Recent Advances in the Biology and Treatment of Acute Promyelocytic Leukemia, страница 3

Some Retinoid-Resistcint Patients Ham Mutations in the Ligand-Binding Domain of the RARci Moiety of PML-RARa

Although essentially all APL patients treated with ATRA enter complete remission (CR), the vast majority will relapse, despite continuedATRA treatment. This development of clinical ATRA resistance has been felt to have primarily a phar-macologic origin, ie, decreased bioavailability of ATRA through any of a number of potential physiologic mechanisms (reviewed in Warrell³⁸). However, it is interesting to note that APL blasts from ATRA-resiatant patients, when cultured in vitro in the presence of ATRA, generally fail to undergo differentiation,³⁹-*¹ suggesting that phannacologic reasons alone may not account completely for clinical ATRA resistance. Although alternative hypotheses have been put forward,⁴² studies in myeloid cell lines (HL-60 and NB4) have suggested that one mechanism for retinoid resistance is the development of mutations in the ligand-binding domain (LBD) of either the endogenousBARa molecule⁴³ (HL-60 cells) or the fusion PML-RARa molecule⁴⁴ (NB4 cells). Whether similar mutations occurred in patients exposed to ATRA remained unclear⁴⁵; recently, however, Dr Robert Gallagher's laboratory⁴⁶ has reported on three patients, each of whom had relapsed after combination therapy with ATRA and chemotherapy, and each of whom had mutations in the LBD of the RAR<x moiety of PML-RARa. Importantly, these mutations were not present at the start of therapy, and the patients' relapsed cells were also resistant to ATRA when cultured in vitro.⁴⁶ These results suggest that a significant fraction ofAPL patients with acquired retinoid resistance may harbor LBD mutations and have relevance for the design of future trials using ATRA in this and other diseases,

CURRENT THERAPY OF APL Central Role of ATRA in APL

ATRA has been used for the treatment of APL for approximately 10 years (reviewed by Warrell¹⁸ and Fenaux et al⁴⁷). In that time, it has become clear that incorporation of ATRA into induction therapy of APL essentially doubles the percentage of long-term disease-free survivors. This occurs primarily through an effect on relapse, as patients who receive ATRA during induction appear to have a relapse rate approximately half that of patients treated with chemotherapy alone (Fig 2). ATRA alone will induce CR in the majority of newly diagnosed patients with APL,¹'²'*⁸'⁵¹ as well as in a significant fraction of APL patients who either relapse after or are refractory to chemotherapy regimens.⁴⁹'⁵⁰'⁵²'⁶³ However, these remissions are short-lived, and ATRA alone will not. cure APL in either the de nova or relapse setting. ATRA is not a cytotoxic agent, but rather has a specific differentiating effect on leukemic promyelocytes, which then presumably undergo spontaneous cell death.

Overview of Recent Phase III Trials

Both phase II, historically controlled,¹'"¹'⁶⁴-⁶⁷ and phase 111 trials!-² have established the utility of ATRA in APL. This discussion will center on the two published phase III trials that directly compared, in a randomized fashion, ATRA (±chemo-therapy) versus chemotherapy alone for induction treatment of APL (Table 2). Both tria^ administered two cycles of relatively standard AML-typeconsolidation chemotherapy. Of note, neither trial showed a statistically significant difference in CR rate between the ATRA and chemotherapy arms (Table 2); furthermore, despite expectations to the contrary, the early death rate was essentially identical in both groups (Table 2). This was not accounted for by an excess of deaths in the ATRA arm from retinoic acid syndrome, since few patients died from this syndrome on either study (Table 2). In both trials, disease- or event-free survival was approximately doubled in the ATRA arm (Fig 2 and Table 2). The North American Intergroup trial additionally randomized patients who achieved CR and completed consolidation to either observation alone or one year of maintenance ATRA. Thus, 48 patients received chemotherapy induction and ATRA maintenance, and it is notable that, at least with current follow-up data, those patients may have a significantly improved outcome compared with patients who received identical chemotherapy, but no maintenance (Fig 2 and Table 2). Finally, there was a suggestion that ATRA maintenance benefited patients who also received ATRA during induction (Fig 2 and Table 2). These two randomized studies have established the standard ofcareinAPL; both suggest that the majority of patients with APL should be long-term disease-free survivors when treated with the appropriate combination of ATRA and chemotherapy.