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Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia
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Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia Houry Leblebjian a,∗ , Daniel J. DeAngelo b , J. Andrew Skirvin a,c,d , Richard M. Stone b , Martha Wadleigh b , Lillian Werner a , Donna S. Neuberg a,e , Sylvia Bartel a,c , Anne M. McDonnell c a
Dana Farber Cancer Institute, Department of Pharmacy Services, Boston, MA, USA Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA c Brigham and Women’s Hospital, Department of Pharmacy Services, Boston, MA, USA d Northeastern University, Department of Pharmacy, Boston, MA, USA e Harvard School of Public Health, Department of Biostatistics, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 22 October 2012 Received in revised form 3 March 2013 Accepted 6 April 2013 Available online xxx Keywords: Acute promyelocytic leukemia Differentiation syndrome All-trans retinoic acid Retinoic acid syndrome ATRA
a b s t r a c t All-trans retinoic acid (ATRA) used for the treatment of APL can lead to the development of differentiation syndrome (DS), a potentially life threatening complication. Since ATRA is metabolized by cytochrome P450 (CYP) enzymes, we sought to identify drug interactions that might be associated with a higher risk for the development of DS in addition to other predictive factors related to the incidence of DS. We identified 60 consecutive patients with APL treated at our institution with ATRA from May 2004 until January 2010. Of the 60 patients identified, 29 (48%) developed DS within a median of 5 days (range 1–31) of ATRA initiation. We did not find any difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. In multivariable analysis, higher peripheral blood blast counts on admission (p = 0.04) as well as higher body mass index (p = 0.003) were associated with developing DS. Out of the 29 patients with DS, there were 4 early deaths of which 2 were attributed to DS compared to no early deaths in the patients who did not develop DS (p = 0.05). Regarding disease-related outcomes, only CR rate was different between patients developing DS versus those who did not develop DS. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia (AML) is characterized by infiltration with malignant atypical promyelocytes, the t(15,17) translocation, leukopenia and coagulopathy. APL treatment conventionally involves a combination of all-trans retinoic acid (ATRA) and anthracycline based chemotherapy although recently, chemotherapy free approaches with ATRA and arsenic trioxide have been successfully employed [1]. Patients with APL are at risk of early death due to bleeding complications secondary to coagulopathies such as thrombocytopenia and disseminated intravascular coagulation (DIC), but ATRA therapy rapidly reverses the DIC. Early death from APL is less than 10% in clinical trials, while it is higher in registry studies (12-24%) [2,3]. ATRA is generally well tolerated and highly beneficial, however, the development of differentiation syndrome (DS; formerly known as retinoic acid syndrome [RAS]) represents a potentially life
∗ Corresponding author at: Dana Farber Cancer Institute, Department of Pharmacy, 450 Brookline Avenue, Boston, MA 02215, USA. Tel.: +1 617 632 5179; fax: +1 617 932 2254. E-mail address: Houry [email protected] (H. Leblebjian).
threatening adverse reaction [4,5]. Frankel et al. defined DS as unexplained fever, weight gain due to peripheral edema, dyspnea, pleural effusion, interstitial pulmonary infiltrates, unexplained hypotension, renal insufficiency, and hyperbilirubinemia [6]. Several studies have evaluated risk factors which may predispose patients to DS. In two large prospective studies, the incidence of DS was reported to be 15-26%, however predictive factors associated with the development of DS were not identified [7,8]. De la Serna et al. reported on more than 700 APL patients treated with ATRA and idarubicin from the PETHEMA LPA96 and LPA99 trials and identified two independent prognostic factors for mortality in patients who developed DS: ECOG score of 2 or greater (p = 0.009) and an albumin level less than 3.5 g/dL (p = 0.045) [9]. Another analysis of PETHEMA APL trials reported a DS incidence of 24.8%. Elevated WBC count at presentation, LDH greater than upper limit of normal, and more than 70% peripheral blasts were the risk factors for moderate DS [10]. In a much smaller study (n = 78) in newly diagnosed or relapsed APL patients, Vahdat et al. found that CD13 expression on the leukemia cells as well as the development of leukocytosis was predictive for DS development [11]. No study has evaluated drug interactions with ATRA as a potential predictive factor for developing DS. ATRA undergoes hydroxylation by the cytochrome P-450 (CYP) system in humans.
