Thrombosis Research 133 S2 (2014) S112–S116

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Thrombo-hemorrhagic deaths in acute promyelocytic leukemia Massimo Brecciaa, Francesco Lo Coco*b,c a

Department of Hematology, Sapienza University, Rome, Italy Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy c Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Rome, Italy b

ARTICLE

INFO

Keywords: Acute promyelocytic leukemia Early death Hemorrhagic death Coagulopathy

ABSTRACT

Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). However, early deaths (ED) mostly due to the diseaseassociated coagulopathy remain the major cause of treatment failure. In particular, hemorrhagic events account for 40-65% of ED and several prognostic factors have been identified for such hemorrhagic deaths, including poor performance status, high white blood cell (WBC) count and coagulopathy. Occurrence of thrombosis during treatment with ATRA may be associated with differentiation syndrome (DS) or represent an isolated event. Some prognostic factors have been reported to be associated with thrombosis, including increased WBC or aberrant immunophenotype of leukemic promyelocytes. Aim of this review is to report the incidence, severity, possible pathogenesis and clinical manifestations of thrombo-haemorrhagic deaths in APL. © 2014 Elsevier Ltd. All rights reserved.

Introduction Acute promyelocytic leukemia (APL) is a distinct leukemic subtype accounting for approximately 10% of acute myeloid leukemia (AML) cases [1]. The disease is characterized by leukemic infiltration of the bone marrow by dysplastic promyelocytes, frequent association with a life-threatening coagulopathy, and an optimal response to targeted treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) [2]. The karyotypic hallmark of APL is the t(15;17) translocation which, at the molecular level involves a fusion between the retinoic acid receptor alpha (RARa) gene on chromosome 17 and a locus named promyelocytic leukemia (PML) on chromosome 15. The resulting PML/RARa chimeric protein has been shown to be involved in APL pathogenesis and represent the target of tailored therapy with ATRA and/or ATO [1,2]. The advent of ATRA has dramatically changed the prognosis of APL. A number of large multicenter studies reported in the past two decades have reported long-term remission rates above 70%-80% using ATRA in combination with chemotherapy [2,3]. In addition, the incorporation of ATO in the treatment approach has resulted in decreased toxicity and further outcome improvements [2]. In spite of this progress, 20-30% of APL patients still died due to complications related to therapy or disease relapse. According to large cooperative trials, ED occurs approximately in 10% of newly diagnosed patients treated with standard ATRA and chemotherapy. However, this rate is considerably higher

* Corresponding author at: Department of Biomedicine and Prevention, University Tor Vergata Via Montpellier 1, 00133 Rome, Italy. Tel.: +39.06.20903222. E-mail address: [email protected] (F. Lo Coco). 0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.

when data from population-based studies are considered. In fact, registry studies reported from the US and Sweden recently showed an ED rate of up to 29%, suggesting that ED data derived from clinical trial do not reflect the “real world” situation. Thrombosis as a major cause of death is less frequently reported ranging from 0.9 to 9.6% when diagnosed at presentation, and from 4% to 9% when diagnosed during the entire induction period. In this review, we report the incidence, the severity, the possible pathogenesis and clinical manifestations of thrombohaemorrhagic deaths in APL. Hemorrhagic early deaths Several haemostatic defects have been reported to occur in APL at presentation: most patients, besides thrombocytopenia, develop disseminated intravascular coaugulopathy (DIC) and systemic fibrinolysis. Approximately half of newly diagnosed patients present with decreased fibrinogen levels < 100 mg/dl [4]. The pathophysiology of the APL associate coagulopathy is extremely complex and the most important mechanism is likely to be mediated by specific properties of the leukemic cell itself, which releases several mediators that can activate DIC, fibrinolysis or proteolysis of other proteins [5,6]. APL cells express two tumor-associated pro-coagulants: tissue factor (TF) and cancer pro-coagulant (CP). TF is an activator of coagulation and its expression is elevated in patients with APL at diagnosis. The pro-coagulant expression is decreased in bone marrow cells when ATRA is given for remission induction and this decrease precedes normalization of laboratory coagulation abnormalities [7,8]. Studies carried out in primary blasts from APL patients have shown elevated levels of urokinase-type plasminogen activator

