients developing hyperleukocytosis received a single dose of GO upon rise of WBC count of /l [21]. future perspectives Early death before treatment or during the initial days of therapy remains the main obstacle to the final cure of APL. Efforts in this area should focus both on education to improve prompt diagnosis and early management and on clinical and laboratory research to identify predictive factors of severe hemorrhage. The use of ATO, the most active single agent in this disease, should be expanded to other patient subsets where there is still very limited experience including high-risk disease, children and the elderly population. Finally, it is likely that oral arsenic derivatives that Table 2. Management of most common treatment-related complications associated with the use of ATRA and/or ATO in APL Complication Related drug Management Differentiation syndrome ATRA and/or ATO The clinical suspect of differentiation syndrome should always lead to the institution of therapy with i.v. dexamethasone 10 mg BID until complete resolution of signs and symptoms Temporary discontinuation of differentiation therapy (ATRA or ATO) is indicated only in case of severe APL differentiation syndrome Pseudotumor cerebri ATRA Temporary discontinuation of ATRA is recommended in case of Pseudotumor cerebri Use of analgesics (opiates) to counteract headache Steroids and diuretics (acetazolamide or osmotic diuretics) QTc prolongation ATO In case of QTc prolongation (calculated with formulas other than Bazett) above 500 ms, ATO should be withheld until normalization of QTc interval and patient monitored with daily ECG until resolution of the prolongation Electrolytes should be monitored and repleted to maintain potassium >2 meq/l and magnesium >1.8 mg/dl Other medications prolonging QTc interval should be possibly discontinued in case of QTc prolongation Hyperleukocytosis Hepatic toxicity ATRA and or ATO ATO or ATRA ATO A cytoreductive agent is recommended in case of WBC increase > /l. Gemtuzumab or anthracyclines (idarubicin and daunorubicin) can be used to control leukocyte count GO, anthracyclines or hydroxyurea has also been used to control WBC rising during induction therapy. Liver enzymes (AST, ALT, bilirubin and alkaline phosphatase) should be monitored during ATO therapy. Upon rise in liver enzymes (>grade 2 CTCAE), ATO and/or ATRA should be temporarily discontinued until normalization of the hepatic function tests Volume 27 No. 8 August 2016 doi: /annonc/mdw

7 reviews have been shown to be equally effective will in the near future substitute the i.v. formulation, in combination with ATRA, thus allowing an entirely oral management of the disease. funding This work has been partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) to FLC (IG 15467) and Associazione Italiana contro le Leucemie (AIL). disclosure FLC received honoraria as a speaker from Teva. The remaining author has declared no conflicts of interest. references 1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111(5): Lallemand-Breitenbach V, Guillemin MC, Janin A et al. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 1999; 189(7): Mistry AR, Pedersen EW, Solomon E et al. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 2003; 17: de Thé H, Chen Z. 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