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Please cite this article in press as: Leblebjian H, et al. Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia. Leuk Res (2013), http://dx.doi.org/10.1016/j.leukres.2013.04.011
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Table 1 Demographic and baseline characteristics on admission of patients with and without differentiation syndrome (univariate analysis). Variable
All patients Median (range)
Overall Age, year Sex Female Body mass index, kg/m2 <25 25–30 30–40 ≥40 WBC count, ×103 /mcL Peripheral bood blast count, % Uric acid, mg/dL LDH, U/L Albumin, g/dL
DS No. (%)
No DS
Median (range)
60 44 (18–79)
1.8 (0.4–67.9) 17 (0–93) 5.1 (2–8.4) 351 (147–1719) 4.2 (3–5.1)
No. (%)
Median (range)
29 52 (22–27)
p value No. (%) 31
43 (18–79)
0.38
36 (60)
15 (52)
21 (68)
13 (22) 9 (15) 29 (48) 9 (15)
3 (10) 5 (17) 12 (41) 9 (31)
10 (32) 4 (13) 17 (54) 0
5.6 (0.4–67.9) 35 (0–93) 5.3 (3–8.4) 387 (147–1719) 4.2 (3–4.8)
The most common enzymes that are thought to be involved in ATRA metabolism are CYP2C8, CYP2C9 and CYP3A4 [12,13]. Many patients receiving ATRA are treated with concomitant medications that are substrates, inducers or inhibitors of these hepatic enzymes. Thus, ATRA levels could fluctuate potentially affecting the adverse event profile. The objective of this study was to retrospectively identify factors, including drug interactions, that might identify patients at risk for ATRA induced DS. We also evaluated the overall incidence of DS, impact of DS on intensive care unit (ICU) admission rates and length of hospital stay. Additionally, we compared therapeutic outcomes including complete remission (CR) rate, overall survival (OS), and relapse free survival (RFS) among patients who developed DS versus patients who did not develop this combination. 2. Methods We performed a retrospective chart review of 60 consecutive patients with confirmed APL treated at Dana Farber/Brigham and Women’s Hospital Cancer Center (DF/BWHCC) between May 2004 and January 2010. We included patients with newly diagnosed APL who were admitted to our institution and received ATRA for induction. All patients fulfilled the morphologic and cytogenetic criteria for the diagnosis of APL (M3 or M3-variant) according to the French–American–British classification. The protocol was approved by the institutional review board. Diagnosis of DS was made retrospectively through chart review and required presence of the following symptoms based on the definition by Frankel et al.: dyspnea, unexplained fever, weight gain more than 5 kg, unexplained hypotension, acute renal failure, hyperbilirubinemia and chest imaging demonstrating interstitial infiltrates and pleural or pericardial effusion [6]. In accordance with other published studies, patients with ≥4 symptoms of DS were classified as severe DS, while patients with 2-3 symptoms were classified as having moderate DS and patients with only one symptom were not included as having DS [10]. Patients were retrospectively evaluated for the development of DS for up to 5 weeks after initiation of ATRA. During ATRA therapy, concurrent medication administrations were recorded for 21 days, since that was the onset of the development of DS in the original Frankel et al. study [6]. The following factors were also analyzed for their prognostic value: age, sex, baseline white blood cell count, percent blast count, serum creatinine, platelet count, body mass index (BMI), uric acid, lactate dehydrogenase (LDH), albumin, and type of chemotherapy used with ATRA. The following data were also collected for patients that experienced DS: time to onset of DS after ATRA initiation, treatment of DS with steroids, and ATRA discontinuation rate. Additionally, presence of coagulopathy (assessed by fibrinogen, D-dimer, PTT [partial thromboplastin time] INR, PT [prothrombin time]), ICU transfer and death from DS were collected. Death was attributed to DS when it occurred in patients with severe DS for whom there was no alternative explanation. Finally, all medications taken by all patients that were known substrates, inhibitors or inducers of CYP450 were collected and identified. All concurrent medications were categorized by CYP 450 enzyme system with which they interacted based on Up-To-Date® , Micromedex® and the Indiana University Division of Pharmacology drug interactions chart [14–16]. The remission induction response was assessed according to the criteria by Cheson et al. [17]. In short, CR was defined as less than 5% blasts and no Auer rods in the bone marrow, an absolute neutrophil count of greater than 1000 neutrophils/mcL, and platelet count of more than 100,000 platelets/mcL. Patients could not have any evidence of extramedulary leukemia. OS was measured from the date of diagnosis
1.1 (0.4–60.8) 12 (0–93) 4.5 (2–7.7) 324 (175–1044) 4.3 (3.2–5.1)
0.29 0.002
0.14 0.05 0.04 0.25 0.17
until death from any cause or censored on the last known date alive. RFS was the date of attaining leukemia-free state until the date of AML relapse or death from any cause, whichever came first or censored on the last known date alive for patients who did not relapse. Duration of CR was calculated from the date of attaining leukemia free state until the last known date of patients who are still in remission. For the univariate analysis, Fisher’s exact test was used to detect the association between each of the potential risk factors and the development of DS. For the multivariable analysis, a logistic regression model was created to identify and evaluate significant prognostic factors, as well as the effect of potential drug – drug interactions. The Kaplan–Meier method was used to summarize median OS.
3. Results Baseline patient characteristics are shown in Table 1. The median age for the entire cohort was 44 years (18-79 years), 60% were female, 75% Caucasian, and the median white blood cell (WBC) count on admission was 1.8 × 103 /mcL (0.4-67.9 × 103 /mcL). All patients received ATRA 45 mg/m2 /day divided into 2 doses and rounded to the nearest 10 mg increment. Concurrent ATRA and chemotherapy with cytarabine and daunorubicin was given in 16 patients (27%), idarubicin in 32 patients (53%), arsenic trioxide in 9 patients (15%), or gemtuzumab ozogamicin in 2 patients (3%) during induction. One patient received the combination of gemtuzumab ozogamicin, arsenic trioxide and ATRA. Twenty nine patients (48%, 90% confidence interval 37-60%) experienced DS (14 [23%] severe [defined as ≥4 symptoms of DS] and 15 [25%] moderate [defined as 2-3 symptoms of DS]). Dyspnea, unexplained fever and interstitial infiltrates were the most common features of DS. Of the 14 patients experiencing severe DS, 8 patients had 4 symptoms, 5 patients had 5 symptoms, and 1 patient had all the symptoms of DS. The frequency of all symptoms of DS is shown in Table 2. Nineteen (66%) of the patients having DS were on diuretics before being diagnosed with DS, which could have explained why the percentage of weight gain as a DS symptom was low in our patients. Twenty six of the 29 patients (90%) who met criteria for severe or moderate DS received treatment with dexamethasone. The mean duration of dexamethasone treatment was eleven days. The three patients who Table 2 Clinical signs and symptoms of the patients diagnosed with DS. Clinical signs and symptoms of DS
