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Effective management of acute promyelocytic leukemia with high risk of fatal intracranial hemorrhage.


The treatment of acute promyelocytic leukemia (APL) has improved remarkably during the last two decades mainly due to disease-specific drugs, such as all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) [1, 2]. However, early death due to fatal complications such as intracranial hemorrhage, before remission occurs in many cases [1, 3]. Despite the improvements in APL treatment, early death remainsa problem with reported early death rates ranging between 7 and 14% [1]. Previous study reported an early death rate of 32% in a study of APL patients at 12 Brazilian institutions receiving treatment with ATRA and anthracyclines. Intracranial hemorrhages, caused by disseminated intravascular coagulation (DIC), hypercoagulability, fibrinolysis, proteolysis and thrombocytopenia, constitute the major cause of early death of APL patients [4, 5]. Thus, prevention of intracranial hemorrhage before remission is important for improvement of prognosis of patients with APL.

The fatal intracranial hemorrhage risk score (FICH) score was introduced to categorize acute myeloid leukemia (AML) patients based on their risk of hemorrhage [6]. The score is derived from 5 items related to the risk of intracranial hemorrhage, with one point each given for white blood cell (WBC) count > 50,000/[micro]L, blood platelet count <35,000 /[micro]L, APL, PT/INR >1.5, and female gender. The sum of these scores is used to define low (0-1), intermediate (2-3), and high (4-5) risk categories. A significant difference in intracranial hemorrhage events was found based on risk factors for hemorrhage upon remission induction in patients with AML [6]. The aim of this study is to examine the relationship between the treatment and intracranial hemorrhage complication in APL patients based on FICH score.


The subjects were 46 patients who were diagnosed with APL from 2000 to 2014 at Nippon Medical School Hospital. Molecularly confirmed diagnosis was defined as a finding of t (15;17) in cytogenetic analysis, andor positivity for PML-RAR in fluorescence in situ hybridization or reverse transcription-PCR analysis. Remission-induction therapy was performed in accordance with Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups (GIMEMA-AIEOP) protocol [7,8]. In short, patients received oral ATRA 45 mg/[m.sup.2] daily, starting on day 1 and continuing until CR or for a maximum of 90 days; 12 mg/[m.sup.2] of intravenous idarubicin (IDA) was added to ATRA on days 2, 4, 6, and 8. In patients younger than 20 years, the dosage of ATRA was reduced to 25 mg/[m.sup.2] daily, whereas the dosage of IDA remained the same. Supportive platelet transfusions were administered only in the presence of overt hemorrhage or if the platelet count was less than 30,000/[micro]L with or without laboratory signs of severe coagulopathy (fibrinogen <150 mg/dL and fibrin degradation products >40 [micro]g/mL). The relationship between remission-induction therapy (ATRA with or without chemotherapy) and changes in CT images of intracranial hemorrhage was examined in 5 patients who developed hemorrhage before remission (including one patient with intracranial hemorrhage before treatment). The relationship between FICH scores and intracranial hemorrhage before remission was examined in all 46 APL patients.


Categorization of the 46 subjects with APL based on FICH scores indicated that 23.9%, 58.6%, and 17.3% were at low, intermediate, and high risk for intracranial hemorrhage, respectively (Table 1).

The actual in cidences of intracrani al hemorrhage were 0%, 0%, and 62.5% in these respective groups, with the incidence being extremely high in the high risk group (Table 2).

Data for a case under follow-up observation is shown in Figure 1. The patient had a WBC count of 35,000 [micro]L at a visit to our hospital, and thus we commenced concomitant treatment with 45 mg/[m.sup.2]/day of ATRA and 12 mg/[m.sup.2]/day idarubicin (IDA), in accordance with GIMEMA-AIEOP protocol. Aggravation of DIC accompanied by tumor lysis occurred after the start of treatment and intracranial hemorrhage developed in the right occipital lobe on day 1. Since coagulation control was difficult with multidisciplinary therapy, the hemorrhage expanded for 1 week until PT/INR was decreased to <1.5. All four patients who developed intracranial hemorrhage after treatment based on GIMEMA-AIEOP protocol showed similar courses.

Based on this experience, we obtained remission without aggravation of intracranial hemorrhage in a patient who developed intracranial hemorrhage before treatment using initial single administration of ATRA for 5 days followed by concomitant chemotherapy with ATRA after improvement of DIC (Figure 2). This is in contrast to most of protocols including GIMEMA-AIEOP protocol, which suggest that chemotherapy should be given concomitantly with ATRA for patients with a WBC count >18,000/[micro]L. The patient developed ATRA syndrome during follow-up observation, but the syndrome was controlled by administration of glucocorticoids.


This paper is, to our knowledge the first paper that suggests the induction therapy focused on FICH. While the cure rates for APL are remarkable, early death continues to be a major cause of treatment failure [9]. The major cause of early death is intracranial hemorrhage.