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(u-PA) and tissue-type plasminogen activator (tPA), together with reduced levels of plasminogen and 2-antiplasmin, which is suggestive of primary fibrinolysis [9-11]. Moreover, APL cells express high levels of annexin-II, which also may lead to primary fibrinolysis. A third potential yet more controversial mechanism in APL coagulopathy reported in the literature is the proteolysis of clotting factors and fibrinogen by granulocytic proteases such as elastase and chymotrypsin [12]. Early deaths (ED) occurring within the first 30 days from diagnosis nowadays represent the major barrier in the cure of APL. The incidence of ED has been reported in large multicenter studies to range between 5% and 10% [13-17]. In the Spanish PETHEMA experience, which reported the cause of induction failure in 732 newly diagnosed APL patients, the ED rate was 7%, with hemorrhages accounting for 69% of them. The PETHEMA group identified as risk factors associated to hemorrhagic death during induction therapy a blast count greater than 30 x 109/l in peripheral blood, presence of laboratory coagulopathy at baseline and abnormal creatinine level. Hemorrhagic deaths were intracranial and pulmonary in 65% and 32% of cases, respectively; they occurred at a median time of 6 days and 9 days, respectively, while only one case was reported of fatal gastrointestinal bleeding [13]. The Japanese group reported 5% of ED rate, with 69% of these events being due to hemorrhage: intracranial bleeding was the most common site of severe hemorrhage occurring in 12 patients, followed by pulmonary hemorrhage (4 patients). Risk factors associated with bleeding in this study were lower fibrinogen level, higher WBC count and worse performance status; bleeding was also associated to differentiation syndrome and pneumonia [14]. In the German experience, the ED rate was 8% with 64% of lethal events being caused by hemorrhage [15]. The GIMEMA group reported a rate of ED of 3.8% in the AIDA study and 7.3% in the previous trial conducted in the pre-ATRA era which used idarubicin alone: CNS bleeding was the most frequent cause of induction mortality and the risk factors associated to bleeding were higher blast count and high hemorrhagic score (>3) in the AIDA study [16]. Another retrospective study including 34 patients treated with ATRA, reported 16 episodes of severe bleeding occurred in 10 patients (29%). Nine patients had diffuse alveolar hemorrhage, three had cerebral hemorrhage, one had intra-abdominal bleeding and three had severe vaginal bleeding. The overall hemorrhagic mortality was 9% [17]. It has been reported that ED rate in APL using populationbased studies is much higher than that described in clinical trials: Jeddi et al reported a small cohort of patients with an ED rate of 16% ED rate mostly due to CNS hemorrhage [18]. The Swedish Adult Acute Leukemia Registry reported an ED rate of 29% (median time of ED occurrence, 4 days) and of 26% within 14 days from diagnosis, in 105 patients diagnosed between 1997 and 2006. Forty-one % of the EDs were due to hemorrhage and 35% of these patients never received ATRA. ED rates increased with age and poor performance status at baseline. Prognostic factors associated to ED were high WBC count, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count [19]. Lehmann recently reported the update of this analysis conducted in a period ranging between 1997 and 2012 on 187 APL patients with a median age of 56 years. ED rate was 24%, which improved if compared to previous report although not for high-risk patients: prognostic factors associated to increased rate of ED were older age, high WBC count and poor performance status. The Sloan Kettering Cancer Center reported an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A whole cohort of 1400 APL patients diagnosed between 1992 and 2007 was analysed. The overall ED rate was 17.3%, and only