No. (%)
Dyspnea Fever Interstitial infiltrates Pericardia effusion Hyperbilirubinemia Weight gain Hypotension Renal insufficiency
28 (97%) 23 (79%) 19 (66%) 15 (52%) 6 (21%) 5 (17%) 5 (17%) 4 (14%)
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Table 3 Complications and outcomes. Variable
All patients Median (range)
All patients ICU admission Coagulopathy Mechanical ventilation ICU LOS (days) Hospital LOS (days) Death CR (N) Duration of CR for patients in remission (months [range]) OS (N alive) Median follow up & 95% CI (months) Chemotherapy administered with ATRA Arsenic trioxide Daunorubicin and cytarabine Idarubicin Hydrea Gemtuzumab
DS No. (%)
No DS
Median (range)
60 13 (22) 10 (17) 9 (15)
No. (%)
Median (range)
29 9 (31) 6 (21) 7 (24)
6(1 − 17) 34(4 − 59)
31 4 (13) 4 (13) 2 (6)
4 (1-17) 33 (4-59) 4 (7) 42 (12, 78)
29
NS
46 (13, 82) 24
53 (31, 62)
47 (37, 53)
7 (24) 10 (34) 12 (41) 3 (10) 2 (7)
did not receive dexamethasone met the criteria for DS during our retrospective review, but were not considered to have DS by the treating team. These three patients did not have any worsening of symptoms and all achieved CR. Of the 29 patients with moderate or severe DS, 23 (79%) had ATRA doses held. Ten and thirteen patients in the moderate and severe groups, respectively had doses of ATRA held. In these patients, ATRA was held for a mean of 5.6 days (range 0-36 days). Twenty of the 23 patients who had ATRA held due to
0 31
0.12 0.73 0.08 0.50 0.84 0.05 0.05
7 (6-15) 34 (19-53) 4 (14) 25
10 (17) 16 (27) 32 (53) 3 (5) 3 (5)
p value No. (%)
3 (10) 6 (19) 20 (65) 0 1 (3)
0.73 0.25 0.12 0.11 0.61
DS had ATRA restarted within 10 days. Four of the patients who were reinitiated on ATRA experienced DS for a second time. The mean and median times to development of DS from the start of ATRA were 9.4 and 5 days, respectively (range 1-31 days). Seventeen patients developed DS ≤ 8 days after initiation of ATRA; the other 12 patients who developed DS did so between days 13 and 31 after initiation of ATRA. The induction regimen did not appear to correlate with the development of DS. On univariate analysis, there
Table 4 Cytochrome P450 medications administered. Variables P450 inhibitors (2C9) Weak Moderate Strong Fluconazole P450 substrates (2C9) Minor Major P450 Inducers (2C9) Weak Strong P450 inhibitors (3A4) Weak Olanzapine Moderate Strong P450 substrates (3A4) Minor Major Ondansetron Oxycodone Simvastatin Esomeprazole P450 inducers (3A4) Weak Strong P450 inhibitors (2C8) Weak Moderate Strong P450 substrates (2C8) Minor Major P450 inducers (2C8) Weak Strong
All Patients (N)
Patients with DS (N)
Patients without DS (N)
33 18 7 6
20 6 2 2
13 12 5 4
50 9
24 4
26 5
4 1
2 0
2 1
24 12 35 0
14 4 14 0
10 8 21 0
1 59 47 37 14 22
1 28 21 19 7 10
0 31 26 18 7 12
6 6
2 2
4 4
40 2 0
18 1 0
22 1 0
0 1
0 0
0 1
4 1
2 0
2 1
p-Value 0.09
0.67 1.0
1.0
0.19
0.48
1.0
1.0
N/A
1.0
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4 Table 5 Most common medications administered. Medication name
No. (%) of patients
CYP activity
Acetaminophen
52 (87)
Allopurinol Vancomycin Ondansetron Ceftazidime Lorazepam Oxycodone Furosemide Diphenhydramine
51 (85) 49 (82) 47 (78) 46 (77) 42 (70) 37 (62) 33 (55) 33 (55)
Minor substrate of 1A2, 2A6, 2C9, 2D6, 2E1, 3A4 Weak inhibitor of 3A4 None None Major substrate of 3A4 None None Major substrate of 3A4 None Moderate inhibitor of 2D6
was a direct association between admission peripheral blast count (p = 0.05), uric acid levels (p = 0.04), and BMI (p = 0.002) with regard to the likelihood of developing DS. (Peripheral blood blast count was dichotomized at 70%, uric acid at 7 mg/dL, and BMI was summarized as a 4 group categorical variable: <25; 25-30; 30-40; and ≥40 kg/m2 ). In multivariable analysis, higher peripheral blood blast percent counts and higher BMI on admission were associated with development of DS (p = 0.04 and p = 0.003, respectively). No differences were observed in rate of DS based on high WBC count, LDH, and albumin on admission. In addition, no differences were seen in the DS rate among patients receiving ATRA and arsenic trioxide with or without gemtuzumab ozogamicin versus other chemotherapy approaches (Table 3). Some of the most commonly administered medications for all patients were acetaminophen (87%), allopurinol (85%), and vancomycin (82%). Table 5 lists medications that were used by >50% of patients. No differences were seen in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates (Table 4). Thirteen (22%) of the 60 patients were admitted to the ICU (31% in DS patients; 13% in remaining patients; p = 0.12). Of these four patients were admitted to the ICU due to arterial or venous thrombotic events. Three of the four patients who did not develop DS but were admitted to the ICU experienced a thrombotic event (stroke, myocardial infarction, or pulmonary embolism). One patient developed severe hypoxia due to chronic obstructive pulmonary disease. One patient with a thrombotic event was on a combination ATRA and arsenic trioxide, while the others were on combination ATRA and chemotherapy with idarubicin (n = 6) or cytarabine and daunorubicin (n = 3). Four of 29 patients with DS died within the first 28 days of ATRA therapy (early death) and 2 of these were attributed to DS (due to respiratory failure) compared to no early deaths in the patients who did not develop DS (p = 0.05). The 2 other deaths in the DS group were due to a myocardial infarction with an ischemic stroke, and a massive intracranial hemorrhage. The patient who died of a myocardial infarction with an ischemic stroke was a high risk APL patient, as defined by the PETHEMA group, who was on a combination therapy with ATRA, arsenic trioxide and gemtuzumab ozogamicin [18]. All of these deaths occurred in patients who developed severe DS. Hospital LOS was similar between patients with DS and without DS, 33 days (4-59 days) versus 34 days (19-53 days), respectively. Fifty-six of the 60 patients achieved CR, for CR rate of 93% (95% CI: 84%, 98%). All induction failures were due to death during induction and all occurred in the group that developed DS. All 31 patients who did not develop DS were evaluable for CR and achieved CR (Table 3). After a median follow up of 47 months, three additional patients have died for a total of 7 patients (4 early deaths mentioned earlier and 3 after long-term follow up). Two late deaths occurred in the group who did not develop DS and were a result of pulmonary embolism and cardiac arrest due to arrhythmia (6%
with 95% CI: 1%, 21%). Overall, 5 out of the 29 (17% with 95% CI: 6%, 36%) patients who developed DS died, four during induction and one from progressive disease 29 months from diagnosis and induction. Overall, six patients relapsed. Of these, four had developed DS during initial induction treatment. Based on the small number of patients who relapsed, median RFS was not reached.
