Cfin. lab. Haemat. 1994, 16, 191-195

CASE REPORT

Life-threatening hepatic toxicity caused by all- trans-retinoic acid in a patient with acute promyelocytic leukaemia

KEISUKE SHIBATA, YOSHINORI SHIMAMOTO, SADATOSHI ISHIBASHI, H I D E K I TOMINAGA, KENJI SUGA & MASAYA YAMAGUCHI Division of Haematology, Department of Internal Medicine, Saga Medical School, 5-1 -1 Nabeshima, Saga, Japan

Accepted for publication 25 November 1993

Keywords: hepatic toxicity, all-trans-retinoic acid (ATRA), acute prornyelocytic leukaemia (APL)

All-trans-retinoic acid (ATRA) has been shown to be a promising therapy for acute promyelocytic leukaemia (APL) by leading this disease to a complete remission without bone marrow aplasia (Huang et al. 1988; Warrell et al. 1991, 1993). Although there are many reports concerning the adverse effects of ATRA, all of these effects are mild and have little clinical importance. With respect to liver function, there are only a few reports of abnormalities. These include transient increases in serum aminotransferases, alkaline phosphatase (ALP) and bilirubin that improved once the administration of ATRA was stopped (Huang et al. 1988; Warrell et al. 1993).

Here, we report a case of APL who developed life-threatening cholestatic jaundice in association with worsened 'disseminated intravascular coagulation (DIC) and secondary renal insufficiency as an adverse effect of ATRA.

Case report

A 39-year-old male was admitted to our hospital because of gingival bleeding in May 1993. The haemogram revealed a haemoglobin concentration of 7.3 g/dl, platelet count of 35 x 109/1 and leucocyte count of 0.7 x 109/1 with 9.0% neutro- phils, 50.0% lymphocytes, 1 .O% monocytes, 8.0% myeloblasts, 1 .O% myelocytes and 3 1 .O% promyelocytes. Bone marrow aspiration showed a hypercellular

Correspondence: Dr Keisuke Shibata, Division of Haematology, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849, Japan.

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192 K. Shibata et al.

Figure 1. Specimens from bone marrow aspirations at the time of diagnosis (A) and a complete remission (B) (Wright-Giemsa stain).

leukaemic marrow including 96.4% promyelocytes with numerous Auer rods (Figure lA), and cytogenetically had a t(15; 17) (q22; q21). The leukaemic cells were cytochemically positive for peroxidase and naphtol-ASD-chloroacetate esterase stains, and immunologically positive for both CD13 and CD33, but negative for HLA-DR. Both the prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged and serum fibrinogen-fibrin degra- dation products-E (FDP-E, normal range; 7-71 ng/ml) were increased to 13 10 ng/ml in addition to hypofibrinogenemia, indicating the complication of DIC. Other laboratory findings including serum aminotransferases were all in normal ranges, and hepatitis virus-associated markers were negative. He was diagnosed as having APL, an M3 subtype of FAB classification for acute myelogenous leukaemia (AML) (Bennett et al. 1976), and oral administration of ATRA (60 mg/m2) was started. Apart from anaemia, both leucocyte and platelet counts were increased together with differentiation of leukaemic promyelocytes to mature neutrophils. On the 38th day after the initiation of therapy, serum aminotransferases began to rise, followed by the elevation of serum bilirubin. Even after the cessation of ATRA, serum bilirubin (normal range; 3-17 pM) was progressively increased to 169 pM, along with elevation of alkaline phosphatase (ALP) and y-glutamyltranspeptidase (y-GTP). In addition to cholestatic jaundice, serum FDP-E increased and renal function was secondarily involved, however, the frequent chest roentgenograms revealed a normal study during the course. He was very exhausted with high-grade fever and painful swelling of legs due to thrombophlebitis secondary to DIC. Thereafter, however, serum bilirubin

Hepatic toxicity of’ ATRA in A P L 193

Plt

150

100 z X

50

0 T.Bil 200

150

f 100

50

0

15 10 X

l o

ATRA 60 rnglrn’ - ....................... .....................................

62.4% hi 8.0% [I 2.8%

F DP-E

. m c

93.5.12 93.6.1

Figure 2. Clinical course.

decreased to be in an almost normal range 18 days after the discontinuation of ATRA. Serum FDP-E also fell to within normal range and his clinical symptoms such as fever and leg pain rapidly resolved (Figure 2). The lymphocyte stimula- tion test (LST) using ATRA showed a normal stimulation index (SI 0.98). Subsequently, a complete remission was obtained in his bone marrow (Figure lB), although the administration of ATRA had been already stopped.

Discussion

ATRA is widely accepted as a differentiation therapy for APL, and is considered to be more safe than intensive chemotherapies in producing a complete remission without any phase of marrow aplasia and the rapid improvement of haemostatic disorders (Huang et al. 1988; Castaigne et al. 1990; Warrell et al. 1991; Fenaux et al. 1992).

In this report, we present a patient with typical APL, who developed life- threatening hepatic toxicity due to ATRA. In addition, this was complicated by painful thrombophlebitis secondary to worsened coagulopathy despite the leuk- emic cells being differentiated to mature neutrophils. Although we attempted to

194 K. Shibata et al.

demonstrate ATRA to be a causative agent of the hepatic toxicity through immunological mechanisms, the LST with this drug revealed a negative result. Nevertheless, as no other drugs used at this time could be considered to have affected liver function, ATRA must be suspected as the causative agent.

In the literature, the adverse effects of ATRA are generally thought to be well tolerated and alleviated once ATRA is discontinued or reduced. Warrell et al. (1991) reported that liver function was never affected in 11 APL patients treated with ATRA. Similar results were described by Chen et al. (1991). Even in other reports than these, hepatic toxicity of ATRA is reported to be mild with only transient elevation of serum aminotransferases, ALP, or bilirubin (Castaigne et al. 1990; Degos et al. 1990; Warrell et al. 1993). In contrast to these findings, there is a report that ATRA may possess more toxic effects such as headache, central nervous system problems and gastrointestinal effects in comparison with other retinoids. Windhorst & Nigra (1982) Frankel et al. (1992) also reported a 28-year- old man with APL, who died of hepatic and renal failure due to the retinoic acid syndrome. Recently, Lee et at. (1993) suggested that there was considerable variation of peak plasma ATRA level in individual patients when ATRA was used in the treatment for various solid tumors. Thus, each patient occasionally seems to show a different reaction against this agent.

We do not know how ATRA caused liver damage in our patient. ATRA, a fat-soluble vitamin, is synthesized from j-carotene through oxidation of retinol in the intestinal mucosa, then transported via the portal circulation to the liver. In the liver, ATRA undergoes conjugation with glucuronic acid and subsequently is secreted in the bile (Goss & McBurney 1992). One possible explanation for ATRA-induced liver dysfunction may be that impaired glucuronidization or secretion of ATRA results in cholestatic jaundice.

To our knowledge, our case is the first report describing life-threatening hepatic side effect of ATRA used in the treatment for APL and improvement after discontinuation of this drug. A minority of patients, when treated with ATRA, may unexpectedly react to this agent, and develop severe toxicity as did our case. In conclusion, liver functions should be strictly monitored during treatment and although the LST is recommended to predict any adverse effects prior to ATRA administration, it failed to do so in this instance.

Acknowledgements

We would like to thank Mr Fumitaka Morito and Mrs Junko I for their helpful assistance in preparing the manuscript.

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