Recent Advances in the Biology and Treatment of Acute Promyelocytic Leukemia, страница 4

SPECIFIC MANAGEMENT PROBLEMS IN APL Coagulopathy

In the chemotherapy era, the coagulopathy that frequently complicates APL was associated with an early hemorrhagic death rate of up to 40% of patients. In clinical practice, rapid improvement of coagulopathy is one of the first signs ofATRA's effectiveness (and, in fact, if not observed, should prompt reconsideration of the diagnosis of APL). Although the pathophysiology of the APL-associ-ated DIG continues to be investigated, release of procoagulant activity from APL blasts plays a major role (reviewed in Tallman and Kwaan⁵⁸). The maturation process induced by ATRA appears to prevent or greatly lessen the release ofprocoagu-lanfcs by APL blasts, compared, for example, with chemotherapy, in which there is often rapid cell lysis with massive procoagulant release. Despite the effectiveness of ATRA in ameliorating the coagulopathy, the early death rate in large seriesof APL patients treated with ATRA remains approximately 10%, and many, if not moat, of these patients continue to die from bleeding. There is universal agreement⁶⁸ that APL patients with significant DIG and hypofibrinogenemia (fibrino-gen < 100) should receive cryoprecipitate to maintain the fibrinogen level above 100 and, if actively bleeding, plasma infusion to correct or improve the prothrombin time (PT) and partial thrombo-plastin time (PTT). In addition, aggressive platelet support is instituted to keep the platelet count at 5:20,000. If these measures fail to correct or improve the hemostatic parameters, heparin infu-sion is considered.⁶⁸ If active bleeding continues, a fibrinolytic inhibitor such as tranexamic acid can be used, but it should be appreciated that cases of fatal thrombosis have been reported with the concurrent use of tranexamic add and ATRA in APL. In the ATRA era, and with aggressive supportive care as outlined earlier, it should be possible to prevent hemorrhagic deaths in the vast majority of APL patients.

Retinoic Acid Syndrome

The primary life-threatening complication of induction therapy with ATRA in APL is the devel-opment of a distinct respiratory distress syndrome, commonly termed the retinoic arid syndrome (RAS) or ATRA syndrome. This entity, first described in detail in 1992 by Frankel et al,⁶⁸ is manifested clinically by fever, dyspnea, and weight gain, in association with clinical and radiographic signs of third-space fluid accumulation (ie, diffuse interstitial pulmonary infiltrates, pleural effusions, peripheral edema) and, occasionally, renal failure and hypotension. The pathophysiology of this syndrome remains obscure, but may involve ATRA-induced alteration of the adhesive properties ofAPL cells.⁶⁰ In the recently reported United States and Canadian Intergroup APL study,² the incidence of RAS was 26% (45 of 173 patients who ••arived ATRA alone as induction therapy), while m the European APL 93 study, the incidence was 15%⁶¹ (61 of 403 patients). There were two and five deaths attributed to RAS, respectively, in the two studies (1.2% in each case). Risk factors for development of the ATRA syndrome have been difficult to establish.⁸¹"⁶³ Although hyperleukocyto-sis is common in patients who develop RAS (in the Intergroup study, the median WBC count at time of development of RAS was 29,400/ul),⁶³ the syndrome can develop in patients with normal or low WBC counts.³-⁵⁹-⁶² With the possible exception of CD13 expression,⁶² no pretreatment clinical factor (age, WBC or platelet count, presence ofDIC) has been found that is predictive for developing rajs 61,62 in the Gruppo Italiano Malattie Emato-logiche Maligne deIFAdulto ATRA plus idarubicin (GIMEMA/AIDA) study, in which 240 patients with APL were given induction therapy with concurrent ATRA plus chemotherapy (idarubicin 12 mg/m² on days 2, 4, 6, and 8), the incidence of "overt" ATRA syndrome waa only 2.5%, and there was only one death.³ This result suggests that concurrent ATRA/chemotherapy may prevent most cases of RAS, perhaps by preventing or greatly ameliorating the rapid leukocytosis frequently observed with ATRA alone. It is important to note that ATRA syndrome is essentially never observed when ATRA is used as maintenance therapy.⁶¹'⁶³