4. Discussion The incidence of DS in APL patients treated with ATRA in addition to chemotherapy at our institution was 48% with an equal distribution of the moderate and severe forms. There was no difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. Higher peripheral blood blast counts and higher BMI on admission were associated with developing DS. Among the patients who developed DS, there were 4 early deaths compared to no early deaths in the patients who did not develop DS. ICU transfer rates were not statistically different in patients when comparing patients who did and did not develop DS. Additionally, there were no differences in CR, RFS and OS for patients who experienced DS when compared to patients who did not experience DS. In the published literature, there is a wide variation in the incidence of DS associated with ATRA in studies ranging from 2% to 31% [4,7,10,11,19–21]. To the best of our knowledge, this is the first study to find that almost half of the patients with APL treated with ATRA developed DS. One reason for the relatively high rate of DS in our study may be under-reporting and/or under-recognition due to lack of uniform definition in the literature. Another reason could be that most literature reports describe patients enrolled on large clinical trials, whereas our report dealt with unselected patients. Additionally, we did not administer prophylactic steroids to ATRA patients, unlike the PETHEMA LPA 96 and the LPA 99 trials. In the LPA 96 trial prophylactic steroids were given to all patients with WBC greater than 5000 cells/mcL, and the LPA 99 study administered steroids to all patients regardless of the WBC count, which may have contributed to a lower incidence of DS [7,9,10,21–23]. ATRA is metabolized to 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo remove trans retinoic acid glucuronide by the CYP hepatic enzyme system. Many CYPs have the ability to metabolize ATRA. These include CYP2C8, CYP3A4, and CYP2C9. ATRA also induces its own metabolism [12,13]. As a result, CYP inhibitors and inducers can affect the levels of ATRA in blood and thus potentially change the toxicity or efficacy of ATRA. Published case reports have addressed drug interactions leading to increased ATRA toxicity. Examples of drug classes which have a potential to interact with ATRA include azole antifungals and corticosteroids [24–27]. Additionally, two reports discuss the diagnosis of pseudomotor cerebri, one of the serious adverse of ATRA, due to the potentiation of ATRA levels by fluconazole and voriconazole [28,29]. Another report discusses the development of hypercalcemia after an APL patient was treated both with itraconazole and ATRA, which might be a possible CYP mediated interaction in between the two drugs [30,31]. In the current study, the lack of impact of CYP inducers or inhibitors on DS development might have been due to the small number of patients on these drugs. For example, only 6 patients of the 60 (10%) were on fluconazole (strong CYP2C9 inhibitor), and no patient was on either voriconazole (strong inhibitor of CYP2C9 and CYP3A4) or itraconazole (strong inhibitor of CYP3A4). Most patients in our study were on weak substrates, inducers or inhibitors of CYP 2C9, CYP3A4, or CYP2C8, or on medications that are renally excreted (Tables 4 and 5). In our study, the predictive factors for DS development were increased blast percentage in blood at admission and high BMI, based on multivariable analysis. Our results confirm the findings
Please cite this article in press as: Leblebjian H, et al. Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia. Leuk Res (2013), http://dx.doi.org/10.1016/j.leukres.2013.04.011
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from Jeddi et al. and Breccia et al. which also identified BMI as a potential risk factor for DS [21,32]. The mechanism of obesity as a risk for DS may be due to high levels of leptin in cells of obese patients, which could play a major role in proliferation and survival of APL cells which express leptin receptors. Tabe et al. has shown that leptin receptors are present on APL promyelocytes and when these cells are exposed to ATRA, cytokine release may be enhanced thus mediating DS [21,33,34]. The Breccia study also reported the estimated cumulative incidence of relapse at 5 years significantly higher in overweight/obese versus underweight/normal patients (31.6% versus 11.2%; p = 0.029) [32]. We noted a trend for a higher risk of relapse in patients who developed DS. There was no difference in OS even though all the deaths during induction were in patients who developed DS. The European APL 93 group reported an increase in relapse rates for patients developing DS, as well as lower 2 year EFS (p = 0.003) and OS (p = 0.03) [7]. In contrast to the LPA 96 and the APL 93, the LPA 99 did not find an increase in relapse rate in patients who developed DS [9,10]. These differences could be due to the different chemotherapy regimens used in these different trials. Higher WBC and platelet count on diagnosis is another risk factor for relapse, in addition to developing DS and higher BMI [35]. DS can be a life-threatening adverse effect of ATRA therapy. In our study we identified a higher than expected level of DS in our patient population (48%) using strict criteria that was originally defined by Frankel et al. Our results also show that patients at high risk of DS are those with increased BMI and peripheral blast count at diagnosis of APL. Use of CYP 450 interacting drugs did not change the patient risk of developing DS. Funding None. Conflicts of interest statement The authors have no conflicts of interest to disclose. Acknowledgments H.L. was involved in the conception and design of the study, acquisition of data, analysis and interpretation of data, as well as writing of the manuscript. D.J.D. was involved in the acquisition of data as well as writing of the manuscript. J.A.S. was involved in the conception and design of the study. L.W and D.S.N. were involved in the analysis and interpretation of data. A.M.M. was involved in the conception and design of the study, analysis and interpretation of data, as well as writing of the manuscript. All authors revised and gave final approval of the manuscript. References [1] Breccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother 2012;13(7):1031–43. [2] Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751–7. [3] 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):1248–54. [4] de Botton S, Chevret S, Coiteux V, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia 2003;17(2):339–42. [5] Patatanian E, Thompson DF. Retinoic acid syndrome: a review. J Clin Pharm Ther 2008;33(4):331–8. [6] Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell Jr RP. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 1992;117(4):292–6.