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a modest change in ED rate was observed over time. ED rate was significantly higher in patients aged  55 years (24.2%). This study showed that the ED rate remains high over the considered time period despite the wide availability of ATRA and appears significantly higher than commonly reported in multicenter clinical trials [20]. The Stanford University reported an ED rate of 19% and 26% at 7 and 30 days of admission, respectively. The Sanz risk stratification was predictive of ED at 7 days but not for death at 30 days. Prognostic factors associated to ED were higher median age, higher WBC count (with a cut-off of 17 x 109/l identified by ROC curve) and coagulopathy (increased INR) [21]. Altman et al. reported an incidence of ED of 11% in 204 APL patients, 61% of them caused by hemorrhage. The majority of ED occurred in the first week (44%) or within two weeks (65%) after presentation. EDs were associated to high WBC count, lower fibrinogen, prolonged PT or PTT, but not with platelet count at diagnosis. ED rate was higher for patients who did not receive ATRA compared to patients who received the drug; in this series, 5 high-risk patients died of bleeding before starting ATRA therapy. The results of this analysis indicated that the percentage of ED increased with the delay in ATRA administration: from 33% of ED for bleeding if ATRA was administered the first day in which APL was suspected, to 70% when ATRA was administered one or more days after the disease was suspected. Hemorrhagic deaths were higher for patients who presented to medical care after 2 or more days of symptoms appearance compared to patients who were referred to medical care on the first day of symptoms [22]. Seftel and colleagues recently reported on the incidence of ED for APL patients in Canada. Data retrieved from the national cancer registry which included 399 APL cases were compared to those obtained from 5 leukemia reference centers (131 patients). In the registry analysis, the ED rate was 21.8% and no significant improvement of either ED or OS was observed improvement over time. By contrast the ED rate in leukemia reference centers was 15% in the whole cohort, 18% in the period 1999-2004 and 11% in the period 2005-2010 and there was a significant outcome improvement over time [23]. Recently, the results of a randomized Italian-German cooperative group study were reported which compared ATO plus ATRA versus standard ATRA and chemotherapy in low and intermediate risk patients with APL [24]. Due to the very low number of events, a comparison of the effect of these distinct regimens on the disease-associated coagulopathy was not feasible; however, this will likely be carried out in a forthcoming update of the study including an extended series of patients. The incidence and prognostic factors for hemorrhagic deaths in APL are reported in Table 1. Occurrence of thrombotic events in APL Thrombotic events appear to be more common in APL than in other acute leukemia patients. In a retrospective study of more than 700 patients in which the rate of thrombotic events was 2.09%, the highest incidence occurred in APL [25]. Based on a Medline search on thrombosis in acute leukemia, De Stefano et al. reported an 8.6% cumulative incidence of such events at 6 months in APL [26]. Previous studies reported a variable prevalence of thrombosis in APL ranging from 2 to 10-15%: a number of factors may account for this variability including treatment with or without ATRA, concomitant use of chemotherapy, different patient demographic and disease characteristics in the analysed series and, finally, heterogeneity in supportive care particularly as concerning the prophylactic use of tranexamic acid. An initial report by Escudier et al in 1996 described 3 patients out of 31 APL cases treated with ATRA who developed thrombotic complications during induction [27].

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Table 1 Incidence of hemorrhagic deaths and associated risk factors in APL Study

Incidence of ED

Incidence of bleeding amongst ED

Bleeding site

PETHEMA [13]

7%

69%

CNS Lung GI

Increased creatinine High blast count in PB Coagulopathy

Japanese [14]

5%

69%

CNS Lung

Lower fibrinogen High WBC Worse PS

GIMEMA [16]

3.8%

nr

CNS

High blast count in PB High hemorrhagic score

Swedish [19]

29%

41%

CNS

Increased creatinine High WBC High LDH High C-protein Low platelet count

Chicago [20]