In most of induction therapy protocols for APL, patients with high white blood cell counts are recommended to receive combination of chemotherapy and ATRA with a focus on ATRA syndrome, but the risk of FICH is not reflected in the treatment regimen. Such a complication may be prevented using initial single administration of ATRA followed by concomitant chemotherapy after treatment for DIC in patients with a high-risk FICH score.

We have succeeded in rescue of a patient who developed intracranial hemorrhage before treatment using initial single administration of ATRA for 5 days followed by concomitant chemotherapy with ATRA after improvement of DIC. We consider that it is important to decrease PT/INR to <1.5 for improvement of intracranial hemorrhage that develops during treatment for APL. However, once chemotherapy is administered, it is extremely difficult to decrease PT/INR to <1.5. In this case, PT/INR <1.5 was achieved by initial single administration of ATRA for 5 days before chemotherapy, and expansion of intracranial hemorrhage was prevented. This approach may increase the risk of ATRA syndrome, but many tactics including glucocorticoids, cytotoxic chemotherapy, mechanical ventilation remains. Thus, further research of large population of APL patients with high-risk FICH should be needed to assess this approach.


[1.] Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, et al. (2011) Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 25: 1128-1134.

[2.] Mi JQ, Li JM, Shen ZX, Chen SJ, Chen Z (2012) How to manage acute promyelocytic leukemia. Leukemia 26: 1743-1751.

[3.] Choudhry A, DeLoughery TG (2012) Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol 87: 596-603.

[4.] de la Serna J, Montesinos P, Vellenga E, Rayon C, Parody R, et al. (2008) Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 111: 3395-3402.

[5.] Di Bona E, Avvisati G, Castaman G, Luce Vegna M, De Sanctis V, et al. (2000) Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol 108: 689-695.

[6.] Kim H, Lee JH, Choi SJ, Lee JH, Seol M, et al. (2006) Risk score model for fatal intracranial hemorrhage in acute leukemia. Leukemia 20: 770-776.

[7.] Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, et al. (1998) Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood 92: 784-789.

[8.] Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, et al. (1997) Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90: 1014-1021.

[9.] Stein EM, Tallman MS (2012) Provocative pearls in diagnosing and treating acute promyelocytic leukemia. Oncology (Williston Park) 26: 636-641.

Hayato Tamai * (#), Satoshi Yamanaka (#), Hiroki Yamaguchi, Kazutaka Nakayama and Koiti Inokuchi

Department of Hematology, Nippon Medical School, Tokyo, 113-8603, Japan

* Corresponding author: Hayato Tamai, MD, Department of Hematology, Nippon Medical School, Sendagi 1-1-5, Bunkyo-Ku, Tokyo 1 13-8603, Japan, Tel: 81-3-3822-2131; Fax: 81-3-5685-1793; E-mail:

(#)--These authors contributed equally to this work.

Received date: November 30, 2015; Accepted date: December 14, 2015; Published date: December 18, 2015

Table 1: Clinical characteristics of patients (n=46) with acute
promyelocytic leukemia.

Characteristics                              n=46 (all)

Sex, n (%)
Male                                         27 (58.6)
Female                                       19 (41.3)
Age, median (range)                          54 (26-87)
Plt (x[10.sup.4]/[micro]l), median (range)   2.2 (0.5-12.7)
WBC (x[10.sup.3]/[micro]l), median (range)   1.8 (0.3-103.4)
PT/INR, median (range)                       1.39 (0.9-3.3)
ATRA syndrome, n (%)                         16 (34.7)
Intracranial Hemorrhage, n (%)               5 (10.8)
FICH score, n (%)
Low                                          11 (23.9)
Intermediate                                 27 (58.6)
High                                         8 (17.3)

Table 2: Clinical characteristics of patients with acute
promyelocytic leukemia based on FICH score.

                                          FICH score

Clinical characteristics    High          Intermediate   Low
                            (4-5) n=8     (2-3) n=27     (0-1) n=11

Intracranial Hemorrhage,    5 (62.5)      0 (0.0)        0 (0.0)
n (%)

Sex, n (%)
Male                        2 (25.0)      15 (55.5)      10 (90.9)

Female                      6 (75.0)      12 (44.4)      1 (9.0)

Age, median (range)         49 (26-74)    55 (21-87)     58 (53-62)

Plt (x[10.sup.4]/           1.5           2.2            4.2
[micro]l), median (range)   (0.6-6.4)     (0.5-20.6)     (1.4-12.7)

WBC (x[10.sup.3]/           39.3          1.9            1.7
[micro]l), median (range)   (0.3-103.4)   (0.4-51.0)     (1.0-4.0)

PT/INR, median (range)      1.75          1.39           1.19
                            (1.52-3.3)    (0.9-2.88)     (0.99-1.58)

ATRA syndrome, n (%)        4 (50.0)      8 (34.7)       3 (37.5)
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Article Details
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Title Annotation:Research Article
Author:Tamai, Hayato; Yamanaka, Satoshi; Yamaguchi, Hiroki; Nakayama, Kazutaka; Inokuchi, Koiti
Publication:Biology and Medicine
Article Type:Report
Date:Jan 1, 2016
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