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Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia Houry Leblebjian a,∗ , Daniel J. DeAngelo b , J. Andrew Skirvin a,c,d , Richard M. Stone b , Martha Wadleigh b , Lillian Werner a , Donna S. Neuberg a,e , Sylvia Bartel a,c , Anne M. McDonnell c a
Dana Farber Cancer Institute, Department of Pharmacy Services, Boston, MA, USA Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA c Brigham and Women’s Hospital, Department of Pharmacy Services, Boston, MA, USA d Northeastern University, Department of Pharmacy, Boston, MA, USA e Harvard School of Public Health, Department of Biostatistics, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 22 October 2012 Received in revised form 3 March 2013 Accepted 6 April 2013 Available online xxx Keywords: Acute promyelocytic leukemia Differentiation syndrome All-trans retinoic acid Retinoic acid syndrome ATRA
a b s t r a c t All-trans retinoic acid (ATRA) used for the treatment of APL can lead to the development of differentiation syndrome (DS), a potentially life threatening complication. Since ATRA is metabolized by cytochrome P450 (CYP) enzymes, we sought to identify drug interactions that might be associated with a higher risk for the development of DS in addition to other predictive factors related to the incidence of DS. We identified 60 consecutive patients with APL treated at our institution with ATRA from May 2004 until January 2010. Of the 60 patients identified, 29 (48%) developed DS within a median of 5 days (range 1–31) of ATRA initiation. We did not find any difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. In multivariable analysis, higher peripheral blood blast counts on admission (p = 0.04) as well as higher body mass index (p = 0.003) were associated with developing DS. Out of the 29 patients with DS, there were 4 early deaths of which 2 were attributed to DS compared to no early deaths in the patients who did not develop DS (p = 0.05). Regarding disease-related outcomes, only CR rate was different between patients developing DS versus those who did not develop DS. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia (AML) is characterized by infiltration with malignant atypical promyelocytes, the t(15,17) translocation, leukopenia and coagulopathy. APL treatment conventionally involves a combination of all-trans retinoic acid (ATRA) and anthracycline based chemotherapy although recently, chemotherapy free approaches with ATRA and arsenic trioxide have been successfully employed [1]. Patients with APL are at risk of early death due to bleeding complications secondary to coagulopathies such as thrombocytopenia and disseminated intravascular coagulation (DIC), but ATRA therapy rapidly reverses the DIC. Early death from APL is less than 10% in clinical trials, while it is higher in registry studies (12-24%) [2,3]. ATRA is generally well tolerated and highly beneficial, however, the development of differentiation syndrome (DS; formerly known as retinoic acid syndrome [RAS]) represents a potentially life
∗ Corresponding author at: Dana Farber Cancer Institute, Department of Pharmacy, 450 Brookline Avenue, Boston, MA 02215, USA. Tel.: +1 617 632 5179; fax: +1 617 932 2254. E-mail address: Houry [email protected] (H. Leblebjian).
threatening adverse reaction [4,5]. Frankel et al. defined DS as unexplained fever, weight gain due to peripheral edema, dyspnea, pleural effusion, interstitial pulmonary infiltrates, unexplained hypotension, renal insufficiency, and hyperbilirubinemia [6]. Several studies have evaluated risk factors which may predispose patients to DS. In two large prospective studies, the incidence of DS was reported to be 15-26%, however predictive factors associated with the development of DS were not identified [7,8]. De la Serna et al. reported on more than 700 APL patients treated with ATRA and idarubicin from the PETHEMA LPA96 and LPA99 trials and identified two independent prognostic factors for mortality in patients who developed DS: ECOG score of 2 or greater (p = 0.009) and an albumin level less than 3.5 g/dL (p = 0.045) [9]. Another analysis of PETHEMA APL trials reported a DS incidence of 24.8%. Elevated WBC count at presentation, LDH greater than upper limit of normal, and more than 70% peripheral blasts were the risk factors for moderate DS [10]. In a much smaller study (n = 78) in newly diagnosed or relapsed APL patients, Vahdat et al. found that CD13 expression on the leukemia cells as well as the development of leukocytosis was predictive for DS development [11]. No study has evaluated drug interactions with ATRA as a potential predictive factor for developing DS. ATRA undergoes hydroxylation by the cytochrome P-450 (CYP) system in humans.