11%

61%

CNS

High WBC count Lower fibrinogen Increased PT or PTT Delayed ATRA administration

Differentiation syndrome was suspected in 2 patients who died of thrombotic complications with multiple thrombosis revealed at autopsy. In the previous series of APL patients treated with chemotherapy, Escudier et al. reported only 1 patient out of 25, with thrombotic complications: the authors concluded that treatment with ATRA may decrease the rate of hemorrhagic events but not that of thrombotic events. The concomitance of ATRA therapy and tranexamic acid was described as a possible triggering mechanism favouring the occurrence of thrombosis in some case reports: Tsukada et al reported a case of severe thromboembolism in 1 patient out of 10 treated with ATRA and chemotherapy [28] and Pogliani et al described a case of acute renal failure occurred during ATRA treatment which however was completely reversible after complete remission [29]. We reported a close relationship between some biological features of APL leukemic cells and development of thrombotic events in patients treated with ATRA and chemotherapy [30]. In this study including 124 patients treated with ATRA and idarubicin we compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 who did not have such complication. Of the 11 who had thrombosis, 5 patients developed deep vein thrombosis, 4 patients a subendocardic ischemia and 2 patients had intraventricular thrombosis. Patients with thrombosis had higher median WBC count (17 x 109/l vs 2.8 x 109/l, p=0.002), higher prevalence of PML/RARA bcr3 type of transcript (72% vs 48%, p=0.01), FLT3ITD mutations (64% vs 28%, p=0.02), CD2 expression (54% vs 19%, p=0.0001) and CD15 expression (36% vs 8%, p=0.016). No correlation was found with age, sex, FAB subtype, differentiation syndrome during induction and thrombophilia [30]. We found that CD2 expression was associated to leukocytosis and we suggested, as reported previously by Claxton et al [31], that CD2 over expression may play a role in leukoagglutination, contributing to tissue damage by microvascular occlusion. A significant association between CD2 and microgranular variant, leukocytosis and high percentage of peripheral blood blasts is reported in the literature [32-35]. In our study [30], 5 of 11 patients who experienced thrombosis had no leukocytosis and were also negative for CD2, but positive for CD15, an antigen that mediates the adhesion to activated endothelial cells through selectins ligand and favours rolling event. It has been reported that ATRA therapy modulates the expression of both CD2 and CD15 [32-34]. As to FLT3-ITD mutation, a study on gene expression profile found that leukemic cells from FLT3-ITD+ patients have increased expression of genes regulating blood coagulation and cell adhesion [35].

Risk factors

In the PETHEMA study, the overall incidence of thrombosis was 5.1%. Six out of 26 patients who died before start of chemotherapy had thrombosis (one acute myocardial infarction, 2 pulmonary embolisms and 3 cerebral strokes). The overall incidence of thrombosis in induction was 4.2% with 18 deep vein thrombosis, 3 acute myocardial infarctions, 7 CNS thromboses and 3 pulmonary embolisms. Risk factors associated to thrombosis in multivariate analysis, were low fibrinogen level at baseline and morphological variant M3 type, but no association was found with FLT3-ITD, or aberrant phenotype (CD2, CD15). The study showed also that DS was strongly associated to higher incidence of thrombotic events, increased hemorrhagic deaths and coagulopathy. The use of prophylactic tranexamic acid did not result in a reduction of hemorrhagic deaths but was associated with a trend towards increased thrombotic events [36]. In a prospective study conducted by PETHEMA cooperative group, the incidence of thrombotic events in 921 patients enrolled in the LPA2005 and LPA2012 trials was 4.1% at diagnosis and 9.3% during induction. Deep vein thrombosis were diagnosed in 17% of patients, whereas 46% were attributed to catheter insertion; myocardial infarction and cerebral stroke accounted for 9% and 12% of events, respectively. A higher incidence of catheter-related thrombosis was associated to higher platelet count, absence of hemorrhages at diagnosis, hypoalbuminemia, male sex, and worse performance status [38]. The potential mechanisms involved in the pathogenesis of thrombotic events in APL are likely associated to both the disease intrinsic characteristics and the use of ATRA, which has a well-known procoagulant effect. The latter is showed by the persistence of increased coagulation activation markers in patients receiving ATRA. In some cases it has been hypothesized that the concomitant use of ATRA and antifibrinolytic agents increased the risk of thrombosis. The majority of studies reporting thrombosis were conducted in the ATRA era: this agent induces differentiation syndrome and may exacerbate the procoagulant state, which may in turn lead to increased risk of thrombotic events, also through increased production of cytokines [6,8]. The incidence and prognostic factors for thrombo-embolic deaths in APL are reported in Table 2. Management and prevention of early deaths Based on the sole clinical suspect of APL, it is mandatory to start as soon as possible ATRA therapy and supportive measures aimed at counteracting the disease-associated coagulopathy. In

