All-Trans Retinoic Acid (Atra) and Tranexamic Acid: A Potentially Fatal Combination In Acute Promyelocytic Leukaemia
Until recently, chemotherapy with a combination of anthracycline and cytosine arabinoside was the most effective treatment for acute promyelocytic leukaemia (APL) ( Fenaux & Degos, 1996). This can be safely combined with anti-fibrinolytic drugs such as tranexamic acid for the attempted prophylaxis of haemorrhage without the occurrence of thrombolytic complications. However, several studies have now demonstrated that all-trans retinoic acid (ATRA) can induce complete remission of APL with progressive improvement in the bone marrow ( Dombret et al, 1993 ) and this has become part of standard treatment. This agent causes acute promyelocytic leukaemia blasts to differentiate into polymorphonuclear leucocytes ( Chomienne et al, 1990 ). ATRA therapy is often associated with a persistent procoagulant tendency that may explain why it is associated with an observed increase in thrombotic events ( Fenaux et al, 1991 ). Anecdotal evidence has emerged that this thrombotic tendency can be exacerbated by combining it with an anti-fibrinolytic such as tranexamic acid ( Hashimoto et al, 1994 ). We here report our experience at this centre on the use of anti-fibrinolytic therapy in combination with ATRA in the management of APL patients.
Between August 1991 and October 1998, we treated 31 cases of APL (15 men and 16 women, median age 42·5 years). All patients receiving ATRA were treated with a dose of 45 mg/m2/d at presentation for 6 weeks or until complete response (less than 5% blasts on bone marrow aspirate). A bone marrow was carried out on d 19 after commencement of therapy to assess remission status. Chemotherapy was instituted if the presentation white blood cell count was initially high (> 50 × 109/l), if it doubled over a 24 h period on ATRA or if the d 19 marrow did not show less than 5% blasts. Such patients received consolidation with DAT chemotherapy (daunorubicin 60 mg/m2 intravenous bolus for d 1–3 of chemotherapy; cytosine arabinoside, initial i.v. bolus, 25 mg/m2 on d 1, followed by 200 mg/m2 daily for 7 d via i.v. infusion pump; oral thioguanine, 100 mg/m2 twice daily from d 1–7). Where tranexamic acid was given, the dose was 1–2 g intravenously for 6 d starting at day 0. All patients received supportive care with platelets and blood to keep the Hb ≥ 10 g/dl and platelets > 20 × 109/l.
Twenty-eight cases were evaluable by conventional cytogenetics and all showed a balanced, reciprocal translocation between chromosome 15,17. The commonest additional chromosomal abnormality was del 17 followed by del 9q–. At presentation, 30 patients had evidence of a coagulopathy which was defined as a prolongation of more than 3 s from reference values in any of the clotting parameters or d-dimers > 1 μg/ml.
Table I shows the number of patients who received the various combinations of ATRA, tranexamic acid and chemotherapy in the study, and the distribution of deaths in these patients. Of the 28 patients who received ATRA, seven died during the period of the study but, of these, only four patients died within 42 d (defined as early deaths). Most notably, all four early deaths were in the group that received only the combination of ATRA and tranexamic acid and three of these patients died as a result of widespread thrombotic complication, defined as organ failure as a result of occlusion of the vasculature. Of the three later deaths, none were due to thrombotic complications. Three patients out of the 28 developed ATRA syndrome, but none died as a result.
| Treatment | Number in group | Total number of deaths | Number of early deaths | Number of deaths assigned to thrombotic events |
|---|---|---|---|---|
| A + T | 4 | 4 | 4 | 3 |
| A + C | 9 | 1 | 0 | 0 |
| A + T + C | 15 | 2 | 0 | 0 |
| T + C | 2 | 1 | 1 | 1 |
| C | 1 | 0 | 0 | 0 |
| Total | 31 | 4 (13%) |
- A, ATRA; T, tranexamic acid; C, chemotherapy.
- Early deaths are defined as deaths on or before day 42.
The most striking feature of this study was that three of the four patients who received only the combination of ATRA and tranexamic acid had a sudden and rapid deterioration in their condition leading to early death. The post-mortem findings were dramatic and implicated thrombosis in the microvasculature as the predominant cause of death. These thromboses were widespread and in unusual sites, as shown for one of the patients in the brain and the kidney in Fig 1.
Post-mortem findings following early death of a patient in the study who received both ATRA and tranexamic acid, showing microthrombi formation in the brain (A) and the kidney (B).
ATRA therapy has revolutionized the management of APL with improved survival and an increased response duration. Although ATRA alone can induce complete remission, a large randomized trial clearly demonstrated advantages in survival by giving ATRA in combination with chemotherapy ( Tallman et al, 1997 ). The estimated overall survival at 3 years in Tallman's study was 71% for patients given both induction chemotherapy and ATRA. At our centre, the corresponding figure was comparable at 76%. Interestingly, although there have been case reports in the literature of thromboembolic events with ATRA alone, both the study by Tallman et al (1997) , in which there were only three such events out of 174 patients, and our study, in which there were no such events out of nine patients, demonstrate that thromboembolic complications with ATRA alone are rare.
The present results represent the largest study to date focusing on early deaths in patients receiving both ATRA and tranexamic acid. The rapid progression to multiorgan failure and the widespread nature of the microthrombi indicates the need for caution in the simultaneous use of both agents. It is noteworthy that the pathology findings in our cases were identical to those described by Hashimoto et al (1994) in their patient whose renal biopsy showed widespread microthrombi with occlusion of the microcapillaries.
From our data, there was no apparent correlation of initial clotting parameters, degree of bleeding and baseline renal function with the likelihood of development of a potentially fatal thromboembolic event. Interestingly, the only death as a result of haemorrhage was also in the group receiving ATRA and tranexamic acid showing that, in our experience, tranexamic acid, as well as increasing the chance of thrombosis, did not always succeed as an anti-haemorrhagic agent.
In conclusion, the benefits of ATRA, particularly in combination with chemotherapy, are well proven. However, our results suggests that ATRA therapy given with tranexamic acid may be a potentially fatal combination. Although in the group of patients with APL, haemorrhage is a significant problem, our experience indicates that this can be treated with supportive platelets and fresh-frozen plasma alone and tranexamic acid should be used cautiously. Our policy now is to give ATRA with chemotherapy on d 0 with blood, platelets and fresh-frozen plasma support.