0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.04.011
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Table 1 Demographic and baseline characteristics on admission of patients with and without differentiation syndrome (univariate analysis). Variable
All patients Median (range)
Overall Age, year Sex Female Body mass index, kg/m2 <25 25–30 30–40 ≥40 WBC count, ×103 /mcL Peripheral bood blast count, % Uric acid, mg/dL LDH, U/L Albumin, g/dL
DS No. (%)
No DS
Median (range)
60 44 (18–79)
1.8 (0.4–67.9) 17 (0–93) 5.1 (2–8.4) 351 (147–1719) 4.2 (3–5.1)
No. (%)
Median (range)
29 52 (22–27)
p value No. (%) 31
43 (18–79)
0.38
36 (60)
15 (52)
21 (68)
13 (22) 9 (15) 29 (48) 9 (15)
3 (10) 5 (17) 12 (41) 9 (31)
10 (32) 4 (13) 17 (54) 0
5.6 (0.4–67.9) 35 (0–93) 5.3 (3–8.4) 387 (147–1719) 4.2 (3–4.8)
The most common enzymes that are thought to be involved in ATRA metabolism are CYP2C8, CYP2C9 and CYP3A4 [12,13]. Many patients receiving ATRA are treated with concomitant medications that are substrates, inducers or inhibitors of these hepatic enzymes. Thus, ATRA levels could fluctuate potentially affecting the adverse event profile. The objective of this study was to retrospectively identify factors, including drug interactions, that might identify patients at risk for ATRA induced DS. We also evaluated the overall incidence of DS, impact of DS on intensive care unit (ICU) admission rates and length of hospital stay. Additionally, we compared therapeutic outcomes including complete remission (CR) rate, overall survival (OS), and relapse free survival (RFS) among patients who developed DS versus patients who did not develop this combination. 2. Methods We performed a retrospective chart review of 60 consecutive patients with confirmed APL treated at Dana Farber/Brigham and Women’s Hospital Cancer Center (DF/BWHCC) between May 2004 and January 2010. We included patients with newly diagnosed APL who were admitted to our institution and received ATRA for induction. All patients fulfilled the morphologic and cytogenetic criteria for the diagnosis of APL (M3 or M3-variant) according to the French–American–British classification. The protocol was approved by the institutional review board. Diagnosis of DS was made retrospectively through chart review and required presence of the following symptoms based on the definition by Frankel et al.: dyspnea, unexplained fever, weight gain more than 5 kg, unexplained hypotension, acute renal failure, hyperbilirubinemia and chest imaging demonstrating interstitial infiltrates and pleural or pericardial effusion [6]. In accordance with other published studies, patients with ≥4 symptoms of DS were classified as severe DS, while patients with 2-3 symptoms were classified as having moderate DS and patients with only one symptom were not included as having DS [10]. Patients were retrospectively evaluated for the development of DS for up to 5 weeks after initiation of ATRA. During ATRA therapy, concurrent medication administrations were recorded for 21 days, since that was the onset of the development of DS in the original Frankel et al. study [6]. The following factors were also analyzed for their prognostic value: age, sex, baseline white blood cell count, percent blast count, serum creatinine, platelet count, body mass index (BMI), uric acid, lactate dehydrogenase (LDH), albumin, and type of chemotherapy used with ATRA. The following data were also collected for patients that experienced DS: time to onset of DS after ATRA initiation, treatment of DS with steroids, and ATRA discontinuation rate. Additionally, presence of coagulopathy (assessed by fibrinogen, D-dimer, PTT [partial thromboplastin time] INR, PT [prothrombin time]), ICU transfer and death from DS were collected. Death was attributed to DS when it occurred in patients with severe DS for whom there was no alternative explanation. Finally, all medications taken by all patients that were known substrates, inhibitors or inducers of CYP450 were collected and identified. All concurrent medications were categorized by CYP 450 enzyme system with which they interacted based on Up-To-Date® , Micromedex® and the Indiana University Division of Pharmacology drug interactions chart [14–16]. The remission induction response was assessed according to the criteria by Cheson et al. [17]. In short, CR was defined as less than 5% blasts and no Auer rods in the bone marrow, an absolute neutrophil count of greater than 1000 neutrophils/mcL, and platelet count of more than 100,000 platelets/mcL. Patients could not have any evidence of extramedulary leukemia. OS was measured from the date of diagnosis
1.1 (0.4–60.8) 12 (0–93) 4.5 (2–7.7) 324 (175–1044) 4.3 (3.2–5.1)
0.29 0.002
0.14 0.05 0.04 0.25 0.17
until death from any cause or censored on the last known date alive. RFS was the date of attaining leukemia-free state until the date of AML relapse or death from any cause, whichever came first or censored on the last known date alive for patients who did not relapse. Duration of CR was calculated from the date of attaining leukemia free state until the last known date of patients who are still in remission. For the univariate analysis, Fisher’s exact test was used to detect the association between each of the potential risk factors and the development of DS. For the multivariable analysis, a logistic regression model was created to identify and evaluate significant prognostic factors, as well as the effect of potential drug – drug interactions. The Kaplan–Meier method was used to summarize median OS.
3. Results Baseline patient characteristics are shown in Table 1. The median age for the entire cohort was 44 years (18-79 years), 60% were female, 75% Caucasian, and the median white blood cell (WBC) count on admission was 1.8 × 103 /mcL (0.4-67.9 × 103 /mcL). All patients received ATRA 45 mg/m2 /day divided into 2 doses and rounded to the nearest 10 mg increment. Concurrent ATRA and chemotherapy with cytarabine and daunorubicin was given in 16 patients (27%), idarubicin in 32 patients (53%), arsenic trioxide in 9 patients (15%), or gemtuzumab ozogamicin in 2 patients (3%) during induction. One patient received the combination of gemtuzumab ozogamicin, arsenic trioxide and ATRA. Twenty nine patients (48%, 90% confidence interval 37-60%) experienced DS (14 [23%] severe [defined as ≥4 symptoms of DS] and 15 [25%] moderate [defined as 2-3 symptoms of DS]). Dyspnea, unexplained fever and interstitial infiltrates were the most common features of DS. Of the 14 patients experiencing severe DS, 8 patients had 4 symptoms, 5 patients had 5 symptoms, and 1 patient had all the symptoms of DS. The frequency of all symptoms of DS is shown in Table 2. Nineteen (66%) of the patients having DS were on diuretics before being diagnosed with DS, which could have explained why the percentage of weight gain as a DS symptom was low in our patients. Twenty six of the 29 patients (90%) who met criteria for severe or moderate DS received treatment with dexamethasone. The mean duration of dexamethasone treatment was eleven days. The three patients who Table 2 Clinical signs and symptoms of the patients diagnosed with DS. Clinical signs and symptoms of DS