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Table 2 Incidence of thrombo-embolic deaths and associated risk factors in APL Reference Ziegler et al [25] De Stefano et al [26]

Breccia et al [30]

Montesinos et al [36]

Incidence

Nr

9.6% (8.6% cumulative incidence at 6 mos)

Nr

8.8%

5.1%

Rodriguez-Veiga et al [37] 4.1% at diagnosis (9.3% during induction)

Acknowledgements None.

Risk factors

6.5%

High WBC CD2/CD15+ FLT3-ITD+ Low fibrinogen M3 variant type High platelet count Hypoalbuminemia Male sex Worse PS

high-risk patients, a delay in ATRA administration appears to contribute to increased bleedings and ED rate [22]. The supportive measures include fresh frozen plasma, fibrinogen and platelet transfusions to maintain a platelet count above 50 x 109/l, and a fibrinogen level above 150 mg/dl, that should both be monitored every day [38]. Supportive care in APL should continue during the entire duration of induction therapy until disappearance of laboratory and clinical signs of the coagulopathy. The GIMEMA group demonstrated in a retrospective study [39], no benefit for the prevention of early haemorrhagic deaths by using heparin. However, some other groups reported that the benefit of lowmolecular-weight heparin could be tested prospectively in a randomised comparison with the aim to reduce the incidence of early haemorrhagic deaths [40,41]. Heparin could also reduce the adhesion of APL leukemic blasts during induction with ATRA and potentially reduce the incidence of thrombotic events. The use of tranexamic acid to reduce the risk of thrombotic events remains controversial. As suggested by the European LeukemiaNet panel, a strict monitoring should be performed in patients with worse prognostic features at baseline, such as active bleeding, hypofibrinogenemia, increased D-Dimers and prolonged prothrombin time or activated partial thromboplastin time, increased WBC count or peripheral blast count, abnormal creatinine, poor performance status. The same panel has also recommended avoiding central venous catheterization, lumbar puncture or other invasive procedures during induction therapy [38]. Conclusions Early death mostly due to severe haemorrhage remains the main cause of failure in APL as reported by recent populationbased studies carried out in developed countries such as the US, Canada and Sweden. The most important measures to reduce hemorrhagic deaths in APL are early and prompt start of ATRA and institution of aggressive supportive care at the first suspicion of the disease, without waiting for molecular confirmation. Thrombosis should also be considered as possible life-threatening manifestation of APL. To reduce the incidence of ED, other important measures are needed including education of physicians for rapid recognition of the disease, and early referral of patients to specialized hematologic centers. As future directions to decrease ED, optimizing treatment for high-risk (i.e. hyperleukocytic) patients is also warranted. As it is well known that cytolysis induced by chemotherapy worsens the APL coagulopathy, it is hoped that future frontline use arsenic trioxide combined to ATRA may allow for considerable reduction in the use of cytotoxic agents. This in turn may favourably impact in patients’ outcome and further increase cure rates in APL.

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Thrombo-hemorrhagic deaths in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). Howe...
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