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Anthracycline-based chemotherapy and ATRA are the mainstays of front-line treatment. Other agents that have recently proved to be highly effective in APL include arsenic trioxide (ATO) and anti-CD33 antibodies. These agents have been mainly used for relapsed patients, although their potential role in front-line therapy is currently under investigation (Estey et al. 2002; Shen et al. 2004). ATO and immunotherapy with anti-CD-33 antibodies are the subject of two dedicated chapters in this volume (see Z. Chen et al. and P.G. Maslak et al.).

The striking sensitivity of APL to anthracyclines was originally reported for daunorubicin by Bernard and colleagues in 1973 (Bernard et al. 1973), and confirmed successively by other European groups who extended this observation to other anthracyclines (Marty et al. 1984; Sanz et al. 1988; Avvisati et al. 1990). The reasons underlying such high sensitivity are unclear, but the absence of the multidrug resistance glycoprotein P170 on APL cells may be an important factor influencing the favorable response to anthracyclines (Paietta et al. 1994; Candoni et al. 2003).

Following the initial results on ATRA reported from China and confirmed by severalgroupsworldwide, anumberofmulticenter trialswereconducted in the 1990s to explore optimal ATRA and chemotherapy combination schedules (e.g., sequential vs simultaneous administration), the role of maintenance, and that of molecular monitoring (reviewed in Sanz et al. 2005). The main results of these studies may be summarized as follows:

  1. The concomitant ATRA plus chemotherapy schedule provides better outcome results compared to the sequential (ATRA followed by chemotherapy) schedule, as demonstrated in a randomized comparison reported by the European APL 1993 study (Fenaux et al. 1999). In addition to better DFS rates, the simultaneous approach is more effective in diminishing the occurrence of overt ATRA syndrome (Fenaux et al. 1999).
  2. The type and intensity of induction and consolidation chemotherapy varied considerably in the reported trials. In particular, polychemotherapy regimens including cytarabine have been used in most of the above studies (Asou et al. 1998; Burnett et al. 1999; Fenaux et al. 1999; Lengfelder et al. 2000; Tallman et al. 2002) while anthracycline-based chemotherapy has been used with ATRA for remission induction by the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) and PETHEMA (Programa para el Tratamiento de Hemopatías Malignas) groups. The GIMEMA and PETHEMA regimens also omitted nonintercalating agents from the consolidation phase, with no apparent reduction of therapeutic efficacy (Mandelli et al. 1997; Sanz et al. 1999). The PETHEMA study showed a substantial benefit of an anthracycline-based consolidation, due also to reduced toxicity (Sanz et al. 1999).
  3. Two randomized trials showed the advantage of including ATRA-based maintenance (Tallman et al. 1997; Fenaux et al. 1999). The European APL 1993 study (Fenaux et al. 1999) suggested further benefit from maintenance with combined ATRA plus low-dose chemotherapy with methotrexate and 6-mercaptopurine. The role of maintenance was also investigated by the GIMEMA group, which adopted the same four randomization arms of the APL 1993 study (ATRA vs chemotherapy vs ATRA+chemotherapy vs observation; Mandelli et al. 1997). Updated results of the GIMEMA study do not seem to confirm a benefit from using maintenance in APL.
  4. All studies reported the clinical relevance of longitudinal RT-PCR monitoring to assess response to therapy. Approximately 50% of patients receiving ATRA plus chemotherapy have detectable PML/RARa transcript in their marrow after completing induction. No correlations were found between the PCR status at the time of morphologic remission achievement and the relapse risk, whereas PCR status after consolidation is highly predictive of outcome (Diverio et al. 1998; Jurcic et al. 2001; Gallagher et al. 2003). After completion of consolidation, 90%-95% of cases tested PCR-negative in the GIMEMA, MRC, and PETHEMA studies (Burnett et al. 1999; Mandelli et al. 1997; Sanz et al. 1999).

As expected, a distinct kinetics of PML/RARa negativization was observed in the German AMLCG (Acute Myeloid Leukemia Cooperative Group) study, in which patients received a double-induction strategy including high-dose cytarabine (TAD/HAM regimen) in association with ATRA (Lengfelder et al. 2000). Up to 91% of patients studied after this induction tested negative by RT-PCR, corresponding to the fraction of molecular remission obtained after two chemotherapy courses in other trials.

In addition to the above multicenter trial results, investigators at the MD Anderson Cancer Center suggested that the liposomal ATRA formulation is more effective compared to orally administered ATRA, and that the amount of chemotherapy needed to cure the disease might be reduced if it were used in combination with liposomal ATRA (Estey et al. 1999). Unfortunately, this formulation is no longer available.

In spite of the dramatic improvement in patient outcome, the above studies left unsolved a number of issues that have been addressed in successive trials designed in 1999-2000, most of which are still ongoing. Investigational areas addressed in current trials are the role of cytarabine, the type and intensity of consolidation, the possibility to differentiate treatment according to the relapse risk, and the place of novel agents such as other retinoids and ATO. The main ongoing multicenter studies in untreated APL are summarized in Table 1.

At present, the results of the Spanish PETHEMA study have been reported (Sanz et al. 2004). According to the design of this trial, patients received after the AIDA (all-frarcs retinoic and idarubicin) induction distinct consolidation approaches based on a predefined relapse risk established at diagnosis (Sanz et al. 2000). The study reported low toxicity, a high degree of compliance, and high antileukemic efficacy, adding ATRA to anthracycline monochemother-apy during both induction and consolidation, with a considerably improved outcome for low- and intermediate-risk patients. As to the high-risk group, unpublished data of the GIMEMA group suggest this category of patients can

Table 1 Current multicenter trials in APL

Group

Induction

Consolidation

Maintenance

U.S. Intergroup

ATRA+DNR+AraC

ATRA+DNR±ATO

ATRA

JALSG

ATRA+IDA+AraC

Polychemotherapy

ATRA vs NO

European

ATRA+DNR±AraC

DNR±AraC

ATRA+CHT

UK MRC

AIDA vs ATRA+DAT

Pethema vs MRC

ATRA+CHT

GAMLCG

TAD/HAM+ATRA

TAD

CHT

GIMEMA

AIDA

Risk-adapted

ATRA+CHT

Pethema

AIDA

Risk-adapted

ATRA+CHT

AIDA, all- trans retinoic acid and idarubicin; AraC, cytosine arabinoside; ATO, arsenic trioxide; ATRA, all- trans retinoic acid; CHT, chemotherapy; DAT, daunorubicin, AraC, 6-thioguanine; DNR, daunorubicin; GAMLCG, German Acute Myeloid Leukemia Cooperative Group; GIMEMA, Gruppo Italiano Malattie Ematologiche dell'Adulto; IDA, idarubicin; JALSG, Japan Acute Leukemia Study Group; PETHEMA, Programa para el Tratamiento de Hemopatias Malignas; UK MRC, United Kingdom Medical Research Council benefit from using a combination including both anthracycline and nonin-tercalating agents with high-dose cytarabine in addition to ATRA. While the results of other addressed issues are being awaited, these data suggest the importance of differentiating front-line treatment in APL patients by reducing the amount of chemotherapy in patients with low WBC, and by intensifying treatment or adding new therapies in hyperleukocytic patients.

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