No. (%)
Dyspnea Fever Interstitial infiltrates Pericardia effusion Hyperbilirubinemia Weight gain Hypotension Renal insufficiency
28 (97%) 23 (79%) 19 (66%) 15 (52%) 6 (21%) 5 (17%) 5 (17%) 4 (14%)
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Table 3 Complications and outcomes. Variable
All patients Median (range)
All patients ICU admission Coagulopathy Mechanical ventilation ICU LOS (days) Hospital LOS (days) Death CR (N) Duration of CR for patients in remission (months [range]) OS (N alive) Median follow up & 95% CI (months) Chemotherapy administered with ATRA Arsenic trioxide Daunorubicin and cytarabine Idarubicin Hydrea Gemtuzumab
DS No. (%)
No DS
Median (range)
60 13 (22) 10 (17) 9 (15)
No. (%)
Median (range)
29 9 (31) 6 (21) 7 (24)
6(1 − 17) 34(4 − 59)
31 4 (13) 4 (13) 2 (6)
4 (1-17) 33 (4-59) 4 (7) 42 (12, 78)
29
NS
46 (13, 82) 24
53 (31, 62)
47 (37, 53)
7 (24) 10 (34) 12 (41) 3 (10) 2 (7)
did not receive dexamethasone met the criteria for DS during our retrospective review, but were not considered to have DS by the treating team. These three patients did not have any worsening of symptoms and all achieved CR. Of the 29 patients with moderate or severe DS, 23 (79%) had ATRA doses held. Ten and thirteen patients in the moderate and severe groups, respectively had doses of ATRA held. In these patients, ATRA was held for a mean of 5.6 days (range 0-36 days). Twenty of the 23 patients who had ATRA held due to
0 31
0.12 0.73 0.08 0.50 0.84 0.05 0.05
7 (6-15) 34 (19-53) 4 (14) 25
10 (17) 16 (27) 32 (53) 3 (5) 3 (5)
p value No. (%)
3 (10) 6 (19) 20 (65) 0 1 (3)
0.73 0.25 0.12 0.11 0.61
DS had ATRA restarted within 10 days. Four of the patients who were reinitiated on ATRA experienced DS for a second time. The mean and median times to development of DS from the start of ATRA were 9.4 and 5 days, respectively (range 1-31 days). Seventeen patients developed DS ≤ 8 days after initiation of ATRA; the other 12 patients who developed DS did so between days 13 and 31 after initiation of ATRA. The induction regimen did not appear to correlate with the development of DS. On univariate analysis, there
Table 4 Cytochrome P450 medications administered. Variables P450 inhibitors (2C9) Weak Moderate Strong Fluconazole P450 substrates (2C9) Minor Major P450 Inducers (2C9) Weak Strong P450 inhibitors (3A4) Weak Olanzapine Moderate Strong P450 substrates (3A4) Minor Major Ondansetron Oxycodone Simvastatin Esomeprazole P450 inducers (3A4) Weak Strong P450 inhibitors (2C8) Weak Moderate Strong P450 substrates (2C8) Minor Major P450 inducers (2C8) Weak Strong
All Patients (N)
Patients with DS (N)
Patients without DS (N)
33 18 7 6
20 6 2 2
13 12 5 4
50 9
24 4
26 5
4 1
2 0
2 1
24 12 35 0
14 4 14 0
10 8 21 0
1 59 47 37 14 22
1 28 21 19 7 10
0 31 26 18 7 12
6 6
2 2
4 4
40 2 0
18 1 0
22 1 0
0 1
0 0
0 1
4 1
2 0
2 1
p-Value 0.09
0.67 1.0
1.0
0.19
0.48
1.0
1.0
N/A
1.0
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4 Table 5 Most common medications administered. Medication name
No. (%) of patients
CYP activity
Acetaminophen
52 (87)
Allopurinol Vancomycin Ondansetron Ceftazidime Lorazepam Oxycodone Furosemide Diphenhydramine
51 (85) 49 (82) 47 (78) 46 (77) 42 (70) 37 (62) 33 (55) 33 (55)
Minor substrate of 1A2, 2A6, 2C9, 2D6, 2E1, 3A4 Weak inhibitor of 3A4 None None Major substrate of 3A4 None None Major substrate of 3A4 None Moderate inhibitor of 2D6
was a direct association between admission peripheral blast count (p = 0.05), uric acid levels (p = 0.04), and BMI (p = 0.002) with regard to the likelihood of developing DS. (Peripheral blood blast count was dichotomized at 70%, uric acid at 7 mg/dL, and BMI was summarized as a 4 group categorical variable: <25; 25-30; 30-40; and ≥40 kg/m2 ). In multivariable analysis, higher peripheral blood blast percent counts and higher BMI on admission were associated with development of DS (p = 0.04 and p = 0.003, respectively). No differences were observed in rate of DS based on high WBC count, LDH, and albumin on admission. In addition, no differences were seen in the DS rate among patients receiving ATRA and arsenic trioxide with or without gemtuzumab ozogamicin versus other chemotherapy approaches (Table 3). Some of the most commonly administered medications for all patients were acetaminophen (87%), allopurinol (85%), and vancomycin (82%). Table 5 lists medications that were used by >50% of patients. No differences were seen in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates (Table 4). Thirteen (22%) of the 60 patients were admitted to the ICU (31% in DS patients; 13% in remaining patients; p = 0.12). Of these four patients were admitted to the ICU due to arterial or venous thrombotic events. Three of the four patients who did not develop DS but were admitted to the ICU experienced a thrombotic event (stroke, myocardial infarction, or pulmonary embolism). One patient developed severe hypoxia due to chronic obstructive pulmonary disease. One patient with a thrombotic event was on a combination ATRA and arsenic trioxide, while the others were on combination ATRA and chemotherapy with idarubicin (n = 6) or cytarabine and daunorubicin (n = 3). Four of 29 patients with DS died within the first 28 days of ATRA therapy (early death) and 2 of these were attributed to DS (due to respiratory failure) compared to no early deaths in the patients who did not develop DS (p = 0.05). The 2 other deaths in the DS group were due to a myocardial infarction with an ischemic stroke, and a massive intracranial hemorrhage. The patient who died of a myocardial infarction with an ischemic stroke was a high risk APL patient, as defined by the PETHEMA group, who was on a combination therapy with ATRA, arsenic trioxide and gemtuzumab ozogamicin [18]. All of these deaths occurred in patients who developed severe DS. Hospital LOS was similar between patients with DS and without DS, 33 days (4-59 days) versus 34 days (19-53 days), respectively. Fifty-six of the 60 patients achieved CR, for CR rate of 93% (95% CI: 84%, 98%). All induction failures were due to death during induction and all occurred in the group that developed DS. All 31 patients who did not develop DS were evaluable for CR and achieved CR (Table 3). After a median follow up of 47 months, three additional patients have died for a total of 7 patients (4 early deaths mentioned earlier and 3 after long-term follow up). Two late deaths occurred in the group who did not develop DS and were a result of pulmonary embolism and cardiac arrest due to arrhythmia (6%
with 95% CI: 1%, 21%). Overall, 5 out of the 29 (17% with 95% CI: 6%, 36%) patients who developed DS died, four during induction and one from progressive disease 29 months from diagnosis and induction. Overall, six patients relapsed. Of these, four had developed DS during initial induction treatment. Based on the small number of patients who relapsed, median RFS was not reached.
4. Discussion The incidence of DS in APL patients treated with ATRA in addition to chemotherapy at our institution was 48% with an equal distribution of the moderate and severe forms. There was no difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. Higher peripheral blood blast counts and higher BMI on admission were associated with developing DS. Among the patients who developed DS, there were 4 early deaths compared to no early deaths in the patients who did not develop DS. ICU transfer rates were not statistically different in patients when comparing patients who did and did not develop DS. Additionally, there were no differences in CR, RFS and OS for patients who experienced DS when compared to patients who did not experience DS. In the published literature, there is a wide variation in the incidence of DS associated with ATRA in studies ranging from 2% to 31% [4,7,10,11,19–21]. To the best of our knowledge, this is the first study to find that almost half of the patients with APL treated with ATRA developed DS. One reason for the relatively high rate of DS in our study may be under-reporting and/or under-recognition due to lack of uniform definition in the literature. Another reason could be that most literature reports describe patients enrolled on large clinical trials, whereas our report dealt with unselected patients. Additionally, we did not administer prophylactic steroids to ATRA patients, unlike the PETHEMA LPA 96 and the LPA 99 trials. In the LPA 96 trial prophylactic steroids were given to all patients with WBC greater than 5000 cells/mcL, and the LPA 99 study administered steroids to all patients regardless of the WBC count, which may have contributed to a lower incidence of DS [7,9,10,21–23]. ATRA is metabolized to 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo remove trans retinoic acid glucuronide by the CYP hepatic enzyme system. Many CYPs have the ability to metabolize ATRA. These include CYP2C8, CYP3A4, and CYP2C9. ATRA also induces its own metabolism [12,13]. As a result, CYP inhibitors and inducers can affect the levels of ATRA in blood and thus potentially change the toxicity or efficacy of ATRA. Published case reports have addressed drug interactions leading to increased ATRA toxicity. Examples of drug classes which have a potential to interact with ATRA include azole antifungals and corticosteroids [24–27]. Additionally, two reports discuss the diagnosis of pseudomotor cerebri, one of the serious adverse of ATRA, due to the potentiation of ATRA levels by fluconazole and voriconazole [28,29]. Another report discusses the development of hypercalcemia after an APL patient was treated both with itraconazole and ATRA, which might be a possible CYP mediated interaction in between the two drugs [30,31]. In the current study, the lack of impact of CYP inducers or inhibitors on DS development might have been due to the small number of patients on these drugs. For example, only 6 patients of the 60 (10%) were on fluconazole (strong CYP2C9 inhibitor), and no patient was on either voriconazole (strong inhibitor of CYP2C9 and CYP3A4) or itraconazole (strong inhibitor of CYP3A4). Most patients in our study were on weak substrates, inducers or inhibitors of CYP 2C9, CYP3A4, or CYP2C8, or on medications that are renally excreted (Tables 4 and 5). In our study, the predictive factors for DS development were increased blast percentage in blood at admission and high BMI, based on multivariable analysis. Our results confirm the findings
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from Jeddi et al. and Breccia et al. which also identified BMI as a potential risk factor for DS [21,32]. The mechanism of obesity as a risk for DS may be due to high levels of leptin in cells of obese patients, which could play a major role in proliferation and survival of APL cells which express leptin receptors. Tabe et al. has shown that leptin receptors are present on APL promyelocytes and when these cells are exposed to ATRA, cytokine release may be enhanced thus mediating DS [21,33,34]. The Breccia study also reported the estimated cumulative incidence of relapse at 5 years significantly higher in overweight/obese versus underweight/normal patients (31.6% versus 11.2%; p = 0.029) [32]. We noted a trend for a higher risk of relapse in patients who developed DS. There was no difference in OS even though all the deaths during induction were in patients who developed DS. The European APL 93 group reported an increase in relapse rates for patients developing DS, as well as lower 2 year EFS (p = 0.003) and OS (p = 0.03) [7]. In contrast to the LPA 96 and the APL 93, the LPA 99 did not find an increase in relapse rate in patients who developed DS [9,10]. These differences could be due to the different chemotherapy regimens used in these different trials. Higher WBC and platelet count on diagnosis is another risk factor for relapse, in addition to developing DS and higher BMI [35]. DS can be a life-threatening adverse effect of ATRA therapy. In our study we identified a higher than expected level of DS in our patient population (48%) using strict criteria that was originally defined by Frankel et al. Our results also show that patients at high risk of DS are those with increased BMI and peripheral blast count at diagnosis of APL. Use of CYP 450 interacting drugs did not change the patient risk of developing DS. Funding None. Conflicts of interest statement The authors have no conflicts of interest to disclose. Acknowledgments H.L. was involved in the conception and design of the study, acquisition of data, analysis and interpretation of data, as well as writing of the manuscript. D.J.D. was involved in the acquisition of data as well as writing of the manuscript. J.A.S. was involved in the conception and design of the study. L.W and D.S.N. were involved in the analysis and interpretation of data. A.M.M. was involved in the conception and design of the study, analysis and interpretation of data, as well as writing of the manuscript. All authors revised and gave final approval of the manuscript. References [1] Breccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother 2012;13(7):1031–43. [2] Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751–7. [3] 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):1248–54. [4] de Botton S, Chevret S, Coiteux V, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia 2003;17(2):339–42. [5] Patatanian E, Thompson DF. Retinoic acid syndrome: a review. J Clin Pharm Ther 2008;33(4):331–8. [6] Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell Jr RP. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 1992;117(4):292–6.
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Please cite this article in press as: Leblebjian H, et al. Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia. Leuk Res (2013), http://dx.doi.org/10.1016/j.leukres.2013.04.011